Glomerular transcriptomics predicts long term outcome and identifies therapeutic strategies for patients with assumed benign IgA nephropathy.

Some patients diagnosed with benign IgA nephropathy (IgAN) develop a progressive clinical course, not predictable by known clinical or histopathological parameters. To assess if gene expression can differentiate between progressors and non-progressors with assumed benign IgAN, we tested microdissected glomeruli from archival kidney biopsy sections from adult patients with stable clinical remission (21 non-progressors) or from 15 patients that had undergone clinical progression within a 25-year time frame. Based on 1 240 differentially expressed genes from patients with suitable sequencing results, we identified eight IgAN progressor and nine non-progressor genes using a two-component classifier. These genes, including APOL5 and ZXDC, predicted disease progression with 88% accuracy, 75% sensitivity and 100% specificity on average 21.6 years before progressive disease was clinically documented. APOL lipoproteins are associated with inflammation, autophagy and kidney disease while ZXDC is a zinc-finger transcription factor modulating adaptive immunity. Ten genes from our transcriptomics data overlapped with an external genome wide association study dataset, although the gene set enrichment test was not statistically significant. We also identified 45 drug targets in the DrugBank database, including angiotensinogen, a target of sparsentan (dual antagonist of the endothelin type A receptor and the angiotensin II type 1 receptor) currently investigated for IgAN treatment. Two validation cohorts were used for substantiating key results, one by immunohistochemistry and the other by nCounter technology. Thus, glomerular mRNA sequencing from diagnostic kidney biopsies from patients with assumed benign IgAN can differentiate between future progressors and non-progressors at the time of diagnosis.

Association between urinary C4d levels and disease progression in IgA nephropathy.

BACKGROUND: C4d mesangial deposition, a hallmark of lectin pathway activation in immunoglobulin A nephropathy (IgAN), has been shown to be associated with risk of kidney failure. To date, the relationship between urinary C4d and renal outcome remain unelucidated. METHODS: A total of 508 patients with biopsy-proven IgAN were enrolled in this study, whose baseline urine samples at the time of biopsy were collected and the levels of urinary C4d were quantified by enzyme-linked immunosorbent assay. The time-averaged C4d (TA-C4d) and the change in proteinuria were measured in sequential urine samples obtained from IgAN patients. The kidney progression event was defined as a 50% estimated glomerular filtration rate (eGFR) decline or end-stage kidney disease or death. RESULTS: After a median follow-up of 36 months, 70 (13.8%) of the participants reached the kidney progression event. Higher levels of urinary C4d/Ucr were found to be associated with decreased eGFR, massive proteinuria, lower serum albumin levels, hypertension, and severe Oxford E and T scores. Upon adjusting for traditional risk factors (including demographics, eGFR, proteinuria, hypertension, Oxford pathologic score and immunosuppressive therapy), elevated levels of urinary C4d/Ucr were independently associated with an increased risk of chronic kidney disease progression [adjusted hazard ratio (HR) per standard deviation increment of log-transformed C4d/Ucr: 1.46; 95% CI 1.04-2.06; P = .030]. In reference to the low C4d group, the risk of poor renal outcome increased for the high C4d group (adjusted HR 1.93; 95% CI 1.05-3.54; P = .033). Additionally, a low baseline C4d level was independently associated with a favorable proteinuria response to immunosuppressive therapy at 3 months (adjusted relative risk 2.20; 95% CI 1.04-4.63, P = .038). CONCLUSION: The urinary C4d, serving as a non-invasive biomarker, is associated with the progression of IgAN and holds the potential to predict proteinuria response in this disease.

A Dynamic Prediction Model for Renal Progression in Primary Membranous Nephropathy.

