Glomerular sieving of anionic and neutral bovine albumins in proteinuric rats

Glomerular sieving of anionic and neutral bovine albumins in proteinuric rats. To characterize the defect in glomerular permeability leading to albuminuria in rats made nephrotic acutely by infusion of hexadimethrine (HDM) or chronically by administration of Adriamycin® (doxorubicin) (Adria), we developed and validated a tissue accumulation method for simultaneous determination of the glomerular sieving coefficients (GSC) of anionic 131I-labeled bovine albumin (BSA-pI 4.9) and 125I-labeled charge-modified neutral BSA (nBSA-pI 7.5 to 8.0). Total filtered marker was calculated by adding marker excreted in the urine to that filtered but reabsorbed by the tubules. The latter was determined by subtracting interstitial marker present in the left kidney, rendered non-filtering by ureteral ligation during mannitol diuresis, from the total marker accumulating within the right, filtering kidney. Experiments showed that markers circulated and were excreted intact and were neither degraded nor deiodinated during the period of the clearance studies.In control animals the GSC of nBSA (0.026 ± 0.004) greatly exceeded that of BSA (0.0006 ± 0.0002), demonstrating the normal charge dependence of permeability. Both proteinuric groups had marked increases in the GSC of BSA (HDM: 0.021 ± 0.005; Adria: 0.025 ± 0.004), which correlated with appearance of rat albumin in their urine. HDM rats also had a twofold increase in the GSC of nBSA (0.049 ± 0.005), indicating alteration of the size dependence of permeability. The absolute increase of GSC of BSA and nBSA was similar, suggesting that albuminuria resulted from appearance of new “pores” in the glomerular filter that were not charge selective for proteins of the size of albumin. Thus, infusion of HDM, which binds to and neutralizes GBM anions, appears to produce albuminuria by inducing a structural change in the glomerular filter. Conversely, Adria rats had no significant increase in the GSC of nBSA (0.031 ± 0.005), indicating no significant change in the size dependence of permeability for proteins of the size of albumin. In these animals, the GSC of the anionic BSA approached that of the neutral nBSA, indicating that Adriamycin induces albuminuria by markedly reducing the normal charge dependence of permeability

Urine Injury Biomarkers and Risk of Adverse Outcomes in Recipients of Prevalent Kidney Transplants: The Folic Acid for Vascular Outcome Reduction in Transplantation Trial

Recipients of kidney transplants (KTR) are at increased risk for cardiovascular events, graft failure, and death. It is unknown whether urine kidney injury biomarkers are associated with poor outcomes among KTRs. We conducted a post hoc analysis of the Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) Trial using a case-cohort study design, selecting participants with adjudicated cardiovascular events, graft failure, or death. Urine neutrophil gelatinase–associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), IL-18, and liver–type fatty acid binding protein (L-FABP) were measured in spot urine samples and standardized to urine creatinine concentration. We adjusted for demographics, cardiovascular risk factors, eGFR, and urine albumin-to-creatinine ratio. Patients had 291 cardiovascular events, 257 graft failure events, and 359 deaths. Each log increase in urine NGAL/creatinine independently associated with a 24% greater risk of cardiovascular events (adjusted hazard ratio [aHR], 1.24; 95% confidence interval [95% CI], 1.06 to 1.45), a 40% greater risk of graft failure (aHR, 1.40; 95% CI, 1.16 to 1.68), and a 44% greater risk of death (aHR, 1.44; 95% CI, 1.26 to 1.65). Urine KIM-1/creatinine and IL-18/creatinine independently associated with greater risk of death (aHR, 1.29; 95% CI, 1.03 to 1.61 and aHR, 1.25; 95% CI, 1.04 to 1.49 per log increase, respectively) but not with risk of cardiovascular events or graft failure. Urine L-FABP did not associate with any study outcomes. In conclusion, among prevalent KTRs, higher urine NGAL, KIM-1, and IL-18 levels independently and differentially associated with greater risk of adverse outcomes

B-Type Natriuretic Peptide and Cardiac Troponin I Are Associated With Adverse Outcomes in Stable Kidney Transplant Recipients

Approximately 200,000 kidney transplant recipients are living in the US; they are at increased risk for cardiovascular and other adverse outcomes. Biomarkers predicting these outcomes are needed. Using specimens collected during the FAVORIT (Folic Acid for Vascular Outcome Reduction In Transplantation) trial, we determined whether plasma levels of B-type natriuretic peptide (BNP) and cardiac troponin I are associated with adverse outcomes in stable kidney transplant recipients

Impact of Achieved Blood Pressure on Cardiovascular Outcomes in the Irbesartan Diabetic Nephropathy Trial

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Baseline Characteristics of Participants in the Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) Trial

