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Showing papers in "Journal of The American Society of Nephrology in 1999"



Journal Article
TL;DR: This review examines the recent progress in the field of angiotensin receptors and notes that multiplicity of these receptors was demonstrated initially on the basis of pharmacologic differences and then confirmed by expression cloning.
Abstract: This review examines the recent progress in the field of angiotensin receptors. Multiplicity of these receptors was demonstrated initially on the basis of pharmacologic differences and then confirmed by expression cloning. AT1 receptors are predominant in the adult. They are widely distributed and mediate all of the known biologic effects of angiotensin II (AngII) through a variety of signal transduction systems, including activation of phospholipases C and A2, inhibition of adenylate cyclase, opening of calcium channels, and activation of tyrosine kinases. AT2 receptors are predominant in the fetus, but also present in adult tissues such as the adrenals, ovaries, uterus, and brain. AngII via these receptors exerts effects often opposed to those mediated by the AT1 receptors. Signal transduction implicates protein tyrosine phosphatase stimulation. AT1 and AT2 receptor expressions are regulated differently, and regulation is also tissue-specific. AT1 and AT2 receptors have been demonstrated in endothelial cells. Activation of AT1 receptors results in production of vasodilatory agents, nitric oxide, and prostacyclin (PGI2), which counteract the direct vasoconstrictor effects of Ang II on the adjacent smooth muscle cells. AT1 receptors on mesangial cells, smooth muscle cells, and fibroblasts are involved in cell growth and fibrosis, the latter being due both to an increase in the synthesis and a decrease in the degradation of the main components of the extracellular matrix. These AT1 receptor-dependent effects are for the most part indirect and mediated by growth factors, cytokines, and other peptides, including endothelin, transforming growth factor-beta1, and platelet-derived growth factor. AngII is metabolized into active fragments by deletion of the terminal amino acids on both ends. AngIII and AngIV are formed by successive deletions of aspartic acid and arginine at the N terminus. AngII (1-7) is obtained by deletion of phenylalanine at the C terminus. AngIII shares the same receptors and exerts the same effects as AngII. AngIV and AngII (1-7) recognize the AT1 and AT2 receptors with a lesser affinity than AngII and, in addition, possess their own receptors that mediate effects often opposed to those of AngII.

810 citations


Journal ArticleDOI
TL;DR: The annual mortality from cardiovascular disease in dialysis patients is substantially higher than in the general population and the 5-yr survival of men >64 yr old starting dialysis is worse than that of men with colon cancer and prostate cancer.
Abstract: The annual mortality from cardiovascular disease in dialysis patients is substantially higher than in the general population ([Figure 1][1]) ([1][2]). The 5-yr survival of men >64 yr old starting dialysis is worse than that of men with colon cancer and prostate cancer ([2][3]). The 5-yr survival of

633 citations


Journal Article
TL;DR: In this paper, the presence of anti-GBM antibodies in the sera and/or kidneys of six humans with glomerulonephritis was found to be a contributing cause of the glomerular injury.
Abstract: These observations established the presence of anti-GBM antibodies in the sera and/or kidneys of six humans with glomerulonephritis. Further, it seems clear that these antibodies do combine with the host's glomeruli in vivo and with GBM antigen of several species in vitro. Transfer of acute glomerulonephritis to normal recipient monkeys was possible with serum or renal eluate IGG from the three patients with anti-GBM antibodies in whom sufficient material was available. Based on this transfer of nephritis and on the presence of these antibodies at the site of injury in the nephritic kidneys of both the patients and the recipient monkeys, it seems likely that they are at least a contributing, if not primary, cause of the glomerular injury. The frequency of anti-GBM antibodies in human nephritis is not certain, but on the basis of preliminary observations it would appear that they are present in all cases of Goodpasture's nephritis and somewhat less than half of the cases of subacute and chronic glomerulonephritis of adults. The nature and source of immunogen stimulating the production of anti-GBM antibodies is not known, but the presence of potentially nephritogenic GBM antigens in normal urine raises the question of possible autoimmunization. From a practical point of view, it appears that patients forming anti-GBM antibodies may not be good candidates for renal transplantation since they are likely to produce in the transplants the nephritic changes already suffered by their own kidneys.

609 citations


Journal ArticleDOI
TL;DR: Overall, the findings suggest that sustained increases in hematocrit levels are associated with improved patient survival, and patients with hematOCrit levels of 33% to less than 36% appear to have the lowest risk for all-cause and cardiac mortality.
Abstract: Although a number of clinical studies have shown that increased hematocrits are associated with improved outcomes in terms of cognitive function, reduced left ventricular hypertrophy, increased exercise tolerance, and improved quality of life, the optimal hematocrit level associated with survival has yet to be determined. The association between hematocrit levels and patient mortality was retrospectively studied in a prevalent Medicare hemodialysis cohort on a national scale. All patients survived a 6-mo entry period during which their hematocrit levels were assessed, from July 1 through December 31, 1993, with follow-up from January 1 through December 31, 1994. Patient comorbid conditions relative to clinical events and severity of disease were determined from Medicare claims data and correlated with the entry period hematocrit level. After adjusting for medical diseases, our results showed that patients with hematocrit levels less than 30% had significantly higher risk of all-cause (12 to 33%) and cause-specific death, compared to patients with hematocrits in the 30% to less than 33% range. Without severity of disease adjustment, patients with hematocrit levels of 33% to less than 36% appear to have the lowest risk for all-cause and cardiac mortality. After adjusting for severity of disease, the impact of hematocrit levels of 33% to less than 36% is vulnerable to the patient sample size but also demonstrates a further 4% reduced risk of death. Overall, these findings suggest that sustained increases in hematocrit levels are associated with improved patient survival.