Objective: This study aimed to build and validate a practical web-based dynamic prediction model for predicting renal progression in patients with primary membranous nephropathy (PMN). Method: A total of 359 PMN patients from The First Affiliated Hospital of Fujian Medical University and 102 patients with PMN from The Second Hospital of Longyan between January 2018 to December 2023 were included in the derivation and validation cohorts, respectively. Renal progression was delineated as a decrease in eGFR of 30% or more from the baseline measurement at biopsy or the onset of End-Stage Renal Disease (ESRD). Multivariable Cox regression analysis was employed to identify independent prognostic factors. A web-based dynamic prediction model for renal progression was built and validated, and the performance was assessed using. An analysis of the receiver operating characteristic and the decision curve analysis. Results: In the derivation cohort, 66 (18.3%) patients experienced renal progression during the follow-up period (37.60 ± 7.95 months). The final prediction rule for renal progression included hyperuricemia (HR=2.20, 95%CI 1.26 to 3.86), proteinuria (HR=2.16, 95%CI 1.47 to 3.18), significantly lower serum albumin (HR=2.34, 95%CI 1.51 to 3.68) and eGFR (HR=1.96, 95%CI 1.47 to 2.61), older age (HR=1.85, 95%CI 1.28 to 2.61), and higher sPLA2R-ab levels (HR=2.08, 95%CI 1.43 to 3.18). Scores for each variable were calculated using the regression coefficients in the Cox model. The developed web-based dynamic prediction model, available online at http://imnpredictmodel1.shinyapps.io/dynnomapp, showed good discrimination (C-statistic = 0.72) and calibration (Brier score, P = 0.155) in the validation cohort. Conclusion: We developed a web-based dynamic prediction model that can predict renal progression in patients with PMN. It may serve as a helpful tool for clinicians to identify high-risk PMN patients and tailor appropriate treatment and surveillance strategies.

23-valent pneumococcal polysaccharide vaccine and the risk of renal progression in older patients with chronic kidney disease.

BACKGROUND: The 23-valent pneumococcal polysaccharide vaccine (PPSV23) ensures favorable outcomes and reduces the risk of cardiac events in patients on dialysis. However, the effect of PPSV23 vaccination on renal function remains unknown, particularly in patients with chronic kidney disease (CKD). Therefore, we investigated the association between PPSV23 efficacy and renal progression in older patients (age ≥ 75 years) with CKD. METHODS: This multicenter, longitudinal cohort study was conducted using data (2008-2016) from the Epidemiology and Risk Factors Surveillance of CKD database. This database was associated with Taiwan's National Health Insurance Research Database (for period: 2008-2019). A total of 1195 older patients with CKD were recruited from 14 hospitals and communities across Taiwan. Renal progression was defined as a > 25% reduction in estimated glomerular filtration rate from the baseline value. RESULTS: A significant reduction in the risk of renal progression was observed in patients who had received PPSV23 (adjusted hazard ratio [HR]: 0.57; 95% confidence interval [CI]: 0.35-0.91). However, when stratified by CKD stage, this significant reduction was observed in patients with early-stage CKD but not in those with late-stage CKD. Furthermore, a significant reduction in the risk of renal progression was noted in male patients and those with hypertension. CONCLUSION: Our findings support the protective effect of PPSV23 against renal deterioration in older patients with CKD.

Exposure to ambient air pollutants with kidney function decline in chronic kidney disease patients.

