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Background and Objectives: Coronavirus disease 2019 is spreading rapidly across the world. This study aimed to assess the characteristics of kidney injury and its association with disease progression and death of patients with coronavirus disease 2019., Design, Setting, Participants, & Measurements: This is a retrospective study. Two representative cohorts were included. Cohort 1 involved severe and critical patients with coronavirus disease 2019 from Wuhan, China. Cohort 2 was all patients with coronavirus disease 2019 in Shenzhen city (Guangdong province, China). Any kidney injury was defined as the presence of any of the following: hematuria, proteinuria, in-hospital AKI, or prehospital AKI. AKI was defined according to the Kidney Disease Improving Global Outcomes (KDIGO) creatinine criteria. The primary outcome was death at the end of follow-up. The secondary outcome was progression to critical illness during the study period., Results: A total of 555 patients were enrolled; 42% of the cases (229 of 549) were detected with any kidney injury, 33% of the cases (174 of 520) were detected with proteinuria, 22% of the cases (112 of 520) were detected with hematuria, and 6% of the cases (29 of 520) were detected with AKI. Of the 29 patients with AKI, 21 cases were recognized as in-hospital AKI, and eight were recognized as prehospital AKI. Altogether, 27 (5%) patients died at the end of follow-up. The death rate was 11% (20 of 174) in patients with proteinuria, 16% (18 of 112) in patients with hematuria, and 41% (12 of 29) in the AKI settings. Multivariable Cox regression analysis showed that proteinuria (hazard ratio, 4.42; 95% confidence interval, 1.22 to 15.94), hematuria (hazard ratio, 4.71; 95% confidence interval, 1.61 to 13.81), and in-hospital AKI (hazard ratio, 6.84; 95% confidence interval, 2.42 to 19.31) were associated with death. Among the 520 patients with noncritical illness at admission, proteinuria (hazard ratio, 2.61; 95% confidence interval, 1.22 to 5.56) and hematuria (hazard ratio, 2.50; 95% confidence interval, 1.23 to 5.08) were found to be associated with progression to critical illness during the study period., Conclusions: Kidney injury is common in coronavirus disease 2019, and it is associated with poor clinical outcomes., Podcast: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2020_09_18_CJN04780420.mp3., (Copyright © 2020 by the American Society of Nephrology.)

IgA nephropathy (IgAN) is an important cause of ESKD for which there are no approved therapies. A challenge for evaluating treatments for IgAN is the usual long time course for progression to ESKD. The aim of this Kidney Health Initiative project was to identify surrogate end points that could serve as reliable predictors of a treatment's effect on long-term kidney outcomes in IgAN and be used as a basis for approval. Proteinuria was identified as the most widely recognized and well studied risk factor for progression to ESKD in IgAN. The workgroup performed a critical review of the data on proteinuria reduction as a surrogate end point for a treatment's effect on progression to ESKD in IgAN. Epidemiologic data indicate a strong and consistent relationship between the level and duration of proteinuria and loss of kidney function. Trial-level analyses of data from 13 controlled trials also show an association between treatment effects on percent reduction of proteinuria and treatment effects on a composite of time to doubling of serum creatinine, ESKD, or death. We conclude that data support the use of proteinuria reduction as a reasonably likely surrogate end point for a treatment's effect on progression to ESKD in IgAN. In the United States, reasonably likely surrogate end points can be used as a basis for accelerated approval of therapies intended to treat serious or life-threatening conditions, such as IgAN. The clinical benefit of products approved under this program would need to be verified in a postmarketing confirmatory trial., (Copyright © 2019 by the American Society of Nephrology.)