567 citations


Journal ArticleDOI
TL;DR: It is concluded that the loss of specific podocyte markers defines a novel dysregulated podocyte phenotype and suggests a common pathomechanism in collapsing FSGS, whether idiopathic or HIV-associated.
Abstract: Podocytes are highly differentiated, postmitotic cells, whose function is largely based on their complex cytoarchitecture. The differentiation of podocytes coincides with progressive expression of maturity markers, including WT-1, CALLA, C3b receptor, GLEPP-1, podocalyxin, and synaptopodin. In collapsing forms of focal segmental glomerulosclerosis (FSGS), including idiopathic FSGS and HIV-associated nephropathy, podocytes undergo characteristic, irreversible ultrastructural changes. This study analyzes the expression pattern of the above differentiation markers and of the proliferation marker Ki-67 in collapsing idiopathic FSGS and HIV-associated nephropathy compared with minimal change disease, membranous glomerulopathy, as well as normal adult and fetal human kidney. In minimal change disease and membranous glomerulopathy, all mature podocyte markers were retained at normal levels despite severe proteinuria and foot process fusion; no cell proliferation was observed. In contrast, in collapsing idiopathic FSGS and HIV-associated nephropathy, there was disappearance of all markers from all collapsed glomeruli and of synaptopodin from 16% of noncollapsed glomeruli. This phenotypic dysregulation of podocytes was associated with cell proliferation in both diseases. It is concluded that the loss of specific podocyte markers defines a novel dysregulated podocyte phenotype and suggests a common pathomechanism in collapsing FSGS, whether idiopathic or HIV-associated.

551 citations


Journal ArticleDOI
TL;DR: C4d in peritubular capillary walls distinguishes AHR from ACR, is more specific and sensitive than traditional criteria, and is a potentially valuable adjunct in the diagnosis of graft dysfunction.
Abstract: The distinction between acute humoral rejection (AHR) and acute cellular rejection (ACR) in renal allografts is therapeutically important, but pathologically difficult. Since AHR is probably mediated by antibodies to the donor endothelium that activate the classical complement pathway, it was hypothesized that peritubular capillary C4d deposition might distinguish this group. Renal biopsies (n = 16) from 10 patients with AHR who had acute graft dysfunction, neutrophils in peritubular capillaries, and a concurrent positive cross-match were stained for C4d by immunofluorescence. Control biopsies for comparison showed ACR (n = 14), cyclosporin A toxicity (n = 6), or no abnormality (n = 4). Peribiopsy sera were tested for anti-donor HLA antibody. C4d deposited prominently and diffusely in the peritubular capillaries in all AHR biopsies (16 of 16). IgM and/or C3 were also present in 19 and 44%, respectively. With two-color immunofluorescence, C4d was localized in basement membranes (type IV collagen+) and in the endothelium (Ulex europaeus agglutinin-I+). In ACR, no more than trace C4d was found in peritubular capillaries (P < 0.0001 versus AHR), and no patient had anti-donor HLA antibodies (0 of 8); 27% had neutrophils in peritubular capillaries. One of six biopsies with cyclosporin A toxicity had similar C4d deposits, and circulating anti-donor class I antibody was detected. Grafts with AHR were lost (40%) more often than those with ACR (0%; P < 0.02). C4d in peritubular capillary walls distinguishes AHR from ACR, is more specific and sensitive than traditional criteria, and is a potentially valuable adjunct in the diagnosis of graft dysfunction.

505 citations


Journal ArticleDOI
TL;DR: It is concluded that a manifest renal allograft infection with PV (BK strain) can persist in heavily immunosuppressed patients with recurrent rejection episodes.
Abstract: . Polyomavirus (PV) exceptionally causes a morphologically manifest renal allograft infection. Five such cases were encountered in this study, and were followed between 40 and 330 d during persistent PV renal allograft infection. Transplant (Tx) control groups without PV graft infection were analyzed for comparison. Tissue and urine samples were evaluated by light microscopy, immunohistochemistry, electron microscopy, and PCR. The initial diagnosis of PV infection with the BK strain was made in biopsies 9 ± 2 mo (mean ± SD) post-Tx after prior rejection episodes and rescue therapy with tacrolimus. All subsequent biopsies showed persistent PV infection. Intranuclear viral inclusion bodies in epithelial cells along the entire nephron and the transitional cell layer were histologic hallmarks of infection. Affected tubular cells were enlarged and often necrotic. In two patients, small glomerular crescents were found. In 54% of biopsies, infection was associated with pronounced inflammation, which had features of cellular rejection. All patients were excreting PV-infected cells in the urine. PV infection was associated with 40% graft loss (2 of 5) and a serum creatinine of 484 ± 326 μmol/L (mean ± SD; 11 mo post-Tx). Tx control groups showed PV-infected cells in the urine in 5%. Control subjects had fewer rejection episodes ( P P = 0.01). It is concluded that a manifest renal allograft infection with PV (BK strain) can persist in heavily immunosuppressed patients with recurrent rejection episodes. PV mainly affects tubular cells and causes necrosis, a major reason for functional deterioration. A biopsy is required for diagnosis. Urine cytology can serve as an adjunct diagnostic tool.

