Search

Rationale & Objective: Prior studies of patients receiving maintenance hemodialysis have shown that, on average, blood pressure (BP) measured predialysis is higher than BP measured at home. We hypothesized that a subset of hemodialysis patients has BP that is higher when measured at home than when measured predialysis and this subgroup of patients has a higher prevalence of left ventricular hypertrophy., Study Design: Prospective cohort., Setting & Participants: 97 hypertensive hemodialysis patients enrolled in the Blood Pressure in Dialysis Study (BID), a randomized trial of comparing target predialysis BP ≤140/90 to 155-165/90 mm Hg., Exposure: Differences between predialysis and next-day home systolic BP measured ≥6 times over 1 year., Outcome: Left ventricular mass index (LVMI) by cardiac magnetic resonance imaging., Analytical Approach: A hierarchical clustering analysis divided patients into 3 clusters based on the average and variability of differences in systolic predialysis and home BP. Clusters were compared with respect to clinical factors and LVMI., Results: Mean differences between predialysis and home systolic BP were 19.1 (95% CI, 17.0 to 21.1) mm Hg for cluster 1 ("home lower"), 3.7 (95% CI, 1.6 to 5.8) mm Hg for cluster 2 ("home and predialysis similar"), and -9.7 (95% CI, -12.0 to -7.4) mm Hg for cluster 3 ("home higher"). Systolic BP declined during dialysis in clusters 1 and 2 but increased in cluster 3. Interdialytic weight gains did not differ. After adjusting for sex and treatment arm, LVMI was higher in cluster 3 than in clusters 1 and 2: differences in means of 10.6 ± 4.96 (SE) g/m 2 (P = 0.04) and 12.0 ± 5.08 g/m 2 (P = 0.02), respectively., Limitations: Limited statistical power., Conclusions: Nearly one-third of participants had home BPs higher than predialysis BPs. These patients had LVMI higher than those with similar or lower BPs at home, indicating that their BP may have been undertreated., (Copyright © 2021 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Eosinophils in kidney disease are poorly understood and are often incidental findings on kidney biopsy. Eosinophilia in blood and renal biopsy tissue is associated with a host of immune and non-immune kidney diseases. The significance of eosinophilia in renal diseases has not been well addressed. We evaluated the presence of peripheral eosinophilia (> 4% of blood leukocytes) with biopsy tissue eosinophilia and their association with end-stage-kidney-disease (ESKD)., Methods: A nested case-control (2:1) of patients who underwent kidney biopsies at Johns Hopkins Hospital and Medical University of South Carolina from 2004 to 2018 were included in the study. From the 616 eligible patients, 178 patients were identified through the registry of kidney biopsies as 18 years or older without missing biopsy reports or hematology results. Controls (n = 154) had no ESKD at the time of case (n = 24) designation and were assembled using incident density sampling and matched on age and sex. The association of peripheral eosinophilia (> 4% of peripheral blood leukocytes) with the risk of progression to ESKD was evaluated using conditional logistic model after adjusting for clinical demographics., Results: Among 178 patients, 65 (37%) had peripheral eosinophilia and 113 (63%) had no eosinophilia. Compared to patients without eosinophilia, patients with peripheral eosinophilia were notably male and had a higher serum creatinine at the time of their biopsy. Peripheral eosinophilia was associated with higher risk of ESKD (OR 15.9 [1.9, 134.7]) adjusted for patient demographics including hypertension, proteinuria and eGFR at the time of kidney biopsy. Peripheral eosinophilia had a significant linear association with kidney tissue eosinophils, 22 (standard deviation [SD] 20) per high power field (hpf) in 4-10% peripheral eosinophilia, 19 (SD 18) per hpf in ≥10% eosinophilia and 3 (SD 7) per hpf in no eosinophilia (P <  0.001)., Conclusions: Peripheral eosinophilia is an independent predictor of tissue eosinophilia and subsequent progression to ESKD. Peripheral eosinophilia may be an early biomarker for underlying inflammation and disease, but further studies to investigate this clinical association are warranted.

Previous reports of glomerular disease in adult patients with autosomal dominant dystrophic epidermolysis bullosa (EB) are limited and include post-infectious glomerulonephritis, IgA nephropathy, amyloidosis, and leukocytoclastic vasculitis. To our knowledge, membranoproliferative glomerulonephritis (MPGN) has not been described before. We report a case of a 39-year-old male with autosomal dominant dystrophic EB, presenting with bilateral leg swelling of one-week duration. There was no other significant past medical history. The physical examination was remarkable for scars and erosions over all body areas, with all extremities with blisters and ulcers covered, absent finger and toenails and bilateral lower extremity edema. Serum creatinine was 0.9 mg/dL, albumin 1.3 g/dL and urine protein excretion 3.7 g/24 h. Viral markers (hepatitis-B, C, and HIV), complement c3 and c4 levels and auto-immune antibody profile all remained negative or within normal limits. Renal ultrasound and echocardiogram were normal. Renal biopsy recovered 14 glomeruli, all with proliferation of mesangial and endothelial cells as well as an expansion of the mesangial matrix, focal segmental sclerosis and amorphous homogeneous deposits demonstrating apple-green birefringence under polarized light with Congo red stain. Our observation emphasizes the importance of recognizing MPGN and secondary amyloidosis in patients with EB, especially with the availability of newer treatment modalities.

Introduction: Chronic kidney disease (CKD), diabetes, and hypertension play a disproportionate role in the growing public health challenge posed by noncommunicable diseases (NCDs) in East Africa. The impact of these NCDs may pose the greatest challenge in rural areas with limited screening and treatment facilities, although precise prevalence estimates of these conditions in rural Tanzania are lacking., Methods: The prevalence of CKD, diabetes, and hypertension, were estimated from a probability sample of adults (n = 739) residing in 2 communities within Kisarawe, a rural district of Tanzania. Following consent, participants were studied in their homes. Random point-of-care (POC) measures of glycosylated hemoglobin and blood pressure, were obtained. Serum creatinine, drawn at the POC and measured at Muhimbili National University, was used to calculate estimated glomerular filtration rate with the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation., Results: The median age was 35 years (interquartile range 25-45 years). Overall the pooled prevalence for CKD stages III, IV, and V was 12.4% (95% confidence interval [CI] = 10.2-14.8). Surprisingly, the prevalence of CKD stage V (3.0%; 95% CI = 2.1-4.4) was high among the youngest age group (18-36 years). The prevalence estimates for prehypertension and hypertension were 38.0% (95% CI = 34.6-41.5) and 19.9% (95% CI = 17.1-22.9), respectively. The prevalence estimates for prediabetes and diabetes were 25.7% (95% CI = 22.6-29.1) and 14.8% (95% CI = 12.4-17.6), respectively., Conclusion: Although this pilot study had a relatively small sample size, the prevalence estimates for CKD, diabetes, and hypertension were higher than we expected based on previous estimates from Tanzania. CKD was not significantly associated with diabetes or hypertension, suggesting the possibility of an alternative causality.

