hronic kidney disease (CKD) affects between 8% and 16% of the population worldwide and is often underrecognized by patients and clinicians. [1][2][3][4] Defined by a glomerular filtration rate (GFR) of less than 60 mL/min/1.73 m 2 , albuminuria of at least 30 mg per 24 hours, or markers of kidney damage (eg, hematuria or structural abnormalities such as polycystic or dysplastic kidneys) persisting for more than 3 months, 5 CKD is more prevalent in low-and middle-income than in highincome countries. 6 Globally, CKD is most commonly attributed to diabetes and/or hypertension, but other causes such as glomerulonephritis, infection, and environmental exposures (such as air pollution, herbal remedies, and pesticides) are common in Asia, sub-Saharan Africa, and many developing countries. 4 Genetic risk factors may also contribute to CKD risk. For example, sickle cell trait and the presence of 2 APOL1 risk alleles, both common in people of African ancestry but not European ancestry, may double the risk of CKD. 4,[7][8][9][10] In the United States, the average rate of GFR decline is approximately 1 mL/min/1.73 m 2 per year in the general pop-ulation, 11,12 and the lifetime risk of developing a GFR of less than 60 mL/min/1.73 m 2 is more than 50%. 13 Early detection and treatment by primary care clinicians is important because progressive CKD is associated with adverse clinical outcomes, including endstage kidney disease (ESKD), cardiovascular disease, and increased mortality. [14][15][16][17] Recent professional guidelines suggest a risk-based approach to the evaluation and management of CKD. 5,[18][19][20] This review includes discussion of new calculators for determining risk of CKD progression that may be useful in clinical practice (eg, https://kidneyfailurerisk.com/) and focuses on the diagnosis, evaluation, and management of CKD for primary care clinicians. Considerations for referral to a nephrologist and dialysis initiation are also covered. MethodsA literature search to April 2019 was conducted using Medline and PubMed with search terms including CKD, chronic renal failure, IMPORTANCE Chronic kidney disease (CKD) is the 16th leading cause of years of life lost worldwide. Appropriate screening, diagnosis, and management by primary care clinicians are necessary to prevent adverse CKD-associated outcomes, including cardiovascular disease, end-stage kidney disease, and death.OBSERVATIONS Defined as a persistent abnormality in kidney structure or function (eg, glomerular filtration rate [GFR] <60 mL/min/1.73 m 2 or albuminuria Ն30 mg per 24 hours) for more than 3 months, CKD affects 8% to 16% of the population worldwide. In developed countries, CKD is most commonly attributed to diabetes and hypertension. However, less than 5% of patients with early CKD report awareness of their disease. Among individuals diagnosed as having CKD, staging and new risk assessment tools that incorporate GFR and albuminuria can help guide treatment, monitoring, and referral strategies. Optimal management of CKD includes cardiovascular ...

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Background: There is strong biologic plausibility to support change in albuminuria as a surrogate endpoint for progression of chronic kidney disease (CKD), but empirical evidence to supports its validity in epidemiologic studies is lacking. Methods: We analyzed 28 cohorts including 693,816 individuals (80% with diabetes) and 7,461 end-stage kidney disease (ESKD) events, defined as initiation of kidney replacement therapy. Percent change in albuminuria was quantified during a baseline period of 1, 2 and 3 years using linear regression. Associations with subsequent ESKD were quantified using Cox regression in Coresh et al.

