Outcomes reported in randomized controlled trials in peritoneal dialysis (PD) are diverse, are measured inconsistently, and may not be important to patients, families, and clinicians. The Standardized Outcomes in Nephrology–Peritoneal Dialysis (SONG-PD) initiative aims to establish a core outcome set for trials in PD based on the shared priorities of all stakeholders. We convened an international SONG-PD stakeholder consensus workshop in May 2018 in Vancouver, Canada. Nineteen patients/caregivers and 51 health professionals attended. Participants discussed core outcome domains and implementation in trials in PD. Four themes relating to the formation of core outcome domains were identified: life participation as a main goal of PD, impact of fatigue, empowerment for preparation and planning, and separation of contributing factors from core factors. Considerations for implementation were identified: standardizing patient-reported outcomes, requiring a validated and feasible measure, simplicity of binary outcomes, responsiveness to interventions, and using positive terminology. All stakeholders supported inclusion of PD-related infection, cardiovascular disease, mortality, technique survival, and life participation as the core outcome domains for PD.

Rationale & Objective Patients with chronic kidney disease (CKD) are particularly sensitive to dietary sodium. We evaluated a self-management approach for dietary sodium restriction in patients with CKD. Study Design Randomized controlled trial. Setting & Participants Nephrology outpatient clinics in 4 Dutch hospitals. 99 adults with CKD stages 1 to 4 or a functioning (estimated glomerular filtration rate ≥ 25 mL/min/1.73 m2) kidney transplant, hypertension, and sodium intake >130 mmol/d. Intervention Routine care was compared with routine care plus a web-based self-management intervention including individual e-coaching and group meetings implemented over a 3-month intervention period, followed by e-coaching over a 6-month maintenance period. Outcomes Primary outcomes were sodium excretion after the 3-month intervention and after the 6-month maintenance period. Secondary outcomes were blood pressure, proteinuria, costs, quality of life, self-management skills, and barriers and facilitators for implementation. Results Baseline estimated glomerular filtration rate was 55.0 ± 22.0 mL/min/1.73 m2. During the intervention period, sodium excretion decreased in the intervention group from 188 ± 8 (SE) to 148 ± 8 mmol/d (P < 0.001), but did not change significantly in the control group. At 3 months, mean sodium excretion was 24.8 (95% CI, 0.1-49.6) mmol/d lower in the intervention group (P = 0.049). At 3 months, systolic blood pressure (SBP) decreased in the intervention group from 140 ± 3 to 132 ± 3 mm Hg (P < 0.001), but was unchanged in the control group. Mean difference in SBP across groups was −4.7 (95% CI, −10.7 to 1.3) mm Hg (P = 0.1). During the maintenance phase, sodium excretion increased in the intervention group, but remained lower than at baseline at 160 ± 8 mmol/d (P = 0.01), while it decreased in the control group from 174 ± 9 at the end of the intervention period to 154 ± 9 mmol/d (P = 0.001). Consequently, no difference in sodium excretion between groups was observed after the maintenance phase. There was no difference in SBP between groups after the maintenance phase. Limitations Limited power, postrandomization loss to follow-up, Hawthorne effect, lack of dietary data, short-term follow-up. Conclusions A coaching intervention reduced sodium intake at 3 months. Efficacy during the maintenance phase was diminished, possibly due to inadvertent adoption of the intervention by the control group. Funding Grant funding from the Netherlands Organization for Health Research and Development and the Dutch Kidney Foundation. Trial registration Registered at ClinicalTrials.gov with study number NCT02132013.

Rationale & Objective Peritoneal dialysis (PD)-related peritonitis carries high morbidity for PD patients. Understanding the characteristics and risk factors for peritonitis can guide regional development of prevention strategies. We describe peritonitis rates and the associations of selected facility practices with peritonitis risk among countries participating in the Peritoneal Dialysis Outcomes and Practice Patterns Study (PDOPPS). Study Design Observational prospective cohort study. Setting & Participants 7,051 adult PD patients in 209 facilities across 7 countries (Australia, New Zealand, Canada, Japan, Thailand, United Kingdom, United States). Exposures Facility characteristics (census count, facility age, nurse to patient ratio) and selected facility practices (use of automated PD, use of icodextrin or biocompatible PD solutions, antibiotic prophylaxis strategies, duration of PD training). Outcomes Peritonitis rate (by country, overall and variation across facilities), microbiology patterns. Analytical Approach Poisson rate estimation, proportional rate models adjusted for selected patient case-mix variables. Results 2,272 peritonitis episodes were identified in 7,051 patients (crude rate, 0.28 episodes/patient-year). Facility peritonitis rates were variable within each country and exceeded 0.50/patient-year in 10% of facilities. Overall peritonitis rates, in episodes per patient-year, were 0.40 (95% CI, 0.36-0.46) in Thailand, 0.38 (95% CI, 0.32-0.46) in the United Kingdom, 0.35 (95% CI, 0.30-0.40) in Australia/New Zealand, 0.29 (95% CI, 0.26-0.32) in Canada, 0.27 (95% CI, 0.25-0.30) in Japan, and 0.26 (95% CI, 0.24-0.27) in the United States. The microbiology of peritonitis was similar across countries, except in Thailand, where Gram-negative infections and culture-negative peritonitis were more common. Facility size was positively associated with risk for peritonitis in Japan (rate ratio [RR] per 10 patients, 1.07; 95% CI, 1.04-1.09). Lower peritonitis risk was observed in facilities that had higher automated PD use (RR per 10 percentage points greater, 0.95; 95% CI, 0.91-1.00), facilities that used antibiotics at catheter insertion (RR, 0.83; 95% CI, 0.69-0.99), and facilities with PD training duration of 6 or more (vs <6) days (RR, 0.81; 95% CI, 0.68-0.96). Lower peritonitis risk was seen in facilities that used topical exit-site mupirocin or aminoglycoside ointment, but this association did not achieve conventional levels of statistical significance (RR, 0.79; 95% CI, 0.62-1.01). Limitations Sampling variation, selection bias (rate estimates), and residual confounding (associations). Conclusions Important international differences exist in the risk for peritonitis that may result from varied and potentially modifiable treatment practices. These findings may inform future guidelines in potentially setting lower maximally acceptable peritonitis rates.

Rationale & Objectives Chronic kidney disease (CKD) is a potent risk factor for macrovascular disease and death. Peripheral artery disease (PAD) is more common in patients with CKD and is associated with lower-limb complications and mortality. We sought to compare the prevalence of PAD in and outside the setting of kidney disease and examine how PAD affects the risk for adverse health outcomes, specifically lower-limb complications, cardiovascular events, and survival. Study Design Retrospective cohort study. Setting & Participants 453,573 adult residents of Manitoba with at least 1 serum creatinine measurement between 2007 and 2014. Exposure PAD defined by hospital discharge diagnosis codes and medical claims. Outcomes All-cause mortality, cardiovascular events, and lower-limb complications, including foot ulcers and nontraumatic amputations. Analytical Approach Survival analysis using Cox proportional hazards models. Results The prevalence of PAD in our study population was 4.5%, and patients with PAD were older, were more likely to be male, and had a higher burden of comorbid conditions, including diabetes and CKD. PAD was associated with higher risks for all-cause mortality, cardiovascular events, and lower-limb complications in patients with estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m2, those with CKD GFR categories 3 to 5 (G3-G5), and those treated by dialysis (CKD G5D). Although HRs for PAD were lower in the CKD population, event rates were higher as compared with those with eGFR ≥ 60 mL/min/1.73 m2. In particular, compared with patients with eGFR ≥ 60 mL/min/1.73 m2 and without PAD, patients with CKD G5D had 10- and 12-fold higher risks for lower-limb complications, respectively (adjusted HRs of 10.36 [95% CI, 8.83-12.16] and 12.02 [95% CI, 9.58-15.08] for those without and with PAD, respectively), and an event rate of 75/1,000 patient-years. Limitations Potential undercounting of PAD and complications using administrative codes and the limited ability to examine quality-of-care indicators for PAD. Conclusions PAD is more common in patients with CKD G3-G5 and G5D compared with those with eGFR ≥ 60 mL/min/1.73 m2 and frequently leads to lower-limb complications. Medical interventions and care pathways specifically designed to slow or prevent the development of lower-limb complications in this population are urgently needed.

Rationale & Objective Health-related quality of life (HRQoL) is a major outcome measure increasingly used in patients with chronic kidney disease (CKD). We evaluated the association between different stages of CKD and the physical and mental health domains of HRQoL. Study Design Cross-sectional study. Setting & Participants 2,693 outpatients with moderate (stage 3, estimated glomerular filtration rate [eGFR], 30-60 mL/min/1.73 m2) or advanced (stages 4-5, estimated glomerular filtration rate < 30 mL/min/1.73 m2, not on kidney replacement therapy [KRT]) CKD under the care of a nephrologist at 1 of 40 nationally representative facilities, 1,658 patients with a functioning kidney transplant, 1,251 patients on maintenance dialysis randomly selected from the national Renal Epidemiology and Information Network registry, and 20,574 participants in the French Decennial Health Survey, representative of the general population. Predictor Severity of kidney disease (moderate CKD, advanced CKD, maintenance dialysis as KRT, and functioning kidney transplant as KRT), compared with a sample of the general population. Outcomes HRQoL scores assessed using the Medical Outcomes Study 36-Item Short Form Health Survey or the Kidney Disease Quality of Life 36 scale. Analytical Approach Age- and sex-standardized (to the general population) prevalence of poor or fair health status was estimated for each study kidney disease group. Analysis of variance was used to estimate adjusted differences in mean physical and mental health scores between the kidney disease subgroups and the general population. Results Mean age was 67.2 ± 12.6 (SD) years for patients with non–KRT-requiring CKD, 69.3 ± 17.7 years for dialysis patients, and 55.3 ± 14.2 years for those with functioning kidney transplants; 60% were men. Age- and sex-standardized health status was perceived as fair or poor in 27% of those with moderate CKD, >40% of those with advanced CKD or receiving dialysis, 12% with a functioning transplant, and 3% of the general population sample. HRQoL physical scores (adjusted for age, sex, education, obesity, and diabetes) were significantly lower in patients in all CKD subgroups than in the general population. For patients receiving dialysis, the magnitude of the difference in physical score versus the general population exceeded 4.5 points, the minimal clinically important difference for this score in this study; for both kidney transplant recipients and patients with advanced CKD, the magnitude of the difference was close to this threshold. For mental score, only dialysis patients had a score that differed from that of the general population by more than the minimal clinically important difference. Limitations Cross-sectional study design for each subpopulation. Conclusions This study highlights the degree to which perceived physical health is lower in the setting of CKD than in the general population, even in the absence of kidney failure, and calls for greater attention to CKD-related quality of life.

