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Rationale & Objective Remission of proteinuria has been shown to be associated with lower rates of kidney disease progression among people with focal segmental glomerulosclerosis (FSGS). The goal of this study was to evaluate whether reductions in proteinuria after treatment are associated with greater kidney survival. Study Design Cohort analysis of clinical trial participants. Setting & Participants Patients with steroid-resistant FSGS enrolled in a randomized treatment trial that compared cyclosporine with mycophenolate mofetil plus dexamethasone. Predictors Reduction in proteinuria measured during 26 weeks after initiating treatment. Outcomes Repeated assessments of estimated glomerular filtration rate (eGFR) and time to a composite outcome of kidney failure or death assessed between 26 weeks and 54 months after randomization. Analytical Approach Multivariable linear mixed-effects models with participant-specific slope and intercept to estimate the association of change in proteinuria over 26 weeks while receiving treatment with the subsequent slope of change in eGFR. Multivariable time-varying Cox proportional hazards models were used to estimate the association of changes in proteinuria with time to the composite outcome. Results 138 of 192 trial participants were included. Changes in proteinuria over 26 weeks were significantly related to eGFR slope. A 1-unit reduction in log-transformed urinary protein-creatinine ratio was associated with a 3.90 mL/min/1.73 m2 per year increase in eGFR (95% CI, 2.01-5.79). This difference remained significant after adjusting for complete remission. There was an analogous relationship between time-varying proteinuria and time to the composite outcome: the HR per 1-unit reduction in log-transformed urinary protein-creatinine ratio was 0.23 (95% CI, 0.12-0.44). Limitations Limited to individuals with steroid-resistant FSGS followed up for a maximum of 5 years. Conclusions These findings provide evidence for the benefit of urinary protein reduction in FSGS. Reductions in proteinuria warrant further evaluation as a potential surrogate for preservation of kidney function that may inform the design of future clinical trials.

Rationale & Objective Evaluating repeated measures of estimated glomerular filtration rate (eGFR) and urinary protein-creatinine ratio (UPCR) over time may enhance our ability to understand the association between changes in kidney parameters and cardiovascular disease risk. Study Design Prospective cohort study. Setting & Participants Annual visit data from 2,438 participants in the Chronic Renal Insufficiency Cohort (CRIC). Exposures Average and slope of eGFR and UPCR in time-updated, 1-year exposure windows. Outcomes Incident heart failure, atherosclerotic cardiovascular disease events, death, and a composite of incident heart failure, atherosclerotic cardiovascular disease events, and death. Analytical Approach A landmark analysis, a dynamic approach to survival modeling that leverages longitudinal, iterative profiles of laboratory and clinical information to assess the time-updated 3-year risk of adverse cardiovascular outcomes. Results Adjusting for baseline and time-updated covariates, every standard deviation lower mean eGFR (19 mL/min/1.73 m2) and declining slope of eGFR (8 mL/min/1.73 m2 per year) were independently associated with higher risks of heart failure (hazard ratios [HRs] of 1.82 [95% CI, 1.39-2.44] and 1.28 [95% CI, 1.12-1.45], respectively) and the composite outcome (HRs of 1.32 [95% CI, 1.11-1.54] and 1.11 [95% CI, 1.03-1.20], respectively). Every standard deviation higher mean UPCR (136 mg/g) and increasing UPCR (240 mg/g per year) were also independently associated with higher risks of heart failure (HRs of 1.58 [95% CI, 1.28-1.97] and 1.20 [95% CI, 1.10-1.29], respectively) and the composite outcome (HRs of 1.33 [95% CI, 1.17-1.50] and 1.12 [95% CI, 1.06-1.18], respectively). Limitations Limited generalizability of annual eGFR and UPCR assessments; several biomarkers for cardiovascular disease risk were not available annually. Conclusions Using the landmark approach to account for time-updated patterns of kidney function, average and slope of eGFR and proteinuria were independently associated with 3-year cardiovascular risk. Short-term changes in kidney function provide information about cardiovascular risk incremental to level of kidney function, representing possible opportunities for more effective management of patients with chronic kidney disease.

