Kidney Stone Pathophysiology, Evaluation and Management: Core Curriculum 2023.

Kidney stone disease, also known as nephrolithiasis or urolithiasis, is a disorder in which urinary solutes precipitate to form aggregates of crystalline material in the urinary space. The incidence of nephrolithiasis has been increasing, and the demographics have been evolving. Once viewed as a limited disease with intermittent exacerbations that are simply managed by urologists, nephrolithiasis is now recognized as a complex condition requiring thorough evaluation and multifaceted care. Kidney stones are frequently manifestations of underlying systemic medical conditions such as the metabolic syndrome, genetic disorders, or endocrinopathies. Analysis of urine chemistries and stone composition provide a window into pathogenesis and direct ancillary studies to uncover underlying diseases. These studies allow providers to devise individualized strategies to limit future stone events. Given its complexity, kidney stone disease is best addressed by a team led by nephrologists and urologists with input from multiple other health professionals including dietitians, endocrinologists, interventional radiologists, and endocrine surgeons. In this installment of AJKD's Core Curriculum in Nephrology, we provide a case-based overview of nephrolithiasis, divided by the individual stone types. The reader will gain a pragmatic understanding of the pathophysiology, evaluation, and management of this condition.

Hyperphosphatemia and its relationship with blood pressure, vasoconstriction, and endothelial cell dysfunction in hypertensive hemodialysis patients.

BACKGROUND: Hyperphosphatemia occurs frequently in end-stage renal disease patients on hemodialysis and is associated with increased mortality. Hyperphosphatemia contributes to vascular calcification in these patients, but there is emerging evidence that it is also associated with endothelial cell dysfunction. METHODS: We conducted a cross-sectional study in hypertensive hemodialysis patients. We obtained pre-hemodialysis measurements of total peripheral resistance index (TPRI, non-invasive cardiac output monitor) and plasma levels of endothelin-1 (ET-1) and asymmetric dimethylarginine (ADMA). We ascertained the routine peridialytic blood pressure (BP) measurements from that treatment and the most recent pre-hemodialysis serum phosphate levels. We used generalized linear regression analyses to determine independent associations between serum phosphate with BP, TPRI, ET-1, and ADMA while controlling for demographic variables, parathyroid hormone (PTH), and interdialytic weight gain. RESULTS: There were 54 patients analyzed. Mean pre-HD supine and seated systolic and diastolic BP were 164 (27), 158 (21), 91.5 (17), and 86.1 (16) mmHg. Mean serum phosphate was 5.89 (1.8) mg/dL. There were significant correlations between phosphate with all pre-hemodialysis BP measurements (r = 0.3, p = .04; r = 0.4, p = .002; r = 0.5, p < .0001; and r = 0.5, p = .0003.) The correlations with phosphate and TPRI, ET-1, and ADMA were 0.3 (p = .01), 0.4 (p = .007), and 0.3 (p = .04). In our final linear regression analyses controlling for baseline characteristics, PTH, and interdialytic weight gain, independent associations between phosphate with pre-hemodialysis diastolic BP, TPRI, and ET-1 were retained (ß = 4.33, p = .0002; log transformed ß = 0.05, p = .005; reciprocal transformed ß = -0.03, p = .047). CONCLUSIONS: Serum phosphate concentration is independently associated with higher pre-HD BP, vasoconstriction, and markers of endothelial cell dysfunction. These findings demonstrate an additional negative impact of hyperphosphatemia on cardiovascular health beyond vascular calcification. TRIAL REGISTRATION: The study was part of a registered clinical trial, NCT01862497 (May 24, 2013).

De novo or recurrent glomerulonephritis and acute tubulointerstitial nephritis after COVID-19 vaccination: A report of six cases from a single center.