Rationale & Objective Glomerular filtration rate (GFR) estimation based on creatinine or cystatin C level is currently the standard method for assessing GFR in epidemiologic research and clinical trials despite several important and well-known limitations. Plasma iohexol clearance has been proposed as an inexpensive method for measuring GFR that could replace estimated GFR in many research projects. However, lack of standardization for iohexol assays and the use of different protocols such as single- and multiple-sample methods could potentially hamper comparisons across studies. We compared iohexol assays and GFR measurement protocols in 3 population-based European cohorts. Study Design Cross-sectional investigation. Setting & Participants Participants in the Age, Gene/Environment Susceptibility-Kidney Study (AGES-Kidney; n = 805), the Berlin Initiative Study (BIS, n = 570), and the Renal Iohexol Clearance Survey Follow-up Study (RENIS-FU; n = 1,324). Tests Compared High-performance liquid chromatography analyses of iohexol. Plasma iohexol clearance calculated using single- versus multiple-sample protocols. Outcomes Measures of agreement between methods. Results Frozen samples from the 3 studies were obtained and iohexol concentrations were remeasured in the laboratory at the University Hospital of North Norway. Lin’s concordance correlation coefficient ρ was >0.96 and Cb (accuracy) was >0.99 for remeasured versus original serum iohexol concentrations in all 3 cohorts, and Passing-Bablok regression did not find differences between measurements, except for a slope of 1.025 (95% CI, 1.006-1.046) for the log-transformed AGES-Kidney measurements. The multiple-sample iohexol clearance measurements in AGES-Kidney and BIS were compared with single-sample GFRs derived from the same iohexol measurements. Mean bias for multiple-sample relative to single-sample GFRs in AGES-Kidney and BIS were −0.25 and −0.15 mL/min, and 99% and 97% of absolute differences were within 10% of the multiple-sample result, respectively. Limitations Lack of comparison with an independent gold-standard method. Conclusions Agreement between the iohexol assays and clearance protocols in the 3 investigated cohorts was substantial. Our findings indicate that plasma iohexol clearance measurements can be compared across these studies.

Thrombotic microangiopathy (TMA) is an emerging complication of oncologic therapy. Cancer-related causes of renal endothelial cell damage include cytotoxic chemotherapies, radiation given for myeloablation, and direct involvement of renal vasculature by tumor cells. Another class of therapeutic agents that has been implicated in TMA is the vascular endothelial growth factor (VEGF) pathway inhibitors, including the anti-VEGF monoclonal antibody bevacizumab and the VEGF receptor tyrosine kinase inhibitor sunitinib. These TMAs have been termed type II cancer drug–induced TMA and are distinguished from those associated with some cytotoxic chemotherapies (ie, type I) in that they are not dose dependent and patients are more likely to demonstrate some recovery of kidney function. Determination of the cause of TMA in oncologic patients often presents a significant challenge because patients frequently receive multiple chemotherapeutic agents simultaneously and clinicopathologic features often demonstrate substantial overlap, regardless of cause. We present a case of TMA with predominantly chronic features in a 70-year-old patient being treated for adenoid cystic carcinoma of the breast with a single agent, a short interfering RNA targeted against Myc (DCR-MYC).

Rationale & Objective Living kidney donors may have a higher risk for death and kidney failure. This study aimed to investigate the long-term mortality experience of living kidney donors compared with members of the general public in Korea who underwent voluntary health examinations. Study Design Cohort study. Setting & Participants We first calculated standardized mortality ratios for 1,292 Korean living kidney donors who underwent donor nephrectomy between 1982 and 2016 and 72,286 individuals who underwent voluntary health examinations between 1995 and 2016. Next we compared survival between the 1,292 living kidney donors and a subgroup of the health examination population (n = 33,805) who had no evident contraindications to living kidney donation at the time of their examinations. Last, a matched comparator group was created from the health examination population without apparent contraindication to donation by matching 4,387 of them to donors (n = 1,237) on age, sex, body mass index, estimated glomerular filtration rate, urine dipstick albumin excretion, previously diagnosed hypertension and diabetes, and era. Exposures Donor nephrectomy. Outcomes All-cause mortality and other clinical outcomes after kidney donation. Analytical Approach First, standardized mortality ratios were calculated separately for living kidney donors and the health examination population standardized to the general population. Second, we used Cox regression analysis to compare mortality between living kidney donors versus the subgroup of the health examination population without evident donation contraindications. Third, we used Cox regression analysis to compare mortality between living kidney donors and matched comparators from the health examination population without apparent contraindication to donation. Results The living kidney donors and health examination population had excellent survival rates compared with the general population. 52 (4.0%) of 1,292 kidney donors died during a mean follow-up of 12.3 ± 8.1 years and 1,072 (3.2%) of 33,805 in the health examiner subgroup without donation contraindications died during a mean follow-up of 11.4 ± 6.1 years. Donor nephrectomy did not elevate the hazard for mortality after multivariable adjustment in kidney donors and the 33,805 comparators (adjusted HR, 1.01; 95% CI, 0.71-1.44; P = 0.9). Moreover, living donors showed a similar mortality rate compared with the group of matched healthy comparators. Limitations Donors from a single transplantation center. Residual confounding owing to the observational study design. Conclusions Kidney donors experienced long-term rates of death comparable to nondonor comparators with similar health status.

Moral distress occurs when individuals are unable to act in accordance with what they believe to be ethically correct or just. It results from a discrepancy between a clinician’s perception of “the right thing to do” and what is actually happening and is perpetuated by perceived constraints that limit the individual from speaking up or enacting change. Moral distress is reported by many clinicians in caring for patients with serious illness, including chronic kidney disease and kidney failure. If left unidentified, unexpressed, or unaddressed, moral distress may cause burnout, exhaustion, detachment, and ineffectiveness. At an extreme, moral distress may lead to a desire to abandon the speciality entirely. This article offers an international perspective on moral distress in nephrology in diverse contexts and health care systems. We examine and discuss the sociocultural factors that contribute to moral distress in nephrology and offer suggestions for interventions from individual provider, facility, and health care systems perspectives to reduce the impact of moral distress on nephrology providers.

Background Myeloperoxidase (MPO) catalyzes the formation of reactive nitrogen species and levels are elevated in patients with chronic kidney disease (CKD). Although increased oxidative stress and inflammation are associated with progression of CKD and cardiovascular disease (CVD), relationships between MPO concentration, CKD progression, CVD, and death remain unclear. Study Design Prospective cohort. Setting & Participants 3,872 participants from the Chronic Renal Insufficiency Cohort (CRIC) who had MPO measured at baseline. Exposure Baseline MPO concentration. Outcomes CKD progression (kidney transplantation, dialysis initiation, or 50% decline in baseline estimated glomerular filtration rate [eGFR] and eGFR ≤ 15 mL/min/1.73 m2), CVD (heart failure, myocardial infarction, or stroke), and death. Analytical Approach Cox proportional hazards models. Results In adjusted analyses, higher MPO level (per 1-SD increase in log-transformed MPO) was associated with 10% higher risk for CKD progression (adjusted HR, 1.10; 95% CI, 1.01-1.19; P = 0.03), 12% higher risk for CVD (adjusted HR, 1.12; 95% CI, 1.03-1.22; P < 0.01), and 13% increased risk for death (adjusted HR, 1.13; 95% CI, 1.04-1.22; P < 0.01). There was evidence for effect modification of the association of MPO level with CKD progression by baseline eGFR (P interaction = 0.02), but not for CVD (P interaction = 0.2) or death (P interaction = 0.1). In stratified analyses, MPO level (per 1-SD increase in log-transformed MPO) was associated with greater risk for CKD progression among participants with eGFR > 45 mL/min/1.73 m2 (adjusted HR, 1.23; 95% CI, 1.03-1.46; P = 0.02) compared with those with eGFR ≤ 45 mL/min/1.73 m2 (adjusted HR, 1.10; 95% CI, 1.02-1.20; P = 0.02). The association of MPO level with CVD and death was no longer significant after adjustment for cardiac biomarkers. Limitations Potential residual confounding, lack of repeated measurements of MPO. Conclusions Higher MPO level was associated with increased risk for CKD progression, but not with CVD and death in patients with CKD from CRIC. Whether therapies aimed at reducing MPO activity can result in improved clinical outcomes is yet to be determined.

Rationale & Objective Studies using a single measurement of fibroblast growth factor 23 (FGF-23) suggest that elevated FGF-23 levels are associated with increased risk for requirement for kidney replacement therapy (KRT) in patients with chronic kidney disease. However, the data do not account for changes in FGF-23 levels as kidney disease progresses. Study Design Case-cohort study. Setting & Participants To evaluate the association between serial FGF-23 levels and risk for requiring KRT, our primary analysis included 1,597 individuals in the Chronic Renal Insufficiency Cohort Study who had up to 5 annual measurements of carboxy-terminal FGF-23. There were 1,135 randomly selected individuals, of whom 266 initiated KRT, and 462 individuals who initiated KRT outside the random subcohort. Exposure Serial FGF-23 measurements and FGF-23 trajectory group membership. Outcomes Incident KRT. Analytical Approach To handle time-dependent confounding, our primary analysis of time-updated FGF-23 levels used time-varying inverse probability weighting in a discrete time failure model. To compare our results with prior data, we used baseline and time-updated FGF-23 values in weighted Cox regression models. To examine the association of FGF-23 trajectory subgroups with risk for incident KRT, we used weighted Cox models with FGF-23 trajectory groups derived from group-based trajectory modeling as the exposure. Results In our primary analysis, the HR for the KRT outcome per 1 SD increase in the mean of natural log–transformed (ln)FGF-23 in the past was 1.94 (95% CI, 1.51-2.49). In weighted Cox models using baseline and time-updated values, elevated FGF-23 level was associated with increased risk for incident KRT (HRs per 1 SD ln[FGF-23] of 1.18 [95% CI, 1.02-1.37] for baseline and 1.66 [95% CI, 1.49-1.86] for time-updated). Membership in the slowly and rapidly increasing FGF-23 trajectory groups was associated with ∼3- and ∼21-fold higher risk for incident KRT compared to membership in the stable FGF-23 trajectory group. Limitations Residual confounding and lack of intact FGF-23 values. Conclusions Increasing FGF-23 levels are independently associated with increased risk for incident KRT.

The majority of patients with chronic kidney disease (CKD) have elevated blood pressure (BP). In patients with CKD, hypertension is associated with increased risk for cardiovascular disease, progression of CKD, and all-cause mortality. New guidelines from the American College of Cardiology/American Heart Association (ACC/AHA) recommend new thresholds and targets for the diagnosis and treatment of hypertension in patients with and without CKD. A new aspect of the guidelines is the recommendation for measurement of out-of-office BP to confirm the diagnosis of hypertension and guide therapy. In this KDOQI (Kidney Disease Outcomes Quality Initiative) perspective, we review the recommendations for accurate BP measurement in the office, at home, and with ambulatory BP monitoring. Regardless of location, validated devices and appropriate cuff sizes should be used. In the clinic and at home, proper patient preparation and positioning are critical. Patients should receive information about the importance of BP measurement techniques and be encouraged to advocate for adherence to guideline recommendations. Implementing appropriate BP measurement in routine practice is feasible and should be incorporated in system-wide efforts to improve the care of patients with hypertension. Hypertension is the number 1 chronic disease risk factor in the world; BP measurements in the office, at home, and with ambulatory BP monitoring should adhere to recommendations from the AHA.