Background and Objectives: Proteinuric diabetic kidney disease frequently progresses to ESRD. Control of BP delays progression, but the optimal BP to improve outcomes remains unclear. The objective of this analysis was to evaluate the relationship between BP and renal outcomes in proteinuric diabetic kidney disease., Design, Setting, Participants, & Measurements: BP data from all 1448 randomized participants in the Veterans Affairs Nephropathy in Diabetes Trial were included in a post hoc analysis. The associations of mean on-treatment BP with the primary end point (decline in eGFR, ESRD, or death), renal end point (decline in eGFR or ESRD), rate of eGFR decline, and mortality were measured., Results: The median (25th, 75th percentile) follow-up time was 2.2 (1.2, 3.0) years. There were 284 primary end points. In univariate analyses, both mean systolic and mean diastolic BPs were strongly associated (P<0.001) with the primary end point. After multivariate adjustment, the hazard of developing the primary end point became progressively higher as mean systolic BP rose from <120 to ≥ 150 mmHg (P=0.02), with a significantly higher hazard ratio for 140-149 versus 120-129 mmHg (1.51 [1.06, 2.15]; P=0.02). There was also a significant association of mean diastolic BP with the hazard of developing the primary end point (P<0.01), with a significantly higher hazard ratio when mean diastolic BP was 80-89 versus 70-79 mmHg (1.54 [1.05, 2.25]; P=0.03); there was also a strong trend when mean diastolic BP was <60 mmHg. Associations between BP and both renal end point and rate of eGFR decline were similar to those with the primary end point. No association of BP with mortality was observed, possibly because of the limited number of mortality events., Conclusions: In patients with proteinuric diabetic kidney disease, mean systolic BP ≥ 140 mmHg and mean diastolic BP ≥ 80 mmHg were associated with worse renal outcomes., (Copyright © 2015 by the American Society of Nephrology.)

Background and Objectives: Malnutrition and/or inflammation may modify the risk relationship of total cholesterol with cardiovascular disease in CKD patients. However, it is unclear whether the relationship of total cholesterol with cardiovascular events and mortality varies by proteinuria., Design, Setting, Participants, & Measurements: This study enrolled 3303 patients with CKD stages 3-5 from a medical center and a regional hospital between November of 2002 and May of 2009 and followed the patients until July of 2010., Results: During a median 2.8-year follow-up, there were 471 (14.3%) deaths and 545 (16.5%) cardiovascular events. In an adjusted Cox model, the two highest quartiles of total cholesterol (hazard ratio, 1.90; 95% confidence interval, 1.16 to 3.13 and hazard ratio, 2.00; 95% confidence interval, 1.18 to 3.39 versus quartile 1, respectively) were associated with a significant higher risk of all-cause mortality in patients with urine protein-to-creatinine ratio<1 g/g (n=1535), but this higher risk was not seen in those patients with urine protein-to-creatinine ratio ≥ 1 g/g (n=1768; hazard ratio, 0.75; 95% confidence interval, 0.53 to 1.07 and hazard ratio, 0.70; 95% confidence interval, 0.49 to 1.02 versus quartile 1, respectively). The interaction between total cholesterol and proteinuria with all-cause mortality was significant (interaction, P=0.05). However, the relationship between total cholesterol and cardiovascular events did not significantly differ by proteinuria (interaction, P=0.91)., Conclusions: The association between cholesterol and mortality is different among patients with different levels of proteinuria. Large-scale clinical trials to evaluate the mortality benefit should specifically target lowering hypercholesterolemia in CKD patients with different levels of proteinuria.

Background and Objectives: The African American Study of Kidney Disease Trial identified risk factors for CKD progression and suggested that GFR level may modify the association between these risk factors and CKD progression or death., Design, Setting, Participants, & Measurements: Enrollment in the African American Study of Kidney Disease Trial occurred between June of 1995 and September of 2001, with median follow-up of 48.6 months. Among 1094 patients with hypertensive kidney disease in the trial, this study tested whether the association between six previously identified risk factors for CKD progression (or death) and a composite clinical outcome (progression of CKD, ESRD, or death) depends on level of GFR. Multivariate Cox regression was used to control for other baseline risk factors., Results: After controlling for baseline risk factors, only proteinuria was more closely associated with the composite clinical outcome at lower levels of GFR (P value for interaction term=0.002); increased hazards of the clinical composite outcome associated with a doubling of proteinuria ranged from 30% (95% confidence interval=21%-39%) with a GFR of 50 to 55% (95% confidence interval=40%-72%) with a GFR of 25., Conclusions: The magnitude of the association between proteinuria and CKD progression, ESRD, or death in the African American Study of Kidney Disease Trial cohort depends on the level of GFR; proteinuria is a stronger independent predictor of the composite clinical outcome at lower levels of GFR. This finding reinforces that African Americans with proteinuria and lower GFR represent a population at particularly high risk for adverse outcomes.

