Emeritus Faculty, Acad Council, Medicine - Nephrology
A differential solute clearance technique has been developed that characterizes the human glomerulus as an ultrafiltration membrane and macromolecular sieve. Filtration and plasma flow markers as well as probe macromolecules of varying size charge are used to determine glomerular ultrafiltration capacity and barrier selectivity in acute and chronic renal injuries. The physiologic characterization of glomerular capillary wall dysfunction is augmented by morphometric analysis of glomeruli from biopsy material. Serial physiologic and morphometric evaluation of several chronic glomerular diseases is being used to elucidate the pathogenesis of progression to renal failure in man. A similar approach that includes an analysis of pathobiology of postischemic injury to proximal tubules is being used to elucidate the mechanisms of filtration failure in acute renal failure.
Relaxin, a potent pregnancy-related hormone, has been proposed to be a major mediator of renal physiology in normal pregnancy. We wished to test relaxin levels in pregnancy and preeclampsia.We performed precise physiologic measurements of kidney function in 38 normal peripartum women and 58 women with preeclampsia. We measured serum relaxin levels prior to delivery and over the first 4 postpartum weeks utilizing a modern, validated ELISA. Results were compared to those of 18 normal women of childbearing age.Relaxin levels were substantially elevated in women prior to delivery (364 ± 268 vs. 15 ± 16 pg/ml) and fell rapidly over the first postpartum week reaching normal non pregnant levels by Week 2 (32 ± 64 vs. 15 ± 16 pg/ml). No differences were seen between relaxin levels in normal pregnancy as compared to preeclampsia (364 ± 268 vs. 376 ± 241 pg/ml) despite substantial and persistent abnormalities in GFR (149 ± 33 vs. 89 ± 25 ml/min), albuminuria (14 vs. 687 mg/g) and mean arterial pressure (80 ± 8 vs. 111 ± 18). Furthermore no correlation could be established between physiologic measures (GFR, MAP, RBF, RVR) and relaxin levels (p > 0.3), either in the overall population or any of the subgroups.Relaxin is indeed significantly elevated in the serum of women during late pregnancy and the early puerperium. However, serum relaxin does not appear to influence BP, renal vascular resistance, renal blood flow or GFR in late pregnancy or in women with preeclampsia.
View details for DOI 10.5414/CNP75226
View details for Web of Science ID 000288817800007
View details for PubMedID 21329633
To elucidate the pathophysiologic changes in the kidney due to aging, we used physiological, morphometric, and imaging techniques to quantify GFR and its determinants in a group of 24 older (? 55 years) compared to 33 younger (? 45 years) living donors. Mathematical modeling was used to estimate the glomerular filtration coefficients for the whole kidney (K(f)) and for single nephrons (SNK(f)), as well as the number of filtering glomeruli (N(FG)). Compared to younger donors, older donors had a modest (15%) but significant depression of pre-donation GFR. Mean whole-kidney K(f), renocortical volume, and derived N(FG) were also significantly decreased in older donors. In contrast, glomerular structure and SNK(f) were not different in older and younger donors. Derived N(FG) in the bottom quartile of older donors was less than 27% of median-derived N(FG) in the two kidneys of younger donors. Nevertheless, the remaining kidney of older donors exhibited adaptive hyperfiltration and renocortical hypertrophy post-donation, comparable to that of younger donors. Thus, our study found the decline of GFR in older donors is due to a reduction in K(f) attributable to glomerulopenia. We recommend careful monitoring for and control of post-donation comorbidities that could exacerbate glomerular loss.
View details for DOI 10.1038/ki.2010.128
View details for Web of Science ID 000281824200011
View details for PubMedID 20463656
View details for PubMedCentralID PMC3353650
The 5-yr survival rate of renal allografts is significantly lower for grafts from older deceased donors than from younger deceased donors. For evaluation of the potential contribution of renal senescence in this shortened graft survival, glomerular function and structure were analyzed in allografts from deceased donors older than 55 yr ("aging") or younger than 40 yr ("youthful"). Aging donors had a significantly higher prevalence of sclerotic glomeruli (P < 0.002), and their nonsclerotic glomeruli tended to be larger, had a larger filtration surface area (P = 0.02), and had a higher single-nephron ultrafiltration coefficient (K(f); P = 0.07), suggesting a compensatory response to functional loss of glomeruli. After serum creatinine reached a stable nadir in the transplant recipients, GFR and its hemodynamic determinants were evaluated and the whole allograft K(f) was computed. Compared with the allografts from youthful donors, allografts from aging donors exhibited a 32% lower GFR, which was exclusively attributable to a 45% reduction in allograft K(f) (both P < 0.001). In addition, the number of functioning glomeruli per allograft was profoundly lower in grafts from aging donors than from youthful donors (3.6 +/- 2.1 x 10(5) versus 8.5 +/- 3.4 x 10(5); P < 0.01), and this could not be explained by the relatively modest 17% prevalence of global glomerulosclerosis in the aging group. The marked reduction in overall glomerular number in many aging donors may lead to a "remnant kidney" phenomenon, potentially explaining the shorter mean survival of these allografts.
View details for DOI 10.1681/ASN.2008030306
View details for Web of Science ID 000262677200025
View details for PubMedID 18815243
View details for PubMedCentralID PMC2615719
Most studies of prognosis in IgA nephropathy (IgAN) have tried to predict dichotomous outcomes based on a small number of clinical or semi-quantitative histological variables in large numbers of patients.We pursued a quite different approach. We measured GFR annually for 4-5 years in 22 adult patients with recently diagnosed IgAN. Quantitative morphology was performed on the diagnostic biopsy specimens and baseline glomerular filtration dynamics were performed at study entry. An initial set of 30 plausible predictor variables (half demographic or physiological, half structural) was reduced to 22 using phylogenetic trees. Least-angle regression (LARS) was used to predict the rate of GFR change from these variablesThe rate of GFR change ranged from a loss of 41 ml/min/year to a gain of 8.6 ml/min/year. We found an optimum predictor set of five baseline variables: the percentage of glomeruli with global sclerosis, the fractional interstitial area, the serum creatinine, the average tuft volume of non-sclerotic glomeruli and the renal plasma flow.The strong predictive relationship of the three structural variables with the slope of GFR in our subjects suggests that even at the time of their initial diagnosis many patients with IgAN already manifest a 'remnant kidney' phenomenon. The distinctive pathophysiological insights derived from this study suggest some of the advantages of intense quantitative investigations applied to a small number of subjects.
View details for DOI 10.1093/ndt/gfm560
View details for Web of Science ID 000253022100034
View details for PubMedID 17890749
We examined the magnitude of adaptive hyperfiltration in the remaining kidney of 16 aging (>57 yr) and 16 youthful (<55 yr) individuals who had undergone a contralateral nephrectomy. Healthy volunteers who were youthful (n = 143) or aging (n = 37) provided control values for the binephric condition. One-kidney glomerular filtration rate (GFR; +42%), renal plasma flow (+38%), plasma oncotic pressure (+2.8 mmHg), and mean arterial pressure (+7.0 mmHg) were all higher in youthful uninephric vs. binephric subjects. Corresponding excesses in aging uninephric vs. binephric subjects were by 38 and 36% and 1.4 and 14.0 mmHg, respectively. Modeling of these data revealed that an isolated increase in either the glomerular ultrafiltration coefficient (K(f)) by 110% or in the transcapillary hydraulic pressure gradient (DeltaP) by 7 mmHg, could account for the observed level of hyperfiltration in youthful uninephric subjects. Corresponding increases for aging uninephric subjects were 61% for K(f) and 5 mmHg for DeltaP. We conclude that the magnitude of adaptive hyperfiltration is similar in aging to that in youthful uninephric subjects, albeit at a lower absolute GFR level. Isolated increases in either K(f) or DeltaP or a combination of smaller increases in both can account for the hyperfiltration. Greater adaptive arterial hypertension in aging than youthful uninephric subjects raises the possibility of a disproportionate role for glomerular hypertension and DeltaP elevation in aging compared with youthful uninephric subjects. Glomerular hypertension could exacerbate the sclerosing glomerulopathy of senescence and lead to renal insufficiency. We recommend that living donors of a kidney transplantation in or beyond the seventh decade be used with caution.
View details for DOI 10.1152/ajprenal.00329.2005.
View details for Web of Science ID 000239658900014
View details for PubMedID 16525160
To assess the benefit of l-arginine, the precursor to nitric oxide, on blood pressure and recovery of the glomerular lesion in preeclampsia.Forty-five women with preeclampsia were randomized to receive either l-arginine or placebo until day 10 postpartum. Primary outcome measures including mean arterial pressure, glomerular filtration rate, and proteinuria were assessed on the third and 10th days postpartum by inulin clearance and albumin-to-creatinine ratio. Nitric oxide, cyclic guanosine 3'5' monophosphate, endothelin-1, and asymmetric-dimethyl-arginine and arginine levels were assayed before delivery and on the third and 10th days postpartum. Healthy gravid women provided control values. Assuming a standard deviation of 10 mm Hg, the study was powered to detect a 10-mm Hg difference in mean arterial pressure (alpha .05, beta .20) between the study groups.No significant differences existed between the groups with preeclampsia before randomization. Compared with the gravid control group, women with preeclampsia exhibited significantly increased serum levels of endothelin-1, cyclic guanosine 3'5' monophosphate, and asymmetric-dimethyl-arginine before delivery. Despite a significant increase in postpartum serum arginine levels due to treatment, no differences were found in the corresponding levels of nitric oxide, endothelin-1, cyclic guanosine 3'5' monophosphate, or asymmetric-dimethyl-arginine between the two groups with preeclampsia. Further, there were no significant differences in any of the primary outcome measures with both groups demonstrating similar levels in glomerular filtration rate and equivalent improvements in both blood pressure and proteinuria.Blood pressure and kidney function improve markedly in preeclampsia by the 10th day postpartum. Supplementation with l-arginine does not hasten this recovery.I.
View details for PubMedID 16582128
In an 8-year longitudinal study of Pima Indians with type 2 diabetes and nephropathy, we used statistical techniques that are novel and depend on minimal assumptions to compare longitudinal measurements of glomerular filtration rate (GFR). Individuals enrolled with new-onset microalbuminuria either progressed to macroalbuminuria (progressors, n = 13) or did not progress (nonprogressors, n = 13) during follow-up. Subjects with new-onset macroalbuminuria at screening were also followed (n = 22). Patients had their GFR determined serially by urinary iothalamate clearances (average 11 clearances; range 6-19). GFR courses of individuals were modeled using an adaptation of smoothing and regression cubic B-splines. Group comparisons were based on five-component vectors of fitted GFR values using a permutation approach to a Hotelling's T(2) statistic. GFR profiles of initially microalbuminuric progressors differed significantly from those of nonprogressors (P = 0.003). There were no significant baseline differences between progressors and nonprogressors with respect to any measured clinical parameters. The course of GFR in the first 4 yr following progression to macroalbuminuria in initially microalbuminuric subjects did not differ from that in newly screened macroalbuinuric subjects (P = 0.27). Without imposing simplifying models on the data, the statistical techniques used demonstrate that the courses of decline of GFR in definable subgroups of initially microalbuminuric diabetic Pima Indians, although generally progressive, follow distinct trajectories that are related to the extent of glomerular barrier dysfunction, as reflected by the evolution from microalbuminuria to macroalbuminuria.
View details for DOI 10.1152/ajprenal.00068.2004
View details for Web of Science ID 000231833300023
View details for PubMedID 15900022
In this study, we found 985 genes that change expression in the cortex and the medulla of the kidney with age. Some of the genes whose transcripts increase in abundance with age are known to be specifically expressed in immune cells, suggesting that immune surveillance or inflammation increases with age. The age-regulated genes show a similar aging profile in the cortex and the medulla, suggesting a common underlying mechanism for aging. Expression profiles of these age-regulated genes mark not only age, but also the relative health and physiology of the kidney in older individuals. Finally, the set of aging-regulated kidney genes suggests specific mechanisms and pathways that may play a role in kidney degeneration with age.
View details for DOI 10.1371/journal.pbio.0020427
View details for PubMedID 15562319
Nephron underdosing and donor kidney-recipient body size mismatch can lead to poor allograft function. The purpose of this study is to examine the relationship between donor kidney volume and posttransplantation graft function by using magnetic resonance imaging (MRI) to obtain renal volumes. Previous investigators used donor body surface area as a surrogate for kidney size or measured renal volume by using ultrasonography; both these techniques are inaccurate measures of renal volume. Intraoperative weights are more accurate, but provide information only after the transplantation is underway. More recently, MRI has been used preoperatively to screen living donors; these novel MRI techniques also provide information regarding renal size.We performed a retrospective analysis of 54 patients who underwent living donor transplantation at our institution from 2000 to 2002. All living donors underwent preoperative renovascular imaging using MRI, and renal volumes were obtained for each donor. A transplant kidney volume-recipient body weight (Vol/Wt) ratio was determined for each donor-recipient pair, and patients were divided into tertiles corresponding to 3 groups: high (>2.7), medium (2 to 2.7), and low (<2) "nephron dose" ratios.Glomerular filtration rate (GFR) correlated with Vol/Wt ratio at 6 and 12 months (r = 0.46; P = 0.0005 and r = 0.41; P = 0.003). At 6 months, mean GFRs in the low, medium, and high groups were 52.4 +/- 2.8 (SEM), 64.5 +/- 6.2, and 82.0 +/- 4.4 mL/min, respectively (P < 0.0005). At 12 months, GFRs in the low, medium, and high groups were 51.6 +/- 3.6, 63.3 +/- 3.8, and 83.9 +/- 5.4 mL/min, respectively (P < 0.0001).Transplantation of donor-recipient pairs with a Vol/Wt ratio less than 2 cm 3 /kg was associated with significantly worse graft function. Donor kidney volumes measured by means of preoperative MRI can be used to calculate Vol/Wt ratios before transplantation and identify patients at risk for a low GFR posttransplantation.