The optimal BP target for patients receiving hemodialysis is unknown. We randomized 126 hypertensive patients on hemodialysis to a standardized predialysis systolic BP of 110-140 mmHg (intensive arm) or 155-165 mmHg (standard arm). The primary objectives were to assess feasibility and safety and inform the design of a full-scale trial. A secondary objective was to assess changes in left ventricular mass. Median follow-up was 365 days. In the standard arm, the 2-week moving average systolic BP did not change significantly during the intervention period, but in the intensive arm, systolic BP decreased from 160 mmHg at baseline to 143 mmHg at 4.5 months. From months 4-12, the mean separation in systolic BP between arms was 12.9 mmHg. Four deaths occurred in the intensive arm and one death occurred in the standard arm. The incidence rate ratios for the intensive compared with the standard arm (95% confidence intervals) were 1.18 (0.40 to 3.33), 1.61 (0.87 to 2.97), and 3.09 (0.96 to 8.78) for major adverse cardiovascular events, hospitalizations, and vascular access thrombosis, respectively. The intensive and standard arms had similar median changes (95% confidence intervals) in left ventricular mass of -0.84 (-17.1 to 10.0) g and 1.4 (-11.6 to 10.4) g, respectively. Although we identified a possible safety signal, the small size and short duration of the trial prevent definitive conclusions. Considering the high risk for major adverse cardiovascular events in patients receiving hemodialysis, a full-scale trial is needed to assess potential benefits of intensive hypertension control in this population., (Copyright © 2018 by the American Society of Nephrology.)

Congestive heart failure (CHF) is the most common discharge diagnosis in the United States and accounts for greater than 1 million hospital discharges annually. CHF is associated with many serum electrolyte abnormalities, the most common and perhaps most significant of which is hyponatremia. CHF with hyponatremia makes the already high morbidity and mortality of CHF even more unfavorable. Further, the usual treatment for CHF with diuretics usually aggravates hyponatremia. Hyponatremia may result in impaired cognition and neurologic performance in a large number of patients, which is usually reversible with correction. The high morbidity and mortality with CHF and hyponatremia are not improved with the usual treatment with diuretics or ultrafiltration. This article provides an overview of the pathophysiology of hyponatremia in CHF. In addition, the authors will explore the various treatment options that are available and the evidence to support their utility.

Background: Maintenance of functional vascular access is crucial for the delivery of hemodialysis. The SyvekPatch is a topical marine microalgal poly-N-acetyl glucosamine hemostat approved by the Food and Drug Administration for use in the local management of bleeding wounds, such as vascular site, percutaneous catheters or tubes, and surgical debridement., Methods: The Preservation of Vascular Access Study was designed to investigate the effectiveness of patch use in reducing failure rates of arteriovenous fistulas or grafts. Data from medical records of patients who received hemodialysis from January 2001 to December 2005 at local ambulatory outpatient hemodialysis units in Charleston, South Carolina were analyzed. To explore whether greater use of the poly-N-acetyl glucosamine patch resulted in more favorable outcomes, patients were categorized into no patch use (n = 183) or 2 groups involving patch use, <70% of hemodialysis sessions (n = 88) or >or=70% of hemodialysis sessions (n = 64). The outcome measure was failure of access site estimated using Poisson regression models., Results: Three hundred thirty-five patients (54% women) with 178 fistulas (44%) and 227 grafts (56%) were included. The study population was predominantly African American (84%), with a median age of 58 years. The adjusted relative rate of access failure involving patch use in <70% of hemodialysis sessions versus no patch use was 0.84 (95% CI, 0.37-1.94), and for patch use in >or=70% of hemodialysis sessions versus no patch use was 0.40 (95% CI, 0.16-1.02; trend P = 0.045)., Conclusions: The Preservation of Vascular Access Study results are consistent with improved access survival with frequent patch use. The application of patch in this population is a simple, well-accepted intervention and warrants further investigation.

The present study was performed to test the hypothesis that under normal physiological conditions and/or during augmentation of kinin levels, intrarenal kinins act on medullary bradykinin B(2) (BKB(2)) receptors to acutely increase papillary blood flow (PBF) and therefore Na(+) excretion. We determined the effect of acute inner medullary interstitial (IMI) BKB(2) receptor blockade on renal hemodynamics and excretory function in rats fed either a normal (0.23%)- or a low (0.08%)-NaCl diet. For each NaCl diet, two groups of rats were studied. Baseline renal hemodynamic and excretory function were determined during IMI infusion of 0.9% NaCl into the left kidney. The infusion was then either changed to HOE-140 (100 microg.kg(-1).h(-1), treated group) or maintained with 0.9% NaCl (time control group), and the parameters were again determined. In rats fed a normal-salt diet, HOE-140 infusion decreased left kidney Na(+) excretion (urinary Na(+) extraction rate) and fractional Na(+) excretion by 40 +/- 5% and 40 +/- 4%, respectively (P < 0.01), but did not alter glomerular filtration rate, inner medullary blood flow (PBF), or cortical blood flow. In rats fed a low-salt diet, HOE-140 infusion did not alter renal regional hemodynamics or excretory function. We conclude that in rats fed a normal-salt diet, kinins act tonically via medullary BKB(2) receptors to increase Na(+) excretion independent of changes in inner medullary blood flow.