Background and Objectives: Relatively little is known about the long-term outcomes of different histologic types of primary glomerulonephritis in Asian populations., Design, Setting, Participants, & Measurements: From 1993 to 2006, 987 patients undergoing renal biopsy were studied, and 580 patients (mean age=44.4 years, male=58.5%) with the four most common forms of glomerulonephritis (membranous nephropathy, focal and segmental glomerulosclerosis, IgA nephropathy, and minimal change disease) were selected for analysis. Median follow-up period was 5.9 (interquartile range=5.7) years., Results: The focal and segmental glomerulosclerosis group displayed the highest incidence of ESRD (25.8%) and the fastest decline of estimated GFR (4.6 ml/min per 1.73 m(2) per year). The IgA nephropathy group also had a higher rate of ESRD than the membranous nephropathy patients (19.2% versus 4.3%, P<0.001). In contrast, the membranous nephropathy group exhibited an overall death rate similar to the focal and segmental glomerulosclerosis group (17.2% versus 14.4%) but higher than the IgA nephropathy and minimal change disease patients (4.6% and 3.7%, respectively, P<0.001). The most powerful predictor for ESRD was focal and segmental glomerulosclerosis, whereas the strongest predictor for all-cause mortality was membranous nephropathy with higher proteinuria. Protectors against ESRD included male sex and higher hemoglobin., Conclusions: Most predictors for ESRD and overall mortality found in this ethnic Chinese cohort were similar to other studies. However, some risk factors linked with distinct glomerular pathologies displayed differential clinical outcomes.

Background: Accurate prediction of prognosis in idiopathic membranous nephropathy (iMN) allows restriction of immunosuppressive therapy to patients at high risk for ESRD. Here we re-evaluate urinary low-molecular-weight proteins as prognostic markers and explore causes of misclassification., Design, Setting, Participants, & Measurements: In a cohort of 129 patients with serum creatinine concentration <135 μmol/L and proteinuria ≥3.0 g/10 mmol, urinary α1- (uα1m) and β2-microglobulin (uβ2m) excretion rate was determined. Urinary α1m and uβ2m-creatinine ratio was also obtained. We defined progression as a rise in serum creatinine ≥50% or ≥25% and an absolute level ≥135 μmol/L., Results: Median survival time was 25 months, and 47% of patients showed progression. The area under the receiver operating characteristic curve for uβ2m was 0.81 (95% CI: 0.73 to 0.89). Using a threshold value of 1.0 μg/min, sensitivity and specificity were 73% and 75%, respectively. Similar accuracy was observed for the uβ2m-creatinine ratio with sensitivity and specificity of 75% and 73%, respectively, at a threshold of 1.0 μg/10 mmol creatinine. Similar accuracy was found for uα1m and uα1m-creatinine ratio. Blood Pressure and cholesterol contributed to misclassification. Repeated measurements improved accuracy in patients with persistent proteinuria: the positive predictive value of uβ2m increased from 72% to 89% and the negative predictive value from 76% to 100%., Conclusions: Urinary excretion of uα2m and uβ2m predict prognosis in iMN. A spot urine sample can be used instead of a timed sample. A repeated measurement after 6 to 12 months increases prognostic accuracy.

Background and Objectives: Vascular calcification is common and severe in chronic kidney disease. Because the consequences of calcification may differ by vascular beds, we sought to test the hypothesis that patients who have diabetes with proteinuria and have significant renal artery calcification (RAC) have a higher risk for progression to ESRD., Design, Setting, Participants, & Measurements: Using electron-beam computed tomography, RAC was computed as the sum of Agatston scores at each of the two renal ostia and renal arteries. Time-to-event analysis was conducted to compare the risk in individuals with or without significant RAC (total score >10)., Results: Of 172 patients with type 2 diabetes and overt proteinuria studied (estimated GFR 56 ± 25 ml/min per 1.73 m(2)), significant RAC was present in 31%. In 33 ± 21 months, 41 progressed to ESRD and 65 reached a composite outcome (ESRD or death). Serum phosphorus was a significant predictor of progression to ESRD but was replaced by the significant RAC in multivariate models that included the latter. Individuals with significant RAC had a higher risk for reaching the composite outcome. In contrast, there was no association between coronary artery calcification scores and progression to ESRD., Conclusions: Significant RAC was an independent predictor of progression to ESRD as well as reaching the composite outcome. Understanding the pathogenesis of RAC would allow determination of whether this risk is potentially modifiable.