Rationale & Objective Dialysis-requiring acute kidney injury (AKI-D) has increased substantially in the United States. We examined trends in and comorbid conditions associated with hospitalizations and in-hospital mortality in the setting of AKI-D among people with versus without diabetes. Study Design Cross-sectional study. Setting & Participants Nationally representative data from the National Inpatient Sample and National Health Interview Survey were used to generate 16 cross-sectional samples of US adults (aged ≥18 years) between 2000 and 2015. Exposure Diabetes, defined using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis codes. Outcome AKI-D, defined using ICD-9-CM diagnosis and procedure codes. Analytical Approach Annual age-standardized rates of AKI-D and AKI-D mortality were calculated for adults with and without diabetes, by age and sex. Data were weighted to be representative of the US noninstitutionalized population. Trends were assessed using join point regression with annual percent change (Δ/y) reported. Results In adults with diabetes, AKI-D increased between 2000 and 2015 (from 26.4 to 41.1 per 100,000 persons; Δ/y, 3.3%; P < 0.001), with relative increases greater in younger versus older adults. In adults without diabetes, AKI-D increased between 2000 and 2009 (from 4.8 to 8.7; Δ/y, 6.5%; P < 0.001) and then plateaued. AKI-D mortality significantly declined in people with and without diabetes. In adults with and without diabetes, the proportion of AKI-D hospitalizations with liver, rheumatic, and kidney disease comorbid conditions increased between 2000 and 2015, while the proportion of most cardiovascular comorbid conditions decreased. Limitations Lack of laboratory data to corroborate AKI diagnosis; National Inpatient Sample data are hospital-level rather than person-level data; no data for type of diabetes; residual unmeasured confounding. Conclusions Hospitalization rates for AKI-D have increased considerably while mortality has decreased in adults with and without diabetes. Hospitalization rates for AKI-D remain substantially higher in adults with diabetes. Greater AKI risk-factor mitigation is needed, especially in young adults with diabetes.

Rationale & Objective Chronic kidney disease (CKD) is a leading cause of morbidity and mortality worldwide, with limited strategies for prevention and treatment. Coffee is a complex mixture of chemicals, and consumption has been associated with mostly beneficial health outcomes. This work aimed to determine the impact of coffee consumption on kidney function. Study Design Genome-wide association study (GWAS) and Mendelian randomization. Setting & Participants UK Biobank baseline data were used for a coffee consumption GWAS and included 227,666 participants. CKDGen Consortium data were used for kidney outcomes and included 133,814 participants (12,385 cases of CKD) of mostly European ancestry across various countries. Exposure Coffee consumption. Outcomes Estimated glomerular filtration rate (eGFR), CKD GFR categories 3 to 5 (G3-G5; eGFR < 60 mL/min/1.73 m2), and albuminuria. Analytical Approach GWAS to identify single-nucleotide polymorphisms (SNPs) associated with coffee consumption in UK Biobank and use of those SNPs in Mendelian randomization analyses of coffee consumption and kidney outcomes in CKDGen. Results 2,126 SNPs were associated with coffee consumption (P < 5 × 10−8), 25 of which were independent and available in CKDGen. Drinking an extra cup of coffee per day conferred a protective effect against CKD G3-G5 (OR, 0.84; 95% CI, 0.72-0.98; P = 0.03) and albuminuria (OR, 0.81; 95% CI, 0.67-0.97; P = 0.02). An extra cup was also associated with higher eGFR (β = 0.022; P = 1.6 × 10−6) after removal of 3 SNPs responsible for significant heterogeneity (Cochran Q P = 3.5 × 10−15). Limitations Assays used to measure creatinine and albumin varied between studies that contributed data and a sex-specific definition was used for albuminuria rather than KDIGO guideline recommendations. Conclusions This study provides evidence of a beneficial effect of coffee on kidney function. Given widespread coffee consumption and limited interventions to prevent CKD incidence and progression, this could have significant implications for global public health in view of the increasing burden of CKD worldwide.

Rationale & Objective Patients receiving twice-weekly or less-frequent hemodialysis (HD) may need to undergo higher ultrafiltration rates (UFRs) to maintain acceptable fluid balance. We hypothesized that higher UFRs are associated with faster decline in residual kidney function (RKF) and a higher rate of mortality. Study Design Retrospective cohort study. Setting & Participants 1,524 patients with kidney failure who initiated maintenance HD at a frequency of twice or less per week for at least 6 consecutive weeks at some time between 2007 and 2011 and for whom baseline data for UFR and renal urea clearance were available. Predictor Average UFR during the first patient-quarter during less-frequent HD (<6, 6-<10, 10-<13, and ≥13 mL/h/kg). Outcome Time to all-cause and cardiovascular death, slope of decline in RKF during the first year after initiation of less-frequent HD (with slopes above the median categorized as rapid decline). Analytical Approach Cox proportional hazards regression for time to death and logistic regression for the analysis of rapid decline in RKF. Results Among 1,524 patients, higher UFR was associated with higher all-cause mortality; HRs were 1.43 (95% CI, 1.09-1.88), 1.51 (95% CI, 1.08-2.10), and 1.76 (95% CI, 1.23-2.53) for UFR of 6 to <10, 10 to <13, and ≥13 mL/h/kg, respectively (reference: UFR < 6 mL/h/kg). Higher UFR was also associated with higher cardiovascular mortality. Baseline RKF modified the association between UFR and mortality; the association was attenuated among patients with renal urea clearance ≥ 5 mL/min/1.73 m2. Higher UFR had a graded association with rapid decline in RKF; ORs were 1.73 (95% CI, 1.18-2.55), 1.89 (95% CI, 1.12-3.17), and 2.75 (95% CI, 1.46-5.18) at UFRs of 6 to <10, 10 to <13, and ≥13 mL/h/kg, respectively (reference: UFR < 6 mL/h/kg). Limitations Residual confounding from unobserved differences across exposure categories. Conclusions Higher UFR was associated with worse outcomes, including shorter survival and more rapid loss of RKF, among patients receiving regular HD treatments at a frequency of twice or less per week.

Rationale & Objective Influenza vaccination is recommended for all adults but particularly for older adults and those with high-risk conditions. Reduced kidney function is an important high-risk condition, but the effectiveness of influenza vaccination across kidney function is uncharacterized. We assessed the effectiveness of influenza vaccination among older adults with and without reduced kidney function. Study Design Observational cohort study. Setting & Participants 454,634 person-seasons among 110,968 individuals 65 years or older in the Geisinger Health System between the 2005 and 2015 influenza seasons, with baseline characteristics matched between those with and without vaccination using inverse probability weighting. Exposures Status of influenza vaccination. Outcomes Incident hospitalization with pneumonia/influenza, coronary heart disease, and heart failure during influenza season stratified by estimated glomerular filtration rate (eGFR; ≥ 60, 30-59, and < 30 mL/min/1.73 m2). Analytical Approach Pooled logistic regression analysis to estimate adjusted ORs. Results In the 2014-2015 influenza season, the prevalence of influenza vaccination was 63.3% without evident difference across eGFR categories. The incidence of hospitalization was higher in lower eGFRs (eg, 2.2% per person-season among those not vaccinated with eGFR < 30 vs 0.7% with ≥ 60 mL/min/1.73 m2 for pneumonia/influenza). Overall, influenza vaccination was associated with lower odds of hospitalization with pneumonia/influenza (OR, 0.86; 95% CI, 0.79-0.93), coronary heart disease (OR, 0.93; 95% CI, 0.88-0.97), and heart failure (OR, 0.92; 95% CI, 0.86-0.99). When assessing by eGFR categories, the association was consistent in eGFR ≥ 30, but not significant in < 30 mL/min/1.73 m2 (ORs of 1.04 [95% CI, 0.79-1.36] for pneumonia/influenza, 1.03 [95% CI, 0.87-1.23] for coronary heart disease, and 1.10 [95% CI, 0.92-1.33] for heart failure). Limitations Possible unmeasured confounding. Conclusions Influenza vaccination was associated with lower risk for hospitalizations with pneumonia/influenza and major cardiac diseases in eGFR ≥ 30 mL/min/1.73 m2. Studies are needed to explore optimal vaccination strategies for eGFR < 30 mL/min/1.73 m2.

Rationale & Objective There may be important transplant-related differences between right and left kidneys, including logistical/surgical considerations about vessel length for the right compared to the left kidney from the same donor. Because US centers choose between the right and left kidney when their recipient is ranked higher on a “match-run,” we sought to determine whether deceased-donor right kidneys have had worse posttransplantation outcomes than left kidneys. Study Design Paired Organ Procurement and Transplantation Network analysis. Setting & Participants Deceased-donor kidney pairs transplanted during 1990 to 2016. Exposure Right versus left kidney controlling for other significant factors. Outcomes Delayed graft function (DGF), all-cause and death-censored graft failure, and mortality. Analytical Approach Multivariable conditional logistic regression for DGF; proportional hazards models (conditional on same donor) for failure/mortality with right kidneys (operationalized as 6-month time-varying coefficients) adjusting for DGF and other confounders. Results 87,112 recipient pairs shared the following donor characteristics: mean age of 41 ± 14 years, 60% males, and 11% with cardiac death. Recipient characteristics were numerically similar by donor kidney side but with some statistical differences given the sample size. Right kidneys had slightly longer cold ischemia time. DGF occurred more often for right kidneys (28% vs 25.8%; P < 0.001; adjusted OR, 1.15 [95% CI, 1.12-1.17]). The adjusted hazard ratio (aHR) for all-cause graft failure with right kidneys within 6 months was 1.07 (95% CI, 1.03-1.11), and was 0.99 (95% CI, 0.97-1.01) thereafter. The aHRs for death-censored graft failure with right kidneys before and after 6 months were 1.11 (95% CI, 1.06-1.16) and 0.96 (95% CI, 0.93-0.99), respectively; the corresonding aHRs for mortality were 0.99 (95% CI, 0.93-1.04) and 1.00 (95% CI, 0.98-1.03), respectively. Limitations Registry data, different transplant eras, reasons for kidney side unavailable. Conclusions There is modest association for transplantation of right kidneys with DGF and graft loss within the first 6 months, which is lost beyond this time point. These findings do not support the use of laterality of deceased-donor kidneys as an important factor in organ acceptance decisions.

Despite optimal anticoagulation and blood pressure control, patients with antiphospholipid syndrome (APS) nephropathy frequently progress to kidney failure, and recurrence after transplantation is common. The mTORC (mechanistic target of rapamycin complex) pathway was recently identified as a potential intermediate and a therapeutic target in vascular lesions associated with APS nephropathy. However, these results were derived from the retrospective analysis of a small cohort of patients receiving sirolimus after kidney transplantation. Therefore, they warranted external validation and the demonstration of the potential benefit of sirolimus in native kidney APS nephropathy. We report a patient with active APS nephropathy lesions occurring on native kidneys, in which endothelial mTORC activation was substantiated at the molecular level. Treatment with sirolimus was shown on a repeat kidney biopsy to successfully inhibit the AKT/mTORC pathway and was associated with significant improvement in kidney function and lesions of vasculopathy. Drug tolerance was excellent during the entire follow-up. This case validates and extends previous observations in kidney transplant recipients and demonstrates that endothelial activation of the AKT/mTORC pathway occurs in the damaged renal vasculature of native kidneys in APS nephropathy. These findings further support the potential of precision medicine and the use of mTORC activation as a biomarker of disease activity and as therapeutic target in patients with APS nephropathy.