Billions of COVID-19 vaccine doses have been administered to combat the ongoing global pandemic caused by severe acute respiratory syndrome coronavirus-2. While these vaccines are considered safe, with most adverse events being mild to moderate and transient, uncommon systemic side effects of the vaccines, including de novo or re-activation of various glomerular diseases have recently been observed. We report 6 patients who developed glomerular or acute tubulointerstitial disease shortly after receiving COVID-19 vaccinations. Five of these patients received mRNA vaccines (3 Moderna, 2 Pfizer-BioNTech) and 1 received adenovirus-26 vector vaccine (Johnson and Johnson/Janssen). Four of our patients developed de novo glomerulonephritis or acute tubulointerstitial nephritis (ATIN), while the other 2 had re-activation of prior glomerulonephritis. Two patients presented with acute kidney injury (AKI) characterized by severe ATIN. While both of them also had evidence of immune complex glomerular disease, ATIN was the dominant feature on the biopsies. Two other patients presented with high-grade proteinuria and AKI. Like the aforementioned patients, these patients had evidence of immune complex glomerular disease, but acute onset nephrotic syndrome was the leading clinical feature. Another patient presented with de novo myeloperoxidase-anti-neutrophil-cytoplasmic-antibody-associated pauci-immune crescentic glomerulonephritis. Yet another patient had re-activation of immunoglobulin-A glomerulonephritis that had been quiescent for several years prior to the vaccination. It is difficult to ascertain any causal relationship between COVID-19 vaccination and onset/recurrence of kidney diseases. However, vigilance about occurrence of such complications is imperative. Importantly, all our cases responded well to the immunosuppressive treatment.

Idiopathic Hypokalemia in Lupus Nephritis: A Newly Recognized Entity.

Background: Various causes of hypokalemia (HK) from renal potassium wasting, including distal renal tubular acidosis (RTA), have been described in lupus nephritis (LN). We report a phenomenon of otherwise unexplained HK among a population with LN. Methods: From our population of 403 patients with LN, we identified a cohort of 20 patients with idiopathic HK, defined by serum potassium <3.5 mmol/L without any apparent explanation. This cohort is compared with 90 LN controls (CON) and ten patients with LN with distal RTA from the same population. Results: The patients with HK had lower median serum potassium compared with CON and RTA subjects (3.26 versus 4.00 versus 3.75 mmol/L, respectively; P<0.001). The median serum bicarbonate was normal in HK and CON, but low in RTA (26.0 versus 25.0 versus 19.4 mmol/L; P<0.001). The median urine pH was abnormally high only in the RTA group (6.00 versus 6.25 versus 6.67; P=0.012). The median serum magnesium was modestly lower in HK compared with the CON and RTA groups (1.73 versus 2.00 versus 1.85 mg/dl; P=0.002). Although both HK and RTA showed a higher rate of seropositivity than CON for anti-Ro/SSA (79% and 80% versus 37%, respectively; P<0.001), only HK revealed a higher rate of seropositivity than CON for anti-RNP (84% versus 42%; P=0.003) and only RTA showed a higher rate of seropositivity than CON for anti-La/SSB (40% versus 12%; P=0.05). Conclusions: A syndrome of idiopathic HK was revealed in 20 out of 403 (5%) of patients within our LN population, and proved to be distinct from the RTA that occurs in LN. Furthermore, it was associated with a distinct pattern of autoantibodies. We speculate that idiopathic HK is the result of a novel target of autoimmunity in LN, affecting renal tubular potassium transport.

How To Build a Successful Urgent-Start Peritoneal Dialysis Program.

In-center hemodialysis (HD) remains the predominant dialysis therapy in patients with ESKD. Many patients with ESKD present in late stage, requiring urgent dialysis initiation, and the majority start HD with central venous catheters (CVCs), which are associated with poor outcomes and high cost of care. Peritoneal dialysis (PD) catheters can be safely placed in such patients with late-presenting ESKD, obviating the need for CVCs. PD can begin almost immediately in the recumbent position, using low fill volumes. Such PD initiations, commencing within 2 weeks of the catheter placement, are termed urgent-start PD (USPD). Most patients with an intact peritoneal cavity and stable home situation are eligible for USPD. Although there is a small risk of PD catheter-related mechanical complications, most can be managed conservatively. Moreover, overall outcomes of USPD are comparable to those with planned PD initiations, in contrast to the high rate of catheter-related infections and bacteremia associated with urgent-start HD. The ongoing coronavirus disease 2019 pandemic has further exposed the vulnerability of patients with ESKD getting in-center HD. PD can mitigate the risk of infection by reducing environmental exposure to the virus. Thus, USPD is a safe and cost-effective option for unplanned dialysis initiation in patients with late-presenting ESKD. To develop a successful USPD program, a strong infrastructure with clear pathways is essential. Coordination of care between nephrologists, surgeons or interventionalists, and hospital and PD center staff is imperative so that patient education, home visits, PD catheter placements, and urgent PD initiations are accomplished expeditiously. Implementation of urgent-start PD will help to increase PD use, reduce cost, and improve patient outcomes, and will be a step forward in fostering the goal set by the Advancing American Kidney Health initiative.