Background and Objectives: Increasing living kidney donation mandates ongoing assessment of living donors for future health risks and revision of national health policy., Design, Setting, Participants, & Measurements: Living kidney donors as reported to the Organ Procurement and Transplant Network database from January 1988 through December 2008 were reviewed for minor medical abnormalities, presence of donor health care coverage, and occurrence of surgical complications and death., Results: At donation in 2008, 19.5% were obese, 2.0% had a history of hypertension, and 3.5% had proteinuria. The median estimated GFR of living donors was 92.2 ml/min. Additionally, 12.2% of donors were reported not to have health insurance at the time of donation. By racial background, 14.9% of black and 17.0% of Hispanic donors did not have insurance at donation. Perioperative complications included blood transfusion (0.4%), reoperation (0.5%), and vascular complications (0.2%). Death occurred within 30 days of donation in 0.03% donating between October 1999 and December 2008. During those same years, overall donor death was 2.8%., Conclusions: Almost one quarter of living donors have medical conditions that may be associated with future health risk. Close follow-up and a registry of these donors are necessary. Only then will we be able to inform prospective living donors most accurately of the real risk of donation on their health and survival. Additionally, these data speak to the need for a national discussion on the provision of health insurance for living donors.

Background and Objectives: Population-based studies have reported outcomes and risk factors for patients with chronic kidney disease (CKD), defined primarily by decreased estimated GFR (eGFR). They are characterized by old age, low proteinuria level, and stage 3 CKD. However, many patients referred to nephrologists are younger and have overt proteinuria and advanced CKD. This study evaluated the association between outcomes and those factors among referred CKD patients., Design, Setting, Participants, & Measurements: We retrospectively reviewed 461 referred patients with stage 3 to 5 CKD from January 2003 to December 2007. Key outcomes were death and ESRD. Patients were followed from the time of first serum creatinine measurement to December 2009., Results: The median age of subjects was 67.0 years, and median follow-up was 3.2 years. Overt proteinuria was present in 57.0% of subjects. For stage 3, 4, and 5 CKD, cumulative mortality and probability of ESRD at 3 years was 9.5 and 6.5%, 11.2 and 27.8%, and 16.5 and 79.1%, respectively. Using proportional-hazards regression models, age was a determinant for death, whereas overt proteinuria was strongly associated with ESRD. Among stage 3 CKD patients older than 65 years without overt proteinuria, the incidence of death before renal replacement therapy (RRT) was 2.8/100 patient-years and none had ESRD. In patients with advanced CKD and overt proteinuria, the incidence of ESRD was substantially higher than that of death before RRT., Conclusions: Stratification by age, proteinuria level, and CKD stage could predict the competing outcomes of death before RRT and ESRD among CKD patients.

Background and Objectives: Acute kidney injury (AKI) is associated with adverse outcomes in critically ill patients. The influence of preexisting chronic kidney disease (CKD) on AKI outcomes is unclear., Design, Setting, Participants, & Measurements: We analyzed data from a prospective observational cohort study of AKI in critically ill patients who received nephrology consultation: the Program to Improve Care in Acute Renal Disease. In-hospital mortality rate, length of stay, and dialysis dependence were compared in patients with and without a prior history of CKD, defined by an elevated serum creatinine, proteinuria, and/or abnormal renal ultrasound within a year before hospitalization. We hypothesized that patients with AKI and prior history of CKD would have lower mortality rates, shorter lengths of stay, and higher rates of dialysis dependence than patients without prior history of CKD., Results: Patients with AKI and a prior history of CKD were older and underwent nephrology consultation earlier in the course of AKI. In-hospital mortality rate was lower (31 versus 40%, P = 0.04), and median intensive care unit length of stay was 4.6 d shorter (14.7 versus 19.3 d, P = 0.001) in patients with a prior history of CKD. Among dialyzed survivors, patients with prior CKD were also more likely to be dialysis dependent at hospital discharge. Differences in outcome were most evident in patients with lower severity of illness., Conclusions: Among critically ill patients with AKI, those with prior CKD experience a lower mortality rate but are more likely to be dialysis dependent at hospital discharge. Future studies should determine optimal strategies for managing AKI with and without a prior history of CKD.