464 citations


Journal ArticleDOI
TL;DR: A model in which the cumulative burden of injury and age exhausts the ability of key cells in epithelium or endothelium to repair and remodel to maintain tissue integrity is proposed, calling this exhaustion “senescence” to emphasize the importance of donor aging and the overlap of the pathologic lesions with age-related changes.
Abstract: Chronic rejection or chronic allograft nephropathy (CAN) is the major cause of failure of kidney transplants other than patient death, and has been extensively reviewed (1‐5). CAN is characterized by functional impairment with nonspecific pathology: tubular atrophy, interstitial fibrosis, and fibrous intimal thickening (FIT) in the arteries, with variable glomerular lesions. The risk of CAN correlates with the input, immune, and load stresses experienced by that kidney. Input refers to the preexisting chronic conditions in the donor (aging, hypertension) plus the acute injury related to the transplant process (brain death, donor maintenance, organ removal, preservation, implantation, reperfusion). Immune stress is due to rejection by antibody or cellular mechanisms, determined by histocompatibility, presensitization, host responsiveness, and the effectiveness of and compliance with immunosuppression. Load reflects hypertension, donor-recipient size disparity, proteinuria, hyperlipidemia, drug toxicity, and infectious agents. Load factors such as donor size and gender probably reflect differences in nephron dose and are relatively weak, suggesting that nephron number does not explain the strong effect of input and immune factors. What distinguishes the transplant from normal tissue is the level of injury. Injury depletes the finite ability of the tissue to repair, and triggers inflammation, which may further stress the parenchyma and vessels, increase immune recognition, and promote fibrosis. In this article we review the problem of human CAN and propose a model in which the cumulative burden of injury and age exhausts the ability of key cells in epithelium or endothelium to repair and remodel to maintain tissue integrity. We term this exhaustion “senescence” to emphasize the importance of donor aging and the overlap of the pathologic lesions with age-related changes, and to suggest analogy with senescent changes observed in cell culture. When the potential of a tissue to repair is exhausted, the endothelial functions decline and the epithelium atrophies; injury-induced inflammation persists, permitting transforming growth factor-b and other mediators to create fibrosis. Thus, fibrosis may be a default for the failure of normal healing. CAN can be minimized by reducing the burden of injury due to immune and nonimmune mechanisms, but grafts with age- and injury-induced changes may still be useful despite their limitations, and few should be discarded. Recent advances in the cellular basis of senescence in vitro may hold clues to the molecular events that limit the repair of key cells.

461 citations


Journal ArticleDOI
TL;DR: Stereologic methods are used to obtain quantitative information about three-dimensional structures based on observations from section planes or--to a limited degree--projections, and special emphasis will be placed on modern stereologic methods, free of assumptions of the structure, size, and shape, etc., so-called UFAPP (unbiased for all practical purposes) stereology methods.
Abstract: . Stereologic methods are used to obtain quantitative information about three-dimensional structures based on observations from section planes or—to a limited degree—projections. Stereologic methods, which are used in biologic research and especially in the research of normal and pathologic kidneys, will be discussed in this review. Special emphasis will be placed on modern stereologic methods, free of assumptions of the structure, size, and shape, etc. , so-called UFAPP (unbiased for all practical purposes) stereologic methods. The basic foundation of all stereology, sampling, will be reviewed in relation to most of the methods discussed. Estimation of error variances and some of the basic problems in stereology will be reviewed briefly. Finally, a few comments will be made about the future directions for stereology in kidney research.

443 citations


Journal ArticleDOI
TL;DR: The longer half-life of NESP is likely to confer a clinical advantage over Epoetin by allowing less frequent dosing in patients treated for anemia.
Abstract: Novel erythropoiesis stimulating protein (NESP) is a hyperglycosylated analogue of recombinant human erythropoietin (Epoetin) which has an increased terminal half-life in animal models. The aim of this study was to extend these observations to humans. Using a double-blind, randomized, cross-over design, the single-dose pharmacokinetics of Epoetin alfa (100 U/kg) and an equivalent peptide mass of NESP were compared following intravenous bolus in 11 stable peritoneal dialysis patients. This was followed by an open-label study to determine the single-dose pharmacokinetics of an equivalent peptide mass of NESP by subcutaneous injection in six of these patients. The mean terminal half-life for intravenous NESP was threefold longer than for intravenous Epoetin (25.3 versus 8.5 h), a difference of 16.8 h (95% confidence interval, 9.4 to 24.2 h, P = 0.0008). The area under the serum concentration-time curve was significantly greater for NESP (291.0 +/- 7.6 ng x h per ml versus 131.9 +/- 8.3 ng x h per ml; mean +/- SEM; P < 0.0005), and clearance was significantly lower (1.6 +/- 0.3 ml/h per kg versus 4.0 +/- 0.3 ml/h per kg; mean +/- SEM; P < 0.0005). The volume of distribution was similar for NESP and Epoetin (52.4 +/- 2.0 ml/kg versus 48.7 +/-2.1 ml/kg; mean +/-SEM). The mean terminal half-life for subcutaneous NESP was 48.8 h. The peak concentration of subcutaneous NESP was approximately 10% of that following intravenous administration, and bioavailability was approximately 37% by the subcutaneous route. The longer half-life of NESP is likely to confer a clinical advantage over Epoetin by allowing less frequent dosing in patients treated for anemia.

Journal ArticleDOI
TL;DR: Results indicate that optimal cytokine removal with CVVH with an AN69 membrane could be achieved with a combination of a high QB/ultrafiltration rate and frequent membrane changes.
Abstract: A potential application of the continuous renal replacement therapies is the extracorporeal removal of inflammatory mediators in septic patients Cytokine elimination with continuous renal replacement therapies has been demonstrated in several clinical studies, but so far without important effects on their serum concentrations Improved knowledge of the cytokine removal mechanisms could lead to the development of more efficient treatment strategies In the present study, 15 patients with septic shock and acute renal failure were observed during the first 24 h of treatment with continuous venovenous hemofiltration (CVVH) with an AN69 membrane After 12 h, the hemofilter was replaced and the blood flow rate (QB) was switched from 100 ml/min to 200 ml/min or vice versa Pre- and postfilter plasma and ultrafiltrate concentrations of selected inflammatory and anti-inflammatory cytokines were measured at several time points allowing the calculation of a mass balance Cytokine removal was highest 1 h after the start of CVVH and after the change of the membrane (ranging from 25 to 43% of the prefilter amount), corresponding with a significant fall in the serum concentration of all cytokines The inhibitors of inflammation were removed to the same extent as the inflammatory cytokines Adsorption to the AN69 membrane appeared to be the main clearance mechanism, being most pronounced immediately after installation of a new membrane and decreasing steadily thereafter, indicating rapid saturation of the membrane A QB of 200 ml/min was associated with a 75% increase of the ultrafiltration rate and a significantly higher convective elimination and membrane adsorption than at a QB of 100 ml/min The results indicate that optimal cytokine removal with CVVH with an AN69 membrane could be achieved with a combination of a high QB/ultrafiltration rate and frequent membrane changes