Assessing Extracellular Volume in Hemodialysis Patients Using Intradialytic Blood Pressure Slopes.

BACKGROUND/AIMS: Extracellular volume (ECV) overload is a mortality risk factor in hemodialysis patients, but no standard approach exists to objectively assess this clinically. We aimed to quantify relationships between slopes of repeated intradialytic blood pressure (BP) measurements and ECV. METHODS: In a cross-sectional study of 71 hemodialysis patients, we calculated BP slopes from all intradialytic measurements using Gaussian regression. We measured extracellular and total body water (TBW) with bioimpedance spectroscopy. We analyzed unconditional and conditional associations between BP slope and volume metrics with mixed linear models and sensitivity analyses using non-linear intradialytic BP trajectory. RESULTS: Mean systolic intradialytic BP slope (IBPS) was -0.06 (0.1) mm Hg/min. Post-dialysis extracellular water (ECW)/weight was the volume metric mostly strongly associated with slope (r = 0.34, p = 0.007 for unconditional analysis; ß = 1.45, p = 0.001 for conditional analysis). Among subjects with post-dialysis systolic BP ≥130 mm Hg, the association strengthened (r = 0.40, p = 0.006; ß = 1.42, p = 0.003). ECV was more strongly associated with the BP slope than with pre-dialysis, post-dialysis, or delta systolic BP (r = -0.07, 0.19, 0.28; p = 0.6, 0.1, 0.03). In nonlinear models, BP trajectory also had the strongest association with post-dialysis ECW/body weight (p < 0.001). CONCLUSIONS: In hypertensive hemodialysis patients, measurements of ECV excess are more strongly associated with IBPSs than with pre-dialysis, post-dialysis, or change in systolic BP. Among varying volume metrics, post-dialysis ECW/weight has the strongest association with these slopes. Determining IBPS is a novel method to optimize clinical assessment of ECV in hemodialysis patients.

Lifetime Risk of Stage 3-5 CKD in a Community-Based Sample in Iceland.

BACKGROUND AND OBJECTIVES: Lifetime risk estimates of CKD can be used effectively in public education campaigns. This study sought to estimate lifetime risk of incident CKD stage 3 and higher in Iceland for people without CKD by the age of 45 years. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This was a prospective cohort study with longitudinal creatinine measurements of residents in Reykjavik, Iceland, from 1967 to 2005. CKD was ascertained by two consecutive eGFR measurements <60 ml/min per 1.73 m(2), development of treated kidney failure, one eGFR<60 ml/min per 1.73 m(2) if the participant died before the next evaluation, or one eGFR<45 ml/min per 1.73 m(2) if it was the last eGFR. RESULTS: Mean follow-up was 25 (SD 10) years. Of the study participants, 727 (19%) developed the outcome and 942 (24%) died first. By age 85 years, the lifetime risks for 45-year-old women and men without prevalent CKD were 35.8% (95% confidence interval [95% CI], 32.7 to 38.9) and 21.3% (95% CI, 18.7 to 23.8), respectively. Risk was higher in individuals with a lower eGFR, hypertension, and a higher body mass index. Lifetime risk for higher stages of CKD 3b and 4 were less common than stage 3a; by age 85 years, the lifetime risks for CKD stages 3a, 3b, and 4 in women were 38.5% (95% CI, 25.8 to 51.1), 19.4% (95% CI, 8.9 to 29.9), and 3.6% (95% CI, 2.2 to 5.0), respectively. CONCLUSIONS: The lifetime risk of developing CKD stage 3 or higher is substantial, emphasizing the importance of strategies to prevent development of CKD throughout the course of life. Estimates are lower than reported using single estimates of GFR, emphasizing the importance of confirming estimates of reduced GFR in studies of CKD.

Risk factors for cardiovascular disease across the spectrum of older age: the Cardiovascular Health Study.