Chronic kidney disease (CKD) has been a global public health problem with many adverse outcomes, but data are lacking regarding the relationship between air pollutants and risk of renal progression in patients with CKD. This study was to investigate whether 1-year average exposure to ambient air pollutants -CO, NO, NO2, SO2, O3, PM2.5, and PM10-is related to renal function deterioration among patients with CKD. A total of 5301 CKD patients were included in this study between October 2008 and February 2016. To estimate each patient's exposure to ambient air pollution, we used the 24-h ambient air pollution concentration monitoring data collected one year prior to renal progression or their last renal function assessment. Renal progression was considered when estimated glomerular filtration rate (eGFR) decreased more than 25% from the baseline eGFR. Cox proportional hazard regression was performed to calculate hazard ratios (HRs). Among 5301 patients with CKD, 1813 (34.20%) developed renal progression during the 30.48 ± 14.99-month follow-up. Patients with the highest quartile exposure to CO [HR = 1.53 (95% CI: 1.24, 1.88)], NO [HR = 1.38 (95% CI: 1.11, 1.71)], NO2 [HR = 1.63 (95% CI: 1.36, 1.97)], SO2 [HR = 2.27 (95% CI: 1.83, 2.82)], PM2.5 [HR = 7.58 (95% CI: 5.97, 9.62)], and PM10 [HR = 3.68 (95% CI: 2.84, 4.78)] had a significantly higher risk of renal progression than those with the lowest quartile exposure. In the multipollutant model, the analyses yielded to similar results. These results reinforce the importance of measures to mitigate air pollution and strategies to prevent worsening of kidney function in patients with CKD. One-year high exposure to ambient CO, NO, NO2, SO2, PM2.5, and PM10 is significantly associated with deteriorated kidney function in patients with CKD among Taiwanese adults.

Measured sodium excretion is associated with CKD progression: results from the KNOW-CKD study.

BACKGROUND: Diet is a modifiable factor of chronic kidney disease (CKD) progression. However, the effect of dietary salt intake on CKD progression remains unclear. Therefore, we analyzed the effect of dietary salt intake on renal outcome in Korean patients with CKD. METHODS: We measured 24-h urinary sodium (Na) excretion as a marker of dietary salt intake in the prospective, multi-center, longitudinal KoreaN cohort study for Outcome in patients With CKD (KNOW-CKD). Data were analyzed from CKD patients at Stages G3a to G5 (n = 1254). We investigated the association between dietary salt intake and CKD progression. Patients were divided into four quartiles of dietary salt intake, which was assessed using measured 24-h urinary Na excretion. The study endpoint was composite renal outcome, which was defined as either halving the estimated glomerular filtration rate or developing end-stage renal disease. RESULTS: During a median (interquartile range) follow-up of 4.3 (2.8-5.8) years, 480 (38.7%) patients developed the composite renal event. Compared with the reference group (Q2, urinary Na excretion: 104.2 ≤ Na excretion < 145.1 mEq/day), the highest quartile of measured 24-h urinary Na excretion was associated with risk of composite renal outcome [Q4, urinary Na excretion ≥192.9 mEq/day, hazard ratio 1.8 (95% confidence interval 1.12-2.88); P = 0.015] in a multivariable hazards model. Subgroup analyses showed that high-salt intake was particularly associated with a higher risk of composite renal outcome in women, in patients <60 years of age, in those with uncontrolled hypertension and in those with obesity. CONCLUSIONS: High salt intake was associated with increased risk of progression in CKD.

Chronic Kidney Disease: Strategies to Retard Progression.

Chronic kidney disease (CKD), defined as the presence of irreversible structural or functional kidney damages, increases the risk of poor outcomes due to its association with multiple complications, including altered mineral metabolism, anemia, metabolic acidosis, and increased cardiovascular events. The mainstay of treatments for CKD lies in the prevention of the development and progression of CKD as well as its complications. Due to the heterogeneous origins and the uncertainty in the pathogenesis of CKD, efficacious therapies for CKD remain challenging. In this review, we focus on the following four themes: first, a summary of the known factors that contribute to CKD development and progression, with an emphasis on avoiding acute kidney injury (AKI); second, an etiology-based treatment strategy for retarding CKD, including the approaches for the common and under-recognized ones; and third, the recommended approaches for ameliorating CKD complications, and the final section discusses the novel agents for counteracting CKD progression.

Improving treatment decisions using personalized risk assessment from the International IgA Nephropathy Prediction Tool.

