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Concept: Kidney diseases

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Proton pump inhibitors (PPIs) are among the most commonly used drugs worldwide and have been linked to acute interstitial nephritis. Less is known about the association between PPI use and chronic kidney disease (CKD).

Concepts: Chronic kidney disease, Kidney, Interstitial nephritis, Kidney diseases, Nephritis

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Background Combination therapy with angiotensin-converting-enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) decreases proteinuria; however, its safety and effect on the progression of kidney disease are uncertain. Methods We provided losartan (at a dose of 100 mg per day) to patients with type 2 diabetes, a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of at least 300, and an estimated glomerular filtration rate (GFR) of 30.0 to 89.9 ml per minute per 1.73 m(2) of body-surface area and then randomly assigned them to receive lisinopril (at a dose of 10 to 40 mg per day) or placebo. The primary end point was the first occurrence of a change in the estimated GFR (a decline of ≥30 ml per minute per 1.73 m(2) if the initial estimated GFR was ≥60 ml per minute per 1.73 m(2) or a decline of ≥50% if the initial estimated GFR was <60 ml per minute per 1.73 m(2)), end-stage renal disease (ESRD), or death. The secondary renal end point was the first occurrence of a decline in the estimated GFR or ESRD. Safety outcomes included mortality, hyperkalemia, and acute kidney injury. Results The study was stopped early owing to safety concerns. Among 1448 randomly assigned patients with a median follow-up of 2.2 years, there were 152 primary end-point events in the monotherapy group and 132 in the combination-therapy group (hazard ratio with combination therapy, 0.88; 95% confidence interval [CI], 0.70 to 1.12; P=0.30). A trend toward a benefit from combination therapy with respect to the secondary end point (hazard ratio, 0.78; 95% CI, 0.58 to 1.05; P=0.10) decreased with time (P=0.02 for nonproportionality). There was no benefit with respect to mortality (hazard ratio for death, 1.04; 95% CI, 0.73 to 1.49; P=0.75) or cardiovascular events. Combination therapy increased the risk of hyperkalemia (6.3 events per 100 person-years, vs. 2.6 events per 100 person-years with monotherapy; P<0.001) and acute kidney injury (12.2 vs. 6.7 events per 100 person-years, P<0.001). Conclusions Combination therapy with an ACE inhibitor and an ARB was associated with an increased risk of adverse events among patients with diabetic nephropathy. (Funded by the Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development; VA NEPHRON-D ClinicalTrials.gov number, NCT00555217 .).

Concepts: Renal failure, Kidney, Nephrology, Dialysis, Diabetic nephropathy, Renal physiology, Angiotensin II receptor antagonist, Kidney diseases

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The association between proton pump inhibitors (PPI) use and risk of acute interstitial nephritis has been described. However, whether exposure to PPI associates with incident CKD, CKD progression, or ESRD is not known. We used Department of Veterans Affairs national databases to build a primary cohort of new users of PPI (n=173,321) and new users of histamine H2-receptor antagonists (H2blockers;n=20,270) and followed these patients over 5 years to ascertain renal outcomes. In adjusted Cox survival models, the PPI group, compared with the H2blockers group, had an increased risk of incident eGFR<60 ml/min per 1.73 m(2)and of incident CKD (hazard ratio [HR], 1.22; 95% confidence interval [95% CI], 1.18 to 1.26; and HR, 1.28; 95% CI, 1.23 to 1.34, respectively). Patients treated with PPI also had a significantly elevated risk of doubling of serum creatinine level (HR, 1.53; 95% CI, 1.42 to 1.65), of eGFR decline >30% (HR, 1.32; 95% CI, 1.28 to 1.37), and of ESRD (HR, 1.96; 95% CI, 1.21 to 3.18). Furthermore, we detected a graded association between duration of PPI exposure and risk of renal outcomes among those exposed to PPI for 31-90, 91-180, 181-360, and 361-720 days compared with those exposed for ≤30 days. Examination of risk of renal outcomes in 1:1 propensity score-matched cohorts of patients taking H2blockers versus patients taking PPI and patients taking PPI versus controls yielded consistent results. Our results suggest that PPI exposure associates with increased risk of incident CKD, CKD progression, and ESRD.