IMPORTANCE It is uncertain whether and when angiotensin-converting enzyme inhibitor (ACE-I) and angiotensin II receptor blocker (ARB) treatment should be discontinued in individuals with low estimated glomerular filtration rate (eGFR).OBJECTIVE To investigate the association of ACE-I or ARB therapy discontinuation after eGFR decreases to below 30 mL/min/1.73 m 2 with the risk of mortality, major adverse cardiovascular events (MACE), and end-stage kidney disease (ESKD). DESIGN, SETTING, AND PARTICIPANTSThis retrospective, propensity score-matched cohort study included 3909 patients from an integrated health care system that served rural areas of central and northeastern Pennsylvania. Patients who initiated ACE-I or ARB therapy from January 1, 2004, to December 31, 2018, and had an eGFR decrease to below 30 mL/min/1.73 m 2 during therapy were enrolled, with follow-up until January 25, 2019.EXPOSURES Individuals were classified based on whether they discontinued ACE-I or ARB therapy within 6 months after an eGFR decrease to below 30 mL/min/1.73 m 2 . MAIN OUTCOMES AND MEASURESThe association between ACE-I or ARB therapy discontinuation and mortality during the subsequent 5 years was assessed using multivariable Cox proportional hazards regression models, adjusting for patient characteristics at the time of the eGFR decrease in a propensity score-matched sample. Secondary outcomes included MACE and ESKD. RESULTSOf the 3909 individuals receiving ACE-I or ARB treatment who experienced an eGFR decrease to below 30 mL/min/1.73 m 2 (2406 [61.6%] female; mean [SD] age, 73.7 [12.6] years), 1235 discontinued ACE-I or ARB therapy within 6 months after the eGFR decrease and 2674 did not discontinue therapy. A total of 434 patients (35.1%) who discontinued ACE-I or ARB therapy and 786 (29.4%) who did not discontinue therapy died during a median follow-up of 2.9 years (interquartile range, 1.3-5.0 years). In the propensity score-matched sample of 2410 individuals, ACE-I or ARB therapy discontinuation was associated with a higher risk of mortality (hazard ratio [HR], 1.39; 95% CI, 1.20-1.60]) and MACE (HR, 1.37; 95% CI, 1.20-1.56), but no statistically significant difference in the risk of ESKD was found (HR, 1.19; 95% CI, 0.86-1.65). CONCLUSIONS AND RELEVANCEThe findings suggest that continuing ACE-I or ARB therapy in patients with declining kidney function may be associated with cardiovascular benefit without excessive harm of ESKD.

Background and objectives Common apolipoprotein L1 (APOL1) variants are associated with increased risk of progressive CKD; however, not all individuals with high-risk APOL1 variants experience CKD progression. Identification of factors contributing to heterogeneity has important scientific and clinical implications.Design, setting, participants, & measurements Using multivariable Cox models, we analyzed data from 693 participants in the African American Study of Kidney Disease and Hypertension to identify factors that modify the association between APOL1 genotypes and CKD progression (doubling of serum creatinine or incident ESRD).Results Participant mean age was 54 years old, median GFR was 49 ml/min per 1.73 m 2 , and 23% had the APOL1 high-risk genotype (two copies of the high-risk allele). Over a mean follow-up of 7.8 years, 288 (42%) participants experienced CKD progression. As previously reported, the high-risk genotype was associated with higher risk of CKD progression compared with the low-risk genotype (hazard ratio [HR], 1.88; 95% confidence interval [95% CI], 1.46 to 2.41). Although we found some suggestion that obesity (HR, 1.48; 95% CI, 1.05 to 2.08 and HR, 2.44; 95% CI, 1.66 to 3.57 for body mass index $30 versus ,30 kg/m 2 ; P interaction =0.04) and increased urinary excretion of urea nitrogen (HR, 1.43; 95% CI, 0.98 to 2.09 versus HR, 2.33; 95% CI, 1.65 to 3.30 for urine urea nitrogen $8 versus ,8 g/d; P interaction =0.04) were associated with lower APOL1-associated risk for CKD progression, these findings were not robust in sensitivity analyses with alternative cut points. No other sociodemographic (e.g., education and income), clinical (e.g., systolic BP and smoking), or laboratory (e.g., net endogenous acid production, urinary sodium and potassium excretions, 25-hydroxy vitamin D, intact parathyroid hormone, or fibroblast growth factor 23) variables modified the association between APOL1 and CKD progression (P interaction .0.05 for each).Conclusions Sociodemographic factors and common risk factors for CKD progression do not seem to alter APOL1-related CKD progression. Additional investigation is needed to identify nontraditional factors that may affect the association between APOL1 and progressive CKD.