View details for DOI 10.1053/j.ajkd.2004.07.012
View details for Web of Science ID 000225044100015
View details for PubMedID 15492954
We evaluated the glomerular filtration rate (GFR) during the second postpartum week in 22 healthy women who had completed an uncomplicated pregnancy. We used physiological techniques to measure GFR, renal plasma flow, and oncotic pressure and computed a value for the two-kidney ultrafiltration coefficient (K(f)). We compared these findings with those in pregnant women previously studied on the first postpartum day as well as nongravid women of reproductive age. Healthy female transplant donors of reproductive age permitted the morphometric analysis of glomeruli and computation of the single-nephron K(f). The aforementioned physiological and morphometric measurements were utilized to estimate transcapillary hydraulic pressure (Delta P) from a mathematical model of glomerular ultrafiltration. We conclude that postpartum day 1 is associated with marked glomerular hyperfiltration (+41%). A theoretical analysis of GFR determinants suggests that depression of glomerular capillary oncotic pressure, the force opposing the formation of filtrate, is the predominant determinant of early elevation of postpartum GFR. A reversal of the gestational hypervolemia and hemodilution, still evident on postpartum day 1, eventuates by postpartum week 2. An elevation of oncotic pressure in the plasma that flows axially along the glomerular capillaries to supernormal levels ensues; however, GFR remains modestly elevated (+20%) above nongravid levels. An analysis of filtration dynamics at this time suggests that a significant increase in Delta P by up to 16%, an approximately 50% increase in K(f), or a combination of smaller increments in both must be invoked to account for the persistent hyperfiltration.
View details for DOI 10.1152/ajprenal.00194.2003
View details for Web of Science ID 000188707500009
View details for PubMedID 14612381
The purpose of the present study was to confirm the extent to which glomerular filtration rate (GFR) is depressed in healthy, aging subjects and to elucidate the mechanism of such hypofiltration.Healthy volunteers aged 18 to 88 years (N = 159) underwent a determination of GFR, renal plasma flow (RPF), afferent oncotic pressure, and arterial pressure. Glomeruli in renal biopsies of healthy kidney transplant donors aged 23 to 69 years (N = 33) were subjected to a morphometric analysis, so as to determine glomerular hydraulic permeability and filtration surface area. The aforementioned GFR determinants were then subjected to mathematical modeling to compute the glomerular ultrafiltration coefficient (Kf) for two kidneys and individual glomeruli.GFR was significantly depressed (P < 0.0001) by 22% in aging (>or=55 years old) compared to youthful subjects (
View details for Web of Science ID 000185226200031
View details for PubMedID 12969161
View details for Web of Science ID 000185226200031
View details for PubMedID 12969161
Insulin-like growth factor (IGF-1) has been shown in animal models to accelerate recovery from acute renal failure (ARF). However, a therapeutic trial of recombinant human (rh) IGF-1 in patients with ARF in the intensive care unit (ICU) failed to demonstrate efficacy . Such patients often had multiple organ failure, recurrent renal injury, and a delay of several days before commencing treatment.To circumvent these confounding factors, we randomized recipients of cadaveric renal allografts to immediate (<5 hours) rhIGF-1 versus placebo therapy (100 mg/kg subcutaneously twice a day for 6 days). Preliminary observations 3 hours posttransplantation in an additional 44 patients revealed a creatinine clearance < or = 20 mL/min to predict protracted ARF. Thus, this value was used to determine study eligibility.Creatinine clearance prior to commencing treatment was not significantly different between the two groups (8 +/- 5 mL/min for IGF-1 and 7 +/- 6 mL/min for placebo; P = 0.39). Inulin clearance on day 7, the primary outcome measure, was 21 +/- 22 mL/min and 19 +/- 19 mL/min in the IGF-1 (N = 19) and placebo (N = 24) groups, respectively (P = 0.67). Secondary outcome measures, including nadir serum creatinines after 6 weeks and need for dialysis, also did not differ between the two groups. We performed an analysis of statistical power using the placebo arm of the trial. Defining a twofold increase above placebo in day 7 glomerular filtration rate (GFR) as of meaningful biologic significance, we determined that the modest sample size used in the present study is adequate.We, thus, conclude that (1) IGF-1 treatment is unlikely to benefit ARF and (2) the transplanted kidney is a good model to screen new agents for ARF that have demonstrated promise in animal trials.
View details for Web of Science ID 000183966500022
View details for PubMedID 12846755
The loss of glomerular visceral epithelial cells (podocytes) has been associated with the development of glomerular sclerosis and loss of renal function. Viability of podocytes recovered from urine of subjects with glomerular disease and of healthy controls was investigated by propidium iodide exclusion and TUNEL staining. Podocyte loss was quantified by cytospin. The growth behavior in culture of urinary cells and their expression of specific markers were examined. The majority of urinary podocytes are viable, although apoptosis occurs in about one-half of the cells. Patients with active glomerular disease excreted up to 388 podocytes/mg creatinine, whereas healthy controls and patients with quiescent disease generally excreted <0.5 podocytes/mg creatinine. The identity of cultured cells was confirmed by their morphology, growth behavior, and expression of podocyte-specific markers. The difference in growth behavior between healthy controls and subjects with active glomerular disease suggests that in active disease viable podocytes detach from the glomerular tuft due to local environmental factors rather than defects in the podocytes per se, whereas in healthy individuals mostly senescent podocytes are shed.
View details for DOI 10.1152/ajprenal.00404.2002
View details for Web of Science ID 000183314500005
View details for PubMedID 12631553
View details for PubMedCentralID PMC3368602
We evaluated the glomerular filtration rate (GFR) in 34 subjects with membranous nephropathy (MN) of new onset. We used physiological techniques to measure GFR, renal plasma flow, and oncotic pressure and computed a value for the two-kidney ultrafiltration coefficient (K(f)). A morphometric analysis of glomeruli in the diagnostic biopsy permitted computation of the single-nephron ultrafiltration coefficient (SNK(f)). MN subjects were divided into two groups: moderate or severe, according to whether GFR was depressed by less or more than 50%. SNK(f) was subnormal but similar in moderate and severe MN. In contrast, two-kidney K(f) was significantly more depressed in severe than in moderate MN. We estimated the total number of functioning glomeruli (N(g)) by dividing two-kidney K(f) by SNK(f). Whereas mean N(g) was similar in controls and moderate MN (1.5 and 1.4-1.7 x 10(6), respectively), it was significantly lower in severe MN (0.5 x 10(6)). This degree of glomerulopenia was not reflected in the rate of global sclerosis. We conclude that a combination of depressed SNK(f) (due to foot process broadening) and profound glomerulopenia accounts for GFR depression of >50% early in the course of MN. The cause of the glomerulopenia remains to be elucidated.
View details for DOI 10.1152/ajprenal.00273.2002
View details for Web of Science ID 000182018200016
View details for PubMedID 12527555
To describe the long-term survival, renal condition, and morbidity outcomes in patients who received total lymphoid irradiation (TLI) for the treatment of lupus nephritis.Twenty-one patients with biopsy-proven, diffuse membranoproliferative glomerulonephritis and significant proteinuria of >2.5 grams/day received TLI from 1980 to 1987 at Stanford University Medical Center. All patients had previously failed to respond to treatment with high-dose corticosteroids or therapy with corticosteroids plus immunosuppressive agents (azathioprine, cyclophosphamide, or chlorambucil).The mean duration of followup since TLI was 10.7 years. Fifteen of 21 patients (71%) remained alive at the time of this assessment. Nine of the 21 patients (43%) survived without developing end-stage renal disease (ESRD). The probability of long-term survival without ESRD and without need for additional immunosuppressive agents after TLI was 19% (4 of 21). Factors predicting renal failure at the time of TLI included elevated creatinine levels, increased interstitial fibrosis on renal biopsy, and increased fractional excretion of immunoglobulin and albumin. Malignancies were found in 4 patients, and opportunistic infections occurred in 7 patients.Overall, patients with lupus nephritis treated with TLI do not appear to have better 10-year survival with lower incidence of ESRD compared with patients in published series treated with conventional immunosuppressive therapies. However, in this series of patients, treatment with conventional immunosuppressive therapies had been unsuccessful and given the limited number of adverse events and the efficacy seen in some patients, TLI appears to be a reasonable therapeutic option for the treatment of severe lupus nephritis among patients who fail to respond under standard cytotoxic regimens.
View details for Web of Science ID 000174946500022
View details for PubMedID 11953979
To test whether magnetic resonance (MR) imaging enables accurate measurement of extraction fraction (EF) in swine with unilateral renal ischemia and to evaluate effects of renal arterial stenosis on EF and single-kidney glomerular filtration rate.High-grade unilateral renal arterial stenoses were surgically created in eight pigs. Direct measurements of renal venous and arterial inulin concentration provided reference standard estimates of single-kidney EF. Pigs were imaged with a 1.5-T imager to estimate EF, renal blood flow, and glomerular filtration rate. A breath-hold inversion-recovery spiral sequence was used to measure T1 of blood in the infrarenal inferior vena cava and renal veins after intravenous administration of gadopentetate dimeglumine, and these data were used to calculate EF. Cine-phase contrast material-enhanced imaging of the renal arteries provided quantitative renal blood flow measurements. Bilateral single-kidney glomerular filtration rate was then determined: glomerular filtration rate = renal blood flow x (1 - hematocrit level) x EF.A statistically significant linear correlation was found between EF, as determined with MR imaging, and inulin (r = 0.77). As compared with kidneys without renal arterial stenosis, kidneys with renal arterial stenosis showed 50% (0.14/0.28) EF reduction (P <.01) and 59% glomerular filtration rate reduction (P <.01).MR imaging shows promise for in vivo measurement of EF and glomerular filtration rate, which may be useful in assessing the clinical importance of renal arterial stenosis.
View details for DOI 10.1148/radiol.2231010420
View details for PubMedID 11930050
IgA nephropathy is a common form of progressive glomerular disease, associated with proliferation of mesangial cells and mesangial deposition of IgA. The present study was designed to investigate functional and morphological covariates of disease severity in patients with IgA nephropathy.Glomerular hemodynamics, permselectivity and ultrastructure were studied in 17 adult patients with IgA nephropathy using inulin, para-aminohippuric acid (PAH) and 3H-Ficoll clearances and morphometric methods. A mathematical model of macromolecule permeation through a heteroporous membrane was used to characterize glomerular permselectivity. Controls consisted of 14 healthy living kidney donors and 12 healthy volunteers.The patients were heterogeneous in their disease severity, but as a group had a decreased glomerular filtration rate (GFR) and increased urinary protein excretion compared to controls [63 +/- 29 SD vs. 104 +/- 23 mL/min/1.73 m2, P < 0.001, and (median) 1.34 vs. 0.11 g/day, P < 0.0001, respectively). A multivariate analysis of structural and functional relationships revealed GFR depression to be most strongly correlated with the prevalence of global glomerular sclerosis (t = -4.073, P = 0.002). Those patients with the most severe glomerular dysfunction had a reduced number of glomerular visceral epithelial cells (podocytes) per glomerulus. The degree of podocytopenia was related to the extent of glomerular sclerosis and of impairment of permselectivity and GFR, with worsening injury below an apparent threshold podocyte number of about 250 cells per glomerulus. There were no corresponding correlations between these indices of injury and the number of mesangial and endothelial cells.Our findings show that podocyte loss is a concomitant of increasing disease severity in IgA nephropathy. This suggests that podocyte loss may either cause or contribute to the progressive proteinuria, glomerular sclerosis and filtration failure seen in this disorder.
View details for Web of Science ID 000174465100030
View details for PubMedID 11918755
This study sought to determine the extent to which GFR is decreased during acute renal allograft rejection in human subjects and to determine the mechanism of the decrease in GFR. Eight patients with biopsy-proven acute rejection were compared with 18 recipients of optimally functioning renal allografts. GFR and renal plasma flow (RPF) were measured as the clearance of inulin and para-aminohippuric acid, respectively. Arterial BP was determined, blood was sampled, and plasma oncotic pressure (pi(A)) was measured. Glomeruli obtained by biopsy during rejection were subjected to morphometric analysis, for determination of K(f). Control morphometric values for healthy glomeruli were provided by 10 living donors from whom biopsies were obtained at the time of organ donation. The subjects in the acute rejection group exhibited a significantly reduced GFR of 17 +/- 4 ml/min per 1.73 m(2), compared with 72 +/- 4 ml/min per 1.73 m(2) for control subjects (P < 0.001). With the use of a sensitivity analysis to take into account the unknown para-aminohippuric acid extraction ratio, the RPF rate was calculated to have likely been significantly decreased, by 45 to 70%, in the acute rejection group. Neither the plasma oncotic pressure nor the mean arterial pressure differed between the two groups. Morphometric analysis revealed no difference in the single-nephron K(f) values for the acute rejection group, compared with the control group. These results indicate that acute renal allograft rejection causes a profound decrease in GFR, which is attributable to a decrease in RPF alone or in combination with a decrease in the glomerular transcapillary hydraulic pressure gradient (DeltaP).
View details for Web of Science ID 000173964000025
View details for PubMedID 11856784
Postischemic injury in 38 recipients of 7-day-old cadaveric renal allografts was classified into sustained (n = 15) or recovering (n = 23) acute renal failure (ARF) according to the prevailing inulin clearance. Recipients of long-standing allografts that functioned optimally (n = 16) and living transplant donors undergoing nephrectomy (n = 10) served as functional and structural controls, respectively. A combination of physiological and morphometric techniques were used to evaluate glomerular filtration rate and its determinants 1-3 h after reperfusion and again on day 7 to elucidate the mechanism for persistent hypofiltration in ARF that is sustained. Glomerular filtration rate in the sustained ARF group on day 7 was depressed by 90% (mean +/- SD); the corresponding fall in renal plasma flow was proportionately less. Neither plasma oncotic pressure nor the single-nephron ultrafiltration coefficient differed between the sustained ARF and the control group, however. A model of glomerular ultrafiltration and a sensitivity analysis were used to compute the prevailing transcapillary hydraulic pressure gradient (DeltaP), the only remaining determinant of DeltaP. This revealed that DeltaP varied between 27 and 28 mmHg in sustained ARF and 32-38 mmHg in recovering ARF on day 7 vs. 47-54 mmHg in controls. Sustained ARF was associated with persistent tubular dilatation. We conclude that depression of DeltaP, perhaps due partially to elevated tubule pressure, is the predominant cause of hypofiltration in the maintenance stage of ARF that is sustained for 7 days.