Marine elasmobranchs maintain internal osmolality higher than their external environment, resulting in an osmotic gradient for branchial water uptake. This gradient is markedly increased in low-salinity habitats. The subsequent increase in water uptake presents a challenge to volume homeostasis. The Atlantic stingray is a marine elasmobranch that inhabits a remarkable range of environmental salinities. We hypothesized that the ability of these stingrays to regulate fluid volume in low-salinity environments is due primarily to a renal glomerular and tubular functional reserve. We tested this hypothesis by measuring renal excretory function after a rapid and sustained 50% reduction in the osmolality of the external medium. Atlantic stingrays were maintained in harbor water [control salinity (CS) approximately 850 mosmol/kgH(2)O] for 1 wk. Rays were then either transferred to diluted harbor water [low salinity (LS) approximately 440 mosmol/kgH(2)O] or maintained in CS for a further 24 h. Renal excretory function was markedly higher in the rays subjected to low salinity. Glomerular filtration rate was threefold higher and urine flow rate ninefold higher in the LS group. The clearance of solute-free water was greater, and solute-free water comprised a significantly larger proportion of the urine output for the stingrays transferred to dilute harbor water. We conclude that 1) the kidneys of Atlantic stingrays have a remarkable glomerular and tubular functional reserve, and 2) the marked increase in renal function attenuates the increase in fluid volume when these fish move into low-salinity habitats.

The cloning of cDNAs encoding facilitated urea transporters (UTs) from the kidneys of the elasmobranchs indicates that in these fish renal urea reabsorption occurs, at least in part, by passive processes. The previously described elasmobranch urea transporter clones from shark (shUT) and stingray (strUT-1) differ from each other primarily because of the COOH-terminus of the predicted strUT-1 translation product being extended by 51-amino acid residues compared with shUT. Previously, we noted multiple UT transcripts were present in stingray kidney. We hypothesized that a COOH terminally abbreviated UT isoform, homologous to shUT, would also be present in stingray kidney. Therefore, we used 5'/3' rapid amplification of cDNA ends to identify a 3'UTR-variant (strUT-1a) of the cDNA that encodes (strUT-1), as well as three, 3'UTR-variant cDNAs (strUT-2a,b,c) that encode a second phloretin-sensitive, urea transporter (strUT-2). The 5'UTR and the first 1,132 nucleotides of the predicted coding region of the strUT-2 cDNAs are identical to the strUT-1 cDNAs. The remainder of the coding region contains only five novel nucleotides. The strUT-2 cDNAs putatively encode a 379-amino acid protein, the first 377 amino acids identical to strUT-1 plus 2 additional amino acids. We conclude that 1) a second UT isoform is expressed in the Atlantic stingray and that this isoform is similar in size to the UT previously cloned from the kidney of the dogfish shark, and 2) at least five transcripts encoding the 2 stingray UTs are derived from a single gene product through alternative splicing and polyadenylation.

We present a case of acute, symptomatic hyponatremia in a young woman that developed after use of 3,4-methylenedioxymethylamphetamine (MDMA), more commonly known as "ecstasy." The patient was treated with 5% saline and had complete recovery. The pathogenesis of MDMA-associated hyponatremia involves excessive water intake and inappropriately elevated antidiuretic hormone (ADH) levels. It seems that young, premenopausal women are at particularly high risk for the development of severe, symptomatic hyponatremia after use of this drug. Review of the literature revealed 4 fatal outcomes from MDMA-associated hyponatremia. All were women and all died from cerebellar tonsillar herniation. We suggest that acute hyponatremia that develops after MDMA use may be a life-threatening condition. Recent recommendation that MDMA users should drink large volumes of water may not be appropriate.

Background: The prevalence of end-stage renal disease (ESRD) has doubled in the past decade, with total costs projected to exceed 16.5 billion dollars by the end of 2002., Methods: The purpose of this prospective study is to determine all costs related to inpatient and outpatient health care utilization incurred by 76 patients with ESRD in an outpatient hemodialysis setting for 1 year. Costs were derived from a computer-based cost-allocation process that distributed cost components and overhead to designated revenue-producing departments., Results: During the 1-year study period, these patients had 1,459 total inpatient and outpatient hospital visits (mean, 19.2 visits/patient; range, 0 to 84 visits/patient). There were 149 general inpatient hospital admissions. Of 238 total emergency room visits, 89 visits resulted in admission to the hospital (37%)., Conclusion: Total hospital costs for all patients for the year were 1,831,880 dollars (actual charges, 2,929,147 dollars). As expected, the greatest hospital cost expenditures were attributed to inpatient hospital admissions (1,419,022 dollars; 77.5% of total). Of total hospital costs, inpatient bed costs were the single highest expenditure. The cost for outpatient hemodialysis therapy was 33,784 dollars/patient-year, consisting of facility costs of 17,200 dollars, outpatient pharmacy costs of 14,100 dollars, and outpatient professional costs of 2,500 dollars/patient-year. Average costs for hospital facility and/or professional fees were 42,730 dollars/patient-year, whereas average costs for outpatient dialysis facility and/or professional fees were 33,784 dollars, for an estimated global cost of 76,515 dollars/patient-year. Our cost estimate for care of this unique inner-city population substantially exceeds those reported earlier by others.

In general, marine elasmobranch fishes (sharks, skates, and rays) maintain body fluid osmolality above seawater, principally by retaining large amounts of urea. Maintenance of the high urea concentration is due in large part to efficient renal urea reabsorption. Regulation of renal urea reabsorption also appears to play a role in maintenance of fluid homeostasis of elasmobranchs that move between habitats of different salinities. We identified and cloned a novel 2.7-kb cDNA from the kidney of the euryhaline Atlantic stingray Dasyatis sabina (GenBank accession no. AF443781). This cDNA putatively encoded a 431-amino acid protein (strUT-1) that had a high degree of sequence identity (71%) to the shark kidney facilitated urea transporter (UT). However, the predicted COOH-terminal region of strUT-1 appears to contain an additional sequence that is unique among cloned renal UTs. Injection of strUT-1 cRNA into Xenopus oocytes induced a 33-fold increase in [(14)C]urea uptake that was inhibited by phloretin. Four mRNA bands were detected in kidney by Northern blot: a transcript at 2.8 kb corresponding to the expected size of strUT-1 mRNA and bands at 3.8, 4.5, and 5.5 kb. Identification of a facilitated UT in the kidney of the Atlantic stingray provides further support for the proposal that passive mechanisms contribute to urea reabsorption by elasmobranch kidney.