Concepts: Kidney, Proportional hazards models, Renal physiology, Creatinine, Interstitial nephritis, Kidney diseases, Nephritis, H2 antagonist

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Background Although inhibitors of the renin-angiotensin-aldosterone system can slow the progression of diabetic kidney disease, the residual risk is high. Whether nuclear 1 factor (erythroid-derived 2)-related factor 2 activators further reduce this risk is unknown. Methods We randomly assigned 2185 patients with type 2 diabetes mellitus and stage 4 chronic kidney disease (estimated glomerular filtration rate [GFR], 15 to <30 ml per minute per 1.73 m(2) of body-surface area) to bardoxolone methyl, at a daily dose of 20 mg, or placebo. The primary composite outcome was end-stage renal disease (ESRD) or death from cardiovascular causes. Results The sponsor and the steering committee terminated the trial on the recommendation of the independent data and safety monitoring committee; the median follow-up was 9 months. A total of 69 of 1088 patients (6%) randomly assigned to bardoxolone methyl and 69 of 1097 (6%) randomly assigned to placebo had a primary composite outcome (hazard ratio in the bardoxolone methyl group vs. the placebo group, 0.98; 95% confidence interval [CI], 0.70 to 1.37; P=0.92). In the bardoxolone methyl group, ESRD developed in 43 patients, and 27 patients died from cardiovascular causes; in the placebo group, ESRD developed in 51 patients, and 19 patients died from cardiovascular causes. A total of 96 patients in the bardoxolone methyl group were hospitalized for heart failure or died from heart failure, as compared with 55 in the placebo group (hazard ratio, 1.83; 95% CI, 1.32 to 2.55; P<0.001). Estimated GFR, blood pressure, and the urinary albumin-to-creatinine ratio increased significantly and body weight decreased significantly in the bardoxolone methyl group, as compared with the placebo group. Conclusions Among patients with type 2 diabetes mellitus and stage 4 chronic kidney disease, bardoxolone methyl did not reduce the risk of ESRD or death from cardiovascular causes. A higher rate of cardiovascular events with bardoxolone methyl than with placebo prompted termination of the trial. (Funded by Reata Pharmaceuticals; BEACON ClinicalTrials.gov number, NCT01351675 .).

Concepts: Renal failure, Chronic kidney disease, Kidney, Nephrology, Hypertension, Diabetes, Kidney transplantation, Kidney diseases

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Renal involvement with significant organ damage is common in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). As a result, it is independently referred to ANCA-associated renal vasculitis. Clinically, ANCA-associated renal vasculitis is characterized by rapidly progressive glomerulonephritis. Pathologically, it is defined by pauci-immune type necrotizing and crescentic glomerulonephritis. According to previous reports from all over the world, the etiology, prevalence, and prognosis of RPGN including ANCA-associated renal vasculitis varies among races and periods. To elucidate the clinical characteristics of Japanese RPGN patients, a registry derived from a questionnaire survey was established in 1999 and maintained until 2006. As a result, 1,772 cases were collected, analyzed, and reported previously. In this mini-review, we outline the characteristic clinical findings of Japanese patients (Asian) with ANCA-associated renal vasculitis, based on the registry data.

Concepts: Inflammation, Kidney, Glomerulonephritis, Windows Registry, Kidney diseases, Rapidly progressive glomerulonephritis, Real estate, IgA nephropathy

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Glomerular injury can be caused by numerous insults including hemodynamics, infections and immunity, hereditary and metabolic diseases, and toxicity. Basic and translational experimental studies in combination with clinical research in patients with renal disease have advanced our understanding of the etiology and pathogenesis of many forms of glomerulonephritis. This new knowledge has facilitated classification and treatment and has contributed to a better outcome of patients with renal disease. Since renal disease almost without exception leads to systemic cardiovascular complications, these advances are also of general health interest. Here, we shall briefly review general principles in the pathology of glomerular injury and discuss recent developments in the study of podocytopathies; membranous glomerulopathy; ANCA-associated vasculitis; C3 glomerulopathies and the role of complement in endothelial injury; and the prognostic value of the renal biopsy in predicting long-term outcome in lupus nephritis, vasculitis and IgA nephropathy.