Immunosuppression in IgA nephropathy (IgAN) should be reserved for patients at high-risk of disease progression, which KDIGO guidelines determine based solely on proteinuria 1g or more/day. To investigate if treatment decisions can be more accurately accomplished using individualized risk from the International IgAN Prediction Tool, we simulated allocation of a hypothetical immunosuppression therapy in an international cohort of adults with IgAN. Two decision rules for treatment were applied based on proteinuria of 1g or more/day or predicted risk from the Prediction Tool above a threshold probability. An appropriate decision was defined as immunosuppression allocated to patients experiencing the primary outcome (50% decline in eGFR or ESKD) and withheld otherwise. The net benefit and net reduction in treatment are the proportion of patients appropriately allocated to receive or withhold immunosuppression, adjusted for the harm from inappropriate decisions, calculated for all threshold probabilities from 0-100%. Of 3299 patients followed for 5.1 years, 522 (15.8%) experienced the primary outcome. Treatment allocation based solely on proteinuria of 1g or more/day had a negative net benefit (was harmful) because immunosuppression was increasingly allocated to patients without progressive disease. Compared to using proteinuria, treatment allocation using the Prediction Tool had a larger net benefit up to 23.4% (95% confidence interval 21.5-25.2%) and a larger net reduction in treatment up to 35.1% (32.3-37.8%). Thus, allocation of immunosuppression to high-risk patients with IgAN can be substantially improved using the Prediction Tool compared to using proteinuria.

Risk of progressive chronic kidney disease in individuals with early-onset type 2 diabetes: a prospective cohort study.

BACKGROUND: The progression trajectory of renal filtration function has not been well characterized in patients with early-onset type 2 diabetes mellitus (T2DM) although albuminuria is often reported in this population. We aim to study the risk of progressive chronic kidney disease (CKD) in individuals with early-onset T2DM. METHODS: In total, 1189 T2DM participants were followed for 3.9 (interquartile range 3.2-4.7) years. Progressive CKD was defined as estimated glomerular filtration rate (eGFR) decline of ≥5 mL/min/1.73 m2 per year. Early-onset T2DM was defined as age at T2DM diagnosis between 18 and 30 years. RESULTS: Compared with later-onset counterparts (N = 1032), participants with early-onset T2DM (N = 157) were more obese and had poorer glycaemic control at baseline. In the follow-up, 24.2% and 15.6% experienced progressive CKD in early-onset and later-onset participants, respectively (P = 0.007). Logistic regression suggested that participants with early-onset T2DM had 2.63-fold [95% confidence interval (CI) 1.46-4.75] higher risk of progressive CKD after accounting for multiple traditional risk factors. Furthermore, the excess risk of progressive CKD associated with early-onset T2DM mainly occurred in participants with preserved renal function [eGFR ≥60 mL/min/1.73 m2, odds ratio (OR) 2.85, 95% CI 1.50-5.42] and was more pronounced in those with diabetes duration <10 years (OR 3.67, 95% CI 1.51-8.90). CONCLUSIONS: Individuals with early-onset T2DM have a higher risk of progressive CKD. The excess risk mainly exhibits in early stage of CKD and cannot be solely attributed to traditional risk factors and a longer diabetes duration.

Circulating ADAMs are associated with renal and cardiovascular outcomes in chronic kidney disease patients.