Rationale & Objective On account of the high prevalence of cardiovascular disease in patients with kidney failure, clinical practice guidelines recommend regular screening for asymptomatic coronary artery disease (CAD) in patients on the kidney transplant waitlist. To date, the cost-effectiveness of such screening has not been evaluated. A Canadian-Australasian randomized controlled trial of screening kidney transplant candidates for CAD (CARSK) is currently is being conducted to answer this question. We conducted a cost-utility analysis to determine, before completion of the trial, the cost-effectiveness of no further screening versus regular screening for asymptomatic CAD and to evaluate potential influential variables that may affect results of the economic evaluation. Study Design A modeled cost-utility analysis. Setting & Population A theoretical cohort of adult Australian and New Zealand kidney transplant candidates on the waitlist. Intervention No further screening for asymptomatic CAD versus regular protocolized screening (annual or second yearly) for CAD after kidney transplant waitlisting. Outcomes Incremental cost-effectiveness ratio, reported as cost per quality-adjusted life-year (QALY). Model, Perspectives, & Timeframe Markov microsimulation model, health system perspective and over a lifetime horizon. Results In the base case, the incremental cost-effectiveness ratio of no further screening was $11,122 per QALY gained when compared with regular screening. No further screening increased survival by 0.49 life-year or 0.35 QALY. One-way sensitivity analyses identified the costs of transplantation in the first year and CAD prevalence as the most influential variables. Probabilistic sensitivity analyses showed that 94% of the simulations were cost-effective below a willingness-to-pay threshold of $50,000 per QALY gained. Limitations Rates of cardiovascular events in waitlisted candidates and transplant recipients are limited in the contemporary era. The results may not be generalizable to populations outside Australia and New Zealand. Conclusions No further screening for CAD after waitlisting is likely to be cost-effective and may improve survival. Precision around CAD prevalence estimates and health care resource use will reduce existing uncertainty.

There is increasing appreciation of nephronophthisis (NPHP) as an autosomal recessive cause of kidney failure and earlier stages of chronic kidney disease among adults. We identified 2 families with presumed adult-diagnosed nonsyndromic NPHP and negative diagnostic genetic testing results from our Renal Genetics Clinic. Both had 2 affected siblings without extrarenal phenotypes. After informed consent, research whole-genome sequencing was undertaken. Biallelic NPHP4 variants were identified in trans and clinically confirmed in all 4 affected individuals, confirming a genetic diagnosis. Participant 1 of the first family (F1P1) had kidney failure diagnosed at 19 years of age. An affected younger sibling (F1P2) reached kidney failure at age 15 years after kidney biopsy suggested NPHP. Pathogenic variants detected in NPHP4 in this family were NM_015102.4:c.3766C>T (p.Gln1256*) and a 31-kb deletion affecting exons 12 to 16. In the second family, F2P3 reached kidney failure at age 27 years having undergone kidney biopsy suggesting NPHP. An affected younger sibling (F2P4) has chronic kidney disease stage 4 at age 39 years. The NPHP4 variants detected were NM_015102.4:c.1998_1999del (p.Tyr667Phefs*23) and c.3646G>T (p.Asp1216Tyr). The latter variant was initially missed in diagnostic sequencing due to inadequate NPHP4 coverage (94.3% exonic coverage). With these reports, we identify NPHP4 as an appreciable genetic cause for adult-diagnosed nonsyndromic NPHP that should be considered by adult nephrologists.

Rationale & Objective Left-sided internal jugular and all subclavian central venous catheters (CVCs) cause thoracic central vein occlusions (TCVOs) more often than right-sided internal jugular catheters. To enable right-sided CVC placement in patients with TCVO, an inside-out access (IOA) approach was established at 3 vascular access centers in Europe involving use of a novel IOA device advanced from the right femoral vein. In the current analysis, we assessed the eligibility and success rate of this IOA approach in a cohort of patients with TCVO requiring a tunneled dialysis catheter. Study Design Retrospective multicenter observational study. Setting & Participants 36 patients with TCVO treated in Vienna, Austria; Oxford, England; or Cologne, Germany, who required hemodialysis access between July 2016 and June 2018. Exposure Application of the IOA approach to gain vascular access. Outcome The primary end point was the success rate of passing the TCVO to gain dialysis access using the IOA approach. Secondary end points were catheter patency at 3 months and procedure-related complications (early infections, bleeding, hematoma, and pericardial effusions). Analytical Approach Descriptive statistics to characterize eligibility, success rate, and complications of the IOA approach. Results 36 patients with TCVO and history of multiple CVCs and arteriovenous fistulas were referred to the participating centers for vascular access. 32 (89%) patients were eligible for the IOA approach. 39 treatments were performed, with 7 patients undergoing the IOA procedure a second time more than 3 months after initial CVC placement. Dialysis access was established successfully in 38 of 39 (97%) implementations of the IOA procedure. Median intervention time was 43 minutes. No complications occurred. Limitations No comparison to other methods to place CVCs and the observational study design. Conclusions The IOA approach is a promising method to enable rapid access to the right jugular vein in the setting of pre-existing TCVO. Additional experience is needed to understand the generalizability of these observations.

Rationale & Objective Women with end-stage kidney disease (ESKD) have decreased fertility and are at increased risk for pregnancy complications. This study examined secular trends and outcomes of obstetric deliveries in a US cohort of women with ESKD. Study Design Retrospective cohort study. Setting & Participants Women aged 18 to 44 years with ESKD and registered in the US Renal Data System from 2002 to 2015. Exposure ESKD modality (hemodialysis [HD], peritoneal dialysis, transplantation). Outcomes Infant delivery, preterm delivery, cesarean delivery. Analytical Approach Unadjusted delivery rates were expressed as number of delivering women per 1,000 patient-years among women aged 18 to 44 years within each year during the study period, stratified by ESKD modality. Logistic regression models were used to evaluate associations of delivery, preterm delivery, and cesarean delivery with patient characteristics. Results The delivery rate in women undergoing HD and women with a kidney transplant increased from 2.1 to 3.6 and 3.1 to 4.6 per 1,000 patient-years, respectively (P < 0.001 for each). The delivery rate in patients undergoing peritoneal dialysis was lower and did not increase significantly (P = 0.9). Women with a transplant were less likely to deliver preterm compared with women undergoing HD (OR, 0.92; 95% CI, 0.84-1.00), though more likely have a cesarean delivery (OR, 1.18; 95% CI, 1.06-1.31). For deliveries occurring in the 2012 to 2015 period, 75% of women treated with HD were prescribed 4 or fewer outpatient HD treatments per week and 25% were prescribed 5-plus treatments per week in the 30 days before delivery. Limitations Ascertainment of outcomes and comorbid conditions using administrative claims data. Conclusions The delivery rate in women of reproductive age with ESKD increased from 2002 to 2015 among those treated with transplantation or HD. Women with a functioning transplant were less likely to deliver preterm, but more likely to have a cesarean delivery. Prescriptions for outpatient intensified HD for pregnant women with ESKD were infrequent in 2012 to 2015.

Rationale & Objective Patients with multiple comorbid conditions are less likely to use an arteriovenous fistula (AVF) for hemodialysis vascular access. Some dialysis facilities have high rates of AVF placement despite having patients with many comorbid conditions. This study describes variation in facility-level use of AVFs across the facility-level burden of patient comorbid conditions. Study Design Retrospective cohort study. Setting & Participants Medicare patients receiving hemodialysis for 1 year or more in US dialysis facilities. Predictors Facility-level burden of patient comorbid conditions; patient characteristics. Outcomes Odds of AVFs versus other access types; facility-level use of AVFs. Analytical Approach Facility-level comorbidity burden was calculated by summing individual comorbid conditions, determining the average per patient, then defining 11 groups based on facility percentile ranking. Generalized estimating equations with a logit link were used to estimate the odds of AVF placement at the patient level. For the facility-level analysis, a generalized estimating equation model with the identity link was fit to characterize the percentage of AVF use at each facility. Results Overall, AVF use was 65.8% in 315,919 prevalent hemodialysis patients among 5,813 facilities. After adjustment for patient characteristics, AVF use was 0.27, 0.30, 1.05, and 1.74 percentage points lower than the median among facilities in the 61st to 70th, 71st to 80th, 81st to 90th, and 91st to 99th percentiles of comorbidity, respectively, and 0.42, 0.63, 1.34, and 1.90 percentage points higher than the median among facilities in the 31st to 40th, 21st to 30th, 11th to 20th, and 1st to 10th percentiles of comorbidity, respectively. Facilities in the greater than 99th percentile of comorbidity burden had AVF use that was 3.47 percentage points lower than the median. Facilities in the less than 1st percentile of comorbidity burden had AVF use that was 2.64 percentage points greater than the median. Limitations Limited to Medicare dialysis-dependent patients treated for 1 year or more. Conclusions After adjustment for patient characteristics, we found small differences in facility rates of AVF use except in the extremes of high or low levels of comorbidity burden. Our study demonstrates that dialysis facilities with a relatively high patient comorbidity burden can achieve similar fistula rates as facilities with healthier patients. Although high comorbidity burden does not explain low facility AVF use, additional study is needed to understand differences in AVF use rates between facilities with similar comorbidity burdens.

Rationale & Objective Chronic kidney disease (CKD), defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2, is a risk factor for cardiovascular morbidity and mortality. Little is known about low birth weight and risk for CKD in middle-aged adults in the general population. We estimated the causal association between birth weight and eGFR in a Dutch cohort of middle-aged men and women. Study Design Retrospective cohort study. Setting & Participants 6,671 participants in the Netherlands Epidemiology of Obesity (NEO) Study. Replication study using data for 133,814 participants studied by the CKDGen consortium. Exposure Birth weight was self-reported and also based on an instrumental variable, 59 birth weight–associated genetic variants, derived from an independent data source. Outcome eGFR at the age of 45 to 65 years. Analytical Approach We assessed the association between self-reported birth weight and eGFR in the NEO Study using multivariable linear regression, adjusted for age, sex, education, smoking, and alcohol use. The effect of the instrument on eGFR was estimated using separate 2-sample Mendelian randomization analyses: one using individual data from the NEO cohort and one using summary data from the CKDGen consortium. Results At baseline, mean eGFR was 86 ± 12.4 (SD) mL/min/1.73 m2. After multivariable adjustment, self-reported birth weight was not associated with kidney function in middle age. Two-sample Mendelian randomization analysis showed that in the NEO cohort, for each 500-g lower birth weight defined using genetic variants, there was a 3.7 (95% CI, 0.5-6.9)–mL/min/1.73 m2 lower eGFR at the age of 45 to 65 years. However, using CKDGen summary-level data, there was a smaller nonsignificant relationship between birth weight and eGFR. Limitations Birth weight was self-reported. Conclusions Lower birth weight defined using genetic variants was associated with lower eGFRs in Dutch middle-aged adults. However, this finding was not replicated within the CKDGen consortium.