Concepts: Immune system, Inflammation, Kidney, Medicine, Cancer, Systemic lupus erythematosus, Glomerulonephritis, Kidney diseases

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Aim: Children with steroidresistant (SR) and steroid-dependent (SD) nephrotic syndrome (NS) pose a treatment challenge. Literature on the use of tacrolimus (TAC), a calcineurin inhibitor, for maintenance treatment of NS is sparse. We aimed to evaluate the efficacy and safety of low-dose, long-term TAC for inducing and sustaining remission in children with SD/SR NS. Methods: Data from patients treated at our center from 1999 to 2009 were analyzed. Results: 40 patients with NS were treated with TAC for 3 - 80-month periods (median 25.2 months). Diagnoses included focal segmental glomerulosclerosis (FSGS) (60%), IgM nephropathy (15%), minimal change disease (20%) and membrano-proliferative glomerulonephritis (MPGN) (5%). 58% of patients had been previously treated with alternate agents. After 1, 2, and 3 years on TAC, complete remission was achieved in 26%, 48%, and 29% of patients; complete or partial remission was achieved in 85%, 100%, and 86%, respectively (p < 0.05). Median time to remission was 41 days (range: 10 - 270 days). FSGS and SR diseases were associated with lower likelihood of remission (p < 0.05). Remission was equally likely in both treatment naïve patients and those who had received prior second-line agents. Conclusion: Our results demonstrate that TAC treatment for children with SR/SD NS is associated with high rates of sustained remission, even when prior second-line agents failed.

Concepts: Kidney, Nephrotic syndrome, Proteinuria, Kidney diseases, Minimal change disease, Focal segmental glomerulosclerosis, Glomerulosclerosis, Sustain

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BACKGROUND: Glomerular podocyte molecules are involved in the pathogenesis of congenital nephrotic syndrome. However, their role in primary nephrotic syndrome is not clear. This study investigated the expression of nephrin, podocin and synaptopodin in primary nephrotic syndrome. METHODS: Eighty-seven patients with primary nephrotic syndrome including minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), membranous nephropathy (MN) and membranoproliferative glomerulonephritis Type I (MPGN) were included in the study. Glomerular expression of nephrin, podocin and synaptopodin was studied in renal biopsies by immunofluorescence and immunohistochemistry. Correlation of expression with clinical and biochemical parameters was performed. RESULTS: The pattern of expression for all podocyte proteins in controls was uniform fine granular along the capillary walls towards the visceral epithelial cell aspect. Glomerular expression of nephrin was present in all renal biopsies and was similar to that in controls. Glomerular synaptopodin expression was seen in all MN and MPGN patients, while it was seen in 74 % (17/23) MCD and 93.5 % (29/31) FSGS. Reduced synaptopodin expression showed no correlation with clinical and biochemical factors. Podocin expression was present in 5/23 MCD (22 %), 3/31 FSGS (9.6 %), 13/17 MN (76.4 %) and 13/16 MPGN (81 %) patients. The reduced expression of podocin significantly correlated with the degree of proteinuria (p = 0.032). No correlation with age, gender and serum creatinine level was observed. CONCLUSION: Reduction of glomerular podocin expression found in MCD and FSGS is related to the amount of proteinuria. Our findings suggest that alteration in podocyte phenotype may not be a primary event and may reflect the degree of podocyte injury in primary nephrotic syndrome.

Concepts: Kidney, Nephrotic syndrome, Proteinuria, Kidney diseases, Minimal change disease, Focal segmental glomerulosclerosis, Membranous glomerulonephritis, Membranoproliferative glomerulonephritis

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It has been argued that the existing epidemiologic data are insufficient to establish a causal link between acute kidney injury (AKI) and subsequent development or progression of chronic kidney disease (CKD), especially given that risk factors for the development of AKI overlap with those for progressive CKD.

Concepts: Renal failure, Chronic kidney disease, Epidemiology, The Link REIT, Kidney diseases

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Endothelin A receptor antagonists (ERAs) decrease residual albuminuria in patients with diabetic kidney disease; however, their clinical utility may be limited by fluid retention. Consequently, the primary objective of this study was to identify predictors for ERA-induced fluid retention among patients with type 2 diabetes and CKD. A secondary objective was to determine if the degree of fluid retention necessarily correlated with the magnitude of albuminuria reduction in those patients receiving ERAs.

Concepts: Kidney, Diabetes mellitus type 2, Diabetes mellitus, Diabetes, Diabetic nephropathy, Kidney transplantation, Kidney diseases, Albuminuria