BACKGROUND: A disintegrin and metalloproteinase (ADAM) 17, also known as tumour necrosis factor α-converting enzyme (TACE), is a metalloproteinase that releases the ectodomains of most growth factors, cytokines, receptors and enzymes and has been associated with the presence of chronic kidney disease (CKD) and cardiovascular (CV) disease. The role of circulating ADAMs in the progression of renal function and CV events in CKD patients is unknown. METHODS: A total of 2570 subjects from an observational and multicentre study with CKD Stages 3-5, CKD Stage 5D and controls without any history of CV disease were studied. Circulating ADAM activity was assessed using a fluorometric technique. Progression of renal disease was defined as a 30% increase in serum creatinine or dialysis requirement after 24 months of follow-up. CV outcomes were assessed after 48 months of follow-up. RESULTS: Patients with advanced CKD had higher ADAM activity as compared with patients with moderate CKD or controls. Male patients with progression of CKD had higher ADAM levels at baseline compared with patients with stable renal function {22.19 relative fluorescence units/µL/h [95% confidence interval (CI) 11.22-37.32] versus 12.15 (7.02-21.50)}. After multivariate adjustment, higher ADAM activity was identified as a risk factor for progression of CKD in male patients [30% increase in the creatinine odds ratio (OR) 2.72 (95% CI 1.58-4.68), P < 0.001; dialysis requirement OR 3.00 (95% CI 1.65-5.46), P < 0.001; dialysis requirement or 30% increase in the creatinine OR 3.15 (95% CI 2.06-4.81), P < 0.001]. ADAM activity was also identified as an independent risk factor for CV events [hazard ratio (HR) 1.68 (95% CI 1.20-2.36), P = 0.003]. CONCLUSIONS: High ADAMs activity levels are independently associated with CKD progression in males and with CV events in CKD patients.

Increased Proteinuria is Associated with Increased Aortic Arch Calcification, Cardio-Thoracic Ratio, Rapid Renal Progression and Increased Overall and Cardiovascular Mortality in Chronic Kidney Disease.

Background: Patients with chronic kidney disease (CKD) are associated with high prevalence rates of proteinuria, vascular calcification and cardiomegaly. In this study, we investigated relationships among proteinuria, aortic arch calcification (AoAC) and cardio-thoracic ratio (CTR) in patients with CKD stage 3A-5. In addition, we investigated correlations among proteinuria and decline in renal function, overall and cardiovascular (CV) mortality. Methods: We enrolled 482 pre-dialysis patients with CKD stage 3A-5, and determined AoAC and CTR using chest radiography at enrollment. The patients were stratified into four groups according to quartiles of urine protein-to-creatinine ratio (UPCR). Results: The patients in quartile 4 had a lower estimated glomerular filtration rate (eGFR) slope, and higher prevalence rates of rapid renal progression, progression to commencement of dialysis, overall and CV mortality. Multivariable analysis showed that a high UPCR was associated with high AoAC (unstandardized coefficient ß: 0.315; p = 0.002), high CTR (unstandardized coefficient ß: 1.186; p = 0.028) and larger negative eGFR slope (unstandardized coefficient ß: -2.398; p < 0.001). With regards to clinical outcomes, a high UPCR was significantly correlated with progression to dialysis (log per 1 mg/g; hazard ratio [HR], 2.538; p = 0.003), increased overall mortality (log per 1 mg/g; HR, 2.292; p = 0.003) and increased CV mortality (log per 1 mg/g; HR, 3.195; p = 0.006). Conclusions: Assessing proteinuria may allow for the early identification of high-risk patients and initiate interventions to prevent vascular calcification, cardiomegaly, and poor clinical outcomes.

Associations of urological malignancies with renal progression and mortality in advanced chronic kidney disease: a propensity-matched cohort study.