View details for Web of Science ID 000173348100011
View details for PubMedID 11788441
The increased utilization of expanded criteria kidney donors has necessitated the reevaluation of multiple donor risk factors to insure the best outcome from this valuable resource. Reports of decreased graft survival in recipients of kidneys from donors with > or =20% glomerular sclerosis (GS) have led many transplant centers to refuse these donor kidneys. The purpose of this study is to compare outcome in recipients of cadaveric donor kidneys with > or =20% GS versus those with <20% or no GS at our center.We retrospectively reviewed 18 donor and 19 recipient and outcome variables in 89 recipients of kidneys, which were biopsied at the time of transplantation, between February 1995 and November 1998. We evaluated outcome based upon the percent of GS and the degree of vasculopathy.Donors with > or =20% GS were older and had more hypertension. Recipients of kidneys with > or =20% GS were older, had higher serum creatinine values at 1 and 2 years, but similar rates of delayed graft function and 2-year graft survival. Vasculopathy did not correlate to any important donor criteria except the percent GS. However, serum creatinine was significantly higher in recipients of kidneys with moderate vasculopathy versus none, up to 2 years after transplantation. There was no significant difference in graft loss based upon vasculopathy.Kidneys from donors with > or =20% GS provide excellent outcome similar to kidneys from donors with no GS.
View details for Web of Science ID 000167021600037
View details for PubMedID 11182400
The development of microalbuminuria in individuals with type 2 diabetes mellitus is associated with a 10-fold increase in the risk of progression to overt nephropathy and eventual end-stage renal failure. The present study reports long-term (up to 8 yr) follow-up of 43 Pima Indians with type 2 diabetes detected on screening to have microalbuminuria. The natural history of albuminuria in these individuals included progression to overt proteinuria (urinary albumin excretion > or = 300 mg/d) in half of the participants by 7 yr of follow-up. The size selectivity of the glomerular barrier was also investigated using dextran sieving and pore theory. Whereas a comparison group of macroalbuminuric Pima Indians had an excess of large pores that served as a macromolecular "shunt," individuals with microalbuminuria had a shunt size no different from long-term diabetic, normoalbuminuric control subjects. An abrupt transition from little or no relationship to a highly significant and positive relationship between increasing albuminuria and shunt size occurred at an albumin-to-creatinine ratio of approximately 3000 mg/g. Shunt size in macroalbuminuric individuals correlated with the extent of foot process broadening. Podocyte foot processes in microalbuminuric participants were not different from those in control subjects. In conclusion, although microalbuminuria in type 2 diabetic Pima Indians often heralds progressive glomerular injury, it is not the result of defects in the size permselectivity of the glomerular barrier but rather of changes in either glomerular charge selectivity or tubular handling of filtered proteins or of a combination of these two factors.
View details for Web of Science ID 000090138500017
View details for PubMedID 11053486
We examined the course of glomerular injury in 12 Pima Indians with long-standing (>8 years) type 2 diabetes mellitus, normal serum creatinine, and microalbuminuria. They were compared with a group of 10 Pima Indians in Arizona with new-onset (<5 years) type 2 diabetes, normal renal function, and normoalbuminuria (<30 mg albumin/g creatinine on random urine specimens).A combination of physiological and morphological techniques was used to evaluate glomerular function and structure serially on two occasions separated by a 48-month interval. Clearances of iothalamate and p-aminohippuric acid were used to determine glomerular filtration rate (GFR) and renal plasma flow, respectively. Afferent oncotic pressure was determined by membrane osmometry. The single nephron ultrafiltration coefficient (Kf) was determined by morphometric analysis of glomeruli and mathematical modeling.The urinary albumin-to-creatinine ratio (median + range) increased from 84 (28 to 415) to 260 (31 to 2232) mg/g between the two examinations (P = 0.01), and 6 of 12 patients advanced from incipient (ratio = 30 to 299 mg/g) to overt nephropathy (>/=300 mg/g). A 17% decline in GFR between the two examinations from 186 +/- 41 to 155 +/- 50 mL/min (mean +/- SD; P = 0.06) was accompanied by a 17% decline in renal plasma flow (P = 0.003) and a 6% increase in plasma oncotic pressure (P = 0.02). Computed glomerular hydraulic permeability was depressed by 13% below control values at both examinations, a result of a widened basement membrane and a reduction in frequency of epithelial filtration slits. The filtration surface area declined significantly, however, from 6.96 +/- 2.53 to 5.51 +/- 1.62 x 105 mm2 (P = 0.01), a change that was accompanied by a significant decline in the number of mesangial cells (P = 0.001), endothelial cells (P = 0.038), and podocytes (P = 0.0005). These changes lowered single nephron Kf by 20% from 16.5 +/- 6.0 to 13.2 +/- 3.6 nL/(minutes + mm Hg) between the two examinations (P = 0.02). Multiple linear regression analysis revealed that among the determinants of GFR, only the change in single nephron Kf was related to the corresponding change in GFR.We conclude that a reduction in Kf is the major determinant of a decline in GFR from an elevated toward a normal range as nephropathy in type 2 diabetes advances from an incipient to an overt stage.
View details for Web of Science ID 000089155700029
View details for PubMedID 10972685
We determined the effect of postischemic injury to the human renal allograft on p-aminohippurate (PAH) extraction (E(PAH)) and renal blood flow. We evaluated renal function in 44 allograft recipients on two occasions: 1-3 h after reperfusion (day 0) and again on postoperative day 7. On day 0 subsets underwent intraoperative determination of renal blood flow (n = 35) by Doppler flow meter and E(PAH) (n = 25) by renal venous assay. Blood flow was also determined in another subset of 16 recipients on postoperative day 7 by phase contrast-cine-magnetic resonance imaging, and E(PAH) was computed from the simultaneous PAH clearance. Glomerular filtration rate (GFR) on day 7 was used to divide subjects into recovering (n = 23) and sustained (n = 21) acute renal failure (ARF) groups, respectively. Despite profound depression of GFR in the sustained ARF group, renal plasma flow was only slightly depressed, averaging 296 +/- 162 ml. min(-1). 1.73 m(-2) on day 0 and 202 +/- 72 ml. min(-1). 1.73 m(-2) on day 7, respectively. These values did not differ from corresponding values in the recovering ARF group: 252 +/- 133 and 280 +/- 109 ml. min(-1). 1.73 m(-2), respectively. E(PAH) was profoundly depressed on day 0, averaging 18 +/- 14 and 10 +/- 7% in recovering and sustained ARF groups, respectively, vs. 86 +/- 6% in normal controls (P < 0.001). Corresponding values on day 7 remained significantly depressed at 65 +/- 20 and 11 +/- 22%, respectively. We conclude that postischemic injury to the renal allograft results in profound impairment of E(PAH) that persists for at least 7 days, even after the onset of recovery. An ensuing reduction in urinary PAH clearance results in a gross underestimate of renal plasma flow, which is close to the normal range in the initiation, maintenance, and recovery stages of this injury.
View details for Web of Science ID 000081923400019
View details for PubMedID 10444587
The objective of this study was to determine whether the glomerular hyperfiltration of pregnancy is maintained even after Caesarean section and, if so, to define the responsible hemodynamics. The dynamics of glomerular filtration were evaluated in 12 healthy women who had just completed an uncomplicated pregnancy and were delivered by Caesarean section. Age-matched but non-gravid female volunteers (n = 22) served as control subjects. GFR in postpartum women was elevated above control values by 41%; 149+/-10 versus 106+/-3 ml/min per 1.73 m2, respectively (P < 0.001). In contrast, corresponding renal plasma flow was the same in the two groups, such that the postpartum filtration fraction was significantly elevated by 20%. Computation of glomerular intracapillary oncotic pressure (piGC) from knowledge of plasma oncotic pressure and the filtration fraction revealed this quantity to be significantly reduced in postpartum women, 20.6+/-1.7 versus 26.1+/-2.0 mmHg in control subjects (P < 0.001). A theoretical analysis of glomerular ultrafiltration suggests that depression of piGC, the force opposing the formation of filtrate, is predominantly or uniquely responsible for the observed postpartum hyperfiltration.
View details for Web of Science ID 000081143900017
View details for PubMedID 10405212
A loss of proximal tubule cell polarity is thought to activate tubuloglomerular feedback, thereby contributing to glomerular filtration rate depression in postischemic acute renal failure (ARF).We used immunomicroscopy to evaluate the segmental distribution of Na+/K+-ATPase in tubules of recipients of cadaveric renal allografts. Fractional excretion (FE) of sodium and lithium was determined simultaneously. Observations were made on two occasions: one to three hours after graft reperfusion (day 0) and again on post-transplant day 7. An inulin clearance below or above 25 ml/min on day 7 was used to divide subjects into groups with sustained (N = 15) or recovering (N = 16) ARF, respectively.In sustained ARF, the fractional excretion of sodium (FENa) was 40 +/- 6% and 11 +/- 5%, and the fractional excretion of lithium (FELi) was 76 +/- 5% and 70 +/- 2% on days 0 and 7, respectively. Corresponding findings in recovering ARF were 28 +/- 2% and 6 +/- 2% for the FENa and 77 +/- 4% and 55 +/- 3% (P < 0.05 vs. sustained) for FELi. Na+/K+-ATPase distribution in both groups was mainly basolateral in distal straight and convoluted tubule segments and collecting ducts. However, Na+/K+-ATPase was poorly retained in the basolateral membrane of proximal convoluted and straight tubule segments in sustained and recovering ARF on both days 0 and 7.We conclude that loss of proximal tubule cell polarity for Na+/K+-ATPase distribution is associated with enhanced delivery of filtered Na+ to the macula densa for seven days after allograft reperfusion. Whether an ensuing activation of tubuloglomerular feedback is an important cause of glomerular filtration rate depression in this form of ARF remains to be determined.
View details for Web of Science ID 000078682200019
View details for PubMedID 10027933
Cytoskeletal proteins associate with specific cell adhesion complexes and membrane proteins and influence the structural and functional organization of polarized epithelial cells in the kidney. Among such proteins that have been studied in cultured cell lines and in animals are the tight junction complex (ZO-1 and occludin), the adherens cell-cell adhesion complex (alpha-, beta-catenin and plakoglobin), and Na+,K+-ATPase, with its associated membrane skeleton proteins ankyrin and fodrin. Although abnormal distribution of these proteins has been implicated in the pathogenesis of various renal diseases, the relevance of these findings to corresponding disease of the human kidney remains to be established. As a first step towards elucidating a role for such proteins in human kidney disease, we undertook a histochemical analysis of the distribution of these proteins in biopsy specimens of human kidney taken from healthy kidney transplant donors. We found each protein to have a characteristic subcellular localization and an intensity of staining that varied among different segments of the nephron in a manner that is consistent with discrete, segmental nephron function.
View details for Web of Science ID 000077379000011
View details for PubMedID 9815284
A growing body of evidence suggests that agents that inhibit the angiotensin-converting enzyme are renoprotective. In experimental animal models of chronic renal injury, such renoprotection can virtually eliminate progression of the renal injury, provided that therapy is started at the time of injury. In humans with chronic renal injury, renoprotection has been successfully demonstrated only late in the course of the renal disease. The rate of progression to end-stage renal failure can be delayed, but progression continues at a slower pace. Further study is required to determine whether earlier intervention can better preserve nephron structure and function. A strategy for future trials is recommended. It emphasizes more sensitive outcome measures so as to achieve greater statistical power.
View details for PubMedID 11443771
Pre-eclampsia is characterized by hypertension, proteinuria and edema. Simultaneous studies of kidney function and structure have not been reported. We wished to explore the degree and nature of glomerular dysfunction in pre-eclampsia.Physiologic techniques were used to estimate glomerular filtration rate (GFR), renal plasma flow and afferent oncotic pressure immediately after delivery in consecutive patients with pre-eclampsia (PET; N = 13). Healthy mothers completing an uncomplicated pregnancy served as functional controls (N = 12). A morphometric analysis of glomeruli obtained by biopsy and mathematical modeling were used to estimate the glomerular ultrafiltration coefficient (Kf). Glomeruli from healthy female kidney transplant donors served as structural controls (N = 8).The GFR in PET was depressed below the control level, 91 +/- 23 versus 149 +/- 34 ml/min/1.73 m2, respectively (P < 0.0001). In contrast, renal plasma flow and oncotic pressure were similar in the two groups (P = NS). A reduction in the density and size of endothelial fenestrae and subendothelial accumulation of fibrinoid deposits lowered glomerular hydraulic permeability in PET compared to controls, 1.81 versus 2.58 x 10(-9) m/sec/PA. Mesangial cell interposition also curtailed effective filtration surface area. Together, these changes lowered the computed single nephron Kf in PET below control, 4.26 versus 6.78 nl/min x mm Hg, respectively.The proportionate (approximately 40%) depression of Kf for single nephrons and GFR suggests that hypofiltration in PET does not have a hemodynamic basis, but is a consequence of structural changes that lead to impairment of intrinsic glomerular ultrafiltration capacity.
View details for Web of Science ID 000076096900022
View details for PubMedID 9767540
To assess the ability of three cine phase-contrast magnetic resonance (MR) imaging techniques to measure normal human renal blood flow (RBF) in vivo.Eighteen healthy volunteers were studied with three cine phase-contrast MR imaging techniques: breath-hold, segmented k-space, two-dimensional, Fourier transform technique (ie, time-resolved imaging with automatic data segmentation, or TRIADS); a breath-hold rapid spiral acquisition; and a non-breath-hold rapid spiral acquisition that allowed resolution of both cardiac and respiratory cycles. In each case, total arterial RBF and blood flow per unit of renal volume were calculated. For each subject, RBF was measured with a standard technique of p-aminohippuric acid (PAH)-clearance hematocrit on the same day as the MR imaging examination was performed.The range of agreement (2 standard deviations, or 95% confidence interval) between RBF measurements obtained with the PAH-clearance hematocrit technique and the various cine phase-contrast techniques varied from +/- 17.6% to +/- 26.5%. The best agreement was obtained with non-breath-hold rapid spiral data, by using data from the end-expiratory phase of respiration.Findings with cine phase-contrast MR imaging employing rapid spiral acquisition are in good agreement with measurements made with PAH-clearance hematocrit and give the promise of clinical measurements of RBF.