OBJECTIVE: The associations of some risk factors with cardiovascular disease (CVD) are attenuated in older age; whereas others appear robust. The present study aimed to compare CVD risk factors across older age. METHODS: Participants (n = 4883) in the Cardiovascular Health Study free of prevalent CVD, were stratified into three age groups: 65-74, 75-84, 85+ years. Traditional risk factors included systolic blood pressure (BP), LDL-cholesterol, HDL-cholesterol, obesity, and diabetes. Novel risk factors included kidney function, C-reactive protein (CRP), and N-terminal pro-B-type natriuretic peptide (NT pro-BNP). RESULTS: There were 1498 composite CVD events (stroke, myocardial infarction, and cardiovascular death) over 5 years. The associations of high systolic BP and diabetes appeared strongest, though both were attenuated with age (p-values for interaction = 0.01 and 0.002, respectively). The demographic-adjusted hazard ratios (HR) for elevated systolic BP were 1.79 (95% confidence interval: 1.49, 2.15), 1.59 (1.37, 1.85) and 1.10 (0.86, 1.41) in participants aged 65-74, 75-84, 85+, and for diabetes, 2.36 (1.89, 2.95), 1.55 (1.27, 1.89), 1.51 (1.10, 2.09). The novel risk factors had consistent associations with the outcome across the age spectrum; low kidney function: 1.69 (1.31, 2.19), 1.61 (1.36, 1.90), and 1.57 (1.16, 2.14) for 65-74, 75-84, and 85+ years, respectively; elevated CRP: 1.54 (1.28, 1.87), 1.33 (1.13, 1.55), and 1.51 (1.15, 1.97); elevated NT pro-BNP: 2.67 (1.96, 3.64), 2.71 (2.25, 3.27), and 2.18 (1.43, 3.45). CONCLUSIONS: The associations of most traditional risk factors with CVD were minimal in the oldest old, whereas diabetes, eGFR, CRP, and NT pro-BNP were associated with CVD across older age.

Fibroblast growth factor 23, the ankle-brachial index, and incident peripheral artery disease in the Cardiovascular Health Study.

BACKGROUND: Fibroblast growth factor 23 (FGF23) has emerged as a novel risk factor for mortality and cardiovascular events. Its association with the ankle-brachial index (ABI) and clinical peripheral artery disease (PAD) is less known. METHODS: Using data (N = 3143) from the Cardiovascular Health Study (CHS), a cohort of community dwelling adults >65 years of age, we analyzed the cross-sectional association of FGF23 with ABI and its association with incident clinical PAD events during 9.8 years of follow up using multinomial logistic regression and Cox proportional hazards models respectively. RESULTS: The prevalence of cardiovascular disease (CVD) and traditional risk factors like diabetes, coronary artery disease, and heart failure increased across higher quartiles of FGF23. Compared to those with ABI of 1.1-1.4, FGF23 per doubling at baseline was associated with prevalent PAD (ABI < 0.9) although this association was attenuated after adjusting for CVD risk factors, and kidney function (OR 0.91, 95% CI 0.76-1.08). FGF23 was not associated with high ABI (>1.4) (OR 1.06, 95% CI 0.75-1.51). Higher FGF23 was associated with incidence of PAD events in unadjusted, demographic adjusted, and CVD risk factor adjusted models (HR 2.26, 95% CI 1.28-3.98; highest versus lowest quartile). The addition of estimated glomerular filtration and urine albumin to creatinine ratio to the model however, attenuated these findings (HR 1.46, 95% CI, 0.79-2.70). CONCLUSIONS: In community dwelling older adults, FGF23 was not associated with baseline low or high ABI or incident PAD events after adjusting for confounding variables. These results suggest that FGF23 may primarily be associated with adverse cardiovascular outcomes through non atherosclerotic mechanisms.

Recovery of kidney function following delayed use of Theralite™ dialyzer in a patient with myeloma cast nephropathy.

We report the case of a 60- year- old man who presented with newly diagnosed multiple myeloma complicated by biopsy-proven acute cast nephropathy, requiring hemodialysis, plasmapheresis and chemotherapy. After remaining dialysis dependent for 5 weeks, a high cut-off (HCO) dialyzer, intended to use for the removal of plasma substances with a molecular weight of up to 45 kDa such as free light chains, was introduced to his outpatient 4-hour hemodialysis regimen with an increase in treatment frequency to 4 sessions per week. Following 6 weeks of dialysis with the HCO dialyzer, serum levels of free κ light chains declined by more than 75%. Concurrently, he recovered kidney function and discontinued dialysis. He subsequently received a successful autologous stem-cell transplant. We discuss the potential merit of using the HCO dialyzer late in the course of the care of patients with myeloma cast nephropathy who are dialysis dependent.

Kidney function and mortality in octogenarians: Cardiovascular Health Study All Stars.