Hyperhomocysteinemia may be a modifiable risk factor for the prevention of arteriosclerotic outcomes in chronic kidney disease (CKD). Few clinical trials of homocysteine lowering have been conducted in persons with CKD prior to reaching end-stage renal disease. Kidney transplant recipients are considered individuals with CKD

Renoprotective effect of the angiotensin-receptro antagonist ibersartan in patients with nephropathy due to type 2 diabetes

Background: It is unknown whether either the angiotensin-II-receptor blocker irbesartan or the calcium-channel blocker amlodipine slows the progression of nephropathy in patients with type 2 diabetes independently of its capacity to lower the systemic blood pressure. Methods: We randomly assigned 1715 hypertensive patients with nephropathy due to type 2 diabetes to treatment with irbesartan (300 mg daily), amlodipine (10 mg daily), or placebo. The target blood pressure was 135/85 mm Hg or less in all groups. We compared the groups with regard to the time to the primary composite end point of a doubling of the base-line serum creatinine concentration, the development of end-stage renal disease, or death from any cause. We also compared them with regard to the time to a secondary, cardiovascular composite end point. Results: The mean duration of follow-up was 2.6 years. Treatment with irbesartan was associated with a risk of the primary composite end point that was 20 percent lower than that in the placebo group (P=0.02) and 23 percent lower than that in the amlodipine group (P=0.006). The risk of a doubling of the serum creatinine concentration was 33 percent lower in the irbesartan group than in the placebo group (P=0.003) and 37 percent lower in the irbesartan group than in the amlodipine group (P<0.001). Treatment with irbesartan was associated with a relative risk of end-stage renal disease that was 23 percent lower than that in both other groups (P=0.07 for both comparisons). These differences were not explained by differences in the blood pressures that were achieved. The serum creatinine concentration increased 24 percent more slowly in the irbesartan group than in the placebo group (P=0.008) and 21 percent more slowly than in the amlodipine group (P=0.02). There were no significant differences in the rates of death from any cause or in the cardiovascular composite end point. Conclusions: The angiotensin-II-receptor blocker irbesartan is effective in protecting against the progression of nephropathy due to type 2 diabetes. This protection is independent of the reduction in blood pressure it causes

Homocysteine-Lowering and Cardiovascular Disease Outcomes in Kidney Transplant Recipients: Primary Results From the Folic Acid for Vascular Outcome Reduction in Transplantation Trial

Kidney transplant recipients, like other patients with chronic kidney disease (CKD), experience excess risk of cardiovascular disease (CVD) and elevated total homocysteine (tHcy) concentrations. Observational studies of patients with CKD suggest increased homocysteine is a risk factor for CVD. The impact of lowering total homocysteine (tHcy) levels in kidney transplant recipients is unknown

National Institutes of Health–Sponsored Clinical Islet Transplantation Consortium Phase 3 Trial: Manufacture of a Complex Cellular Product at Eight Processing Facilities

Eight manufacturing facilities participating in the National Institutes of Health–sponsored Clinical Islet Transplantation (CIT) Consortium jointly developed and implemented a harmonized process for the manufacture of allogeneic purified human pancreatic islet (PHPI) product evaluated in a phase 3 trial in subjects with type 1 diabetes. Manufacturing was controlled by a common master production batch record, standard operating procedures that included acceptance criteria for deceased donor organ pancreata and critical raw materials, PHPI product specifications, certificate of analysis, and test methods. The process was compliant with Current Good Manufacturing Practices and Current Good Tissue Practices. This report describes the manufacturing process for 75 PHPI clinical lots and summarizes the results, including lot release. The results demonstrate the feasibility of implementing a harmonized process at multiple facilities for the manufacture of a complex cellular product. The quality systems and regulatory and operational strategies developed by the CIT Consortium yielded product lots that met the prespecified characteristics of safety, purity, potency, and identity and were successfully transplanted into 48 subjects. No adverse events attributable to the product and no cases of primary nonfunction were observed

Physician access and early nephrology care in elderly patients with end-stage renal disease

Early nephrology care may improve treatment outcomes of patients with end-stage renal disease. We sought to examine if physician access affects early nephrology care defined as visiting a nephrologist 12 to 4 months before initiating dialysis. The study population consisted of elderly patients starting hemodialysis whose demographic characteristics and initial dialysis therapy were derived from form 2728 files of the Centers for Medicare & Medicaid Services. Early nephrology care, chronic kidney disease and co-morbidities along with access to local non-nephrologist physicians and nephrologists were identified based on Medicare claims and/or United States 2000 Census data. About one-third of elderly patients received early nephrology care prior to initiating dialysis. Patients living in an area with a large number of non-nephrologist physicians or living relatively far away from a nephrologist had a lower likelihood of getting early nephrology care prior to initiating dialysis while those in an area with more practicing nephrologists were more likely to get early nephrology care. The study shows that physician access significantly influences the use of early nephrology care among elderly patients progressing to end-stage renal disease in the United States