Cetaceans (whales and dolphins) always excrete urine with an osmolality markedly higher than that of plasma. Although the mechanisms by which cetaceans concentrate urine have not been elucidated, data support a role for medullary urea accumulation in this process, as is the case for terrestrial mammals. Therefore, we hypothesized that facilitated urea transporters are present in the kidney of cetaceans. Using 5'/3'-rapid amplification of cDNA ends, we cloned a 2.7-kb cDNA from the kidney of the short-finned pilot whale Globicephala macrorhynchus. The putative open-reading frame encoded a 397-amino acid protein [pilot whale urea transporter A2 (whUT-A2)] that has 94% amino acid sequence identity to the A2 isoform of the human urea transporter (hUT-A2). Heterologous expression of whUT-A2 cRNA in Xenopus oocytes induced phloretin-inhibitable urea transport. Although Northern analysis and RT-PCR indicated that whUT-A2 was exclusively expressed in kidney, Western blotting using a polyclonal antibody to rat UT-A1/UT-A2 detected various immunoreactive proteins in kidney and other tissues. Furthermore, RT-PCR analysis suggested the presence of alternatively spliced UT-A transcripts in the kidney as well as extrarenal tissues. We conclude that renal urea transporters are highly conserved among mammals inhabiting terrestrial and pelagic environments. A urea-based concentrating mechanism, presumably evolved to meet the demands of an arid terrestrial environment, may have contributed a fortuitous preadaptation that enabled the ancestors of cetaceans to reinvade the sea.

We evaluated 52 renal grafts transplanted into 41 patients with a pretransplantation diagnosis of Alport's syndrome. Overall 1-, 5-, and 10-year patient and graft survival rates were 95.1%, 90.2%, and 80.5% and 86.8%, 66%, and 45.3%, respectively. Although 14% of renal graft biopsy specimens examined with immunofluorescent microscopy showed linear glomerular basement membrane (GBM) immunoglobulin G deposits, only 1 of 41 patients (2.4%) or 52 grafts (1.9%) developed posttransplantation anti-GBM disease. The incidence of anti-GBM disease was 3.1% (1 of 32 patients) in a subgroup of male transplant recipients. Our analysis suggests that the incidence of anti-GBM disease in transplant recipients with Alport's syndrome is less than previously reported. In addition, it does not appear that HLA-DR alleles, which predispose to the development of anti-GBM disease in native kidneys, have a role in transplant recipients with Alport's syndrome posttransplantation. However, immunosuppression level may have a pathophysiological role in the development of anti-GBM disease. The majority of grafts in transplant recipients with Alport's syndrome failed because of chronic allograft nephropathy (69% of grafts) and acute rejection (22% of grafts). A history of previous acute rejection was the only factor that significantly affected graft outcome., (Copyright 2002 by the National Kidney Foundation, Inc.)

We used a cultured murine cell model of the inner medullary collecting duct (mIMCD-3 cells) to examine the regulation of the ubiquitous sodium-proton exchanger, Na+/H+ exchanger isoform 1 (NHE-1), by a prototypical G protein-coupled receptor, the bradykinin B2 receptor. Bradykinin rapidly activates NHE-1 in a concentration-dependent manner as assessed by proton microphysiometry of quiescent cells and by 2'-7'-bis[2-carboxymethyl]-5(6)-carboxyfluorescein fluorescence measuring the accelerated rate of pH(i) recovery from an imposed acid load. The activation of NHE-1 is blocked by inhibitors of the bradykinin B2 receptor, phospholipase C, Ca2+/calmodulin (CaM), and Janus kinase 2 (Jak2), but not by pertussis toxin or by inhibitors of protein kinase C and phosphatidylinositol 3'-kinase. Immunoprecipitation studies showed that bradykinin stimulates the assembly of a signal transduction complex that includes CaM, Jak2, and NHE-1. CaM appears to be a direct substrate for phosphorylation by Jak2 as measured by an in vitro kinase assay. We propose that Jak2 is a new indirect regulator of NHE-1 activity, which modulates the activity of NHE-1 by increasing the tyrosine phosphorylation of CaM and most likely by increasing the binding of CaM to NHE-1.

1. In this study 3 protocols were utilized to determine the role of endogenous kinins in the resistance of the inbred Dahl (Rapp) salt-resistant (SR/Jr) rats to high salt diet-induced blood pressure elevation. 2. The bradykinin B2 receptor antagonist, Hoe 140 (D-Arg[Hyp3, Thi5, D-Tic7, Oic8]-bradykinin) at doses of either 10-20 or 20-40 nmol day(-1) (subcutaneously (s.c), via osmotic minipumps, for either 1 or 3 weeks during a high (8%) salt diet) effectively blocked or attenuated the hypotensive responses to 100-1000 ng of bradykinin. 3. In the first protocol, 5 week old SR/Jr rats treated with Hoe 140 (10-20 nmol day(-1), n = 9, s.c., via osmotic minipumps) for 3 weeks and concomitantly fed high (8%) NaCl diet had significantly higher conscious tail cuff blood pressures (BPc) at 1 and 3 weeks when compared with rats treated with vehicle (0.9% NaCl, n = 6). The differences in BPc between the 2 groups were 13 mmHg (P < 0.001) after 1 week and 8 mmHg (P < 0.05) after 3 weeks of treatment. 4. In the second protocol, 5 week old SR/Jr rats were treated with Hoe 140 (20-40 nmol day(-1), n = 8, s.c., via osmotic minipumps) or vehicle (n = 8) for 3 weeks. During the first week of treatment the rats were fed normal (0.8%) NaCl diet. The rats were then switched to 8% NaCl for 2 remaining weeks of the protocol. The mean BPc of Hoe 140-treated rats was not significantly different from that of the vehicle-treated rats when fed 0.8% NaCl diet. In contrast, rats treated with Hoe 140 and concomitantly fed high (8%) NaCl diet had significantly increased BPc (123+/-2 vs 111 +/- 1 mmHg, P < 0.001 for the Hoe 140- and vehicle-treated rats, respectively). 5. In the third protocol, treatment with Hoe 140 (20 40 nmol day(-1), s.c., via osmotic minipumps) during high salt diet did not increase BPc in rats that were pre-exposed to the high salt diet for 2 weeks. 6. At the end of 3 weeks of study, blood pressure was measured via an arterial catheter during pentobarbitone-induced anaesthesia. Rats treated with Hoe 140 for 1 or 3 weeks had significantly lower mean arterial blood pressures than the vehicle-treated rats. 7. Our findings suggest that in SR/Jr rats, kinin activation of bradykinin B2 receptors at least partially contributes to early regulatory mechanisms that resist an increase in blood pressure following exposure to a high salt diet. The mechanism underlying the decreased blood pressure during pentobarbitone anaesthesia of SR/Jr rats chronically treated with Hoe 140 has yet to be elucidated.