Journal ArticleDOI
TL;DR: It is confirmed that ADMA is accumulated in ESRD, and hemodialysis and peritoneal dialysis patients exhibit significantly lower ADMA levels than do HD-treated patients.
Abstract: Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of endothelial nitric oxide (NO) synthase. Its concentration is elevated in patients with end-stage renal disease (ESRD), in part because it is excreted via the kidneys. In this study, the plasma concentrations of ADMA, symmetric dimethylarginine, and L-arginine were determined in relation to plasma nitrate levels (as an index of NO formation) for a group of 80 patients with ESRD. The effects of two treatment methods, i.e., hemodialysis (HD) and peritoneal dialysis (PD), and the role of the presence of atherosclerotic disease were evaluated. Forty-three patients receiving HD and 37 patients receiving PD were compared with healthy control subjects. Plasma L-arginine and dimethylarginine levels were determined by HPLC, using precolumn derivatization with o-phthaldialdehyde. Plasma nitrate levels were determined by gas chromatography-mass spectrometry. Predialysis ADMA concentrations in HD-treated patients were approximately sixfold higher than those in the control group (6.0+/-0.5 versus 1.0+/-0.1 micromol/L; P < 0.05). Plasma nitrate concentrations were significantly lower in HD-treated patients, which suggests that ADMA may inhibit NO synthase. In contrast, plasma ADMA levels and nitrate concentrations in PD-treated patients were similar to those in control subjects. Plasma L-arginine concentrations were not significantly decreased in patients with ESRD. ADMA concentrations were significantly decreased 5 h after HD, compared with baseline values. ADMA levels were significantly higher in HD-treated patients with manifest atherosclerotic disease than in HD-treated patients without atherosclerotic disease (7.31+/-0.70 versus 3.95+/-0.52 micromol/L; P < 0.05). This study confirms that ADMA is accumulated in ESRD. PD-treated patients exhibit significantly lower ADMA levels than do HD-treated patients. Accumulation of ADMA may be a risk factor for the development of endothelial dysfunction and cardiovascular disease in patients with ESRD.

Journal ArticleDOI
TL;DR: It is concluded that late referral to the nephrologist is common in the United States and is associated with poor pre-ESRD care.
Abstract: Despite improvements in dialysis care, mortality of patients with end-stage renal disease (ESRD) remains high. One factor that has thus far received little attention, but might contribute to morbidity and mortality, is the timing of referral to the nephrologist. This study examines the hypothesis that late referral of patients to the nephrologist might lead to suboptimal pre-ESRD care. Clinical and laboratory data were obtained from the patient records and electronic databases of New England Medical Center, its affiliated dialysis unit (Dialysis Clinics, Inc., Boston), and the office records of the outpatient nephrology clinic. Early (ER) and late (LR) referral were defined by the time of first nephrology encounter greater than or less than 4 mo, respectively, before initiation of dialysis. Multivariate models were built to explore factors associated with LR, and whether LR is associated with hypoalbuminemia or late initiation of dialysis. Of the 135 patients, 30 (22%) were referred late. There were no differences in age, gender, race, and cause of ESRD between ER and LR patients. However, there were significant differences in insurance coverage between these two groups. In the multivariate analysis, patients covered by health maintenance organizations were more likely to be referred late (odds ratio = 4.5) than patients covered by Medicare. Compared to ER, LR patients were more likely to have hypoalbuminemia (56% versus 80%), hematocrit <28% (33% versus 55%), and predicted GFR <5 ml/min per 1.73 m2 (17% versus 40%) at the start of dialysis, and less likely to have received erythropoietin (40% versus 17%) or have a functioning permanent vascular access for the first hemodialysis (40% versus 4%). It is concluded that late referral to the nephrologist is common in the United States and is associated with poor pre-ESRD care. Pre-ESRD care of patients treated by nephrologists was also less than ideal. The patient-, physician-, and system-related factors behind this observation are unclear. Meanwhile, pre-ESRD educational efforts need to target patients, generalists, and nephrologists.

Journal ArticleDOI
TL;DR: Investigation of the aquaporins is providing detailed molecular insight into the fundamental physiology and pathophysiology of water balance and water balance disorders, suggesting a role for AQP2 in the development of water retention.
Abstract: The discovery of aquaporin membrane water channels by Agre and coworkers answered a long-standing biophysical question of how water specifically crosses biologic membranes, and provided insight, at the molecular level, into the fundamental physiology of water balance and the pathophysiology of water balance disorders. Of nine aquaporin isoforms, at least six are known to be present in the kidney at distinct sites along the nephron and collecting duct. Aquaporin-1 (AQP1) is extremely abundant in the proximal tubule and descending thin limb, where it appears to provide the chief route for proximal nephron water reabsorption. AQP2 is abundant in the collecting duct principal cells and is the chief target for vasopressin to regulate collecting duct water reabsorption. Acute regulation involves vasopressin-regulated trafficking of AQP2 between an intracellular reservoir and the apical plasma membrane. In addition, AQP2 is involved in chronic/adaptational regulation of body water balance achieved through regulation of AQP2 expression. Importantly, multiple studies have now identified a critical role of AQP2 in several inherited and acquired water balance disorders. This concerns inherited forms of nephrogenic diabetes insipidus and several, much more common acquired types of nephrogenic diabetes insipidus where AQP2 expression and/or targeting are affected. Conversely, AQP2 expression and targeting appear to be increased in some conditions with water retention such as pregnancy and congestive heart failure. AQP3 and AQP4 are basolateral water channels located in the kidney collecting duct, and AQP6 and AQP7 appear to be expressed at lower abundance at several sites including the proximal tubule. This review focuses mainly on the role of AQP2 in water balance regulation and in the pathophysiology of water balance disorders.