View details for Web of Science ID 000075488200028
View details for PubMedID 9722853
Glomerular function and structure were serially evaluated in 15 patients with membranous nephropathy who exhibited relapsing nephrosis and chronic depression of GFR. GFR declined from 56+/-8 (mean+/-SEM) at onset to 31+/-4 ml/min per 1.73 m2 after a 2- to 5-yr period of observation (P < 0.05). An analysis of filtration dynamics suggested persistent elevation of net ultrafiltration pressure. To examine a possible role for declining intrinsic glomerular filtration capacity as the basis for the observed hypofiltration, glomeruli in the baseline and a repeat biopsy (performed after a median of 28 mo) were subjected to morphometric analysis and mathematical modeling. Analysis of the baseline biopsy revealed a reduction in filtration slit frequency and thickening of the glomerular basement membrane, lowering computed hydraulic permeability by 66% compared with normal kidney donors. In contrast, filtration surface area was increased by 37% as a result of glomerular hypertrophy. The repeat biopsy revealed persistent depression of hydraulic permeability, primarily owing to foot process broadening. An additional finding was a decrease in filtration surface area from baseline in patent glomeruli, possibly due to encroachment on the capillary lumen of an increasingly widened basement membrane. Also, a striking increase in the prevalence of global glomerulosclerosis from 7+/-2% to 23+/-4% was found between the two biopsies, suggesting a significant loss of functioning nephrons. It is concluded that hypofiltration in membranous nephropathy is the consequence of a biphasic loss of glomerular ultrafiltration capacity, initially owing to impaired hydraulic permeability that is later exacerbated by a superimposed loss of functioning glomeruli and of filtration surface area.
View details for Web of Science ID 000074970900005
View details for PubMedID 9697660
Postischemic injury in recipients of 3-7-d-old renal allografts was classified into sustained (n = 19) or recovering (n = 20) acute renal failure (ARF) according to the prevailing inulin clearance. Recipients of optimally functioning, long-standing allografts and living donors undergoing nephrectomy served as functional (n = 14) and structural controls (n = 10), respectively. Marked elevation above control of fractional clearance of dextrans of graded size was consistent with transtubular backleak of 57% of filtrate (inulin) in sustained ARF. No backleak was detected in recovering ARF. To explore a structural basis for backleak, allograft biopsies were taken intraoperatively, 1 h after reperfusion in all recipients, and again on day 7 after transplant in a subset (n = 10). Electron microscopy revealed disruption of both apical and basolateral membranes of proximal tubule cells in both sustained and recovering ARF, but cell exfoliation and tubule basement membrane denudation were negligible. Histochemical analysis of membrane-associated adhesion complexes confirmed an abnormality of proximal but not distal tubule cells, marked in sustained ARF but not in recovering ARF. Staining for the zonula occludens complex (ZO-1) and adherens complex (alpha, beta, and gamma catenins) revealed diminished intensity and redistribution of each cytoskeletal protein from the apico-lateral membrane boundary. We conclude that impaired integrity of tight junctions and cell-cell adhesion in the proximal tubule provides a paracellular pathway through which filtrate leaks back in sustained allograft ARF.
View details for Web of Science ID 000073808800004
View details for PubMedID 9593761
We studied eight healthy volunteers and eight nephrotic subjects to compare the glomerular sieving coefficients (theta) of dextran, a linear polymer of glucopyranose, with those of Ficoll, a spherical polysucrose. Over a molecular radius (rs) interval of 20-70 A, theta for a given Ficoll was uniformly lower than corresponding theta for a dextran of equivalent rs. For each macromolecular species, the theta of molecules with rs > 50 A was selectively enhanced in nephrotic vs. healthy subjects. Analysis of either dextran or Ficoll sieving curves with pore theory revealed the glomerular barrier to have a bimodal pore size distribution: a lower mode of restrictive pores with a lognormal distribution of radii and an upper mode of large shuntlike pores. Nephrotics differed from controls in that the lower mode was broadened and shifted to pores of smaller mean size, but the prominence of shuntlike pores was enhanced by an order of magnitude. Both the mean radius of restrictive pores and the magnitude of the shunt pathway were substantially smaller when estimated from Ficoll than dextran sieving. We interpret the more realistic values for pore parameters derived from Ficoll than dextran sieving to indicate 1) that the normal glomerular barrier prevents albuminuria by virtue of a combination of both charge- and size-selective properties and 2) that a combined impairment of both barrier charge selectivity and size selectively are required to account for the observed level and composition of proteinuria in our nephrotic subjects.
View details for Web of Science ID A1997XV83400012
View details for PubMedID 9321916
Delayed graft function is a form of postischemic acute renal failure. It lowers glomerular filtration rate in large part by depressing the glomerular transcapillary hydraulic pressure difference, the driving force for the formation of filtrate. Loss of proximal tubule cell polarity, impaired sodium reabsorption and tubuloglomerular feedback-mediated afferent arteriolar constriction are all implicated. A link between delayed graft function and chronic allograft injury is evident. The ensuing impairment of graft survival makes urgent the need for further elucidation of delayed graft function and a search for an effective therapy.
View details for Web of Science ID A1997XK26600017
View details for PubMedID 9263693
We studied glomerular function longitudinally for 36-120 mo in 21 patients undergoing treatment for diffuse, proliferative lupus nephritis. We determined glomerular filtration rate (GFR) and glomerular oncotic pressure (IIGC) and computed the two-kidney ultrafiltration coefficient (Kf) at 6- to 12-mo intervals. The relationships and cross talk among the three variables over time were then analyzed by eigenfunction regression and canonical correlations. We also performed a morphometric analysis of serial biopsies and computed single-nephron Kf in patent glomeruli at baseline and after 36-94 mo of follow-up. Patients were divisible into progressors (n = 12) or nonprogressors (n = 9) according to the presence or absence, respectively, of an irrevocable decline in GFR over time. Examination of longitudinal variables revealed GFR to be strongly related to Kf in all patients and inversely related to IIGC in progressors. By serial morphometric analysis we observed a threefold increase in the prevalence of global sclerosis in progressors but unchanged prevalence in nonprogressors. Whereas single-nephron Kf of remnant glomeruli increased to supernormal levels in nonprogressors, the absence of this compensatory phenomenon in progressors permitted GFR and Kf to decline in parallel with the declining number of functional glomeruli.
View details for Web of Science ID A1997XK45000019
View details for PubMedID 9249604
Kidney biopsies from Pima Indians with type II diabetes were analyzed. Subjects were classified clinically as having early diabetes (n = 10), microalbuminuria (n = 17), normoalbuminuria, despite a duration of diabetes equal to that of the subjects with microalbuminuria (n = 12), or clinical nephropathy (n = 12). Subjects with microalbuminuria exhibited moderate increases in glomerular and mesangial volume when compared with those with early diabetes, but could not be distinguished from subjects who remained normoalbuminuric after an equal duration of diabetes. Subjects with clinical nephropathy exhibited global glomerular sclerosis and more prominent structural abnormalities in nonsclerosed glomeruli. Marked mesangial expansion was accompanied by a further increase in total glomerular volume. Glomerular capillary surface area remained stable, but the glomerular basement membrane thickness was increased and podocyte foot processes were broadened. Broadening of podocyte foot processes was associated with a reduction in the number of podocytes per glomerulus and an increase in the surface area covered by remaining podocytes. These findings suggest that podocyte loss contributes to the progression of diabetic nephropathy.
View details for Web of Science ID A1997WE31100024
View details for PubMedID 9006003
View details for PubMedCentralID PMC507802
Forty-one patients with a nephrotic syndrome and biopsy-proven membranous nephropathy were administered a 3 to 6-month course of cyclosporine (CsA;4 to 5 mg/kg per day). Differential solute clearances were used to evaluate glomerular function, before and after therapy. CsA lowered median proteinuria by 56%, from 7.3 to 3.2 g/24 h (P < 0.0001). Corresponding mean increments in serum albumin, immunoglobulin G, and oncotic pressure values were 31, 32, and 26%, respectively (all P < 0.0001). Arterial pressure, GFR, and renal plasma flow remained constant, but CsA restored the dextran-sieving curve toward normal, lowering the computed fraction of shunt-like pores by 25% (P < 0.05). In 14 instances, a cross-over design was used to randomly assign patients to 3 months of CsA versus 3 months of enalapril (10 to 30 mg daily), separated by a 1-month washout interval. Although enalapril lowered arterial pressure by 8 mm Hg (P < 0.01), it had no effect on proteinuria, plasma protein composition, filtration dynamics, or dextran sieving (all P = not significant). CsA dependence of proteinuria, indicated by relapsing nephrosis after CsA withdrawal, required additional courses of CsA to maintain proteinuria subnephrotic in most patients. In six patients with declining GFR during prolonged CsA treatment, a repeat biopsy showed more prominent immune deposits and a thicker glomerular basement membrane than at baseline. It was concluded that: (1) CsA lowers proteinuria in MN in part, by enhancing barrier size-selectivity; (2) lack of comparable efficacy of enalapril suggests that the antiproteinuric effect of CsA is related to its immuno-suppressive rather than glomerulodepressor properties; but (3) judged by repeat biopsy, CsA does not prevent continuing autoantibody formation in this disorder.
View details for Web of Science ID A1996TZ30600015
View details for PubMedID 8785399
We evaluated the postischemic renal injury in 22 patients undergoing renal transplantation. Renal tissue obtained 45 to 60 minutes after reperfusion of the allograft was stained with specific antibodies against the delta subunit of Na+/K(+)-ATPase, fodrin and ankyrin. The distribution of each cytoskeletal protein was analyzed by laser confocal microscopy. Subsequent allograft function was assessed on two occasions, 1 to 3 and 36 hours post-reperfusion, respectively. Recipients were divided into two groups: those who achieved a normal GFR on post-transplant day 3 (group 1, N = 12) and those with persistent hypofiltration (group 2, N = 10). Patients of both groups exhibited impaired sodium reabsorption and isosthenuria one to three hours postoperatively, but these abnormalities persisted on day 3 only in group 2 subjects with persistent hypofiltration. Abnormalities of Na+/K(+)-ATPase, ankyrin and fodrin were confined to proximal tubule cells and were marked only in the subjects of group 2. They consisted of redistribution of each cytoskeletal protein from the basolateral membrane to the cytoplasm. We conclude that postischemic injury to a renal allograft results in a loss of polarity of proximal tubule cells. We propose that ensuing impairment of proximal sodium reabsorption could activate tubuloglomerular feedback, thereby contributing to the protracted hypofiltration that characterizes this form of postischemic, acute renal failure.
View details for Web of Science ID A1995RV92600045
View details for PubMedID 8569093
Circulating atrial natriuretic peptide (ANP) levels and glomerular binding sites for ANP were examined in 23 subjects undergoing renal transplantation. Subjects were divided into two groups, group 1 (n = 12) with prompt and group 2 (n = 11) with delayed allograft function. Sixty to 180 min after graft reperfusion, renovascular resistance was threefold higher and glomerular filtration rate (GFR) depressed by 79% in group 2 vs. group 1. Corresponding median plasma ANP (114 vs. 140 pg/ml) and guanosine 3',5'-cyclic monophosphate (cGMP) levels (22 vs. 28 pmol/ml) were similarly elevated in the two groups [P = not significant (NS)]. Autoradiographic analysis of glomeruli in an allograft biopsy revealed the median density of total receptors (24 vs. 28 fmol/mm3), A receptors (15 vs. 19 fmol/mm3), and C receptors (6 vs. 9 fmol/mm3) for ANP to also be similar in group 2 vs. group 1, respectively (P = NS). By postoperative day 3, allograft GFR averaged only 6 +/- 2 in group 2 vs. 59 +/- 4 ml/min in group 1. Median plasma ANP levels doubled in each group to 262 and 251 pg/ml, respectively (P = NS). However, median values for plasma levels (38 vs. 17 pmol/ml) and the fractional clearance of cGMP (1.9 vs. 1.2) were significantly higher in group 2 than group 1. We conclude that, despite an adequate density of glomerular ANP receptors and enhanced cGMP generation, neither renal vasoconstriction nor hypofiltration is alleviated by a progressive elevation of plasma ANP levels in renal transplant recipients with sustained postischemic injury. We infer that constricted afferent arterioles are unresponsive to the vasorelaxant action of endogenous ANP in this form of postischemic, acute renal failure.
View details for Web of Science ID A1995RK17900016
View details for PubMedID 7631826
The detection of overt albuminuria (> 300 mg/g creatinine) in the absence of azotemia was used to diagnose early nephropathy in 34 Pima Indians with NIDDM of 16 +/- 1 years duration. Differential solute clearances were performed serially to define the course of the glomerular injury over 48 months. At baseline, the GFR (107 +/- 5 ml/min), filtration fraction and sieving coefficients of relatively permeant dextrans (< 52 A) were all depressed below corresponding values in 20 normoalbuminuric Pima Indians with a similar duration of NIDDM. Over the ensuing 48 months the GFR (-34%) and filtration fraction (-13%) in the nephropathic patients declined further. The sieving coefficients of large, nearly impermeant dextrans (> 56 A radius) increased selectively and fractional clearances of albumin and IgG increased correspondingly by > 10-fold. Analysis of the findings with pore theory revealed: (1) a progressive decline in pore density and the ultrafiltration coefficient (Kf); and (2) broadening of glomerular pore-size distribution that resulted in greater prominence of large pores (> 70 A radius). We conclude that increasing loss of intrinsic ultrafiltration capacity is the predominant cause of the early and progressive decline in GFR that follows the development of nephropathy in NIDDM. We speculate that progressive impairment of barrier size-selectivity contributes to but does not fully account for the increasingly heavy proteinuria that is observed early in the course of this disorder.