This study tested the hypothesis that intrarenal kinins play a regulatory role in electrolyte excretion by altering Cl- absorption in the collecting duct. We measured Cl- and insulin concentrations in tubular fluid samples obtained from medullary collecting ducts (MCD) of Dahl/Rapp salt-resistant (SR/ Jr) rats by microcatheterization of ducts of Bellini before and after treatment with the bradykinin receptor antagonist HOE-140. Tubular fluid was obtained from paired terminal inner medullary (t-IMCD) and outer medullary (OMCD) collecting duct sites of the left kidney. HOE-140 (n = 7) or vehicle (n = 5) was infused intravenously, and the collections were repeated. HOE-140 did not alter glomerular filtration rate but decreased urine flow rate (P < 0.05) and absolute and fractional Cl- excretion (P < 0.01). HOE-140 did not alter the fraction of filtered Cl- delivered (FDCl) to the OMCD but decreased FDCl to the t-IMCD from 2.3 +/- 0.3 to 1.3 +/- 0.3% (P < 0.05). The fraction of filtered Cl- absorbed per millimeter between the collection sites was increased from 0.2 +/- 0.1 to 0.6 +/- 0.1% (P < 0.05). Fractional absorption of water along the MCD was also increased (P < 0.05). No changes in excretory function or tubular Cl- or water absorption were observed in vehicle-treated rats. These studies show that kinin B2 receptor blockade enhances Cl- and water absorption in the MCD, a finding that supports a role of renal kinins in the regulation of NaCl and water excretion.

Calciphylaxis is a rare and life-threatening complication that is estimated to occur in 1% of patients with ESRD each year. Typically, extensive microvascular calcification and occlusion/thrombosis leads to violaceous skin lesions, which progress to nonhealing ulcers and sepsis. Secondary infection of skin lesions is common, often leading to sepsis and death. The lower extremities are predominantly involved (roughly 90% of patients). Patients with skin involvement over the trunk or proximal extremities have a poorer prognosis. Although most calciphylaxis patients have abnormalities of the calcium:phosphate axis or elevated levels of parathyroid hormone, these abnormalities do not appear to be fundamental to the pathophysiology of the disorder, and the etiology of calciphylaxis remains unclear. Recently, functional protein C deficiency has been hypothesized to cause a hypercoagulable state that could induce thrombosis in small vessels, with resulting skin ischemia, necrosis, and gangrene. The lack of understanding of the pathophysiology of the disease results in treatments that are equally unsatisfactory. Patients who undergo parathyroidectomy have a tendency to improve, but the prognosis for the disease is poor and mortality remains high.

In passive Heymann nephritis (PHN), angiotensin-converting enzyme inhibition (ACEI) or a low dietary protein intake decreases albuminuria (UAlbV). Although this reduction in albuminuria appears to result from an improvement in glomerular permselectivity, the effect of these treatments on albumin permeation and absorption by the nephron has not been clarified. This study used micropuncture techniques to examine the effect of these two treatments on albumin permeation (by measuring the delivery of albumin to the proximal tubule) and the tubular absorption of albumin. PHN rats (12-18 days after injection of FX1A) were switched from 23% to either 40% protein diet (HP), 40% protein diet and concomitantly treated with enalapril (40 mg.kg-1.day-1) (HPE), or to 8% (LP) protein diet for 4-6 days. Although left kidney glomerular filtration rate (GFR) did not differ among the groups, UAlbV from the left kidney in LP and HPE was only 20-40% of that observed for the HP group. In protocol 1, the fractional recovery of albumin (FRAlb) in urine was calculated following injection of artificial tubular fluid containing [14C]inulin and 125I-labeled albumin into the earliest identifiable proximal loops. There were no differences in FRAlb among the three groups. In protocol 2, timed quantitative collections of tubular fluid were obtained from proximal tubular loops. The rate of albumin delivery to the earliest accessible loops of the proximal tubule was significantly lower for the LP and HPE groups compared with the HP group. For each group, albumin concentration corrected for water absorption was not altered along the proximal tubule. The data indicate that alterations of dietary protein intake or ACEI treatment results in large changes in the delivery of albumin at the proximal tubule that could singularly account for the changes in urinary albumin excretion.

This study examined the role of endogenous kinins in the alteration of renal hemodynamics induced by low-dose converting enzyme inhibition in hydropenic normotensive rats and in the nonclipped kidney of hydropenic two-kidney, one clip hypertensive rats. Infusion of a bradykinin B2 receptor antagonist (D-Arg0,[Hyp3,Thi5,8,D-Phe7]-bradykinin, 1 or 10 micrograms.kg-1.min-1) did not alter renal function of normotensive rats. In a second series of experiments, infusion of enalaprilat at 0.1 mg.kg-1.h-1 increased renal blood flow (P < .01) and decreased renal vascular resistance (P < .01). The superimposition of the kinin antagonist at 1 micrograms.kg.min-1 during the enalaprilat infusion decreased renal blood flow to a value similar to the preenalaprilat baseline and significantly different from the mean of the two enalaprilat periods before and after the addition of the kinin antagonist--the "mean effect of enalaprilat." The decrease in renal blood flow induced by the kinin antagonist was associated with an increase in renal vascular resistance above the mean effect of enalaprilat (P < .025). In two-kidney, one clip hypertensive rats, systemic infusion of enalaprilat augmented the hemodynamics of the nonclipped kidney by a degree similar to that in normotensive rats. In contrast to normotensive rats, superimposition of the kinin antagonist did not alter the enalaprilat-induced change in blood flow or vascular resistance of the nonclipped kidney. The results of this study suggest that endogenous kinins contribute to the increased renal function induced by low-dose converting enzyme inhibition in hydropenic normotensive rats but appear to contribute less to the enalaprilat-induced alterations of renal function in the nonclipped kidney of two-kidney, one clip hypertensive rats.