OBJECTIVES: To examine the association between kidney function and all-cause mortality in octogenarians. DESIGN: Retrospective analysis of prospectively collected data. SETTING: Community. PARTICIPANTS: Serum creatinine and cystatin C were measured in 1,053 Cardiovascular Health Study (CHS) All Stars participants. MEASUREMENTS: Estimated glomerular filtration rate (eGFR) was determined using the Chronic Kidney Disease Epidemiology Collaboration creatinine (eGFR(CR) ) and cystatin C one-variable (eGFR(CYS) ) equations. The association between quintiles of kidney function and all-cause mortality was analyzed using unadjusted and adjusted Cox proportional hazards models. RESULTS: Mean age of the participants was 85, 64% were female, 66% had hypertension, 14% had diabetes mellitus, and 39% had prevalent cardiovascular disease. There were 154 deaths over a median follow-up of 2.6 years. The association between eGFR(CR) and all-cause mortality was U-shaped. In comparison with the reference quintile (64-75 mL/min per 1.73 m(2) ), the highest (≥ 75 mL/min per 1.73 m(2) ) and lowest (≤ 43 mL/min per 1.73 m(2) ) quintiles of eGFR(CR) were independently associated with mortality (hazard ratio (HR) = 2.49, 95% confidence interval (CI) = 1.36-4.55; HR = 2.28, 95% CI = 1.26-4.10, respectively). The association between eGFR(CYS) and all-cause mortality was linear in those with eGFR(CYS) of less than 60 mL/min per 1.73 m(2) , and in the multivariate analyses, the lowest quintile of eGFR(CYS) (<52 mL/min per 1.73 m(2) ) was significantly associated with mortality (HR = 2.04, 95% CI = 1.12-3.71) compared with the highest quintile (>0.88 mL/min per 1.73 m(2) ). CONCLUSION: Moderate reduction in kidney function is a risk factor for all-cause mortality in octogenarians. The association between eGFR(CR) and all-cause mortality differed from that observed with eGFR(CYS) ; the relationship was U-shaped for eGFR(CR) , whereas the risk was primarily present in the lowest quintile for eGFR(CYS) .

Predictors of sudden cardiac death: a competing risk approach in the hemodialysis study.

BACKGROUND AND OBJECTIVES: There are few data on risk factors for sudden cardiac death (SCD) in patients undergoing hemodialysis (HD). The study objective was to identify predictors associated with various causes of death in the Hemodialysis (HEMO) Study and to develop a prediction model for SCD using a competing risk approach. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this analysis of 1745 HEMO participants, all-cause mortality was classified as SCD, non-SCD, and noncardiac death. Predictors for each cause of death were evaluated using cause-specific Cox proportional hazards models, and a competing risk approach was used to calculate absolute risk predictions for SCD. RESULTS: During a median follow-up of 2.5 years, 808 patients died. Rates of SCD, non-SCD, and noncardiac death were 22%, 17%, and 61%, respectively. Predictors of various causes of death differ somewhat in HD patients. Age, diabetes, peripheral vascular disease, ischemic heart disease, serum creatinine, and alkaline phosphatase were independent predictors of SCD. The 3-year C-statistic for SCD was 0.75 (95% confidence interval, 0.70-0.79), and calibration was good (χ(2)=1.1; P=0.89). At years 3 and 5 of follow-up, the standard Cox model overestimated the risk for SCD as compared with the competing risk approach on the relative scale by 25% and 46%, respectively, and on the absolute scale by 2% and 6%, respectively. CONCLUSIONS: Predictors of various causes of death differ in HD patients. The proposed prediction model for SCD accounts for competing causes of death. External validation of this model is required.

ß-Blockers for prevention of sudden cardiac death in patients on hemodialysis: a propensity score analysis of the HEMO Study.

BACKGROUND: Hemodialysis patients have an elevated risk of sudden cardiac death. Although the efficacy of ß-blockers for the prevention of sudden cardiac death has been proven in the general population, little evidence exists in patients with kidney failure. STUDY DESIGN: Post hoc analysis of the Hemodialysis (HEMO) Study. SETTING & PARTICIPANTS: Participants enrolled in the HEMO Study from May 1995 to February 2001. INTERVENTION: ß-Blocker use ascertained through self-reported questionnaires and dialysis clinic charts. OUTCOMES: Sudden cardiac death adjudicated by a committee as a secondary outcome of interest. MEASUREMENTS: We used Cox proportional hazards regression models, competing risk survival analysis, propensity score matching, and covariate adjustment to study the association of ß-blockers with sudden cardiac death. RESULTS: 1,747 patients were included in this study, and 521 were on ß-blocker therapy at baseline. Mean age was 58 years, 57% were women, and 39% had ischemic heart disease (IHD) at baseline. Baseline ß-blocker use was not associated with lower risk of sudden cardiac death in univariate (cause-specific HR, 0.89; 95% CI, 0.64-1.24), multivariable (cause-specific HR, 0.87; 95% CI, 0.62-1.22), or propensity-matched (cause-specific HR, 0.91; 95% CI, 0.55-1.50) analyses. There was a significant interaction between ß-blocker use and sudden cardiac death (interaction P = 0.03) in patients with (cause-specific HR, 0.65; 95% CI, 0.42-1.01) and without IHD (cause-specific HR, 1.61; 95% CI, 0.92-2.80). LIMITATIONS: Observational nature of the study. CONCLUSIONS: In hemodialysis patients without preexisting IHD, ß-blocker use was not associated with lower risk of sudden cardiac death. However, there was a trend toward benefit in those with IHD.