View details for PubMedID 7543961
Postischemic filtration failure in experimental animals results primarily from depression of the transcapillary hydraulic pressure difference (delta P), a quantity that cannot be determined in humans. To circumvent this limitation we determined the GFR and each of its remaining determinants in transplanted kidneys. Findings in 12 allografts that exhibited subsequent normofiltration (group 1) were compared with those in 11 allografts that exhibited persistent hypofiltration (group 2). Determinations were made intraoperatively in the exposed graft after 1-3 h of reperfusion. GFR (6 +/- 2 vs 29 +/- 5 ml/min) and renal plasma flow by Doppler flow meter (140 +/- 30 vs 315 +/- 49 ml/min) were significantly lower in group 2 than group 1. Morphometric analysis of glomeruli obtained by biopsy and a structural hydrodynamic model of viscous flow revealed the glomerular ultrafiltration coefficient to be similar, averaging 3.5 +/- 0.6 and 3.1 +/- 0.2 ml/(min.mmHg) in group 2 vs 1, respectively. Corresponding values for plasma oncotic pressure were also similar, averaging 19 +/- 1 vs 21 +/- 1 mmHg. We next used a mathematical model of glomerular ultrafiltration and a sensitivity analysis to calculate the prevailing range for delta P from the foregoing measured quantities. This revealed delta P to vary from only 20-21 mmHg in group 2 vs 34-45 mmHg in group 1 (P < 0.001). Further morphometric analysis revealed the diameters of Bowman's space and tubular lumens, as well as the percentage of tubular cells that were necrotic or devoid of brush border, to be similar in the two groups. We thus conclude (a) that delta P depression is the predominant cause of hypofiltration in this form of postischemic injury; and (b) that afferent vasoconstriction rather than tubular obstruction is the proximate cause of the delta P depression.
View details for Web of Science ID A1995QG20900052
View details for PubMedID 7860766
Previous studies have established that in a variety of human glomerulopathies the reduced glomerular filtration rate (GFR) is due to a marked lowering of the ultrafiltration coefficient (Kf). To identify the factors which lower Kf, we measured the filtering surface area per glomerulus, filtration slit frequency, basement membrane thickness, and GFR and its determinants in patients with minimal change and membraneous nephropathies and in age-matched healthy controls. Overall values of Kf for the two kidneys were calculated from GFR, renal plasma flow rate, systemic colloid osmotic pressure, and three assumed values for the transcapillary pressure difference. "Experimental" values of the glomerular hydraulic permeability (kexp) were then calculated from Kf, glomerular filtering surface area, and estimates of the total number of nephrons of the two kidneys. Independent estimates of the glomerular hydraulic permeability (kmodel) were obtained using a recent mathematical model that is based on analyses of viscous flow through the various structural components of the glomerular capillary wall. Individual values of basement membrane thickness and filtration slit frequency were used as inputs in this model. The results indicate that the reductions of Kf in both nephropathies can be attributed entirely to reduced glomerular hydraulic permeability. The mean values of kexp and kmodel were very similar in both disorders and much smaller in the nephrotic groups than in healthy controls. There was good agreement between kexp and kmodel for any given group of subjects. It was shown that, in both groups of nephrotics, filtration slit frequency was a more important determinant of the water flow resistance than was basement membrane thickness. The decrease in filtration slit frequency observed in both disorders caused the average path length for the filtrate to increase, thereby explaining the decreased hydraulic permeability.
View details for Web of Science ID A1994PF35400035
View details for PubMedID 8083359
There is at present no noninvasive method that reliably measures blood flow in the poorly functioning renal allograft. The present study was designed to evaluate phase-contrast cine magnetic resonance imaging (PC-cine-MRI) for this purpose. We recruited for study 18 patients who had received kidney transplants 13-66 months earlier from closely related living donors. As judged by the glomerular filtration rate, which was elevated for a single kidney (76 +/- 4 ml/min 1.73 m2), allograft function was excellent, permitting the assumption of unimpaired renal extraction of paminohippuric acid (PAH). Allograft blood flow was determined consecutively on the same day, first by the standard PAH clearance technique and they by the product of the velocity of protons and renal vein cross-sectional area using PC-cine-MRI. MRI determinations could not be completed because of claustrophobia in two patients and failure to image the terminus of the allograft vein another two. Comparison of blood flow in the remaining 14 subjects revealed the two techniques to be strongly related (r = 0.91, P < 0.001). On the average, the renal blood flow rate was similar by each method; 732 +/- 62 by PAH clearance and 703 +/- 69 ml/min by PC-cine-MRI, but the agreement among individuals between the two methods was only modest, with a 95% confidence interval of agreement from -214 to +254 ml/min. We conclude that PC-cine-MRI provides a fairly accurate and noninvasive method for determining the rate of blood flow in the transplanted kidney. With further refinement it should permit the role of depressed blood flow in a variety of acute and chronic forms of human allograft dysfunction to be elucidated in humans for the first time.
View details for Web of Science ID A1994NP05700007
View details for PubMedID 8197605
Physiologic and morphologic techniques were used to elucidate the determinants of the glomerular filtration rate in 62 nephrotic patients with membranous nephropathy and 104 healthy controls. Renal plasma flow, glomerular filtration rate, afferent oncotic pressure and dextran sieving coefficients were determined. Mathematical models of glomerular filtration were then used to compute likely upper bounds for the ultrafiltration coefficient and pore area/length ratio (a measure of pore density). These upper bounds for each measure of intrinsic ultrafiltration capacity were both depressed by 75% in membranous nephropathy. A corresponding excess of ultrafiltration pressure (versus control), attributable solely to reduced intracapillary oncotic pressure was by 12 mm Hg. Glomerular morphometry revealed peripheral capillary filtration surface area to be enhanced in membranous nephropathy (3.27 x 10(5) vs. 2.03 x 10(5) micron2). However, there was a massive reduction in filtration slit frequency due to epithelial podocyte broadening (336 vs. 1204 slits/mm capillary length) as well as marked thickening of the glomerular basement membrane (1130 vs. 388 nm). We conclude that the latter two findings lower the ultrafiltration coefficient in membranous nephropathy by depressing the hydraulic permeability of the glomerular capillary wall. We propose that this abnormality is solely responsible for the hypofiltration observed in a majority of patients with this disease.
View details for Web of Science ID A1994MR13600013
View details for PubMedID 8164424
To compare the accuracy of 16-frame cine phase-contrast (PC) magnetic resonance (MR) imaging with those of two breath-hold PC techniques in the measurement of renal artery blood flow.In vitro flow measurements were performed in a segment of harvested human artery embedded in gel. For the cine PC acquisition, respiratory motion was simulated. In eight subjects with recently obtained para-amino-hippurate-clearance renal blood flow data, renal artery flow measurements were subsequently performed with two breath-hold imaging techniques and with cine PC imaging during shallow respiration.Breath-hold sequences were significantly more accurate than conventional cine PC sequences both in vitro (P < .005) and in vivo (P < .05). Cine PC imaging tended to overestimate flow (in vivo mean, 24.47% +/- 9.94), reflecting artifactual enlargement of the apparent vessel size.Reliable blood flow measurements in the renal artery are possible with breath-hold PC MR imaging.
View details for Web of Science ID A1994MW44400017
View details for PubMedID 8284383
The glomerular capillary wall imposes a remarkably efficient barrier to the passage of proteins the size of albumin and larger. The development of heavy proteinuria signifies impairment of the function of this barrier. Because endogenous proteins of graded size are heterogeneous with respect to their molecular charge and undergo extensive tubular reabsorption, they are not useful for quantifying the extent of barrier dysfunction. An alternative approach is to determine the fractional clearance of uncharged and non-reabsorbable polymers of graded size. When combined with a hydrodynamic theory of solute transport through a heteroporous membrane, the intrinsic properties of healthy and diseased glomerular capillary walls can be inferred. This approach reveals the nephrotic range proteinuria that attends minimal change nephropathy to be associated with impairment of both the size- and charge-selective properties of glomerular capillary walls.
View details for Web of Science ID A1994MU92100028
View details for PubMedID 8142207
Physiologic and morphologic techniques were used to elucidate the determinants of the GFR in 25 nephrotic patients with minimal change nephropathy. They were divided into two groups according to the finding of either a normal (Group 1, N = 13) or a depressed (Group 2, N = 12) inulin clearance. RPF, afferent oncotic pressure, and dextran sieving coefficients were determined. Mathematical models of glomerular ultrafiltration were then used to compute likely upper bounds for the ultrafiltration coefficient and pore area/length ratio (a measure of pore density). The upper bounds for each measure of intrinsic ultrafiltration capacity were depressed below estimated normal values in healthy controls by 55 and 47% in Group 1 patients and by 86 and 83% in Group 2 patients with minimal change nephropathy. A corresponding excess of ultrafiltration pressure (versus control), attributable solely to reduced intracapillary oncotic pressure, was by 10.8 and 11.5 mm Hg, respectively. Glomerular morphometry revealed peripheral capillary filtration surface area to be preserved in both minimal change nephropathy groups. However, a significant reduction in filtration slit frequency due to epithelial podocyte broadening correlated with the computed ultrafiltration coefficient across the two minimal change nephropathy groups (r = 0.65; P < 0.001). It was concluded that podocyte deformation invariably lowers the ultrafiltration coefficient and pore area/length ratio in minimal change nephropathy but that an offsetting reduction in intracapillary oncotic pressure prevents the GFR from declining in many cases. However, the models presented here predict that the depression of capillary oncotic pressure is insufficient to compensate when the ultrafiltration coefficient is lowered by substantially more than half and that it is in this circumstance that minimal change nephropathy is most likely to be accompanied by glomerular hypofiltration.
View details for Web of Science ID A1994MZ64000009
View details for PubMedID 8025231
We used dextran sulfate (DS) to evaluate barrier charge selectivity in 11 nonproteinuric subjects and in 11 patients with the nephrotic syndrome due to either membranous nephropathy or minimal change nephropathy. The 3H-DS preparation spanned a molecular radius interval of 10-24 A and exhibited size-dependent protein binding in vitro. Urine and ultrafiltrates of plasma were separated by size into narrow fractions using gel permeation chromatography. The sieving coefficient (theta) for ultrafilterable DS of 15A radius averaged 0.68 +/- 0.03 in nonproteinuric vs. 0.95 +/- 0.05 in nephrotic subjects (P < 0.001). Uncharged dextrans of broad size distribution were used to evaluate barrier size-selectivity in separate groups of nonproteinuric subjects (n = 19) and nephrotic patients with either minimal change (n = 20) or membranous nephropathy (n = 27). The value of theta for an uncharged dextran of similarly small radius (approximately 18 A) was significantly larger than that observed for DS in nonproteinuric subjects, but was similar in nephrotic individuals. Further, impaired barrier size-selectivity, as assessed by the sieving profile for uncharged dextrans (18-60 A radius), failed to account fully for the observed level of albuminuria in almost half of the patients with either minimal change (9/20) or membranous nephropathy (12/27). Together these findings suggest that the human glomerular capillary wall normally provides an electrostatic barrier to filtration of negatively charged macromolecules such as albumin, and that impairment of this electrostatic barrier contributes to the magnitude of albuminuria in the nephrotic syndrome.
View details for Web of Science ID A1993MF29100026
View details for PubMedID 8227342
The glomerular capillary wall imposes a remarkably efficient barrier to the passage of proteins the size of albumin and larger. The development of heavy proteinuria signifies impairment in the function of this barrier. Because endogenous proteins of graded size are heterogeneous with respect to their molecular charge, and undergo extensive tubular reabsorption, they are not useful for quantifying the extent of barrier dysfunction. An alternative approach is to determine the fractional clearance of uncharged and nonreabsorbable polymers of graded size. When combined with a hydrodynamic theory of solute transport through a heteroporous membrane, the intrinsic properties of healthy and diseased glomerular capillary walls can be inferred. This approach reveals the nephrotic range proteinuria that attends membranous nephropathy to be associated with impairment of both the size- and charge-selective properties of glomerular capillary walls.
View details for Web of Science ID A1993MR95500002
View details for PubMedID 8116683
We determined oncotic pressure (pi) by membrane osmometry and assayed total protein (TP) and albumin (Alb) concentrations in plasma of 102 nephrotic subjects and 27 healthy controls. All three quantities were markedly depressed in the nephrotic group. When plasma was serially diluted and concentrated, nephrotic but not control plasma also exhibited a highly variable change point in the nonlinear relationship between TP or Alb and pi. Absent a unique change point, we developed quadratic models which incorporated TP, Alb, and (TP x Alb) to prospectively predict pi in unperturbed plasma. The ability of the most successful quadratic model to predict pi in afferent or efferent arteriolar plasma was limited; the prediction errors reached 10 mmHg in nephrotic and 6 mmHg in control subjects. The nephrotic model coefficients also differed significantly from control and pointed to an important influence of nonalbumin proteins on pi in nephrotic plasma. Investigation of the intrinsic membrane properties of diseased glomerular capillary walls requires precise knowledge of pi. For this purpose we recommend that pi be directly determined by membrane osmometry rather than calculated from protein concentration(s).
View details for Web of Science ID A1993LL13300112
View details for PubMedID 8322891
To investigate the possible role of cytokines in the mediation of glomerular injury in the nephrotic syndrome, the levels of interleukin (IL)-1 beta, IL-2, interferon (IFN)-alpha, IFN-gamma, and tumor necrosis factor-alpha (TNF-alpha) were measured in patients with primary nephrotic syndrome. These patients had minimal change nephropathy (MCN), focal and segmental glomerulosclerosis (FSGS), or membranous nephropathy (MN) on biopsy. Cytokine levels were assessed by immunoradiometric assays, and specimens consisted of plasma, urine, and the culture supernate of mitogen-stimulated peripheral blood mononuclear cells (PBMC). Only TNF-alpha was found to be significantly elevated, in the plasma and urine of patients with FSGS and MN, above that found in healthy control subjects and patients with MCN. The elevation of TNF-alpha could not be shown to correlate with the length or severity of the nephrotic syndrome or with loss of body mass. IL-1 beta, IL-2, IFN-alpha, and IFN-gamma levels were not elevated. In culture, mitogen-stimulated PBMC from all three groups of nephrotic subjects released an excess of TNF-alpha compared with controls, a response not consistently observed for the other cytokines measured. The findings of this survey of cytokine levels in nephrotic patients support the possibility that TNF-alpha may play a pathogenic role in the induction or maintenance of glomerular barrier dysfunction in humans.