BackgroundProteomic profiling may allow identification of plasma proteins that associate with subsequent changesin kidney function, elucidating biologic processes underlying the development and progression of CKD.MethodsWe quantified the association between 4877 plasma proteins and a composite outcome of ESKD or decline in eGFR by ≥50% among 9406 participants in the Atherosclerosis Risk in Communities (ARIC) Study (visit 3; mean age, 60 years) who were followed for a median of 14.4 years. We performed separate analyses for these proteins in a subset of 4378 participants (visit 5), who were followed at a later time point, for a median of 4.4 years. For validation, we evaluated proteins with significant associations (false discovery rate <5%) in both time periods in 3249 participants in the Chronic Renal Insufficiency Cohort (CRIC) and 703 participants in the African American Study of Kidney Disease and Hypertension (AASK). We also compared the genetic determinants of protein levels with those from a meta-analysis genome-wide association study of eGFR.ResultsIn models adjusted for multiple covariates, including baseline eGFR and albuminuria, we identified 13 distinct proteins that were significantly associated with the composite end point in both time periods, including TNF receptor superfamily members 1A and 1B, trefoil factor 3, and β-trace protein. Of these proteins, 12 were also significantly associated in CRIC, and nine were significantly associated in AASK. Higher levels of each protein associated with higher risk of 50% eGFR decline or ESKD. We found genetic evidence for a causal role for one protein, lectin mannose-binding 2 protein (LMAN2).ConclusionsLarge-scale proteomic analysis identified both known and novel proteomic risk factors for eGFR decline.

Objective Among African Americans, the APOL1 risk variants have been associated with various types of kidney disease and chronic kidney disease progression. We aimed to determine whether these same risk variants also confer an increased risk for cardiovascular disease (CVD). Approach and Results In a cohort of African Americans with hypertension-attributed chronic kidney disease followed for up to 12 years, we used Cox proportional hazards models to estimate the relative hazard of a composite CVD outcome (cardiovascular death or hospitalization for myocardial infarction, cardiac revascularization procedure, heart failure, or stroke) for the APOL1 high- (2 risk variants) versus low-risk (0–1 risk variant) genotypes. We adjusted for age, gender, ancestry, smoking, heart disease history, body mass index, cholesterol, randomized treatment groups, and baseline and longitudinal estimated glomerular filtration rate (eGFR), systolic blood pressure, and proteinuria. Among 693 participants with APOL1 genotyping available (23% high-risk), the high-risk group had lower mean eGFR (44.7 vs. 50.1 ml/min/1.73 m2) and greater proteinuria (median 0.19 vs. 0.06) compared to the low-risk group at baseline. There was no significant association between APOL1 genotypes and the composite CVD outcome in both unadjusted (HR=1.23; 95% CI: 0.83 to 1.81) and fully adjusted (HR=1.16; 95% CI: 0.77 to 1.76) models; however, in using an additive model, APOL1 high-risk variants were associated with increased cardiovascular mortality. Conclusions Among African Americans with hypertension-attributed chronic kidney disease, APOL1 risk variants were not associated with an overall risk for CVD, though some signals for cardiovascular mortality were noted.

BackgroundTwo coding variants in the apo L1 gene (APOL1) are strongly associated with kidney disease in blacks. Kidney disease itself increases the risk of cardiovascular disease, but whether these variants have an independent direct effect on the risk of cardiovascular disease is unclear. Previous studies have had inconsistent results.MethodsWe conducted a two-stage individual participant data meta-analysis to assess the association of APOL1 kidney-risk variants with adjudicated cardiovascular disease events and death, independent of kidney measures. The analysis included 21,305 blacks from eight large cohorts.ResultsOver 8.9±5.0 years of follow-up, 2076 incident cardiovascular disease events occurred in the 16,216 participants who did not have cardiovascular disease at study enrollment. In fully-adjusted analyses, individuals possessing two APOL1 kidney-risk variants had similar risk of incident cardiovascular disease (coronary heart disease, myocardial infarction, stroke and heart failure; hazard ratio 1.11, 95% confidence interval, 0.96 to 1.28) compared to individuals with zero or one kidney-risk variant. The risk of coronary heart disease, myocardial infarction, stroke and heart failure considered individually was also comparable by APOL1 genotype. APOL1 genotype was also not associated with death. There was no difference in adjusted associations by level of kidney function, age, diabetes status, or body-mass index.ConclusionsIn this large, two-stage individual participant data meta-analysis, APOL1 kidney-risk variants were not associated with incident cardiovascular disease or death independent of kidney measures.