BACKGROUND: Urological malignancy (UM) in patients with chronic kidney disease (CKD) is an added burden to their overall morbidity and mortality. UM is itself a common cause of CKD. Understanding the associations of UM with outcomes in advanced CKD can help in optimisation of the management of these patients. This study investigates the distribution and association of urological malignancy with outcomes (renal progression and mortality) in patients with advanced non-dialysis dependent CKD. METHODS: The study was conducted in 2637 of 3115 patients recruited in the Salford Kidney Study between the years 2002 and 2016. A comparative analysis was performed between 160 patients with UM (at baseline and incident) and 2477 patients with no malignancy. Cox-regression models and Kaplan-Meir estimates were used to explore the association between the presence of UM with mortality and renal outcome. Linear regression analysis was used to calculate the rate of progression of CKD in the groups. A 1:3 propensity score matched cohort of 640 patients was generated and utilised in the above analyses. RESULTS: 4.4% had a history of UM at baseline with the annual incident rate being 0.37%. The site of malignancy was the kidney in 40% with comparable numbers for prostatic malignancy (39%). 70% (111/160) of UM patients had a medical cause as their primary diagnosis for CKD. Over a median follow up of 4 years, 34% (905) patients died. In the matched sample, the proportion of deaths was similar between the groups (UM 44% versus no malignancy 48%, p = 0.36). 30% reached end-stage renal disease (ESRD) with no difference between the groups. In the Cox-regression model, UM did not prove to be a risk factor associated with either all-cause mortality (HR:1.03; CI: 0.79-1.35; p = 0.81) or reaching ESRD (HR:1.12; CI: 0.80-1.58; p = 0.49). The rate of decline in estimated glomerular filtration rate (eGFR) was similar between the groups (- 1.05 vs - 1.25 mL/min/1.73m2/year, p = 0.31). CONCLUSIONS: There was no correlation observed between UM and all-cause mortality or ESRD. Medical causes of CKD have a significant influence on the outcomes in patients with UM, whereas the UM did not. Hence, a coordinated approach with early liaison between the urology and nephrology teams is needed in the management of UM patients with CKD.

Dysmetabolic markers predict outcomes in autosomal dominant polycystic kidney disease.

BACKGROUND: Overweight and obesity were recently associated with a poor prognosis in patients with autosomal dominant polycystic kidney disease (ADPKD). Whether the metabolic consequences of obesity as defined by the metabolic syndrome (MS) are also linked with disease progression remains untested. METHODS: Eligible ADPKD patients with different stages of CKD (n = 105) and 105 non-diabetic controls matched for CKD stage were enrolled in the study. Groups were evaluated at baseline for presence of MS, blood markers of metabolism, homeostasis model assessment of insulin resistance (HOMA-IR) score, and biochemical markers of inflammation (hs-CRP, IL-1ß, IL-6, TNF-α and PON-1). MS was defined according to the National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATP III). Patients were followed for 12 months and progression defined as a decrease in baseline eGFR > 10%. RESULTS: MS and hypertension were more prevalent amongst ADPKD patients than in the control group. Meanwhile, markers of inflammation such as hs-CRP (3.63 [3.45-5.17] vs. 4.2 [3.45-8.99] mg/dL; p = 0.014), IL-6 (21.65 [14.1-27.49] vs. 24.9 [16.23-39.4] pg/mL; p = 0.004) and IL-1ß (21.33 [15.8-26.4] vs. 26.78 [18.22-35] pg/mL; p < 0.001) levels were all more elevated in ADPKD patients than in non-diabetic CKD subjects. In multivariate analysis having a truncating PKD1 mutation predicted (OR 1.25 [1.09-1.43]; p = 0.002) fulfilling the MS criteria. Finally, ADPKD patients fulfilling MS criteria had a significantly more rapid progression during 12 months of follow-up than did those that did not (OR 3.28 [1.09-9.87]; p = 0.035). CONCLUSIONS: Our data supports the notion that dysmetabolisms part of the ADPKD phenotype and associated with a poor outcome, especially in patients with a truncating PKD1 mutation.

Is immunoglobulin A nephropathy different in different ethnic populations?

Immunoglobulin A nephropathy (IgAN) is one of the commonest global patterns of primary glomerulonephritis and remains a leading cause of chronic kidney disease and end-stage renal disease. The sole diagnostic criterion of IgAN remains the presence of dominant mesangial immunoglobulin A deposits on kidney biopsy. Beyond this defining feature, there is significant heterogeneity in the epidemiology, clinical presentation, renal progression and long-term outcomes of IgAN in different ethnic populations. Mirroring this heterogeneity in clinical phenotypes, there is also marked ethnic variation in the extent of histopathological lesions observed on kidney biopsy, which may partly explain the well-documented differences in response to immunomodulatory agents reported in different regions of the world. In parallel, disparities have been identified in genetic association studies and key pathogenic pathways in different ethnic populations. Understanding the basis for these differences in IgAN has important implications for both clinical care and future research. In this review, we will examine the impact of ethnicity on the epidemiology, clinical presentation and outcomes, pathogenesis and genetic associations in IgAN.