Journal ArticleDOI
TL;DR: The balance of evidence is more consistent with the hypothesis of a beneficial effect of protein restriction than with the contrary hypothesis of no beneficial effect, and the authors suggest that physicians incorporate the results of these secondary analyses into their interpretation of the findings of the MDRD Study.
Abstract: The Modification of Diet in Renal Disease (MDRD) Study was the largest randomized clinical trial to test the hypothesis that protein restriction slows the progression of chronic renal disease. However, the primary results published in 1994 were not conclusive with regard to the efficacy of this intervention. Many physicians interpreted the failure of the MDRD Study to demonstrate a beneficial effect of protein restriction over a 2- to 3-yr period as proving that this therapy does not slow disease progression. The authors believe that this viewpoint is incorrect, and is the result of misinterpretation of inconclusive evidence as evidence in favor of the null hypothesis. Since then, numerous secondary analyses of the MDRD Study have been undertaken to clarify the effect of protein restriction on the rate of decline in GFR, urine protein excretion, and onset of end-stage renal disease. This review describes some of the principles of secondary analyses of randomized clinical trials, presents the results of these analyses from the MDRD Study, and compares them with results from other randomized clinical trials. Although these secondary results cannot be regarded as definitive, the authors conclude that the balance of evidence is more consistent with the hypothesis of a beneficial effect of protein restriction than with the contrary hypothesis of no beneficial effect. Until additional data become available, physicians must continue to make recommendations in the absence of conclusive results. The authors suggest that physicians incorporate the results of these secondary analyses into their interpretation of the findings of the MDRD Study.

Journal ArticleDOI
TL;DR: BP values in young male whites increased significantly with increasing BMI values but were independent of the C825T polymorphism, suggesting that hypertension associated with the 825T allele could be a consequence of obesity.
Abstract: Recently, it was demonstrated that one allele (825T) of the gene encoding the G protein beta3 subunit (GNB3) is associated with hypertension in Germans. This study investigates a possible association with obesity in young male Germans, Chinese, and black South Africans with low, intermediate, and high 825T allele frequencies, respectively. In each of these three distinct cohorts, the 825T allele frequency was increased significantly in overweight (body mass index [BMI] > or =25 kg/m2) and obese individuals (BMI >27 kg/m2) compared to those with normal weight. The 825T allele frequencies in these three BMI groups were, respectively, 29.5, 39.3, and 47.7% in Germans, 46.8, 53.9, and 58.6% in Chinese, and 83.1, 87.7, and 90.9% in South Africans. In each of these three distinct groups, the 825T allele was significantly associated with obesity with odds ratios between 2 and 3. More urban than rural black Africans were overweight despite similar 825T allele frequencies in both populations, which underscores the role of both genetic and environmental factors. BP values in young male whites increased significantly with increasing BMI values but were independent of the C825T polymorphism, suggesting that hypertension associated with the 825T allele could be a consequence of obesity. Genotyping of 5254 individuals from 55 native population samples from Africa, the Americas, Europe, Asia, Australia, and New Guinea demonstrated highest 825T allele frequencies in black Africans (82%) and intermediate values in east Asians (47%). It is anticipated that high frequencies of the 825T allele in Africans and Asians may contribute to an obesity and hypertension epidemic if Westernization of lifestyles continues.

Journal ArticleDOI
TL;DR: Micropuncture experiments support the concept that stimulation of tubular Na+/glucose cotransport by reducing the tubuloglomerular feedback signal at the macula densa may contribute to glomerular hyperfiltration in diabetic rats.
Abstract: An increase in Na+/glucose cotransport upstream to the macula densa might contribute to the increase in single nephron GFR (SNGFR) in early diabetes mellitus by lowering the signal of the tubuloglomerular feedback, i.e., the luminal Na+, Cl-, and K+ concentration sensed by the macula densa. To examine this issue, micropuncture experiments were performed in nephrons with superficial glomeruli of streptozotocin-induced diabetes mellitus in rats. First, in nondiabetic control rats, ambient early distal tubular concentrations of Na+, Cl-, and K+ were about 21, 20, and 1.2 mM, respectively, suggesting collection sites relatively close to the macula densa. Second, glomerular hyperfiltration in diabetic rats was associated with a reduction in ambient early distal tubular concentrations of Na+, Cl-, and K+ by 20 to 28%, reflecting an increase in fractional reabsorption of these ions up to the early distal tubule. Third, in diabetic rats, early proximal tubular application of phlorizin, an inhibitor of Na+/glucose cotransport, elicited (1) a greater reduction in absolute and fractional reabsorption of Na+, Cl-, and K+ up to the early distal tubule, and (2) a greater increase in early distal tubular concentration of these ions, which was associated with a more pronounced reduction in SNGFR. These findings support the concept that stimulation of tubular Na+/glucose cotransport by reducing the tubuloglomerular feedback signal at the macula densa may contribute to glomerular hyperfiltration in diabetic rats. Glomerular hyperfiltration in diabetic rats serves to compensate for the rise in fractional tubular reabsorption to partly restore the electrolyte load to the distal nephron.