Rationale & Objective Idiopathic retroperitoneal fibrosis (IRF) is a rare disorder of unknown cause. Medical therapy can induce remission, but disease relapses are common. This study sought to characterize long-term outcomes of IRF and the factors associated with disease recurrences. Study Design Retrospective cohort study. Setting & Participants Retrospective analysis of 50 patients with IRF prospectively followed up for 8.9 (IQR, 4.7-12.7) years at a tertiary-care referral center. Exposures Demographic, clinical, treatment, and laboratory parameters, including measures of autoimmunity. Outcome Disease relapse. Analytical Approach Proportional hazards analysis for the subdistribution of competing risks. Results 49 patients received medical treatment and 35 underwent interventional procedures. All patients experienced a clinical response (defined as regression of disease-related symptoms and hydronephrosis, and decrease in the maximal transverse diameter of the retroperitoneal mass on computed tomography of >50%), 44 of whom responded within 1 year. The remaining 6 responded over a median of 2.95 years after starting therapy. 40 patients were alive at last observation, 1 receiving maintenance dialysis and 15 with estimated glomerular filtration rate < 60 mL/min/1.73 m2. Patient survival at 5, 10, and 15 years was 95%, 84%, and 68%, respectively. 19 (38%) patients had at least 1 relapse (occurring a median of 5.19 years after starting therapy), defined as an increase in serum creatinine level of at least 30% or recurrence/development of hydronephrosis and ≥20% increase in the maximal transverse diameter of the retroperitoneal mass on computed tomography. Cumulative incidences of relapse at 5, 10, and 15 years were 21%, 41%, and 48%, respectively. Baseline antinuclear antibody positivity and male sex were associated with relapse (subdistribution hazard ratios [sHRs] of 5.35 [95% CI, 2.15-13.27] and 4.94 [95% CI, 1.32-18.57], respectively), while higher corticosteroid therapy dosage at 1 year (sHR for relapse per 1-mg/d greater dosage, 0.91 [95% CI, 0.84-0.98]) and treatment with prednisone alone or with tamoxifen (sHR for relapse of 0.25 [95% CI, 0.07-0.85] vs other therapies) were associated with lower rate of relapse. Limitations Small sample size and variable approaches to therapy. Conclusions IRF relapses were common and were experienced more frequently by male patients. Corticosteroids alone or with tamoxifen were associated with a lower rate of relapse. The strong association of antinuclear antibody positivity with relapse supports the hypothesis of an autoimmune pathogenesis of IRF.

Rationale & Objective The association between bariatric surgery, type 2 diabetes, and chronic kidney disease (CKD) is poorly understood. We studied whether remission of type 2 diabetes induced by bariatric surgery influences markers of kidney disease, if CKD is associated with remission of diabetes after bariatric surgery, and if baseline levels of gut hormones and peptides modify these associations. Study Design Prospective observational study. Study Participants 737 bariatric surgery patients with type 2 diabetes who participated in a multicenter cohort study for up to 5 years. Predictors Demographics, blood pressure, medications, type of bariatric surgery, anthropometrics, markers of kidney disease, and circulating levels of gut hormones and peptides. Outcomes Estimated glomerular filtration rate (eGFR), urinary albumin excretion, prognostic risk for CKD, and remission of diabetes. Analytical Approach Linear mixed models for eGFR; generalized linear mixed models with logit link for albuminuria, prognostic risk for CKD, and diabetes remission. Results Remission of diabetes at 5 years post–bariatric surgery was not independently associated with eGFR but was associated with lower risk for moderate/severe increase in albuminuria (risk ratio, 0.66; 95% CI, 0.48-0.90) and stabilization in prognostic risk for CKD. These findings were modified by baseline ghrelin level. Lower preoperative eGFR and greater prognostic risk for CKD were independently associated with reduced likelihood of diabetes remission. The association with preoperative GFR was modified by C-peptide level. Higher baseline circulating ghrelin level was independently associated with a lower prognostic risk for CKD. Limitations A minority of participants had baseline CKD; lack of comparison group; no information on duration of diabetes, other clinical end points, or kidney biopsy results. Conclusions Remission of type 2 diabetes 5 years after bariatric surgery was associated with improvements in albuminuria and stabilized prognostic risk for CKD, but not with eGFR. Lower kidney function and greater prognostic risk at the time of bariatric surgery was linked to a lower likelihood of diabetes remission. These results highlight the need to identify the mechanisms through which bariatric surgery may delay the long-term progression of CKD in type 2 diabetes.

Myeloproliferative neoplasms (MPNs) are associated with somatic mutations of genes including JAK2, CALR, or MPL in hematopoietic stem cells. Various glomerular lesions are known to be involved in MPN-related glomerulopathy, including mesangial hypercellularity, segmental sclerosis, features of chronic thrombotic microangiopathy, and intracapillary hematopoietic cell infiltration. Renal extramedullary hematopoiesis (EMH) is uncommon, but it is reported to occur in the setting of MPN; however, to our knowledge, there have been no reports of renal EMH with pathologically verified mutations. We report the case of a 65-year-old woman with MPN who had a CALR mutation and developed nephrotic syndrome. Kidney biopsy showed the typical findings of MPN-related glomerulopathy. CALR mutation–specific immunostaining of the kidney revealed immunopositive cells in the EMH lesion of the interstitium, indicating that renal EMH was caused by CALR-mutated cells. Based on these findings, we diagnosed nephrotic syndrome caused by MPN-related glomerulopathy. After initiation of steroid therapy, the patient’s proteinuria gradually decreased and she achieved an incomplete remission. Additionally, the patient was prescribed the JAK inhibitor ruxolitinib and maintained incomplete remission. There is no established treatment for MPN-related glomerulopathy; therefore, further studies are needed to elucidate its pathophysiology.

Dysproteinemic kidney diseases occur when B- or plasma cell clones produce pathogenic monoclonal immunoglobulins or light chains that cause kidney damage. The clinical presentation of these disorders ranges from sub–nephrotic-range proteinuria or microscopic hematuria with preserved kidney function to severe nephrotic syndrome to severe acute kidney injury or rapidly progressive glomerulonephritis. These monoclonal immunoglobulins can cause a variety of histologic patterns of injury, including cast nephropathy, glomerular and tubular deposition diseases, amyloidosis, and inflammatory glomerulonephritis. The underlying clonal disorder may meet criteria for overt multiple myeloma or systemic lymphoma. In recent years, there has been increased recognition and study of dysproteinemic kidney diseases that occur in the setting of smaller clonal plasma and B-cell populations, which are classified as monoclonal gammopathies of renal significance. Regardless of clonal cell burden, the goal of treatment is to achieve a hematologic response (ie, improvement or resolution of the monoclonal protein) by eradicating the underlying clone. Organ-specific responses are dependent on achieving hematologic response. Without appropriate treatment, many of these disorders are associated with high rates of progressive kidney disease and end-stage kidney disease. In this installment of AJKD's Core Curriculum in Nephrology, we review the pathogenesis, diagnosis, and treatment of dysproteinemic kidney diseases.

Immune checkpoint inhibitors are increasingly used to treat a variety of solid-organ and hematologic cancers. However, overactivation of the immune system can lead to immune-related adverse events, which are increasingly recognized in the kidney. There have been only rare reported cases of checkpoint inhibitor–associated glomerulonephritis and renal vasculitis, although vasculitis in other organs has been well described. We report 4 cases of renal vasculitis or pauci-immune glomerulonephritis after checkpoint inhibitor therapy. Three patients had renal small- to medium-vessel vasculitis and 1 had focally crescentic pauci-immune glomerulonephritis. Three patients presented with acute kidney injury, and 1 presented with nephrotic syndrome and hematuria. Three patients were tested for antineutrophil cytoplasmic antibodies, which were negative. The time from checkpoint inhibitor initiation to immune-related adverse event presentation ranged from 2 weeks to 24 months. Three patients were treated with glucocorticoids, resulting in clinical resolution. Our series demonstrates that renal vasculitis and pauci-immune glomerulonephritis are important considerations in the differential diagnosis of checkpoint inhibitor–related reductions in kidney function.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of disorders characterized by inflammation and destruction of small- and medium-sized blood vessels and the presence of circulating ANCA. Clinical disease phenotypes include granulomatosis with polyangiitis, microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis, and renal-limited vasculitis. Serologic classification of AAV into proteinase 3–ANCA disease and myeloperoxidase-ANCA disease correlates with a number of disease characteristics. AAV has a predilection for the kidney, with >75% of patients having renal involvement characterized by rapidly progressive glomerulonephritis. The cause and pathogenesis of AAV are multifactorial and influenced by genetics, environmental factors, and responses of the innate and adaptive immune system. Randomized controlled trials in the past 2 decades have refined the therapy of AAV and transformed AAV from a fatal disease to a chronic illness with relapsing course and associated morbidity. This article in AJKD’s Core Curriculum in Nephrology series provides a detailed review of the epidemiology, pathogenesis, diagnosis, and advances in the management of AAV.

Rationale & Objective Angiotensin-converting enzyme (ACE) inhibitors are beneficial in heart failure with reduced ejection fraction (HFrEF). We sought to describe longitudinal trends in estimated glomerular filtration rate (eGFR) in HFrEF and how ACE-inhibitor therapy influences these changes. Study Design Post hoc analysis of trial data. Settings & Participants Symptomatic (Treatment Trial, n = 2,423) and asymptomatic (Prevention Trial, n = 4,094) patients from the Studies of Left Ventricular Dysfunction (SOLVD). Exposure Enalapril versus placebo. Outcomes Early and long-term eGFR slope (ie, within and after the first 6 weeks) and 4 kidney end points: (1) serum creatinine level increase by ≥0.3 mg/dL, (2) >30% eGFR decline, (3) >40% eGFR decline, and (4) incident eGFR < 30 mL/min/1.73 m2. Analytical Approach Shared parameter models, multivariable Cox regression models. Results Baseline mean eGFR was lower in the Treatment Trial than in the Prevention Trial, 69.5 ± 19.8 (SD) versus 76.2 ± 18.6 mL/min/1.73 m2. Following randomization, an early eGFR decline occurred in the enalapril group; however, slopes during the median 3-year follow-up were not statistically different by randomization arm in either the Treatment Trial (−0.84 in enalapril vs −1.36 mL/min/1.73 m2 per year in placebo; P = 0.08) or Prevention Trial (−1.27 in enalapril vs −1.36 mL/min/1.73 m2 per year in placebo; P = 0.7). Random assignment to enalapril treatment increased the risk for all 4 outcomes in the Treatment Trial in the first 6-week period (HRs were 1.48 [95% CI, 1.10-1.99] for creatinine increase by ≥0.3 mg/dL; 1.38 [95% CI, 0.98-1.94] for eGFR decline > 30%; 2.60 [95% CI, 1.30-5.21] for eGFR decline > 40%; and 4.71 [95% CI, 1.78-12.50] for eGFR < 30 mL/min/1.73 m2), but after the first year was not significantly associated with increased risk. A similar albeit less pronounced pattern was observed in the Prevention Trial, with risks present only in the early period. Limitations Creatinine results were not blinded, making it possible that ACE-inhibitor/placebo dosing was influenced by creatinine level. Conclusion Kidney function decline is slow in HFrEF. Although random assignment to enalapril treatment results in a statistically increased risk for kidney surrogates, the risk is limited to the early phase and late eGFR slopes and risks are not different by randomly assigned group.