Chronic kidney disease in octogenarians.

BACKGROUND AND OBJECTIVES: There are limited data on the prevalence of chronic kidney disease (CKD) and its clinical importance in the very old. We examined the prevalence of CKD in octogenarians and its association with cardiovascular disease (CVD). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In a cross-sectional analysis of 1028 participants from the Cardiovascular Health Study All Stars, we evaluated association of prevalent CKD with CVD using multivariable logistic regression. CKD was defined as eGFR of <60 ml/min per 1.73 m(2). GFR was estimated using CKD-Epi creatinine and cystatin C equations that incorporate coefficients for age, gender, and race (eGFR(EPI), eGFR(CYS3var)) and the one-variable cystatin C equation (eGFR(CYS1var)). Prevalent CVD was defined as a composite of coronary heart disease, heart failure, and stroke. RESULTS: Mean age was 86 years, 64% were women, 86% were Caucasians, 14% had diabetes, and 39% had prevalent CVD. Mean eGFR(EPI), eGFR(CYS3var), and eGFR(CYS1var) were 59, 62, and 70 ml/min per 1.73 m(2), and 51%, 46%, and 33% had CKD, respectively. Associations of CKD with CVD varied by equation in adjusted analyses: CKD(EPI) (OR, 1.53; 95% CI, 1.15 to 2.03), CKD(CYS3var) (OR, 1.67; 95% CI, 1.25, 2.23), and CKD(CYS1var) (OR, 2.09; 95% CI, 1.55, 2.83). CONCLUSIONS: Reduced eGFR is highly prevalent in octogenarians, and the eGFR(CYS1var) equation yielded the lowest prevalence of CKD but the strongest association with prevalent CVD. Because there are no validated estimating equations in the elderly, estimation of kidney function on the basis of on any one equation should be interpreted with caution.

Cystatin C and albuminuria as risk factors for development of CKD stage 3: the Multi-Ethnic Study of Atherosclerosis (MESA).

BACKGROUND: The growing burden and morbidity of chronic kidney disease (CKD) warrant effective strategies for identifying those at increased risk. We examined the association of cystatin C level and albuminuria with the development of CKD stage 3. STUDY DESIGN: Prospective observational study. SETTING & PARTICIPANTS: 5,422 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) with estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m(2). PREDICTOR: Participants were categorized into 4 mutually exclusive groups: the presence or absence of microalbuminuria (albumin-creatinine ratio >17 and >25 µg/mg in men and women, respectively) in those with or without cystatin C level ≥1.0 mg/L. OUTCOMES & MEASUREMENTS: Incident CKD stage 3 was defined as eGFR <60 mL/min/1.73 m(2) at the third or fourth visit and an annual decrease >1 mL/min/1.73 m(2). Poisson regression was used to evaluate incident rate ratios in unadjusted and adjusted analyses that include baseline eGFR. RESULTS: Mean age was 61 years, 49% were men, 38% were white, 11% had diabetes, 13.7% had cystatin C level ≥1 mg/L, 8.4% had microalbuminuria, and 2.7% had cystatin C level ≥1 mg/L with microalbuminuria. 554 (10%) participants developed CKD stage 3 during a median follow-up of 4.7 years, and adjusted incidence rate ratios were 1.57 (95% CI, 1.19-2.07), 1.37 (95% CI, 1.13-1.66), and 2.12 (95% CI, 1.61-2.80) in those with microalbuminuria, cystatin C level ≥1 mg/L, and both, respectively, compared with those with neither. LIMITATIONS: Relatively short follow-up and absence of measured GFR. CONCLUSIONS: Cystatin C level and microalbuminuria are independent risk factors for incident CKD stage 3 and could be useful as screening tools to identify those at increased risk.