A model to predict disease progression in patients with autosomal dominant polycystic kidney disease (ADPKD): the ADPKD Outcomes Model.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the leading inheritable cause of end-stage renal disease (ESRD); however, the natural course of disease progression is heterogeneous between patients. This study aimed to develop a natural history model of ADPKD that predicted progression rates and long-term outcomes in patients with differing baseline characteristics. METHODS: The ADPKD Outcomes Model (ADPKD-OM) was developed using available patient-level data from the placebo arm of the Tolvaptan Efficacy and Safety in Management of ADPKD and its Outcomes Study (TEMPO 3:4; ClinicalTrials.gov identifier NCT00428948). Multivariable regression equations estimating annual rates of ADPKD progression, in terms of total kidney volume (TKV) and estimated glomerular filtration rate, formed the basis of the lifetime patient-level simulation model. Outputs of the ADPKD-OM were compared against external data sources to validate model accuracy and generalisability to other ADPKD patient populations, then used to predict long-term outcomes in a cohort matched to the overall TEMPO 3:4 study population. RESULTS: A cohort with baseline patient characteristics consistent with TEMPO 3:4 was predicted to reach ESRD at a mean age of 52 years. Most patients (85%) were predicted to reach ESRD by the age of 65 years, with many progressing to ESRD earlier in life (18, 36 and 56% by the age of 45, 50 and 55 years, respectively). Consistent with previous research and clinical opinion, analyses supported the selection of baseline TKV as a prognostic factor for ADPKD progression, and demonstrated its value as a strong predictor of future ESRD risk. Validation exercises and illustrative analyses confirmed the ability of the ADPKD-OM to accurately predict disease progression towards ESRD across a range of clinically-relevant patient profiles. CONCLUSIONS: The ADPKD-OM represents a robust tool to predict natural disease progression and long-term outcomes in ADPKD patients, based on readily available and/or measurable clinical characteristics. In conjunction with clinical judgement, it has the potential to support decision-making in research and clinical practice.

Membranous Nephropathy: Quantifying Remission Duration on Outcome.

Although change in proteinuria has been proposed as a surrogate for long-term prognosis in membranous nephropathy (MGN), variability in proteinuria levels and lag between these changes and acceptable end points, such as ESRD, has limited its utility. This cohort study examined the prognostic significance of remission duration in 376 patients with biopsy-proven idiopathic/primary MGN who achieved a remission after a period of nephrotic-range proteinuria. We defined complete remission (CR), partial remission (PR), and relapse as proteinuria ≤0.3, 0.4-3.4, and ≥3.5 g/d after CR or PR, respectively. The exposure variable was the remission status of patients at fixed landmarks (3, 6, 12, 24, and 36 months) after the date of first remission. The primary outcome was ESRD or 50% reduction in eGFR. We fitted Cox proportional hazards models to examine the association of remission status at each landmark and the primary end point. Persistent remission associated with unadjusted hazard ratios for the primary outcome that ranged by landmark from 0.35 (95% confidence interval, 0.20 to 0.61) to 0.56 (95% confidence interval, 0.31 to 1.04). Separate analyses for PR and CR yielded similar results. After adjustment, maintaining remission associated with significantly reduced risk of the primary outcome at all landmarks. Durable remissions associated with improved renal survival. Although the longer the remission, the greater the improvement, patients with remission durations as short as 3 months had improved renal prognosis compared with patients who relapsed. This study validates and quantifies PR and CR as surrogates for long-term outcome in MGN.

Effect of Strict Volume Control on Renal Progression and Mortality in Non-Dialysis-Dependent Chronic Kidney Disease Patients: A Prospective Interventional Study.