Journal ArticleDOI
TL;DR: Dual transplants of marginal kidneys are as safe and tolerated as single transplants, and possibly offer an improved filtration power without exposing the recipient to enhanced risk of delayed renal function recovery, acute allograft rejection, or major surgical complications.
Abstract: Dual transplant of marginal kidneys otherwise not considered for single transplant may give access to an expanded pool of cadaveric organs without exposing recipients to the drawbacks of a limited nephron mass supply. This prospective, case-control study compares adverse events and graft outcome in 24 recipients of two marginal kidneys from donors who were >60 yr old or who had diabetes, hypertension, or non-nephrotic proteinuria (cases), with that of 48 age- and gender-matched control subjects who received single ideal grafts at the same center and were given the same immunosuppressive therapy. Marginal kidneys with no macroscopic abnormalities were selected for the double transplant on the basis of a predefined score of histologic damage. Six-month patient and kidney survival was 100% with both of the procedures. Incidence (20.8% versus 20.8%) and median (range) duration of posttransplant anuria (5 [2 to 12] versus 7 [2 to 13] days) were comparable in cases and control subjects, respectively. Time to normal serum creatinine and mean serum creatinine values at each time visit were comparable as well, but with significantly lower levels in cases compared with control subjects from month 2 to last follow-up (1.56 +/- 0.65 versus 1.74 +/- 0.73 mg/dl, P = 0.04). Diastolic BP values averaged during the entire posttransplant period were significantly lower in cases than in control subjects (83.2 +/- 11.5 versus 85.1 +/- 12.5 mmHg, respectively, P = 0.008). Donor/recipient body weight ratio was the only covariate significantly associated at univariate (P = 0.002) and multivariate (P = 0.001) analysis with last available serum creatinine concentrations. Incidence of acute allograft rejections (20.8% versus 18.8%) and of major surgical complications was comparable in the two groups. No renal artery or vein thrombosis was reported in either group. Dual transplants of marginal kidneys are as safe and tolerated as single transplants, and possibly offer an improved filtration power without exposing the recipient to enhanced risk of delayed renal function recovery, acute allograft rejection, or major surgical complications.

Journal ArticleDOI
TL;DR: It is evident that a better understanding of both interdialytic fluid status and fluid changes during hemodialysis is required to develop a precise measure of fluid balance and the need for a marker of adequacy for fluid removal is explored.
Abstract: . Fluid balance is an integral component of hemodialysis treatments to prevent under- or overhydration, both of which have been demonstrated to have significant effects on intradialytic morbidity and long-term cardiovascular complications. Fluid removal is usually achieved by ultrafiltration to achieve a clinically derived value for “dry weight.” Unfortunately, there is no standard measure of dry weight and as a consequence it is difficult to ascertain adequacy of fluid removal for an individual patient. Additionally, there is a lack of information on the effect of ultrafiltration on fluid shifts in the extracellular and intracellular fluid spaces. It is evident that a better understanding of both interdialytic fluid status and fluid changes during hemodialysis is required to develop a precise measure of fluid balance. This article describes the current status of dry weight estimation and reviews emerging techniques for evaluation of fluid shifts. Additionally, it explores the need for a marker of adequacy for fluid removal.

Journal ArticleDOI
TL;DR: This new immortalized mammalian CCD clonal cell line has retained a high level of epithelial differentiation and sodium transport stimulated by aldosterone and therefore represents a useful mammalian cell system for identifying the genes controlled by a Aldosterone.
Abstract: The final control of sodium balance takes place in the cortical collecting duct (CCD) of the nephron, where corticosteroid hormones regulate sodium reabsorption by acting through mineralocorticoid (MR) and/or glucocorticoid (GR) receptors. A clone of principal CCD cells (mpkCCDc14) has been established that is derived from a transgenic mouse (SV40 large T antigen under the control of the SV40 enhancer/L-type pyruvate kinase promoter). Cells grown on filters form polarized monolayers with high electrical transepithelial resistance (R(T) approximately 4700 ohm x cm2) and potential difference (P(D) approximately -50 mV) and have an amiloride-sensitive electrogenic sodium transport, as assessed by the short-circuit current method (Isc approximately 11 microA/cm2). Reverse transcription-PCR experiments using rat MR primers, [3H]aldosterone, and [3H]dexamethasone binding and competition studies indicated that the mpkCCDc14 cells exhibit specific MR and GR. Aldosterone increased Isc in a dose- (10(-10) to 10(-6) M) and time-dependent (2 to 72 h) manner, whereas corticosterone only transiently increased Isc (2 to 6 h). Consistent with the expression of 11beta-hydroxysteroid dehydrogenase type 2, which metabolizes glucocorticoids to inactive 11-dehydroderivates, carbenoxolone potentiated the corticosterone-stimulated Isc. Aldosterone (5x10(-7) M)-induced Isc (fourfold) was associated with a three- to fivefold increase in alpha-ENaC mRNA (but not in those for beta- or gamma-ENaC) and three- to 10-fold increases in alpha-ENaC protein synthesis. In conclusion, this new immortalized mammalian CCD clonal cell line has retained a high level of epithelial differentiation and sodium transport stimulated by aldosterone and therefore represents a useful mammalian cell system for identifying the genes controlled by aldosterone.

Journal ArticleDOI
TL;DR: Three types of transmembrane proteins have been identified within the tight junction, but it remains to be determined how they provide the molecular basis for regulating the paracellular permeability for water, solutes, and immune cells.
Abstract: Three types of transmembrane proteins have been identified within the tight junction, but it remains to be determined how they provide the molecular basis for regulating the paracellular permeability for water, solutes, and immune cells. Several of these proteins localize specifically within the continuous cell-to-cell contacts of the tight junction. One of these, occludin, is a cell adhesion molecule that has been demonstrated to influence ion and solute permeability. The claudins are a family of four-membrane spanning proteins; unexpectedly, other members of this family have already been characterized without recognizing their relationship to tight junctions. Junction adhesion molecule, the most recently identified tight junction component, is a member of the Ig superfamily and influences the paracellular transmigration of immune cells. A plaque of cytoplasmic proteins under the junction may be responsible for scaffolding the transmembrane proteins, creating a link to the perijunctional actin cytoskeleton and transducing regulatory signals that control the paracellular barrier.