With implementation of the Kidney Allocation System, the growth of kidney paired donation programs, and advances in desensitization and immunosuppression, the outlook for “untransplantable” kidney transplantation candidates has never been more promising. The Kidney Allocation System prioritized compatible matches for candidates with calculated panel-reactive antibody levels of 98%, 99%, or 100% and broadened allocation of non-A1 and non–A1-B subgroup kidneys to blood group type B candidates. Concurrently, the growth of kidney paired donation programs and use of incompatible transplantation as part of kidney paired donation to achieve “more compatible” kidney transplantation has improved options for candidates with an incompatible living donor. Finally, advances in desensitization and immunosuppression have strengthened the ability to manage donor-specific antibodies and antibody-mediated rejection. Although no patient should be labeled “untransplantable” due to blood group type or donor-specific antibody, all candidates should be provided with individualized and realistic counseling regarding their anticipated wait times for deceased donor or kidney paired donation matching, with early referral to expert centers when needed. In this Perspective, we consider blood group type ABO incompatibility, HLA antigen incompatibility, antibody-mediated rejection, kidney paired donation, and recent developments in incompatible transplantation in more depth and recommend an approach to the sensitized candidate.

Background Timely follow-up of abnormal laboratory results is important for high-quality care. We sought to identify risk factors, facilitators, and barriers to timely follow-up of an abnormal estimated glomerular filtration rate (eGFR) for the diagnosis of chronic kidney disease. Study Design Mixed-methods study: retrospective electronic health record (EHR) analyses, physician interviews. Setting & Participants Large integrated health care delivery system. Quantitative analyses included 244,540 patients 21 years or older with incident abnormal eGFRs from January 1, 2010, to December 31, 2015, ordered by 7,164 providers. Qualitative analyses included 15 physician interviews. Exposures Patient-, physician-, and system-level factors. Outcome Timely follow-up of incident abnormal eGFRs, defined as repeat eGFR obtained within 60 to 150 days, follow-up testing before 60 days that indicated normal kidney function, or diagnosis before 60 days of chronic kidney disease or kidney cancer. Analytical Approach Multivariable robust Poisson regression models accounting for clustering within provider were used to estimate risk ratios (RRs) and 95% CIs for lack of timely follow-up. Team coding was used to identify themes from physician interviews. Results 58% of patients lacked timely follow-up of their incident abnormal eGFRs (ie, had a care gap). An abnormal creatinine result flag in the EHR was associated with better follow-up (RR for care gap, 0.65; 95% CI, 0.64-0.66). Patient online portal use and physician panel size were weakly associated with follow-up. Patients seen by providers behind on managing their EHR message box were at higher risk for care gaps. Physician interviews identified system-level (eg, panel size and assistance in managing laboratory results) and provider-level (eg, proficiency using EHR tools) factors that influence laboratory result management. Limitations Unable to capture intentional delays in follow-up testing. Conclusions Timely follow-up of abnormal results remains challenging in an EHR-based integrated health care delivery system. Strategies improving provider EHR message box management and leveraging health information technology (eg, flagging abnormal eGFR results), making organizational/staffing changes (eg, increasing the role of nurses in managing laboratory results), and boosting patient engagement through better patient portals may improve test follow-up.

Rationale & Objective Contaminated water and other fluids are increasingly recognized to be associated with health care–associated infections. We investigated an outbreak of Gram-negative bloodstream infections at 3 outpatient hemodialysis facilities. Study Design Matched case-control investigations. Setting & Participants Patients who received hemodialysis at Facility A, B, or C from July 2015 to November 2016. Exposures Infection control practices, sources of water, dialyzer reuse, injection medication handling, dialysis circuit priming, water and dialysate test findings, environmental reservoirs such as wall boxes, vascular access care practices, pulsed-field gel electrophoresis, and whole-genome sequencing of bacterial isolates. Outcomes Cases were defined by a positive blood culture for any Gram-negative bacteria drawn July 1, 2015 to November 30, 2016 from a patient who had received hemodialysis at Facility A, B, or C. Analytical Approach Exposures in cases and controls were compared using matched univariate conditional logistic regression. Results 58 cases of Gram-negative bloodstream infection occurred; 48 (83%) required hospitalization. The predominant organisms were Serratia marcescens (n = 21) and Pseudomonas aeruginosa (n = 12). Compared with controls, cases had higher odds of using a central venous catheter for dialysis (matched odds ratio, 54.32; lower bound of the 95% CI, 12.19). Facility staff reported pooling and regurgitation of waste fluid at recessed wall boxes that house connections for dialysate components and the effluent drain within dialysis treatment stations. Environmental samples yielded S marcescens and P aeruginosa from wall boxes. S marcescens isolated from wall boxes and case-patients from the same facilities were closely related by pulsed-field gel electrophoresis and whole-genome sequencing. We identified opportunities for health care workers’ hands to contaminate central venous catheters with contaminated fluid from the wall boxes. Limitations Limited patient isolates for testing, on-site investigation occurred after peak of infections. Conclusions This large outbreak was linked to wall boxes, a previously undescribed source of contaminated fluid and biofilms in the immediate patient care environment.

Rationale & Objective Identifying patients who are likely to transfer from peritoneal dialysis (PD) to hemodialysis (HD) before transition could improve their subsequent care. This study developed a prediction tool for transition from PD to HD. Study Design Retrospective cohort study. Setting & Participants Adults initiating PD between January 2008 and December 2011, followed up through June 2015, for whom data were available in the US Renal Data System (USRDS). Predictors Clinical characteristics at PD initiation and peritonitis claims. Outcomes Transfer to HD, with the competing outcomes of death and kidney transplantation. Analytical Approach Outcomes were ascertained from USRDS treatment history files. Subdistribution hazards (competing-risk) models were fit using clinical characteristics at PD initiation. A nomogram was developed to classify patient risk at 1, 2, 3, and 4 years. These data were used to generate quartiles of HD transfer risk; this quartile score was incorporated into a cause-specific hazards model that additionally included a time-dependent variable for peritonitis. Results 29,573 incident PD patients were followed up for a median of 21.6 (interquartile range, 9.0-42.3) months, during which 41.2% transferred to HD, 25.9% died, 17.1% underwent kidney transplantation, and the rest were followed up to the study end in June 2015. Claims for peritonitis were present in 11,733 (40.2%) patients. The proportion of patients still receiving PD decreased to <50% at 22.6 months and 14.2% at 5 years. Peritonitis was associated with a higher rate of HD transfer (HR, 1.82; 95% CI, 1.76-1.89; P < 0.001), as were higher quartile scores of HD transfer risk (HRs of 1.31 [95% CI, 1.25-1.37), 1.51 [95% CI, 1.45-1.58], and 1.78 [95% CI, 1.71-1.86] for quartiles 2, 3, and 4 compared to quartile 1 [P < 0.001 for all]). Limitations Observational data, reliant on the Medical Evidence Report and Medicare claims. Conclusions A large majority of the patients who initiated renal replacement therapy with PD discontinued this modality within 5 years. Transfer to HD was the most common outcome. Patient characteristics and comorbid diseases influenced the probability of HD transfer, death, and transplantation, as did episodes of peritonitis.

Rationale & Objective Renal arteriolar microangiopathic lesions may occur in immunoglobulin A nephropathy (IgAN), but their role in disease progression remains unclear. We sought to understand the prevalence and character of microangiopathic lesions in IgAN and their role in disease progression. Study Design A retrospective cohort study. Setting & Participants In this study, we enrolled a Chinese cohort with 944 adult patients with IgAN who had been followed up for at least 1 year. Predictors Renal arteriolar microangiopathic lesions. Outcomes Composite kidney end point event defined as a >50% reduction in estimated glomerular filtration rate, end-stage kidney disease, or death. Analytical Approach All kidney biopsies were independently reviewed by 2 investigators. Renal arteriolar microangiopathic lesions were detected using light microscopy. Multivariable Cox regression analysis was used to test the association between microangiopathic lesions and the outcomes. Results Overall, 194 (20.6%) patients had renal arteriolar microangiopathic lesions. Patients with microangiopathic lesions presented with higher blood pressures, more severe proteinuria, and lower estimated glomerular filtration rates (all P < 0.001) than patients without microangiopathic lesions. After a median follow-up of 4.2 years, 75 (38.7%) patients with microangiopathic lesions and 83 (11.1%) patients without these lesions reached the composite kidney end point (P < 0.001). In a multivariable Cox regression model adjusting for clinical and pathologic variables available at the time of biopsy, the presence of microangiopathic lesions was an independent risk factor for kidney failure (HR, 1.95; 95% CI, 1.34-2.83; P < 0.001). Renal vascular sclerosis (arterial intimal fibrosis or arteriolar hyalinosis) was not a risk factor for kidney disease progression (P = 0.5). Limitations A single Chinese center’s experience, retrospective study, most patients were not tested for hemolytic markers (for example, haptoglobin level, lactate dehydrogenase level, and schistocytes). Conclusions Renal arteriolar microangiopathic lesions are frequent in IgAN and their presence is independently associated with progression to kidney failure. If confirmed in other patient cohorts, such lesions could be considered for inclusion in formal classification schemes of IgAN.

Rationale & Objective Compared with others, black and low-income patients receiving dialysis are less likely to receive kidney transplantation (KT) education within dialysis centers. We examined the efficacy of 2 supplementary KT education approaches delivered directly to patients. Study Design Prospective, 3-arm parallel-group, randomized, controlled trial. Settings & Participants Adult, black, and white low-income patients receiving dialysis in Missouri. Intervention Patients were randomly assigned to 1 of 3 educational conditions: (1) standard of care, usual KT education provided in dialysis centers (control); (2) Explore Transplant @ Home patient-guided, 4 modules of KT education sent directly to patients using print, video, and text messages; and (3) Explore Transplant @ Home educator-guided, the patient-guided intervention plus 4 telephonic discussions with an educator. Outcomes Primary: patient knowledge of living (LDKT) and deceased donor KT (DDKT). Secondary: informed decision making, change in attitudes in favor of LDKT and DDKT, and change in the number of new steps taken toward KT. Results In intent-to-treat analyses, patients randomly assigned to educator- and patient-guided interventions had greater knowledge gains (1.4 point increase) than control patients (0.8 point increase; P = 0.02 and P = 0.01, respectively). Compared with control patients, more patients randomly assigned to educator- and patient-guided interventions were able to make informed decisions about starting KT evaluation (82% vs 91% and 95%; P = 0.003), pursuing DDKT (70% vs 84% and 84%; P = 0.003), and pursuing LDKT (73% vs 91% and 92%; P < 0.001). Limitations Potential contamination because of patient-level randomization; no assessment of clinical end points. Conclusions Education presented directly to dialysis patients, with or without coaching by telephone, increased dialysis patients’ KT knowledge and informed decision making without increasing educational burden on providers. Funding Source This project was funded by the National Institutes of Health and Health Resources and Services Administration. Trial Registration Registered at ClinicalTrials.gov with study number NCT02268682.