Background and Objectives: Although early studies suggest that patients with idiopathic membranous nephropathy (MGN) and subnephrotic range proteinuria overall do well, these studies were small and follow-up was short or difficult to discern., Design, Setting, Participants, & Measurements: Three hundred ninety-five cases of idiopathic MGN with at least 12 mo of follow-up from the Toronto Glomerulonephritis Registry were reviewed to determine the outcome of the subgroup of patients that presented with subnephrotic range proteinuria. Onset and follow-up data included mean arterial pressure (MAP) and creatinine clearance (CrCl) as determined by the Cockcroft-Gault equation. Outcome variables included the rate of progression (slope of CrCl), 50% reduction in initial CrCl, and end-stage renal disease (ESRD)., Results: One hundred eight (27% of the total) patients presented with subnephrotic proteinuria and almost 40% (42 of 108) of this subgroup remained subnephrotic. Their long-term slope was -0.93 ml/min/yr. In contrast, those who subsequently developed nephrotic range proteinuria had a progression rate almost four times faster (-3.52 ml/min/yr). The majority who developed nephrotic syndrome did so within the first year of follow-up. The only distinguishing baseline feature between the two groups was a higher level of urine protein in the group that subsequently developed nephrotic syndrome (1.98 [0.3 to 3.4] versus 2.43 [0.5 to 3.4] g/d)., Conclusions: Patients with MGN and sustained subnephrotic range proteinuria have an excellent prognosis. Conservative management with close monitoring is recommended given the difficulty predicting which patients will develop nephrotic range proteinuria and then progress more rapidly.

Both angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) can slow the progression of diabetic nephropathy. Even with ACEI or ARB treatment, the proportion of patients who progress to end-stage renal disease (ESRD) remains high. Interventions that achieve more complete blockade of the renin-angiotensin system, such as combination ACEI and ARB, might be beneficial. This approach may decrease progression of nondiabetic kidney disease. In diabetic nephropathy, combination therapy decreases proteinuria, but its effect in slowing progression is unknown. In addition, the potential for hyperkalemia may limit the utility of combined therapy in this population. VA NEPHRON-D is a randomized, double-blind, multicenter clinical trial to assess the effect of combination losartan and lisinopril, compared with losartan alone, on the progression of kidney disease in 1850 patients with diabetes and overt proteinuria. The primary endpoints are time to (1) reduction in estimated GFR (eGFR) of > 50% (if baseline < 60 ml/min/1.73 m(2)); (2) reduction in eGFR of 30 ml/min/1.73 m(2) (if baseline > or = 60 ml/min/1.73 m(2)); (3) progression to ESRD (need for dialysis, renal transplant, or eGFR < 15 ml/min/1.73 m(2)); or (4) death. The secondary endpoint is time to change in eGFR or ESRD. Tertiary endpoints are cardiovascular events, slope of change in eGFR, and change in albuminuria at 1 yr. Specific safety endpoints are serious hyperkalemia (potassium > 6 mEq/L, requiring admission, emergency room visit, or dialysis), all-cause mortality, and other serious adverse events. This paper discusses the design and key methodological issues that arose during the planning of the study.

Background and Objectives: Dense deposit disease (DDD) is a rare disorder that most commonly affects children. This study reports the largest North American series addressing clinicopathologic and outcome differences in children and adults., Design, Setting, Participants, & Measurements: Thirty-two patients with DDD were analyzed from the archives of Columbia University between 1977 and 2007. Characteristic intramembranous electron-dense deposits defined all diagnoses., Results: The cohort included 14 children (<16 yr) and 18 adults, with 39% of adults >60 yr. The female/male ratio was 1.9. At presentation, the mean 24-h urine protein was 4.6 g, nephrotic syndrome was present in 33%, renal insufficiency in 59%, and hematuria in 87% of patients. Compared with adults, children had lower incidence of renal insufficiency and were more likely to have reduced C3. Histologic pattern included membranoproliferative, mesangial, endocapillary, and crescentic glomerulonephritis. Treatment included immunosuppression (IS) alone in seven, renin angiotensin system (RAS) blockade alone in six, and combined IS/RAS blockade in 11. On follow-up (mean 63 mo) available in 27 patients, 26% had complete response, 48% had persistent renal dysfunction, and 26% had ESRD. Correlates of ESRD were older age and higher creatinine at biopsy, the absence of combined IS/RAS blockade therapy and the presence of subepithelial humps, but not histologic pattern. On multivariate analysis, age and creatinine emerged as the only independent predictors of ESRD., Conclusions: DDD is clinically and pathologically heterogeneous. Adults have worse outcome than children, despite similar treatment. Combined IS/RAS blockade appears superior to either agent alone.