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TL;DR: Therapy is initially directed toward optimizing the delivery of dialysis, correcting anemia with recombinant erythropoietin, and controlling the degree of secondary hyperparathyroidism with vitamin D.
Abstract: In summary, sexual dysfunction is a common finding in both men and women with chronic renal failure. Common disturbances include erectile dysfunction in men, menstrual abnormalities in women, and decreased libido and fertility in both sexes. These abnormalities are primarily organic in nature and are related to uremia as well as the other comorbid conditions that frequently accompany the chronic renal failure patient. Fatigue and psychosocial factors related to the presence of a chronic disease are also contributory factors. Disturbances in the hypothalamic-pituitary-gonadal axis can be detected before the need for dialysis but continue to worsen once dialytic therapy is initiated. Impaired gonadal function is prominent in uremic men, whereas the disturbances in the hypothalamicpituitary axis are more subtle. By contrast, central disturbances are more prominent in uremic women. Therapy is initially directed toward optimizing the delivery of dialysis, correcting anemia with recombinant erythropoietin, and controlling the degree of secondary hyperparathyroidism with vitamin D. For many practicing nephrologists, sildenafil has become the first-line therapy in the treatment of impotence. In the hypogonadal man whose only complaint is decreased libido, testosterone may be of benefit. Regular gynecologic follow-up is required in uremic women to guard against potential complications of unopposed estrogen effect. Uremic women should be advised against pregnancy while on dialysis. Successful transplantation is the most effective means of restoring normal sexual function in both men and women with chronic renal failure.

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TL;DR: Anti-glomerular basement membrane disease (anti-GBM) is a rare but well-characterized cause of glomerulonephritis and autoantibodies directed at specific antigenic targets within the glomerular and/or pulmonary basement membrane.
Abstract: Anti-glomerular basement membrane disease (anti-GBM) is a rare but well-characterized cause of glomerulonephritis. It is defined by the presence of autoantibodies directed at specific antigenic targets within the glomerular and/or pulmonary basement membrane. These antibodies bind to the α3 chain

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TL;DR: The glomerulus is a tuft of anastomosing capillaries located within Bowman's capsule that has a complex morphology that facilitates a unique filtration.
Abstract: Ultrafiltration of plasma during formation of the primary urine in the glomeruli is a major function of the kidney. The glomerulus is a tuft of anastomosing capillaries located within Bowman's capsule. The glomerular capillary wall has a complex morphology that facilitates a unique filtration

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TL;DR: It is proposed that there is increased intrarenal AngII production in type 2 diabetes mellitus, which could account for suppressed circulating renin, the exaggerated renal vasodilator response to irbesartan, and the therapeutic effectiveness of interrupting the renin system in diabetic nephropathy.
Abstract: Although diabetic nephropathy is often a low renin state, the renin system appears to be implicated in its pathogenesis. In this study, it was hypothesized that the low plasma renin activity (PRA) is misleading, masking and perhaps reflecting an activated intrarenal renin system. PRA and renal vascular responses (inulin and para-aminohippurate clearance) to graded doses of an angiotensin II (AngII) antagonist, irbesartan, were assessed in eight healthy volunteers and 12 patients with type 2 diabetes mellitus and nephropathy on a 10 mmol Na intake, to activate the renin system. Basal PRA was suppressed in type 2 diabetes mellitus compared with the healthy subjects (0.58 +/- 0.14 versus 1.58 +/- 0.28 ng/L per s, mean +/- SEM; P < 0.01). Despite the low PRA, renal perfusion rose more in response to irbesartan in type 2 diabetes mellitus (714 +/- 83 to 931 +/- 116 ml/min; P = 0.002) than normal (624 +/- 29 to 772 +/- 49 ml/min; P = 0.008). The youngest patients were hyperfiltrating and showed the largest rise in renal plasma flow in response to irbesartan, whereas renal plasma flow rose less and GFR fell in patients with low basal GFR. PRA rose in response to irbesartan more gradually in the patients with type 2 diabetes mellitus, but ultimately matched the normal response. To account for the apparent paradox of a heightened renal hemodynamic response to an AngII antagonist in the face of a low PRA in type 2 diabetes mellitus, and the rise in PRA following the AngII antagonist, it is proposed that there is increased intrarenal AngII production in type 2 diabetes mellitus. This increase could account for suppressed circulating renin, the exaggerated renal vasodilator response to irbesartan, and the therapeutic effectiveness of interrupting the renin system in diabetic nephropathy.

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TL;DR: The ensemble of histologic renal lesions defined in this study should aid in the separation of the lesions found in cases of secondary APS, especially systemic lupus erythematosus, into those lesions related to APS and those related to the underlying disease.
Abstract: Even 10 yr after the identification of the antiphospholipid syndrome (APS), renal involvement in the course of APS is still relatively unrecognized, and is probably underestimated. The association of anticardiolipin antibodies and/or lupus anticoagulant with the development of a vaso-occlusive process involving numerous organs is now confirmed. In a multicenter study, 16 cases of "primary" APS (PAPS) were found and followed for 5 yr or more, all with renal biopsy. In all 16 cases of PAPS, there was a vascular nephropathy characterized by small vessel vaso-occlusive lesions associated with fibrous intimal hyperplasia of interlobular arteries (12 patients), recanalizing thrombi in arteries and arterioles (six patients), and focal cortical atrophy (10 patients). In combination, these led to progressive destruction of the kidney, accelerated by acute glomerular and arteriolar microangiopathy in five patients. Focal cortical atrophy is a distinctive lesion, present in 10 biopsies, and likely represents the histologic and functional renal analogue to the multiple cerebral infarcts detected on imaging studies. The clinical hallmark of this vascular nephropathy in PAPS is systemic hypertension, only variably associated with renal insufficiency, proteinuria, or hematuria. The ensemble of histologic renal lesions defined in this study should aid in the separation of the lesions found in cases of secondary APS, especially systemic lupus erythematosus, into those lesions related to APS and those related to the underlying disease.