View details for Web of Science ID A1993KR81600002
View details for PubMedID 8447300
Glomerular function was evaluated longitudinally over a 24- to 48-month period in 18 patients with diabetic glomerular disease (DGD) manifested by proteinuria. GFR was determined by iothalamate clearance at 4-month intervals. The patients were divided into two groups: Group 1 (N = 9) had subnephrotic proteinuria and an initially normal GFR of 91 +/- 8 mL/min. Group 2 (N = 9) had nephrotic-range proteinuria, and initial GFR was reduced to 53 +/- 5 mL/min. Serial GFR fluctuated over time in Group 1, but no trend towards hypofiltration was evident. In contrast, GFR declined linearly in Group 2 at 1.1 +/- 0.3 mL/min per month. The transglomerular sieving of uncharged dextrans of graded size was analyzed and initially revealed a uniform reduction in glomerular pore density and an enhancement of shuntlike pores. Pore density was initially reduced by 80% and declined further after 24 months in nephrotic Group 2; corresponding pore density in subnephrotic Group 1 was reduced by half but remained constant. Renal biopsy of four members of Group 1 revealed a 22% prevalence of global glomerulosclerosis. Remaining open glomeruli exhibited hypertrophy, excessive extracellular matrix, and deformation of epithelial podocytes. The latter abnormality appeared to be the predominant determinant of lowered ultrafiltration capacity. It was inferred that trials of therapy to attenuate the progression of DGD should be initiated at a functional level similar to that in subnephrotic Group 1. Because GFR is unlikely to decline over a 2- to 4-yr period, it is suggested that such trials be extended for longer periods. Alternatively, morphometric analysis of serial renal biopsies may shorten the time needed to demonstrate effective renoprotection in DGD.
View details for PubMedID 8439648
Glomerular permselectivity and dynamics were evaluated serially in 14 nephrotic patients with membranous glomerulopathy (MG). Analysis of transglomerular dextran sieving, before and again after proteinuria remitted, revealed persistent depression by 60-80% of glomerular pore density and the two-kidney ultrafiltration coefficient, Kf. The glomerular filtration rate was lowered by half on each occasion. Morphometric examination of glomeruli in a second group of 16 nephrotic patients with MG revealed a low prevalence of glomerulosclerosis (5 +/- 3%) and a twofold increase in filtration surface due to marked glomerular hypertrophy. Presumably, widening by threefold of the basement membrane and/or epithelial podocytes accounted for the computed reduction in ultrafiltration capacity. There was no correlation between glomerular structure and the subsequent course of MG over the ensuing 24-96 mo. Rather, a twofold expansion of the interstitial compartment predicted those who went on to exhibit progressive renal insufficiency. We conclude that increasing resistance to water flow by walls of patent and perfused glomerular capillaries is the proximate cause of progressive renal insufficiency in MG.
View details for Web of Science ID A1992KF37700085
View details for PubMedID 1282782
We administered a 12-week course of cyclosporine (CsA) (4 to 6 mg/kg/24 h) to nephrotic patients with membranous glomerulopathy (MG). Nephrotic patients with minimal change nephropathy (MCN) served as a comparison group. We evaluated the effects of CsA on proteinuria, glomerular function, and the release of cytokines by peripheral blood mononuclear cells in culture. Proteinuria was restored to normal levels within 2 to 4 weeks in MCN. Proteinuria declined from nephrotic to subnephrotic levels (< 3,500 mg/24 h) in 10 of 14 patients with MG, also within 2 to 4 weeks of onset of therapy. The four nonresponders exhibited a rapidly progressive and presumably irreversible form of MG culminating in renal failure. On average, fractional clearances of albumin and IgG declined by 59% and 73% in MG (P < 0.005); corresponding declines in MCN were by 99% (P < .0001). Corresponding rates of glomerular filtration in each glomerular injury remained unchanged. A strong trend for proteinuria to relapse after CsA was withdrawn was evident in both disorders. The release of tumor necrosis factor (TNF)-alpha by mononuclear cells in culture was enhanced in each glomerular injury, both before and after the course of CsA. We conclude that the proteinuria in most cases of MG exhibits a responsiveness to CsA that is qualitatively similar to, but less complete than, that in MCN. The rapidity with which barrier function improves suggests a possible role for cell-mediated immune injury in MG.
View details for Web of Science ID A1992JX14400005
View details for PubMedID 1442759
The findings that circulating levels of atrial natriuretic peptide (ANP) are elevated in diabetic nephropathy and that the magnitude of the urinary excretion rate of cGMP in response to hypervolemia-induced ANP release is blunted have recently been reported. The purpose of this study was to determine whether these abnormalities are associated with the down-regulation of ANP receptors. Because biologically active (A) ANP receptors in the kidney are inaccessible, we have examined the binding of (125I alpha)ANP to clearance (C) receptors on platelets obtained from patients with diabetic nephropathy. Scatchard analysis revealed a reduction in such binding sites compared with those in healthy controls: 12 +/- 2 versus 19 +/- 2 per platelet, respectively (P less than 0.001). The dissociation constant, Kd, was higher: 66.7 +/- 33.1 versus 38.5 +/- 11 pM, respectively (P less than 0.02). The reduced number of receptors could reflect the down-regulation of ANP C receptors in response to an elevation of plasma levels of ANP, the median value of which was 10.6 versus 7.1 pmol/L in controls (P less than 0.05). Alternatively, the findings could represent a primary adaptation by C receptors to elevate plasma ANP levels and increase the availability of the peptide to biologically active renal receptors. The latter adaptation would serve to mitigate the sodium retention that attends diabetic nephropathy.
View details for Web of Science ID A1992JK69400013
View details for PubMedID 1327260
We used differential solute clearances and a theoretical analysis of glomerular ultrafiltration and dextran sieving to characterize the hemodynamic response of nine healthy humans to infusion of isoncotic, 5% albumin in saline or saline vehicle alone. During albumin infusion (10.2 +/- 0.2 ml.kg-1.30 min-1) plasma volume increased by 18%, but oncotic pressure rose by only 0.8 mmHg. Despite the hypervolemia, renal blood flow (RBF) declined by 140 ml/min and glomerular filtration rate (GFR) declined by 16 ml/min during the infusion. RBF increased progressively postinfusion, exceeding baseline by 135 ml/min after 4 h; GFR was restored to baseline. Although oncotic pressure declined by 2 mmHg, a similar transient decline in GFR (-13 ml/min) was associated also with infusion of saline vehicle alone (9.4 +/- 0.3 ml.kg-1.30 min-1), which increased plasma volume by 9%. Sieving coefficients of dextrans (radius 32-42 A) were lowered during and after either infusion, a phenomenon that we compute to reflect a reduction in glomerular pore size. Assuming that the transcapillary hydraulic pressure difference was not lowered, we calculate that there was a simultaneous depression of the ultrafiltration coefficient (Kf) during volume expansion with saline and possibly also to a lesser extent with albumin. The hypofiltration during either infusion delayed the onset of a natriuretic response until the filtered sodium load was restored to baseline in the postinfusion period. We propose that the net effect of changes in intracapillary pressures and Kf during volume expanding infusions is to transiently lower GFR, thereby preventing the human kidney from mounting an immediate natriuretic response to acute hypervolemia.
View details for Web of Science ID A1992JJ96000093
View details for PubMedID 1380773
This study assesses the ability of a cardiac-gated phase-contrast magnetic resonance imaging (MRI) technique to measure renal blood flow (RBF) noninvasively in humans.In nine normal volunteers, total RBF in the renal arteries and in the left renal vein was estimated by MRI and correlated with RBF determined by the clearance of para-aminohippuric acid (CPAH) and the hematocrit level.Correlation of RBF estimated from left renal vein flow, with RBF by CPAH-hematocrit, yielded r = .86 (P less than .003). Repeated measurement of RBF by MRI demonstrated a high degree of reproducibility, with coefficients of variation ranging from 4.8% to 8.9%. However, the MRI measurements of arterial flow did not significantly correlate with the standard measurements.Reproducible noninvasive measurement of normal RBF is possible with the phase-contrast MRI technique used to measure renal venous blood flow.
View details for Web of Science ID A1992HX03500010
View details for PubMedID 1607260
Sieving coefficients of uncharged dextrans of graded size (radii 30 to 60 A) were used to characterize barrier size-selectivity in nonazotemic diabetic humans with microalbuminuria (Group 1, N = 11) or macroalbuminuria (Group 2, N = 21). Compared to a non-diabetic control group (N = 21) the low radius end of the sieving profile was depressed, whereas the high radius end was elevated in each diabetic group, more so in Group 2 than Group 1. A heteroporous membrane model revealed the major portion of the glomerular barrier to be perforated by restrictive pores of approximately 56 A radius in all three groups. However, in keeping with a parallel trend for GFR, the relative density of restrictive pores was control greater than Group 1 greater than Group 2. The remaining minor portion of the barrier was perforated by large, shunt-like pores, the relative prominence of which ranked Group 2 greater than Group 1 greater than control. Although the hypothetical, fractional clearance of macromolecules attributable to the shunt-like pores varied directly with fractional clearances of albumin and IgG, the progressive increment in the latter fractional protein clearances in the two diabetic groups was disproportionate. This raises the possibility that factors in addition to barrier size defects contribute to the development, magnitude and composition of proteinuria early in the course of diabetic glomerular disease.(ABSTRACT TRUNCATED AT 250 WORDS)
View details for Web of Science ID A1992HM53500019
View details for PubMedID 1381005
Three distinct receptor types for natriuretic peptides (NP) have been identified in human tissue. "A" and "B" receptors initiate biological actions, whereas the "C" receptor has a clearance function. It has been proposed that the natural ligand for the B receptor is c-type natriuretic peptide (CNP), rather than atrial natriuretic peptide (ANP), and that the B receptor is only found in the central nervous system (CNS) and is responsible for all NP-mediated effects in the CNS. Contrary to this hypothesis, we have identified, by means of the polymerase chain reaction (PCR), the B receptor in human kidney tissue. To detect A and C receptors, the PCR reaction was performed with primers which yielded predicted 600 and 378 base pair (bp) products, respectively. For the B receptor, 3 different primer sets were used, resulting in the expected 785, 453 and 228 bp fragments. Restriction mapping of the latter two products with Rsa I yielded the expected fragment numbers and sizes, indicating the PCR products were from B receptor mRNA. These results indicate that the human kidney has B as well as A and C receptors. Thus CNP may have a renal as well as a CNS site of action.
View details for Web of Science ID A1992HH37000075
View details for PubMedID 1309350
We have analyzed the efficiency with which p-amino-hippuric acid (PAH) is extracted (EPAH) by patients with healthy kidneys (n = 13) or kidneys damaged by chronic cyclosporin nephropathy (n = 21) or primary glomerulopathy (n = 12); respective values (mean +/- SE) for EPAH were 0.87 +/- 0.03, 0.77 +/- 0.03, and 0.69 +/- 0.04. Judged by a 131I-hippuran-to-PAH clearance ratio of 0.75 +/- 0.05, extraction ratio of hippuran was less efficient than EPAH in three glomerulopathic patients. A direct relationship was defined between EPAH and glomerular filtration rate (GFR) (r = 0.54) or calculated efferent oncotic pressure (IIE; r = 0.41, P less than 0.01). Curve fitting by means of quadratic spline functions revealed GFR and IIE to be additive in predicting EPAH (R2 = 0.45). Linear model prediction methods and a sample reuse technique failed to predict EPAH reliably from GFR and preglomerular oncotic pressure (IIA); however, 95% prediction intervals exceed 0.30 EPAH units in width. We conclude that oncotic pressure (presumably reflecting albumin concentration) along with GFR is predictive of EPAH depression in humans with chronic renal disease. However, even sophisticated curve-fitting techniques are too imprecise for accurate prediction of EPAH in a given individual. We submit that renal venous sampling to determine EPAH continues to be necessary for the accurate determination of the rate of plasma flow in the injured human kidney.
View details for Web of Science ID A1991GK86900112
View details for PubMedID 1928382
Physiologic and morphologic techniques have been used to study kidneys of 200 cardiac transplant recipients treated with either low- or high-dose cyclosporine. After 12 months, both low- (4.6 +/- 0.4) and high-dose cyclosporine (6.3 +/- 0.3 mg/kg/24 h; P less than 0.01) were associated with depression of glomerular filtration rate below values in a third group of 100 recipients never exposed to cyclosporine by 40 to 47%. Determination of renovascular pressures and flows as well as analysis of transglomerular sieving of dextrans revealed renal vascular resistance in cyclosporine-treated recipients to be elevated greater than twofold, due largely to an increase in preglomerular resistance. Morphologic changes in renal tissue of both cyclosporine groups included an occlusive afferent arteriolopathy with downstream collapse or sclerosis of glomeruli. Ischemic nephrons were associated with patchy fibrosis of the surrounding interstitium. Follow-up for up to 9 yr reveals persistent but stable azotemia, on average. Longitudinal physiologic studies over a 48-month period (N = 15) during which cyclosporine was reduced in dosage (to 3.1 +/- 0.3 mg/kg) or withdrawn revealed a persistently reduced but constant level of glomerular filtration rate. Increasing ischemic glomerular collapse and sclerosis were observed at repeat renal biopsy. Remnant (spared) glomeruli exhibited hypertrophy; presumably elevated single nephron glomerular filtration rate maintained two-kidney glomerular filtration rate constant despite the declining fraction of functional glomeruli. By actuarial analysis, the cumulative incidence of end-stage renal failure in cardiac transplant recipients treated at this institution from 1980 onwards with continuous cyclosporine therapy has reached 10%.(ABSTRACT TRUNCATED AT 250 WORDS)
View details for Web of Science ID A1991GB96700007
View details for PubMedID 1932643
Differential solute clearances were used to characterize glomerular function in 20 Pima Indians with noninsulin-dependent diabetes mellitus (NIDDM) of less than 3 yr duration. 28 Pima Indians with normal glucose tolerance served as controls. In the diabetic group, the glomerular filtration rate (GFR, iothalamate clearance) exceeded the control value by 15% (140 +/- 6 vs. 122 +/- 5 ml/min, P less than 0.01). A corresponding 12% increase in renal plasma flow (RPF) was not statistically significant and did not account fully for the observed hyperfiltration, suggesting a concomitant elevation of the ultrafiltration pressure or coefficient. The median albumin excretion ratio in NIDDM exceeded control by almost twofold (10.1 vs. 5.8 mg/g creatinine), a trend which just failed to achieve statistical significance (P = 0.06). Fractional clearances of dextrans of broad size distribution were also elevated in diabetic subjects, significantly so for larger dextrans of between 48 and 60 A radius. A theoretical analysis of dextran transport through a heteroporous membrane revealed glomerular pores in NIDDM to be uniformly shifted towards pores of larger size than in controls. We conclude that an impairment of barrier size selectivity combined with high GFR elevates the filtered protein load in NIDDM of recent onset. We propose that enhanced transglomerular trafficking of protein may predispose to sclerosis of glomeruli in those Pima Indians with NIDDM who ultimately develop diabetic nephropathy.