The effects of chronic angiotensin II (Ang II) receptor blockade (losartan) or converting enzyme inhibition (enalapril) on blood pressure (BP), urinary albumin excretion (Ualb V), renal histology and the hemodynamic and excretory function of the clipped and nonclipped kidneys were studied in two-kidney, one-clip (2-K 1-C) rats. One day after clipping the right renal artery, male Wistar rats were divided into three groups receiving: (1) losartan, 20 mg/kg/day (N = 7), (2) enalapril, 20 mg/kg/day (N = 8), or (3) no treatment (controls, N = 9) for three weeks. Both losartan and enalapril treatments maintained conscious BP at comparably lowered levels compared to control animals (116 +/- 6 mm Hg and 113 +/- 2 mm Hg vs. 188 +/- 11 mm Hg, respectively, P < 0.01). Treatment also prevented the increase in Ualb V, observed for the untreated group, three weeks after clipping (1.7 +/- 0.5 and 0.7 +/- 0.1 mg/24 hr vs. 17.8 +/- 7 mg/24 hr, respectively, P < 0.01). After three weeks of treatment, acute study of renal function during pentobarbital anesthesia revealed higher values of GFR and RPF and lowered vascular resistance for nonclipped kidneys from the losartan and enalapril groups compared to the corresponding kidneys from control animals. Despite the lower BP of both treated groups, clipped kidney GFR and RPF were unchanged compared to the control group. Ualb V for nonclipped kidneys from untreated rats was approximately 5- to 10-fold higher than in the nonclipped kidneys from the treated groups.(ABSTRACT TRUNCATED AT 250 WORDS)

It is now clear that specific angiotensin-dependent mechanisms contribute importantly to the pathophysiology of hypertension (HT) and altered renal function in models of two-kidney, one-clip (2-K, 1-C) HT in rats. The discovery of specific antagonists for angiotensin-converting enzyme and the newer angiotensin receptor and kinin receptor antagonists have allowed delineation of the contributions of these hormones to altered renal function in these models. The focus of interest in most of these studies has been the nonclipped kidney, which would be expected to ameliorate elevated blood pressure by exhibiting a pressure diuresis and natriuresis in the environment of systemic HT. Antagonism of the renin-angiotensin system in rat models of renal vascular HT indicates that the effects of angiotensin attenuate renal hemodynamic and excretory behavior, particularly in the nonclipped kidney. Furthermore, angiotensin attenuates the efficiency of autoregulation of renal hemodynamics in the nonclipped kidney. Function of the clipped kidney appears to be both angiotensin and perfusion pressure dependent. Evidence that inhibition of angiotensin reverses or improves these altered hemodynamic and excretory functions indicates that angiotensin may contribute importantly to the pathophysiology of HT in these models by altering or impairing the ability of the nonclipped or "normal" kidney to excrete sodium and volume. The precise roles of altered activity of vasodilator hormones to contribute to these alterations of renal function remains to be defined.

To elucidate the role of the vasoconstrictor thromboxane A2(TXA2) in post-obstructive nephropathy, we examined the effect of the TXA2 receptor antagonist GR32191(GR) on renal function and histopathology in the post-obstructed kidney (POK) in rats. Rats pre-treated with 3 or 6 mg/kg i.p. of GR prior to ureteral obstruction and maintained on b.i.d. doses of GR were compared to vehicle-treated and sham-operated controls. Renal hemodynamic, clearance and excretory function were assessed in each kidney following relief of 24 hours of unilateral ureteral obstruction. The histology of each kidney was evaluated. Mean clearances of inulin for the POK were significantly greater in the treated rats (0.42 +/- 0.06 ml/min at 6 mg/kg) than in controls (0.13 +/- 0.04 ml/min) and a dose-response effect was observed (P < 0.05). Paraaminohippurate clearance was increased by > 150% and renal vascular resistance was reduced by 50% in GR treated animals compared with controls (P < 0.05). Histopathologic findings in the untreated POK were typical of early obstruction. In the GR treated groups these changes were much less severe. These data support an important role for TXA2 in the pathogenesis of post-obstructive nephropathy.

During the past year, a number of significant publications have provided data that clearly establish the basis for the important role of the tissue kallikrein-kinin system in cardiovascular control and renal function. These publications include a report of advances in techniques for system component measurement, reports of the localization of central bradykinin receptors and an alteration in the sensitivity of the central bradykinin system in hypertension, and a description of the effects of new kinin receptor antagonists on our understanding of endogenous and exogenous kinin-induced vasorelaxation and its possible alteration in hypertension. Several significant reports describe the potentiation of endogenous kinin action by kininase inhibitors and establish the important interaction between kininase activity and kinin control of blood pressure.

Previous studies have shown that hydropenic one-kidney, one-clip (1-K, 1-C) hypertensive HT rats exhibit impaired autoregulation of glomerular filtration rate (GFR) in response to reduced arterial perfusion pressure. We investigated the possible role of altered tubuloglomerular feedback (TGF) activity in this phenomenon. Uninephrectomized Wistar rats were studied acutely 3 weeks after placing silver clips (0.2 mm) on the renal artery. Experiments were performed in 1-K,1-C HT rats and in uninephrectomized control animals. TGF activity was assessed as changes in proximal tubule stop-flow pressure (SFP) in response to orthograde microperfusion from 0 to 80 nl/min into late proximal tubule segments. Only the highest perfusion rates (approximately 40 nl/min) into late proximal tubule segments resulted in maximal decreases in SFP, indicating a marked rightward shift of overall TGF activity in 1-K,1-C HT rats. Similar responses were observed in the uninephrectomized animals. In contrast, changes of SFP were observed at lower perfusion rates in normal animals and maximal responses were observed at perfusion rates of approximately 20 nl/min. These observations are consistent with the possibility that altered TGF activity contributes to impaired autoregulation of GFR in 1-K,1-C HT rats in response to reduced renal perfusion pressure. In response to treatment with i.v. captopril, the 1-K,1-C HT rats exhibited marked decreases in systemic arterial pressure associated with decreases in SFP and virtually complete inhibition of TGF activity. It is attractive to hypothesize that these alterations in TGF characteristics in the 1-K,1-C HT rats play a significant pathophysiologic role in the acute renal dysfunction observed in response to acute decreases of blood pressure during conditions of augmented angiotensin activity. Additional future studies will allow us to address the precise role for intrarenal angiotensin in these phenomena.