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TL;DR: Human renal tissues from patients with DN or IgA nephropathy were examined with specific antibodies to characterize most, if not all, carbonyl modifications of proteins by autoxidation products of carbohydrates, lipids, and amino acids, and these data suggest a broad derangement in nonenzymatic biochemistry in diabetic glomerular lesions.
Abstract: . Advanced glycation end products (AGE) include a variety of protein adducts whose accumulation has been implicated in tissue damage associated with diabetic nephropathy (DN). It was recently demonstrated that among AGE, glycoxidation products, whose formation is closely linked to oxidation, such as carboxymethyllysine (CML) and pentosidine, accumulate in expanded mesangial matrix and nodular lesions in DN, in colocalization with malondialdehyde-lysine (MDA-lysine), a lipoxidation product, whereas pyrraline, another AGE structure whose deposition is rather independent from oxidative stress, was not found within diabetic glomeruli. Because CML, pentosidine, and MDA-lysine are all formed under oxidative stress by carbonyl amine chemistry between protein amino group and carbonyl compounds, their colocalization suggests a local oxidative stress and increased protein carbonyl modification in diabetic glomerular lesions. To address this hypothesis, human renal tissues from patients with DN or IgA nephropathy were examined with specific antibodies to characterize most, if not all, carbonyl modifications of proteins by autoxidation products of carbohydrates, lipids, and amino acids: CML (derived from carbohydrates, lipids, and amino acid), pentosidine (derived from carbohydrates), MDA-lysine (derived from lipids), 4-hydroxynonenal-protein adduct (derived from lipids), and acrolein-protein adduct (derived from lipids and amino acid). All of the protein adducts were identified in expanded mesangial matrix and nodular lesions in DN. In IgA nephropathy, another primary glomerular disease leading to end-stage renal failure, despite positive staining for MDA-lysine and 4-hydroxynonenal-protein adduct in the expanded mesangial area, CML, pentosidine, and acrolein-protein adduct immunoreactivities were only faint in glomeruli. These data suggest a broad derangement in nonenzymatic biochemistry in diabetic glomerular lesions, and implicate an increased local oxidative stress and carbonyl modification of proteins in diabetic glomerular tissue damage (“carbonyl stress”).

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TL;DR: This review focuses on those drugs that have been shown to have immunosuppressive activity in patients and shows a statistically significant reduction in the incidence of acute rejection produced by these new drugs, which has not been accompanied by increases in infection and malignancy rates.
Abstract: In recent years, many new immunosuppressive drugs have been discovered and developed for clinical use in transplantation. This review focuses on those drugs (leflunomide, mycophenolate mofetil, sirolimus, tacrolimus) that have been shown to have immunosuppressive activity in patients. Different anti-interleukin-2 receptor antibodies are also reviewed as an example of a resurgence of development in the area of monoclonal antibodies. The price for reducing the incidence of allograft rejection by improved immunosuppression was thought to be a proportional increase in the incidence of infection and malignancy. Data from Phase III clinical trials of new immunosuppressants, however, show a statistically significant reduction in the incidence of acute rejection produced by these new drugs, which has not been accompanied by increases in infection and malignancy rates. The wide array of new drugs offers the opportunity to use combinations that block different pathways of immune activation while at the same time selecting drug combinations with nonoverlapping toxicity profiles so that doses of each single drug can be reduced below toxicity levels. The immunosuppressive therapy for patients can be tailored according to their individual needs.

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TL;DR: MRP2, the first cloned ATP-dependent export pump for anionic conjugates detected in human kidney, may be involved in renal excretion of various anionic endogenous substances, xenobiotics, and cytotoxic drugs.
Abstract: Human kidney proximal tubule epithelia express the ATP-dependent export pump for anionic conjugates encoded by the MRP2 (cMRP/cMOAT) gene (symbol ABCC2). MRP2, the apical isoform of the multidrug resistance protein, is an integral membrane glycoprotein with a molecular mass of approximately 190 kD that was originally cloned from liver and localized to the canalicular (apical) membrane domain of hepatocytes. In this study, MRP2 was detected in human kidney cortex by reverse transcription-PCR followed by sequencing of a 826-bp cDNA fragment and by immunoblotting using two different antibodies. Human MRP2 was localized to the apical brush-border membrane domain of proximal tubules by double and triple immunofluorescence microscopy including laser scanning microscopy. The expression of MRP2 in renal cell carcinoma was studied by reverse transcription-PCR and immunoblotting in samples from patients undergoing tumor-nephrectomy without prior chemotherapy. Clear-cell carcinomas, originating from the proximal tubule epithelium, expressed MRP2 in 95% (18 of 19) of cases. Immunofluorescence microscopy of MRP2 in clear-cell carcinoma showed a lack of a distinct apical-to-basolateral tumor cell polarity and an additional localization of MRP2 on intracellular membranes. MRP2, the first cloned ATP-dependent export pump for anionic conjugates detected in human kidney, may be involved in renal excretion of various anionic endogenous substances, xenobiotics, and cytotoxic drugs. This conjugate-transporting ATPase encoded by the MRP2 gene has a similar substrate specificity as the multidrug resistance protein MRP1, and may contribute to the multidrug resistance of renal clear-cell carcinomas.