View details for PubMedID 1864963
We evaluated the renal and hormonal responses to volume expansion induced by water immersion in subjects with diabetic nephropathy (n = 12) and in healthy control subjects (n = 9). Immersion induced similar average increments in sodium excretion (+/- 223 vs. 176 mumol/min) and comparable decrements in renovascular resistance (RVR; -15 vs. -16 U). However, whereas the control subjects responded uniformly, the response among diabetic subjects was highly variable, with a subset of patients exhibiting paradoxical antinatriuresis and vasoconstriction. Immersion was associated with marked elevation of atrial natriuretic peptide (ANP) in plasma of diabetic versus control subjects (61 +/- 9 vs. 19 +/- 2 pM, respectively; P less than 0.001). Yet for each picomolar increment in plasma ANP during immersion, the corresponding increases in urinary excretion of cyclic guanosine monophosphate (26 vs. 279 pmol/min) and sodium (9 vs. 47 mumol/min) and the reciprocal lowering of RVR (0.7 vs. 1.9 U) were blunted in the diabetic versus control group. Volume contraction in the postimmersion period was associated with disproportionate antinatriuresis and renal vasoconstriction in the diabetic group, despite a persistent elevation of ANP (29 +/- 2 vs. 16 +/- 2 pM, P less than 0.01). We propose that renal insensitivity to ANP in diabetic nephropathy could contribute to altered vasoreactivity and abnormal excretory responsiveness to changing plasma volume. Blunted natriuresis in response to ANP release and enhanced sodium retention during volume contraction could account for the expanded extracellular fluid volume that has consistently been reported to accompany the development of diabetic nephropathy.
View details for Web of Science ID A1991FU96200017
View details for PubMedID 1647996
Fractional clearances (theta) of uncharged dextrans (radii 28-60 A) were used to characterize glomerular dysfunction in 34 nephrotic humans with either minimal-change nephropathy (MCN) or focal, segmental glomerulosclerosis (FSGS). A theoretical analysis of theta of dextran with a heteroporous membrane model revealed a similar alteration, more marked in FSGS than MCN. The number of restrictive pores perforating the major membrane component was reduced in parallel with the prevailing glomerular filtration rate (GFR). Parallel shuntlike pores in the remaining membrane component were more prominent, pointing to impaired size selectivity. However, the theta of large (60 A) dextrans attributable to these shunts exceeded control in FSGS only, suggesting that coexistent impairment of charge selectivity contributed importantly to the proteinuria in MCN. Membrane properties returned toward normal when MCN remitted. Glomerular morphometry revealed the frequency of epithelial filtration slits to vary with the extent of membrane dysfunction. Despite offsetting hypertrophy of remnant glomeruli in FSGS, a loss of filtration surface due to sclerosis likely contributed to the more marked reductions in pore number and GFR observed in this disorder than in MCN.
View details for Web of Science ID A1991FM77800089
View details for PubMedID 1709791
Patients with diffuse, proliferative lupus nephritis (DPLN) were subjected to differential solute clearances (n = 22) and serial renal biopsy (n = 11) before and again after 6-12 mo of immunosuppressive therapy. Glomerular sieving of dextrans of graded size was analyzed with a heteroporous membrane model. This revealed active DPLN to be associated with 1) a reduction of overall pore density accompanied by a 53% depression of glomerular filtration rate (GFR), and 2) appearance of a subset of large, nondiscriminatory pores, which accounted for the observed nephrotic level of proteinuria. Morphometric analysis of biopsy tissue provided evidence of reduced filtration surface area due to global or segmental occlusion of capillary loops in glomerular tufts. Activity of DPLN resolved posttreatment. A computed increase in pore density was associated with a 24% increment in GFR; a marked reduction in the fraction of shuntlike pores was accompanied by a parallel reduction of proteinuria into a subnephrotic range. Repeat biopsy revealed diminished glomerular cellularity, fewer immune deposits, and an ensuing increase in the fraction of tuft area occupied by patent loops. Epithelial filtration slit frequency also increased. Neither functional nor structural recovery was complete, however. Residual pore density approximated only 23-35% of that in healthy controls, and corresponding shuntlike pores were threefold more prominent. We conclude that severe DPLN is only partially reversible by current modalities of treatment and that the ensuing residual injury is far more severe than suggested by conventional tests of renal function.
View details for Web of Science ID A1991FM77800088
View details for PubMedID 2035658
Differential solute clearances were used to examine the effects of enalapril on glomerular barrier function in 16 proteinuria patients with diabetic glomerulopathy. In these patients, a 90-day course of enalapril reduced arterial pressure without lowering renal plasma flow or glomerular filtration rate. Glomerular clearances of dextrans of broad size distribution (28 to 60 A) were lowered significantly. Theoretical analysis of the dextran clearance profiles revealed that enalapril shifted glomerular pore size distribution to a smaller size. This change in barrier size selectivity was associated with a reduction in fractional albumin and immunoglobulin G clearances during enalapril therapy; urinary protein excretion tended to decrease in parallel. These results indicate that converting enzyme inhibition diminishes glomerular permeability to proteins in diabetic nephropathy by enhancing barrier size selectivity. Because enalapril therapy did not alter the renal plasma flow rate or glomerular filtration rate, these results further suggest that the primary action of enalapril may be to modulate the intrinsic membrane properties of the glomerular barrier.
View details for Web of Science ID A1990FT10100005
View details for PubMedID 16989068
Unchanged dextrans of graded size (28-60 A) were used to evaluate barrier size-selectivity in 56 proteinuric patients with diabetic glomerular disease. Transglomerular sieving was enhanced selectively for dextrans of greater than 46 A radius. A mathematical model of hindered solute transport through a porous membrane showed that this finding reflected the development in the glomerular barrier of a subset of enlarged, non-discriminatory pores. Although few in number, these enlarged pores accounted for both the magnitude and the composition of the observed proteinuria. We conclude that impaired barrier size-selectivity underlies the proteinuria of diabetic glomerular disease, and that impairment of barrier charge-selectivity need not be invoked in this circumstance.
View details for Web of Science ID A1990DB95400009
View details for PubMedID 2332816
Continuous therapy with an angiotensin-converting enzyme (ACE) inhibitor has been shown to have a glomerular vasodepressor effect in the newly diabetic rat and to largely prevent subsequent development of severe sclerosing glomerular injury. Preliminary studies in humans with established diabetic glomerular injury reveal that ACE inhibitor therapy has an antiproteinuric effect and may also slow the decline in glomerular filtration rate that usually attends this disorder. Although promising, the human studies are inconclusive because of short duration and other limitations in experimental technique and study design. Additional trials are required to confirm more positively this amelioration of human diabetic glomerular injury by ACE inhibitor therapy.
View details for Web of Science ID A1990DB92700005
View details for PubMedID 2345590
Uncharged dextrans of graded size (28-60 A) were used to evaluate glomerular barrier size selectivity in 13 nephrotic patients with diffuse proliferative lupus nephritis. Transglomerular sieving was enhanced selectively for dextrans of greater than 46 A radius when the nephritis was active and restored towards normal by immunosuppressive therapy. A mathematical model of hindered solute transport through a porous membrane revealed these findings to reflect the prevalence in the glomerular barrier of a subset of enlarged, nondiscriminatory pores. Although few in number, such enlarged pores accounted for both the magnitude and composition of observed proteinuria. We infer that impaired barrier size selectivity underlies the proteinuria that attends lupus nephritis, and that impairment of barrier charge selectivity need not be invoked in this circumstance.
View details for Web of Science ID A1990EH63400005
View details for PubMedID 1701613
Differential solute clearances were used to examine the effects of a 90-day course of enalapril on glomerular barrier function in 16 proteinuric patients with diabetic glomerulopathy. By day 90, plasma renin and prorenin became elevated, and arterial pressure declined. Transglomerular passage of dextrans of broad size distribution (radii 28-60 A) was lowered significantly. In a subset of 8 patients, withdrawal of enalapril was followed after an additional 30 days by a return of renin levels and arterial pressure to pretreatment levels. The dextran-sieving profile also returned to baseline, becoming uniformly elevated above treated day-90 levels. A theoretical analysis of the serial dextran-sieving profiles indicated that enalapril shifted glomerular pore size distribution to smaller size. These changes in barrier size selectivity were associated with a reduction in fractional albumin and IgG clearances during enalapril therapy and a subsequent rise in these quantities after its withdrawal; urinary protein excretion rate tended to vary in parallel. We conclude that inhibition of converting enzyme in humans with established diabetic glomerulopathy diminishes glomerular permeability to proteins by enhancing barrier size selectivity. Because neither enalapril therapy nor its withdrawal influenced the glomerular filtration or renal plasma flow rates significantly, we propose that the primary action of enalapril may be to modulate the intrinsic membrane properties of the glomerular barrier.
View details for Web of Science ID A1990CG67100012
View details for PubMedID 1698674
Angiotensin II (ANG II) infusion has been reported to impair barrier size selectivity and exacerbate proteinuria in the rat. To examine whether this is also true of humans, we infused a pressor dose of ANG II into seven healthy controls and seven nephrotic patients. A prompt depression of glomerular filtration rate (GFR) and renal plasma flow was observed in each group (P less than 0.01). Surprisingly, the excretion rates of albumin (5.3 +/- 1.6 to 2.8 +/- 0.3 in controls and 4,791 +/- 1,244 to 3,833 +/- 800 micrograms/min in nephrotics) and immunoglobulin G (1.5 +/- 0.4 to 0.8 +/- 0.2 and 305 +/- 87 to 255 +/- 94 micrograms/min, respectively) fell significantly during ANG II infusion. Fractional clearances of dextrans of broad size distribution (radii 34-54 A) were uniformly elevated by ANG II infusion in controls but tended to decline in nephrotics. A heteroporous model of the glomerular capillary wall revealed ANG II to have a negligible effect on membrane-pore structure. However, the depressed GFR lowered the rate at which macromolecule-rich filtrate was formed through a subset of nondiscriminatory pores from 272 to 176 microliters/min in controls and from 394 to 334 microliters/min in nephrotics. We conclude that, in striking contrast to the rat, pressor ANG II infusion has little or no influence on barrier size selectivity in humans but exerts an antiproteinuric effect by lowering the filtered protein load.
View details for Web of Science ID A1989AV33000097
View details for PubMedID 2478034
Treatment with total lymphoid irradiation (TLI) and corticosteroids markedly reduced activity of systemic lupus erythematosis in 10 patients with diffuse proliferative lupus nephritis (DPLN) complicated by a nephrotic syndrome. Physiologic and morphometric techniques were used serially before, and 12 and 36 mo post-TLI to characterize the course of glomerular injury. Judged by a progressive reduction in the density of glomerular cells and immune deposits, glomerular inflammation subsided. A sustained reduction in the fractional clearance of albumin, IgG and uncharged dextrans of radius greater than 50 A, pointed to a parallel improvement in glomerular barrier size-selectivity. Corresponding changes in GFR were modest, however. A trend towards higher GFR at 12 mo was associated with a marked increase in the fraction of glomerular tuft area occupied by patent capillary loops as inflammatory changes receded. A late trend toward declining GFR beyond 12 mo was associated with progressive glomerulosclerosis, which affected 57% of all glomeruli globally by 36 mo post-TLI. Judged by a parallel increase in volume by 59%, remaining, patent glomeruli had undergone a process of adaptive enlargement. We propose that an increasing fraction of glomeruli continues to undergo progressive sclerosis after DPLN has become quiescent, and that the prevailing GFR depends on the extent to which hypertrophied remnant glomeruli can compensate for the ensuing loss of filtration surface area.
View details for Web of Science ID A1989AN25900027
View details for PubMedID 2760219
Continuous therapy with an angiotensin-converting enzyme (ACE) inhibitor has been shown to have a glomerular vasodepressor effect in the newly diabetic rat and to largely prevent the subsequent development of a severe, sclerosing glomerular injury. Preliminary studies in humans with established diabetic glomerular injury (DGI) reveal that ACE inhibitor therapy has an antiproteinuric effect and may also show the decline in glomerular filtration rate that usually attends this disorder. Although promising, the human studies are inconclusive because of short duration and other limitations in experimental technique and study design. Additional trials are needed to confirm a specific effect of ACE inhibitor therapy to ameliorate human diabetic glomerular injury.
View details for Web of Science ID A1989R802700007
View details for PubMedID 2643307
To elucidate the mechanisms by which indomethacin lowers proteinuria, we studied 20 patients with the nephrotic syndrome. We performed differential macromolecule clearances before and after 3 days of therapy (150 mg/24 h). The fractional clearances of albumin and immunoglobulin G (IgG) decreased by 42 +/- 7 and 44 +/- 10%, respectively (P less than 0.05). Separation of IgG into fractions by preparative electrofocusing in eight selected individuals revealed a proportionate reduction of fractional clearances among anionic (pI = 5.0), neutral (pI = 7.5), and cationic species (pI = 8.5) of IgG. Indomethacin elevated the fractional clearance of uncharged dextrans of radius 28-44 A, while depressing those of dextrans of radius 50-60 A. A heteroporous model that depicts the major portion of the glomerular capillary wall as an isoporous membrane (pore radius = 56 A) and the minor portion as a nondiscriminatory shunt, revealed the former to be unchanged and the latter to be less prominent following indomethacin. A lower fraction of total filtrate volume permeating the shunt, together with a concomitant lowering of overall glomerular filtration rate by 24%, reduced the absolute rate of flux of macromolecule-rich fluid through the shunt pathway from 0.40 to 0.25 ml.min-1.73(-2) (P less than 0.01). We conclude that indomethacin lowered the filtered protein load by restoring barrier size-selectivity while reducing the rate of glomerular ultrafiltration.