The scope and the magnitude of the roles which angiotensin plays in the generation and maintenance of elevated blood pressure in models of renal vascular hypertension are continuing to expand. It is now clear that specific angiotensin dependent mechanisms contribute importantly to the pathophysiology of hypertension and altered renal function in models of two-kidney, one clip hypertension in rats. The generation of angiotensin in the local intrarenal environment of the kidney is a new and potentially important mechanism contributing to altered renal function in these models. Application of antagonists of the renin-angiotensin system to rat models of renal vascular hypertension indicate that the effects of angiotensin attenuate renal hemodynamic and excretory behavior, particularly in the nonclipped kidney. Further, angiotensin may attenuate the efficiency of autoregulation of renal hemodynamics in the nonclipped kidney. Evidence that inhibition of angiotensin reverses or improves these altered hemodynamic and excretory functions indicate that angiotensin may contribute importantly to the pathophysiology of hypertension in these models by altering or impairing the ability of the nonclipped or normal kidney to excrete sodium and volume.

1. Previous studies have shown that administration of converting enzyme inhibitor (CEI, SQ 20 881) to two-kidney, one-clip Goldblatt hypertensive (GH) rats clipped for 3-4 weeks resulted in marked increases in glomerular filtration rate (GFR), water and sodium excretion by the non-clipped kidneys. The clipped kidneys exhibited reduced function that was due, in part, to the reductions in arterial pressure. To evaluate further the hypothesis that the renal responses to CEI were due primarily to the inhibition of angiotensin II rather than other factors, we infused the angiotensin II competitive blocker, saralasin, into GH rats under sodium pentobarbital anaesthesia and examined renal haemodynamics and excretory function of each kidney before and during saralasin infusion and after cessation of saralasin infusion. 2. Saralasin reduced mean arterial blood pressure from 164 +/- 4 to 124 +/- 4 mmHg. Despite the profound fall of arterial pressure, significant increases in renal blood flow from 5.82 +/- 0.22 to 9.15 +/- 0.76 ml/min and glomerular filtration rate from 1.46 +/- 0.10 to 2.18 +/- 0.14 ml/min were observed in the non-clipped kidneys. Renal vascular resistance decreased from 2.34 (+/- 0.14) x 10(5) to 1.17 (+/- 0.19) x 10(5) kPa 1(-1) s [2.34 (+/- 0.14) x 10(6) to 1.17 (+/- 0.19) x 10(6) dyn s cm-5]. Also, concomitant diuresis and kaliuresis and a delayed natriuresis occurred. 3. The clipped kidneys exhibited reductions in renal blood flow, GFR and excretory function during saralasin infusion. 4. Normal rats receiving the identical dose of saralasin responded with a slight but significant decrease in arterial pressure. The increase in renal blood flow and GFR were less than those observed in the non-clipped kidneys of hypertensive rats. 5. These data provide further support to the hypothesis that an angiotensin II-mediated elevation in renal vascular resistance and impairment of renal function exist in the non-clipped kidneys of GH rats.

1. Micropuncture and clearance experiments in two-kidney, one-clip renal vascular hypertensive rats examined the ability of the kidney contralateral to renal vascular stenosis to maintain renal function during conditions of reduced renal arterial blood pressure. 2. At their respective spontaneous blood pressures, renal vascular resistance was higher and glomerular filtration rate (GFR) and renal blood flow were not different in the contralateral kidneys of the hypertensive rats (170 +/- 5 mmHg) compared with normal animals (129 +/- 1 mmHg). Urine flow and absolute and fractional excretion of electrolyte were greater from the kidneys of the hypertensive animals. However, pressures in cortical structures were similar in the two groups. 3. As blood pressure was reduced acutely, the kidney contralateral to the renal artery stenosis achieved only small decreases in renal vascular resistance that failed to allow GFR, renal blood flow or pressures in cortical structures to be maintained. In contrast, normal rats efficiently autoregulated renal vascular resistance to allow GFR, renal blood flow and cortical pressures to be unchanged as blood pressure was altered between 130 and 115 mmHg. Urine flow and electrolyte excretion decreased to a greater extent in the hypertensive kidneys; at comparable blood pressure these indices of excretory function were not different in the two groups. 4. These observations indicate that the contralateral kidney can maintain normal haemodynamic and glomerular function only at elevated blood pressure and suggest the possibility that the impaired capacity to autoregulate renal resistances may contribute to the maintenance of hypertension observed in this model.

The unique morphology of the juxtaglomerular complex has resulted in many investigations evaluating its potential physiological roles. One hypothesis that has stimulated considerable interest is that feedback signals originating from distal tubule cells, presumably at the macula densa segment, participate in the phenomenon of renal autoregulation. Data obtained from dog experiments indicate tha autoregulation of single nephron glomerular filtration rate (SNGFR) is most consistently observed when fluid delivery to the early distal tubule is not interrupted. In contrast, techniques that interfere with normal orthograde fluid delivery to the distal nephron have usually resulted in increases in SNGFR and an inability to exhibit appropriate autoregulatory responses to decreases in arterial pressure. There is considerable uncertainty concerning the nature of the intraluminal component of the early distal tubule fluid responsible for initiating feedback responses. The studies reported in this paper have indicated that feedback mediated decreases in stop-flow pressure and SNGFR in response to increases in distal microperfusion rate can occur with a variety of artificial perfusion solutions, including solutions that contain low concentrations of chloride, sodium, or total electrolytes. Microperfusion studies in the rat have demonstrated that feedback mediated decreases in stop-flow pressure can occur in the absence of associated increases in distal tubule fluid chloride concentration. These results are consistent with the concept that some function of distal tubule fluid osmolality or distal tubule solute delivery may participate in the initiation of feedback signals.