A pragmatic cluster-randomized trial (CRT) is a research design that may be used to efficiently test promising interventions that directly inform dialysis care. While the Ottawa Statement on the Ethical Design and Conduct of Cluster Randomized Trials provides general ethical guidance for CRTs, the dialysis setting raises additional considerations. In this article, we outline ethical issues raised by pragmatic CRTs in dialysis facilities. These issues may be divided into 7 key domains: justifying the use of cluster randomization, adopting randomly allocated individual-level interventions as a facility standard of care, conducting benefit-harm analyses, gatekeepers and their responsibilities, obtaining informed consent from research participants, patient notification, and including vulnerable participants. We describe existing guidelines relevant to each domain, illustrate how they were considered in the Time to Reduce Mortality in End-Stage Renal Disease (TiME) trial (a prototypical pragmatic hemodialysis CRT), and highlight remaining areas of uncertainty. The following is the first step in an interdisciplinary mixed-methods research project to guide the design and conduct of pragmatic CRTs in dialysis facilities. Subsequent work will expand on these concepts and when possible, argue for a preferred solution.

Rationale & Objective Ventricular assist devices (VADs) are used for end-stage heart failure not amenable to medical therapy. Acute kidney injury (AKI) in this setting is common due to heart failure decompensation, surgical stress, and other factors. Little is known about national trends in AKI diagnosis and AKI requiring dialysis (AKI-D) and associated outcomes with VAD implantation. We investigated national estimates and trends for diagnosed AKI, AKI-D, and associated patient and resource utilization outcomes in hospitalizations in which implantable VADs were placed. Study Design Cohort study of 20% stratified sample of US hospitalizations. Setting & Participants Patients who underwent implantable VAD placement in 2006 to 2015. Exposure No AKI diagnosis, AKI without dialysis, AKI-D. Outcomes In-hospital mortality, length of stay, estimated hospitalization costs. Analytical Approach Multivariate logistic and linear regression using survey design methods to account for stratification, clustering, and weighting. Results An estimated 24,140 implantable VADs were placed, increasing from 853 in 2006 to 3,945 in 2015. AKI was diagnosed in 56.1% of hospitalizations and AKI-D occurred in 6.5%. AKI diagnosis increased from 44.0% in 2006 to 2007 to 61.7% in 2014 to 2015; AKI-D declined from 9.3% in 2006 to 2007 to 5.2% in 2014 to 2015. Mortality declined in all AKI categories but this varied by category: those with AKI-D had the smallest decline. Adjusted hospitalization costs were 19.1% higher in those with diagnosed AKI and 39.6% higher in those with AKI-D, compared to no AKI. Limitations Administrative data; timing of AKI with respect to VAD implantation cannot be determined; limited pre-existing chronic kidney disease ascertainment; discharge weights not derived for subpopulation of interest. Conclusions A decreasing proportion of patients undergoing VAD implantation experience AKI-D, but mortality among these patients remains high. AKI diagnosis with VAD implantation is increasing, possibly reflecting changes in AKI surveillance, awareness, and coding.

Women with chronic kidney disease (CKD) are faced with complex decisions and significant challenges during their reproductive years. Contraceptive choices have a variety of side effects that can disproportionately affect women with CKD, limiting choice. CKD itself and the therapies needed to treat severe disease can affect future fertility. When conception is desired, young women with CKD must plan meticulously because an ill-timed pregnancy can result in disease progression or flare and exposure of an unborn child to potentially teratogenic medications. Among women with CKD, pregnancy risks are substantial, with up to 10-fold higher risk for preeclampsia and 6-fold higher risk for preterm delivery. These pregnancy complications associated with inadequate placentation also increase maternal and newborn risks for cardiovascular morbidity and mortality and progression to kidney failure later in life. As such, it is the obligation of every nephrologist caring for women of reproductive age to provide guidance in the choice of methods to prevent unplanned pregnancies, to choose treatments that preserve fertility, and to participate in shared decision making that optimizes pregnancy timing and outcomes. In this perspective, we review the many challenges associated with reproductive counseling in women with CKD.

Total-body potassium (K+) content and appropriate distribution of K+ across the cell membrane is vitally important for normal cellular function. Total-body K+ content is determined by changes in excretion of K+ by the kidneys in response to intake levels. Under normal conditions, insulin and β-adrenergic tone also make important contributions in maintaining internal distribution of K+. However, despite these homeostatic pathways, disorders of altered K+ homeostasis are common. Appreciating the pathophysiology and regulatory influences that determine the internal distribution and external balance of K+ is critical in designing effective treatments to restore K+ homeostasis. We provide an up-to-date review of the regulatory aspects of normal K+ physiology as a preface to highlighting common disorders in K+ homeostasis and their treatment. This review of K+ homeostasis is designed as a resource for clinicians and a tool for educators who are teaching trainees to understand the pivotal factors involved in K+ balance.

Tick-borne illnesses are a growing problem in the United States. Human granulocytic anaplasmosis (HGA), carried by the Ixodes scapularis tick, is caused by Anaplasma phagocytophilum. While the clinical manifestations of HGA may be protean, ranging from asymptomatic infection to life-threatening multiorgan failure, renal involvement is uncommon. We report a case of a 64-year-old man presenting with a febrile illness and acute nephritis in the setting of HGA infection. The patient’s kidney biopsy was characterized by a membranoproliferative glomerulonephritis pattern and acute interstitial inflammation. After appropriate antibiotic treatment and high-dose steroids, the patient had a marked improvement in kidney function, although a subsequent recrudescence of nephritis required a 6-month course of additional steroids. As the prevalence of tick-borne diseases continues to spread across the United States, raising awareness of the potential for atypical presentations is important, particularly because early diagnosis and treatment can be curative and prevent further complications.

Kidney failure is common in patients with a monoclonal gammopathy, most frequently due to hypercalcemia or myeloma cast nephropathy. Immunoglobulin crystallization is an uncommon phenomenon that also results in kidney injury. We report the case of a 74-year-old man with recurrent renal colic and acute kidney injury. He presented with κ light chain Bence-Jones proteinuria, hypogammaglobulinemia, anemia, and high plasma κ light chain level, leading to the diagnosis of κ light chain multiple myeloma. One calculus was collected and its analysis revealed a unique protein structure consisting of κ immunoglobulin free light chain. Genetic sequencing of the κ light chain identified a subgroup of variable domain previously identified as prone to crystallization. Eight cycles of cyclophosphamide-bortezomib-dexamethasone chemotherapy resulted in a partial hematologic response and kidney recovery without recurrence of renal colic. This rare case of urinary light chain nephrolithiasis highlights the importance of genetic and molecular analysis of the immunoglobulin variable domain to better understand the wide spectrum of monoclonal gammopathies.

Rationale & Objective Surveillance blood work is routinely performed in maintenance hemodialysis (HD) recipients. Although more frequent blood testing may confer better outcomes, there is little evidence to support any particular monitoring interval. Study Design Retrospective population-based cohort study. Setting & Participants All prevalent HD recipients in Ontario, Canada, as of April 1, 2011, and a cohort of incident patients commencing maintenance HD in Ontario, Canada, between April 1, 2011, and March 31, 2016. Exposure Frequency of surveillance blood work, monthly versus every 6 weeks. Outcomes The primary outcome was all-cause mortality. Secondary outcomes were major adverse cardiovascular events, all-cause hospitalization, and episodes of hyperkalemia. Analytical Approach Cox proportional hazards with adjustment for demographic and clinical characteristics was used to evaluate the association between blood testing frequency and all-cause mortality. Secondary outcomes were evaluated using the Andersen-Gill extension of the Cox model to allow for potential recurrent events. Results 7,454 prevalent patients received care at 17 HD programs with monthly blood sampling protocols (n = 5,335 patients) and at 8 programs with blood sampling every 6 weeks (n = 2,119 patients). More frequent monitoring was not associated with a lower risk for all-cause mortality compared to blood sampling every 6 weeks (adjusted HR, 1.16; 95% CI, 0.99-1.38). Monthly monitoring was not associated with a lower risk for any of the secondary outcomes. Results were consistent among incident HD recipients. Limitations Unmeasured confounding; limited data for center practices unrelated to blood sampling frequency; no information on frequency of unscheduled blood work performed outside the prescribed sampling interval. Conclusions Monthly routine blood testing in HD recipients was not associated with a lower risk for death, cardiovascular events, or hospitalizations as compared with testing every 6 weeks. Given the health resource implications, the frequency of routine blood sampling in HD recipients deserves careful reassessment.

Rationale & Objective Risk factors for kidney failure are the basis of live kidney donor candidate evaluation. We quantified risk for end-stage kidney disease (ESKD) by the biological relationship of the donor to the recipient, a risk factor that is not addressed by current clinical practice guidelines. Study Design Retrospective cohort study. Setting & Participants A cohort of 143,750 US kidney donors between 1987 and 2017. Exposure Biological relationship of donor and recipient. Outcome ESKD. Donors’ records were linked to national dialysis and transplantation registries to ascertain development of the outcome. Analytic Approach Donors were observed over a median of 12 (interquartile range, 6-18; maximum, 30) years. Survival analysis methods that account for the competing risk for death were used. Results Risk for ESKD varied by orders of magnitude across donor-recipient relationship categories. For Asian donors, risks compared with unrelated donors were 259.4-fold greater for identical twins (95% CI, 19.5-3445.6), 4.7-fold greater for full siblings (95% CI, 0.5-41.0), 3.5-fold greater for offspring (95% CI, 0.6-39.5), 1.0 for parents, and 1.0 for half-sibling or other biological relatives. For black donors, risks were 22.5-fold greater for identical twin donors (95% CI, 4.7-107.0), 4.1-fold for full siblings (95% CI, 2.1-7.8), 2.7-fold for offspring (95% CI, 1.4-5.4), 3.1-fold for parents (95% CI, 1.4-6.8), and 1.3-fold for half-sibling or other biological relatives (95% CI, 0.5-3.3). For white donors, risks were 3.5-fold greater for identical twin donors (95% CI, 0.5-25.3), 2.0-fold for full siblings (95% CI, 1.4-2.8), 1.4-fold for offspring (95% CI, 0.9-2.3), 2.9-fold for parents (95% CI, 2.0-4.1), and 0.8-fold for half-sibling or other biological relatives (95% CI, 0.3-1.6). Limitations Insufficient sample size in some race and relationship groups. Absence of data for family history of kidney disease for donors biologically unrelated to their recipients. Conclusions Marked differences in risk for ESKD across types of donor-recipient relationship were observed for Asian, black, and white donors. These findings warrant further validation with more robust data to better inform clinical practice guidelines.