View details for Web of Science ID A1989R955200088
View details for PubMedID 2463770
To elucidate the abnormality of body fluid homeostasis that attends the nephrotic syndrome, we compared the atrial hormonal and renal excretory and vasomotor responses to water immersion of nephrotic patients (N = 10) with those of healthy controls (N = 9). Nephrotics exhibited depressed baseline levels of atrial natriuretic peptide (ANP, P less than 0.05) and lower rates of urine flow and sodium excretion (P less than 0.01). Although immersion-induced hypervolemia increased plasma ANP to equivalent levels (75 +/- 19 vs. 60 +/- 6 pg/ml), the disparity in corresponding urinary flow (5 +/- 1 vs. 13 +/- 2 ml/min, P less than 0.01) and sodium excretion (171 +/- 42 vs. 540 +/- 65 muEq/min, P less than 0.01) grew larger. In contrast, immersion caused an equivalent reduction of renal vascular resistance by 16 and 17%, respectively (P less than 0.01). Despite higher renal plasma flow and lower oncotic pressure of plasma, the glomerular filtration rate remained constant during immersion in both groups. Similar constancy of fractional clearances of dextrans of graded size suggests that immersion may have lowered the glomerular transcapillary hydraulic pressure difference (delta P). We conclude that renal vasomotor responsiveness to hypervolemia is preserved in nephrotics, but that the mediatory role of ANP in this response is uncertain. By contrast, diminished responsiveness of the distal nephron to the natriuretic action of endogenous ANP could contribute to edema formation in the nephrotic syndrome.
View details for Web of Science ID A1988R041300012
View details for PubMedID 2974905
Physiologic and morphologic techniques were used to study kidneys of cardiac transplant recipients treated with either low-dose (low-CsA) or high-dose (high-CsA) cyclosporine. After 12 months both low-CsA (4.6 +/- 0.4) and high-CsA (6.3 +/- 0.3 mg/Kg/24 hr, p less than 0.01) were associated with azotemia and hypertension; GFR with each regimen was depressed below values in a third group treated without CsA (no-CsA) by 40-47%, while corresponding renal vascular resistance was elevated greater than 2-fold (P less than 0.01). Morphologic changes in both CsA groups included an obliterative arteriolopathy with downstream collapse or sclerosis of glomeruli. Determination of renal arcuate vein occlusion pressure revealed an increasing renal artery-to-peritubular capillary pressure gradient between 1 and 12 months of CsA therapy. Fractional clearances of dextrans of graded size were elevated at each time compared with the no-CsA group. Analysis of dextran transport with an isoporous membrane model indicates that transglomerular hydraulic pressure difference (delta P) approximated 39 with no-CsA, but was reduced with low-CsA therapy to about 30 at 1 month, and about 34 mmHg after 12 months. We conclude that chronic CsA therapy induces constriction and eventual occlusion of afferent arterioles, causing downstream glomerular damage that is irreversible. Low versus high dosage of CsA confers only marginal protection against this serious microvascular injury.
View details for Web of Science ID A1988R314600013
View details for PubMedID 3057692
Differential macromolecule clearances were used to elucidate the mechanism of proteinuria in patients with diabetic glomerulopathy. Uncharged dextrans of graded size, combined with albumin and IgG separated into narrow fractions of varying charge by preparative electrofocusing, were used to probe the filtration barrier. Analysis of the fractional clearance profile of dextrans in the 30- to 60-A interval revealed a small fraction of filtrate volume (0.0023-0.0097) permeating large nonrestrictive glomerular pores and correlating strongly with the fractional clearances of albumin (r = .88, P less than .001) or IgG (r = .91, P less than .001). The fractional clearance of the most anionic species of albumin [isoelectric point (pI) 4.0-4.5] significantly exceeded that of less anionic species (pI 4.5-5.5) at all levels of proteinuria. A corresponding increase in fractional clearance of anionic (pI 4.5-5.0) over neutral (pI 7.0-7.5) IgG species was observed in patients with subnephrotic-range proteinuria. We conclude that a loss of barrier size selectivity underlies proteinuria in diabetic glomerulopathy. In addition, either facilitated filtration of polyanions or preferential tubular reabsorption of polycations can be invoked to explain the final composition of urinary protein. Similar loss of size selectivity combined with enhanced fractional clearance of anionic IgG in a group of nondiabetic patients with nephrotic syndrome indicates that the foregoing abnormality of renal protein handling is not unique to diabetic glomerulopathy.
View details for Web of Science ID A1988P944800008
View details for PubMedID 3410164
The effect of 45-min clamping of the renal artery was studied in the conscious uninephrectomized rat to reproduce the syndrome of hemodynamically mediated acute renal failure in humans after a single ischemic insult. Twenty-four hours after ischemia, creatinine clearance was reduced by 90%, whereas fractional excretion of sodium was markedly increased; over the subsequent 5 days, both values returned to normal. The animals were nonoliguric. Fractional clearances of graded sizes of neutral dextrans (radii 20-44 A), employed to detect transtubular backleak of inulin, were not significantly different 24 or 48 h postischemia from those in normal animals. The implication that the normal fractional dextran clearances excluded tubular backleak was tested directly by microinjecting [methoxy-3H]inulin into the proximal tubule. In most tubules injected, the recovery of radioactivity in the urine was markedly lower 24 and 48 h postischemia than that in normal rats; in a few injected tubules of postischemic kidneys, recovery was not different from that in normal animals. The low recovery of radioactive inulin was accounted for, at least in part, by transtubular backleak, as shown in experiments in which rats subjected to renal ischemia were cross-transfused with normal animals. These studies indicate that, despite the normal fractional dextran clearances, most tubules were severely injured as shown by tubule backleak of inulin.
View details for Web of Science ID A1988P625900059
View details for PubMedID 2457326
The cardiac release and total body and renal clearances and the hemodynamic, renal and endocrine effects of increasing doses of atrial natriuretic peptide were investigated in 12 patients with severe chronic congestive heart failure. Immunoreactive arterial plasma levels of atrial natriuretic peptide were 10-fold higher than normal and there was no correlation between aortic atrial natriuretic peptide and cardiac filling pressures. The heart released atrial natriuretic peptide into the coronary sinus. The kidney, though a major clearance site, accounted for only 33% of the total body clearance. Administration of 0.3 micrograms/kg per min atrial natriuretic peptide produced significant changes in heart rate (95 +/- 4 to 85 +/- 4 beats/min) and mean arterial (92 +/- 8 to 77 +/- 9 mm Hg), right atrial (13 +/- 3 to 8 +/- 2 mm Hg) and mean pulmonary artery occluded (27 +/- 3 to 14 +/- 3 mm Hg) pressures. Atrial natriuretic peptide increased cardiac index (2.25 +/- 0.18 to 2.83 +/- 0.3 liters/min per m2) and stroke work index (21 +/- 1.5 to 29 +/- 3.4 g/m2), whereas systemic vascular resistance (1,424 +/- 139 to 1,033 +/- 97 dynes.s.cm(-5)) decreased. Infusion of 0.1 microgram/kg per min atrial natriuretic peptide increased urinary flow 128%, fractional excretion of sodium 133% and fractional excretion of potassium 35%. The filtration fraction increased from 29 +/- 2 to 31 +/- 4%. This represented a disproportionate rise in glomerular filtration rate over renal plasma flow. Plasma aldosterone and norepinephrine decreased whereas plasma renin activity remained unchanged. In association with these hemodynamic, excretory and endocrine changes, the urinary excretion of cyclic guanosine monophosphate doubled. Placebo had no effect. These results showed that, despite high circulating levels of atrial natriuretic peptide, administration of this hormone in heart failure is associated with potentially beneficial hemodynamic, renal and endocrine effects.
View details for Web of Science ID A1988P162200024
View details for PubMedID 2967855
Seventeen patients with intractable lupus nephritis and nephrotic syndrome were treated with total lymphoid irradiation. Statistically significant improvement in mean renal disease and serologic activity parameters occurred within 3 months and persisted for at least 3 years. Although there was a marked reduction of T helper cell numbers and function after total lymphoid irradiation, recovery of these parameters was not associated with a return of disease activity. Risks of sterility, severe infections, and hematologic malignancy appeared to be lower than with alkylating agents.
View details for Web of Science ID A1988P390700005
View details for PubMedID 3260782
We examined the role of cardiac atria in the renal response to sequential volume expansion and contraction, during and directly following water immersion. In immersed healthy volunteers (group 1, n = 9) atrial diameter, plasma levels of atrial natriuretic peptide (ANP), and natriuresis increased, whereas renal vascular resistance (RVR) and filtration fraction declined. Each parameter changed in an opposite direction postimmersion. An analysis of transglomerular dextran transport suggests that transglomerular hydraulic pressure difference (delta P) changed in parallel with filtration fraction. Baseline atrial diameter, plasma ANP, RVR, and filtration fraction were significantly elevated in nine recipients of denervated cardiac allografts (group 2). Atrial diameter and plasma ANP changed in parallel with group 1 during and after immersion. However, corresponding reciprocal changes in RVR were smaller and filtration fraction remained constant throughout. From transglomerular dextran transport, we compute that delta P increased progressively during and after immersion, suggesting predominant efferent arteriolar tone. The postimmersed state was associated also with enhanced sodium retention despite sixfold higher plasma ANP than in group 1. These findings are consistent with an effect of cardiac denervation to leave unopposed efferent sympathetic nervous traffic to the kidney. They suggest that the latter is an important modulator of the renal response to changing plasma volume in humans.
View details for Web of Science ID A1988N029100070
View details for PubMedID 2965518
We evaluated a chronic renal injury in 37 cardiac transplant recipients treated for 12 to 24 months with cyclosporine (CsA). Twenty-four cardiac transplant recipients treated with azathioprine for more than 24 months served as controls. Despite equivalent cardiac performance, GFR in those treated with CsA was depressed, 47 +/- 3 versus 94 +/- 4 ml/min/1.73 m2 (P less than 0.001). CsA therapy was also associated with significant elevation of renal vascular resistance (RVR), proteinuria, arterial hypertension, and impaired intrarenal conversion of inactive prorenin to active renin. Histopathological changes associated with CsA included an obliterative arteriolopathy with deposition of proteinaceous material in necrotic arteriolar walls, and associated tubulointerstitial damage. A minority of glomeruli exhibited either ischemic collapse or sclerosis. Area perimeter analysis revealed enlargement of the remaining glomeruli with significant expansion of the mesangium. Longitudinal examination over a 48 month period (N = 15) during which CsA was reduced in dosage or withdrawn revealed persistent hypofiltration, increasingly elevated RVR and heavier proteinuria. Further histopathological deterioration was observed when renal tissue was sampled a second time in six patients, and three members of the experimental group developed end-stage renal disease. We conclude that continuous CsA therapy for more than 12 months causes a chronic injury to renal microvessels that is rarely reversible and potentially progressive.
View details for Web of Science ID A1988M031600014
View details for PubMedID 3283402
Differential solute clearances and hormone assays were used to characterize the effect of a large, protein-rich meal (1.5 g/kg) on glomerular function in 12 healthy volunteers (group I) and 12 patients with chronic glomerular disease (group II). Changes from baseline during 3 h after the meal included an elevation of plasma osmolality, progressive urinary concentration, and increasingly positive fluid balance. Plasma renin activity and arginine vasopressin levels (measured in group II only) increased significantly. Nevertheless, the rate of peak postmeal renal plasma flow became elevated by 13 and 33% in groups I and II, respectively. Corresponding peak increases in postmeal glomerular filtration rate exceeded baseline by 10 and 16%. In the proteinuric subjects of group II the fractional clearances of albumin, IgG and uncharged dextrans in the radius interval 36-54 A, declined significantly after the meal. A similar depression of the fractional dextran-clearance profile was observed also in group I. Applying the fractional clearances of relatively permeant dextrans (radii less than or equal to 44 A) to a model of hindered solute transport through an isoporous membrane, we estimate that transmembrane hydraulic pressure difference increased by 12% in group I and by between 0 to 12% in group II after protein ingestion. We conclude (i) that oral protein ingestion increases glomerular ultrafiltration pressure and rate in both normal and diseased glomeruli, (ii) that this hemodynamic response may be mediated in part by the glomerulopressor hormones angiotensin II and arginine vasopressin, and (iii) that the foregoing hemodynamic changes exert no acute adverse effect on glomerular barrier size-selectivity.
View details for Web of Science ID A1988L600500036
View details for PubMedID 3275694
View details for PubMedID 3334683
We evaluated the size-selective properties of the glomerular barrier in 30 patients in whom diabetic nephropathy was associated with urinary IgG losses. Neutral dextrans of graded size were used to characterize glomerular membrane-pore structure. A fractional IgG clearance (relative to freely permeable inulin) smaller or greater than 0.001 was used to distinguish patients with minor (group 1, N = 14) and major (group 2, N = 16) urinary IgG leakage, respectively. Fractional clearances of dextrans (theta D) of smaller size (radii 20-40 A) were similar, but those of larger dextrans (radii 42-60 A) were elevated in group 2 relative to group 1 patients. When plotted on log-normal probability coordinates, the correlation between theta D and radius in healthy subjects is linear, suggesting that glomerular pores form one population with a normal distribution. In diabetic nephropathy with urinary IgG leakage, however, theta D for large molecules was elevated and departed from linearity, suggesting a bimodal pore size distribution within the glomerular membrane. A pore model of solute transport revealed (1) the upper pore mode was highly permeable to large dextrans equivalent in size to IgG and (2) the fraction of glomerular filtrate permeating the large pores was greater in group 2 than in group 1 patients with diabetic nephropathy, 6% versus 3%, respectively. We conclude that urinary IgG leakage in diabetic nephropathy is determined by the development of a subpopulation of enlarged pores. The magnitude of urinary IgG losses appears to be a function of the membrane area-fraction occupied by the enlarged pores.
View details for Web of Science ID A1983QU64900008
View details for PubMedID 6086024