Patients requiring hemodialysis for end-stage renal disease are vulnerable to wide fluctuations in plasma potassium concentration [K+]p. Dialysis of K+ can result in rapid and large changes of [K+]p and result in significant morbidity. Since blood is routinely diverted extracorporeally to the dialyzer, the measurement of [K+]p could be made 'on-line' in this circuit with an ion-selective electrode (ISE) with negligible additional risk. Valinomycin/tetraphenylborate embedded in polyvinylchloride (PVC) electrodes of high K:Na selectivity were manufactured in our laboratory. The electrodes were calibrated in vitro and placed in a T diverter tube upstream from the dialyzer. Intermittently small amounts of blood were diverted to flow past the electrode allowing measurement of the electrical potential developed between the ISE half cell and a Ag:AgCl electrode placed 4 mm from the valinomycin membrane which could be read as [K+]p ISE. Blood flowing through the T diverter was then collected in glass tubes for measurement of [K+]p by flame photometry. Forty-six comparative measurements were made for 6 patients who had given informed consent for study. Least squares regression analysis for all observations gave a correlation coefficient of 0.95 and a regression equation of y = 1.1 X -0.39. Only six samples were discrepant by 0.5 mmol/l, and all of these had [K+]p greater than 5.0 mmol/l where the ISE measurements were less precise. Although the correlation of the two techniques was less than perfect, the ISE shows potential utility for monitoring trends of [K+]p instantaneously during hemodialysis.

Neural and angiotensin-mediated influences that alter hemodynamic and excretory behavior of the nonclipped kidney of two-kidney, one clip hypertensive rats were assessed by sequential acute surgical denervation of the nonclipped kidney and intravenous infusion of converting enzyme inhibitor (SQ 20881), 3 mg/kg X hr. Normal and two-kidney, one clip hypertensive rats (0.2-mm silver clip on the right renal artery 3-4 weeks before study) were prepared to allow study of each kidney. Mean arterial blood pressure of two-kidney, one clip hypertensive rats fell significantly from control values of 149 +/- 6 to 135 +/- 6 mm Hg after denervation of the nonclipped kidney. Despite this decrease in arterial pressure, the nonclipped kidney exhibited significant increases in glomerular filtration rate (from 1.00 +/- 0.08 to 1.24 +/- 0.08 ml/min), sodium excretion (from 88 +/- 39 to 777 +/- 207 nEq/min), fractional sodium excretion (from 0.06 +/- 0.02 to 0.54 +/- 0.14%), and urine flow rate (from 3.7 +/- 0.5 to 8.2 +/- 1.1 microliter/min). A significant decrease in glomerular filtration rate (from 1.12 +/- 0.07 to 0.85 +/- 0.08 ml/min) with no change in excretory function was observed for the clipped kidney following denervation of the nonclipped kidney. Intravenous addition of converting enzyme inhibitor significantly increased renal blood flow (from 7.0 +/- 1.3 to 10.6 +/- 1.5 ml/min) and sodium excretion (from 777 +/- 207 to 1384 +/- 425 nEq/min) for the nonclipped kidney; blood pressure decreased from 135 +/- 6 to 123 +/- 4 mm Hg, and renal vascular resistance decreased significantly (from 22 +/- 3 to 13 +/- 2 mm Hg X min/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

This study evaluated the responses of each kidney of two-kidney, one clip Goldblatt hypertensive rats to acute volume loading to delineate the contribution of elevated perfusion pressure to the mechanisms of the exaggerated natriuresis in this model of hypertension. Eleven Goldblatt animals (0.2 mm clip 3 weeks prior to study) were studied at spontaneous blood pressure for each kidney's response to volume loading. In 11 other Goldblatt animals an aortic clamp between the renal arteries allowed reduction of perfusion pressure for the left, nonclipped kidney to normal levels. Ten normal rats served as controls. Renal function was examined during control periods and following the infusion of 3.5% body wt of 154 mM X liter-1 NaCl at 22.5 ml X hr-1. An exaggerated natriuresis was observed for the left, nonclipped kidney of the hypertensive Goldblatt rats, while the clipped kidney exhibited an attenuated natriuresis compared to either kidney of normal control rats. Reduction of perfusion pressure to the nonclipped kidney of Goldblatt animals to normal levels resulted in reduced clearance and excretory function before volume loading and attenuated its natriuretic response to levels less than those for the Goldblatt group at spontaneous, hypertensive blood pressure. The exaggerated natriuresis observed at hypertensive blood pressure was attributable to increases of filtered load of Na+ and reduced fractional absorption. These observations indicate that an exaggerated natriuresis occurs in the two-kidney, one clip Goldblatt hypertensive rat and that this phenomenon depends on the elevated renal perfusion pressure to the nonclipped kidney.

The present study was performed to evaluate superficial nephron responses of the nonclipped kidney to angiotensin I converting enzyme inhibitor (CEI) (SQ 20,881, 3 mg . kg-1 . h-1) in two-kidney, one-clip Goldblatt hypertensive (GH) rats. Late proximal and early distal tubule collections were obtained before and during CEI. Significant increases in glomerular filtration rate, urine flow, sodium excretion, proximal and distal tubule flow rates, and single nephron glomerular filtration rate (from 24.6 +/- 1.7 to 27.5 +/- 1.6 nl/min) occurred despite reductions in arterial blood pressure (from 160 +/- 5 to 137 +/- 6 mmHg) during CEI. Proximal tubule absolute and fractional reabsorption of fluid, chloride, and total solute decreased significantly. In the nephron segment between the two collection sites, there were increases in absolute but decreases in fractional reabsorption. At the distal tubule level, fractional reabsorption but not absolute reabsorption decreased significantly. Proximal and distal tubule hydrostatic pressures increased significantly while peritubular capillary pressure decreased slightly. Responses following inhibition of angiotensin II formation suggest that there exists an angiotensin II-mediated enhancement in tubular reabsorption in the nonclipped kidney of Goldblatt hypertensive rats.

The effects of captopril on mean arterial blood pressure and proximal tubular fluid reabsorption (JV) were examined in anaesthetized normotensive rats and in the non-clipped kidneys of two-kidney, one-clip Goldblatt hypertensive rats. In the normotensive animals, captopril reduced arterial blood pressure from 121 +/- SD 9 to 106 +/- 10 mmHg and JV decreased from 3.78 +/- 0.45 to 2.57 +/- 0.58 X 10(-4) mm3 mm-2 s-1. Captopril had a greater effect on blood pressure in the hypertensive animals (172 +/- 17 reduced to 133 +/- 23 mmHg) although the decrease in JV from 3.62 +/- 0.12 to 2.40 +/- 0.40 was similar to that observed in normotensive animals. These results provide evidence that, in the anaesthetized rat, angiotensin II contributes to the maintenance of the rate of proximal fluid reabsorption. The magnitude of the angiotensin-stimulated component of proximal fluid absorption is similar in normotensive and two-kidney, one-clip Goldblatt hypertensive rats.