Rationale & Objective Immune activation is fundamental to the pathogenesis of many kidney diseases. Innate immune molecules such as soluble urokinase-type plasminogen activator receptor (suPAR) have been linked to the incidence and progression of chronic kidney disease (CKD). Whether other biomarkers of immune activation are associated with incident kidney failure with replacement therapy (KFRT) in African Americans with nondiabetic kidney disease is unclear. Study Design Prospective cohort. Setting & Participants African American Study of Kidney Disease and Hypertension (AASK) participants with available baseline serum samples for biomarker measurement. Predictors Baseline serum levels of soluble tumor necrosis factor receptor 1 (sTNFR1), sTNFR2, tumor necrosis factor α (TNF-α), and interferon γ (IFN-γ). Outcomes Incident KFRT, all-cause mortality. Analytical Approach Cox proportional hazards models. Results Among 500 participants with available samples, mean glomerular filtration rate was 44.7 mL/min/1.73 m2, and median urinary protein-creatinine ratio was 0.09 g/g at baseline. Over a median follow up of 9.6 years, there were 161 (32%) KFRT and 113 (23%) death events. In models adjusted for demographic and clinical factors and baseline kidney function, each 2-fold higher baseline level of sTNFR1, sTNFR2, and TNF-α was associated with 3.66-fold (95% CI, 2.31-5.80), 2.29-fold (95% CI, 1.60-3.29), and 1.35-fold (95% CI, 1.07-1.71) greater risks of KFRT, respectively; in comparison, each doubling of baseline suPAR concentration was associated with 1.39-fold (95% CI, 1.04-1.86) greater risk of KFRT. sTNFR1, sTNFR2, and TNF-α were also significantly associated with death (up to 2.2-fold higher risks per 2-fold higher baseline levels; P ≤ 0.01). IFN-γ was not associated with either outcome. None of the biomarkers modified the association of APOL1 high-risk status (genetic risk factors for kidney disease among individuals of African ancestry) with KFRT (P > 0.05 for interaction). Limitations Limited generalizability to other ethnic groups or causes of CKD. Conclusions Among African Americans with CKD attributed to hypertension, baseline levels of sTNFR1, sTNFR2, and TNF-α but not IFN-γ were associated with KFRT and mortality.

RATIONALE & OBJECTIVE: Screening for chronic kidney disease (CKD) is recommended for patients with diabetes and hypertension as stated by the respective professional societies. However, CKD, a silent disease usually detected at later stages, is associated with low socioeconomic status (SES). We assessed whether adding census tract SES status to the standard screening approach improves our ability to identify patients with CKD. STUDY DESIGN: Screening test analysis. SETTINGS & PARTICIPANTS: Electronic health records (EHR) of 256,162 patients seen at a health care system in the 7-county Minneapolis/St. Paul area and linked census tract data. EXPOSURE: The first quartile of census tract SES (median value of owner-occupied housing units 25 years of age with a bachelor’s degree or higher 30 mg/g, or urinary protein-creatinine ratio >150 mg/g, or urinary analysis [albuminuria] >30 mg/d). ANALYTICAL APPROACH: Sensitivity, specificity, and number needed to screen (NNS) to detect CKD if we screened patients who had hypertension and/or diabetes and/or who lived in low-SES tracts (belonging to the first quartile of any of the 3 measures of tract SES) versus the standard approach. RESULTS: CKD was prevalent in 13% of our cohort. Sensitivity, specificity, and NNS of detecting CKD after adding tract SES to the screening approach were 67% (95% CI, 66.2%−67.2%), 61% (95% CI, 61.1%−61.5%), and 5, respectively. With the standard approach, sensitivity of detecting CKD was 60% (95% CI, 59.4%−60.4%), specificity was 73% (95% CI, 72.4%−72.7%), and NNS was 4. LIMITATIONS: One health care system and selection bias. CONCLUSIONS: Leveraging patients’ addresses from the EHR and adding tract-level SES to the standard screening approach modestly increases the sensitivity of detecting patients with CKD at a cost of decreased specificity. Identifying further factors that improve CKD detection at an early stage are needed to slow the progression of CKD and prevent cardiovascular complications.

Background Vitamin D has key roles in regulating systems that could be important in the pathobiological state of proteinuria. Because of this, it could be helpful in treating patients with proteinuric renal diseases. The objective is to determine the effect of oral paricalcitol on protein excretion in patients with proteinuric chronic kidney disease. Study Design Double-blind randomized study. Setting & Participants 61 patients with estimated glomerular filtration rate of 15 to 90 mL/min/1.73 m 2 and protein excretion greater than 400 mg/24 h. Intervention Randomization to 6 months of treatment with paricalcitol, 1 μg/d, or placebo. Outcomes & Measurements The predefined primary end point was to compare change in mean spot urinary protein-creatinine ratio between the baseline measurement and the last study evaluation (6 months in study completers) between the 2 groups. Every 4 weeks, there was measurement of serum intact parathyroid hormone, serum calcium, serum phosphorus, serum creatinine, and urine spot protein and creatinine. Results At baseline, mean urinary protein-creatinine ratios were 2.6 and 2.8 g/g in the placebo and paricalcitol groups, respectively. At final evaluation, mean ratios were 2.7 and 2.3, respectively. Changes in protein excretion from baseline to last evaluation were +2.9% for controls and −17.6% for the paricalcitol group ( P = 0.04). A 10% decrease in proteinuria occurred in controls (7 of 27; 25.9%) and the paricalcitol group (16 of 28; 57.1%; P = 0.03). Limitations The relatively small sample size limits the extent to which results should be generalized. Conclusions Paricalcitol resulted in a significant reduction in protein excretion in patients with proteinuric renal disease.