OBJECTIVE: The aim of this study was to examine the effect of volume status on the progressions of renal disease in normovolemic and hypervolemic patients with advanced non-dialysis-dependent chronic kidney disease (CKD) who were apparently normovolemic in conventional physical exam-ination. MATERIALS AND METHODS: This was a prospective interventional study performed in a group of stage 3-5 CKD patients followed up for 1 year. Three measurements were made for volume and renal status for every patient. The fluid status was assessed by a bioimpedance spectroscopy method. A blood pressure (BP) value > 130/80 mm Hg prompted the initiation or dose increment of diuretic treatment in normovolemic patients. RESULT: Forty-eight patients (48%) were hypervolemic. At the end of the 1-year follow-up, hypervolemic patients were found to have a significantly lower estimated glomerular filtration rate and higher systolic BP compared to baseline. Hypervolemia was associated with an increased incidence of death. CONCLUSION: We have shown that maintenance of normovolemia with diuretic therapy in normovolemic patients was able to slow down and even improve the progression of renal disease. Volume overload leads to an increased risk for dialysis initiation and a decrease in renal function in advanced CKD. Volume overload exhibits a stronger association with mortality in CKD patients.

Regression of Renal Disease by Angiotensin II Antagonism Is Caused by Regeneration of Kidney Vasculature.

Chronic renal insufficiency inexorably progresses in patients, such as it does after partial renal ablation in rats. However, the progression of renal diseases can be delayed by angiotensin II blockers that stabilize renal function or increase GFR, even in advanced phases of the disease. Regression of glomerulosclerosis can be induced by angiotensin II antagonism, but the effect of these treatments on the entire vascular tree is unclear. Here, using microcomputed tomography and scanning electron microscopy, we compared the size and extension of kidney blood vessels in untreated Wistar rats with those in untreated and angiotensin II antagonist-treated Munich Wistar Frömter (MWF) rats that spontaneously develop kidney disease with age. The kidney vasculature underwent progressive rarefaction in untreated MWF rats, substantially affecting intermediate and small vessels. Microarray analysis showed increased Tgf-ß and endothelin-1 gene expression with age. Notably, 10-week inhibition of the renin-angiotensin system regenerated kidney vasculature and normalized Tgf-ß and endothelin-1 gene expression in aged MWF rats. These changes were associated with reduced apoptosis, increased endothelial cell proliferation, and restoration of Nrf2 expression, suggesting mechanisms by which angiotensin II antagonism mediates regeneration of capillary segments. These results have important implications in the clinical setting of chronic renal insufficiency.

Podocyte p53 Limits the Severity of Experimental Alport Syndrome.

Alport syndrome (AS) is one of the most common types of inherited nephritis caused by mutation in one of the glomerular basement membrane components. AS is characterized by proteinuria at early stage of the disease and glomerular hyperplastic phenotype and renal fibrosis at late stage. Here, we show that global deficiency of tumor suppressor p53 significantly accelerated AS progression in X-linked AS mice and decreased the lifespan of these mice. p53 protein expression was detected in 21-week-old wild-type mice but not in age-matched AS mice. Expression of proinflammatory cytokines and profibrotic genes was higher in p53(+/-) AS mice than in p53(+/+) AS mice. In vitro experiments revealed that p53 modulates podocyte migration and positively regulates the expression of podocyte-specific genes. We established podocyte-specific p53 (pod-p53)-deficient AS mice, and determined that pod-p53 deficiency enhanced the AS-induced renal dysfunction, foot process effacement, and alteration of gene-expression pattern in glomeruli. These results reveal a protective role of p53 in the progression of AS and in maintaining glomerular homeostasis by modulating the hyperplastic phenotype of podocytes in AS.

Proton Pump Inhibitors and Risk of Incident CKD and Progression to ESRD.

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 (H2 blockers; 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 H2 blockers group, had an increased risk of incident eGFR<60 ml/min per 1.73 m2 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 H2 blockers 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.