To examine whether tacrolimus is more effective and safe than cyclosporine (CsA) in inducing remission in patients with steroid-resistant nephrotic syndrome (SRNS).Randomized controlled trial, nonblind, parallel group.Tertiary-care hospital; 41 consecutive patients with idiopathic SRNS, estimated glomerular filtration rate greater than 60 mL/min/1.73 m(2), and histological characteristics showing minimal change disease, focal segmental glomerulosclerosis, or mesangioproliferative glomerulonephritis were randomly assigned to treatment with tacrolimus (n = 21) or CsA (n = 20).Tacrolimus (0.1 to 0.2 mg/kg/d) or CsA (5 to 6 mg/kg/d) for 1 year; cotreatment with alternate-day prednisolone and enalapril.Patients achieving complete remission (urinary protein-creatinine ratio0.2 g/g and serum albuminor = 2.5 g/dL) or partial remission (urinary protein-creatinine ratio, 0.2 to 2 g/g, and serum albuminor =2.5 g/dL) at 6 and 12 months; time to remission; proportion with relapses; side effects.No patient was lost to follow-up. After 6 months of therapy, remission occurred in 18 (85.7%) and 16 patients (80%) treated with tacrolimus and CsA, respectively (relative risk [RR], 1.07; 95% confidence interval [CI], 0.81 to 1.41). Rates of remission at 12 months were also similar (RR, 1.14; 95% CI, 0.84 to 1.55). The proportion of patients who experienced relapse was significantly greater in those receiving CsA compared with tacrolimus (RR, 4.5; 95% CI, 1.1 to 18.2; P = 0.01). The decrease in blood cholesterol levels was greater with tacrolimus compared with CsA (difference in mean values, 45.1 mg/dL; 95% CI, 19.1 to 71.2). Persistent nephrotoxicity necessitating stoppage of medicine was seen in 4.7% and 10% patients, respectively. Cosmetic side effects (hypertrichosis and gum hypertrophy) were significantly more frequent in CsA-treated patients (P0.001).Single-center study, small sample size, and short duration of follow-up.Tacrolimus or CsA in combination with low-dose steroids show similar efficacy in inducing remission in patients with SRNS. Therapy with tacrolimus is a promising alternative to CsA in view of the lower risk of relapses and lack of cosmetic side effects.

Background Some studies have shown that the normal range of glomerular filtration rate (GFR) was lower in an Indian population than in western populations. To verify these findings and determine whether it is physiological or an expression of subclinical disease, we measured GFR in a cohort of healthy Indian adults by using more stringent criteria to define "healthy" than used in previous studies. Study Design Cross-sectional study. Setting and Participants 109 healthy adults being evaluated for kidney donation with normal blood pressure, body mass index, urinalysis results, and protein excretion and symmetrical function on radionuclide renogram. Subjects followed a vegetarian diet with 1 g/kg of protein intake for 10 days before the study. Predictors Age, sex, relation to recipient (relative versus spouse), body surface area, body mass index, kidney size, serum creatinine level, and urinary protein-creatinine ratio. Outcome and Measurements GFR measured as plasma clearance of technetium 99m diethyl-triamine-penta-acetic acid before and after amino-acid infusion (protein-induced hyperfiltration). Measurements were performed after a 12-hour fast. Results Mean baseline GFR was 82.4 ±12.7 mL/min/1.73 m 2 (95% confidence interval, 80.0 to 84.8). Mean stimulated GFR was 104.7 ± 16.1 mL/min/1.73 m 2 (95% confidence interval, 101.6 to 107.8). Measured mean protein-induced hyperfiltration was 27.3% ± 10.04% (range, 6.7% to 56%). In multivariable linear regression analysis, younger age, spousal donor, and larger average kidney size were associated with significantly greater baseline GFR, and only greater baseline GFR was associated significantly with stimulated GFR. Limitations Dietary protein intake was not measured; a habitual low-protein diet cannot be excluded as a cause of low GFR. Conclusions Basal GFR is significantly lower than the normal value of 120 to 130 mL/min/1.73 m 2 in western populations. The conventional cutoff value of 60 mL/min/1.73 m 2 for defining chronic kidney disease might not be appropriate in India.