Rationale & Objective Pulmonary hypertension (PH) contributes to cardiovascular disease and mortality in patients with chronic kidney disease (CKD), but the pathophysiology is mostly unknown. This study sought to estimate the prevalence and consequences of PH subtypes in the setting of CKD. Study Design Observational retrospective cohort study. Setting & Participants We examined 12,618 patients with a right heart catheterization in the Duke Databank for Cardiovascular Disease from January 1, 2000, to December 31, 2014. Exposures Baseline kidney function stratified by CKD glomerular filtration rate category and PH subtype. Outcomes All-cause mortality. Analytical Approach Multivariable Cox proportional hazards analysis. Results In this cohort, 73.4% of patients with CKD had PH, compared with 56.9% of patients without CKD. Isolated postcapillary PH (39.0%) and combined pre- and postcapillary PH (38.3%) were the most common PH subtypes in CKD. Conversely, precapillary PH was the most common subtype in the non-CKD cohort (35.9%). The relationships between mean pulmonary artery pressure, pulmonary capillary wedge pressure, and right atrial pressure with mortality were similar in both the CKD and non-CKD cohorts. Compared with those without PH, precapillary PH conferred the highest mortality risk among patients without CKD (HR, 2.27; 95% CI, 2.00-2.57). By contrast, in those with CKD, combined pre- and postcapillary PH was associated with the highest risk for mortality in CKD in adjusted analyses (compared with no PH, HRs of 1.89 [95% CI, 1.57-2.28], 1.87 [95% CI, 1.52-2.31], 2.13 [95% CI, 1.52-2.97], and 1.63 [95% CI, 1.12-2.36] for glomerular filtration rate categories G3a, G3b, G4, and G5/G5D). Limitations The cohort referred for right heart catheterization may not be generalizable to the general population. Serum creatinine data in the 6 months preceding catheterization may not reflect true baseline CKD. Observational design precludes assumptions of causality. Conclusions In patients with CKD referred for right heart catheterization, PH is common and associated with poor survival. Combined pre- and postcapillary PH was common and portended the worst survival for patients with CKD

Rationale & Objectives Few studies have investigated racial disparities in survival among dialysis patients in a manner that considers risk factors and mortality during the phase of kidney disease before maintenance dialysis. Our objective was to explore racial variations in survival among dialysis patients and relate them to racial differences in comorbid conditions and rates of death in the setting of kidney disease not yet requiring dialysis therapy. Study Design Retrospective cohort study. Settings & Participants 3,288 black and white participants in the Chronic Renal Insufficiency Cohort (CRIC), none of whom were receiving dialysis at enrollment. Exposure Race. Outcome Mortality. Analytic Approach Cox proportional hazards regression was used to examine the association between race and mortality starting at: (1) time of dialysis initiation and (2) entry into the CRIC. Results During 7.1 years of median follow-up, 678 CRIC participants started dialysis. Starting from the time of dialysis initiation, blacks had lower risk for death (unadjusted HR, 0.67; 95% CI, 0.51-0.87) compared with whites. Starting from baseline CRIC enrollment, the strength of the association between some risk factors and dialysis was notably stronger for whites than blacks. For example, the HR for dialysis onset in the presence (vs absence) of heart failure at CRIC enrollment was 1.30 (95% CI, 1.01-1.68) for blacks versus 2.78 (95% CI, 1.90-4.50) for whites, suggesting differential severity of these risk factors by race. When we included deaths occurring both before and after dialysis, risk for death was higher among blacks (vs whites) starting from CRIC enrollment (HR, 1.41; 95% CI, 1.22-1.64), but this finding was attenuated in adjusted models (HR, 1.08; 95% CI, 0.91-1.28). Limitations Residual confounding. Conclusions The apparent survival advantage among blacks over whites treated with dialysis may be attributed to selected transition of a subset of whites with more severe comorbid conditions onto dialysis.

Rationale & Objective Left ventricular (LV) hypertrophy and dysfunction are associated with adverse outcomes in hemodialysis patients. Hypertension and hypervolemia play important roles in these cardiac abnormalities. We report on the prespecified secondary outcome, echocardiographic indexes of LV function, from a previously reported study of the effect of lung ultrasound (US)-guided dry weight reduction on systolic blood pressure. Study Design Single-blind randomized trial. Settings & Participants 71 clinically euvolemic hypertensive hemodialysis patients in Greece and Slovenia. Intervention The active intervention group’s (n = 35) volume removal was guided by the total number of lung US B-lines observed every week before a midweek dialysis session. The usual-care group (n = 36) was treated using standard-of-care processes that did not include acquisition of US data. Outcomes 2-dimensional and tissue Doppler echocardiographic indexes at baseline and study end (8 weeks) that evaluated left and right heart chamber sizes, as well as systolic and diastolic function. Results Overall, 19 (54%) patients in the active intervention and 5 (14%) in the usual-care group had ultrafiltration intensification (P < 0.001) during follow-up; changes in US B-lines (−5.3 ± 12.5 vs +2.2 ± 7.6; P < 0.001) and dry weight (−0.71 ± 1.39 vs +0.51 ± 0.98 kg; P < 0.001) significantly differed between the active and usual-care groups. Inferior vena cava diameter decreased in the active compared with the usual-care group (−0.43 ± 4.00 vs 0.71 ± 4.82 cm; P = 0.03) at study end. Left (LA) and right (RA) atrial dimensions decreased more in the active group (LA surface, −1.09 ± 4.61 vs 0.93 ± 3.06 cm2; P = 0.03; RA surface −1.56 ± 6.17 vs 0.47 ± 2.31; P = 0.02). LA volume index nominally decreased more in the active group (−2.43 ± 13.14 vs 2.95 ± 9.42 mL/m2), though this was of borderline statistical significance (P = 0.05). Reductions in LV end-diastolic diameter and volume were marginally greater in the active group. The change in LV filling pressures was significantly different in the active compared with the usual-care group (early transmitral diastolic velocities ratio [E/e′], −0.38 ± 3.14 vs 1.36 ± 3.54; P = 0.03; E wave deceleration time, 35.43 ± 85.25 vs −18.44 ± 50.69; P = 0.002]. Systolic function indexes were unchanged in both groups. In multivariable analysis, US B-line reduction was associated with a reduction in the E/e′ LV ratio (OR, 4.542; 95% CI, 1.266-16.292; P = 0.02). Limitations Exploratory study; small sample size. Conclusions A US-guided strategy for dry weight reduction is associated with decreased cardiac chamber dimensions and LV filling pressure, but no difference in systolic performance compared with usual care in hypertensive hemodialysis patients. Funding European Renal Association–European Dialysis and Transplant Association. Trial Registration Registered at ClinicalTrials.gov with study number NCT03058874.

Asia is the largest and most populated continent in the world, with a high burden of kidney failure. In this Policy Forum article, we explore dialysis care and dialysis funding in 17 countries in Asia, describing conditions in both developed and developing nations across the region. In 13 of the 17 countries surveyed, diabetes is the most common cause of kidney failure. Due to great variation in gross domestic product per capita across Asian countries, disparities in the provision of kidney replacement therapy (KRT) exist both within and between countries. A number of Asian nations have satisfactory access to KRT and have comprehensive KRT registries to help inform practices, but some do not, particularly among low- and low-to-middle-income countries. Given these differences, we describe the economic status, burden of kidney failure, and cost of KRT across the different modalities to both governments and patients and how changes in health policy over time affect outcomes. Emerging trends suggest that more affluent nations and those with universal health care or access to insurance have much higher prevalent dialysis and transplantation rates, while in less affluent nations, dialysis access may be limited and when available, provided less frequently than optimal. These trends are also reflected by an association between nephrologist prevalence and individual nations’ incomes and a disparity in the number of nephrologists per million population and per thousand KRT patients.

Rationale & Objective Heavy chain deposition disease (HCDD) is a rare consequence of monoclonal immunoglobulin deposition disease that has not been well characterized in non-white populations. To explore the clinicopathologic characteristics and outcomes of HCDD in Chinese individuals, we report on a case series assembled in a single center in China. Study Design Case series. Setting & Participants 25 patients with biopsy-proven HCDD were studied retrospectively. Results 14 men and 11 women with an average age of 50.3 years were studied. The patients presented with hypertension (76%), edema (96%), anemia (84%), serum creatinine level > 1.2 mg/dL (68%), nephrotic-range proteinuria (56%), and microscopic hematuria (80%). One (4%) patient had multiple myeloma diagnosed. Serum immunofixation electrophoresis showed that 10 of 21 (48%) patients were positive for monoclonal immunoglobulin. Hypocomplementemia of C3 was found in 68% of patients. Nodular mesangial sclerosis was identified in all patients by using light microscopy. Using immunofluorescence, all 25 patients had deposition of heavy chains of immunoglobulin G class (γ1, 13; γ2, 2; γ3, 6; γ4, 2; γ1 and γ4, 1; and γ2 and γ4, 1). During an average of 40.1 months of follow-up of 20 patients, 65% had improved kidney function, 10% had worsening kidney function, and 25% progressed to kidney failure. Mean values for kidney and patient survival were 37.8 and 40.1 months, respectively. Kidney survival was higher among patients who received chemotherapy. Limitations Retrospective study, single-center experience. Conclusions In this case series of HCDD in a single center in China, the heavy chain deposits seen in the kidney biopies of all individuals were of immunoglobulin G class. Chemotherapy improved kidney function, especially among individuals in an early stage of the disease.

Rationale & Objective Metabolic acidosis associated with chronic kidney disease (CKD) may contribute to muscle dysfunction and bone disease. We aimed to test whether treatment with sodium bicarbonate improves muscle and bone outcomes. Study Design Multicenter, randomized, placebo-controlled, clinical trial. Setting & Participants 149 patients with CKD stages 3 and 4 between July 2011 and April 2016 at 3 centers in Cleveland, OH, and the Bronx, NY. Intervention Sodium bicarbonate (0.4 mEq per kg of ideal body weight per day) (n = 74) or identical-appearing placebo (n = 75). Outcomes Dual primary outcomes were muscle function assessed using sit-to-stand test and bone mineral density. Muscle biopsies were performed at baseline and 2 months. Participants were seen at baseline and 2, 6, 12, and 24 months. Results Mean baseline serum bicarbonate level was 24.0 ± 2.2 (SD) mEq/L and mean baseline estimated glomerular filtration rate was 36.3 ± 11.2 mL/min/1.73 m2. Baseline characteristics did not differ between groups. Mean serum bicarbonate levels in the intervention arm during follow-up were 26.4 ± 2.2, 25.5 ± 2.3, 25.6 ± 2.6, and 24.4 ± 2.8 mEq/L (at 2, 6, 12, and 24 months). These were significantly higher than in the placebo group (P < 0.001). Compared to the placebo group, participants randomly assigned to sodium bicarbonate treatment had no significant differences in sit-to-stand time (5 repetitions: P = 0.1; and 10 repetitions P = 0.07) or bone mineral density (P = 0.3). Sodium bicarbonate treatment caused a decrease in serum potassium levels that was of borderline statistical significance (P = 0.05). There were no significant differences in estimated glomerular filtration rates, blood pressure, weight, serious adverse events, or levels of muscle gene expression between the randomly assigned groups. Limitations Initial mean serum bicarbonate level was in the normal range. Conclusions Sodium bicarbonate therapy in patients with CKD stages 3 and 4 significantly increases serum bicarbonate and decreases potassium levels. No differences were found in muscle function or bone mineral density between the randomly assigned groups. Larger trials are required to evaluate effects on kidney function. Funding National Institutes of Health grant. Trial Registration Registered at ClinicalTrials.gov with study number NCT01452412

Rationale & Objective Patients receiving dialysis report very low physical activity. We implemented a pilot trial to assess the feasibility of a pedometer-based intervention to gather preliminary evidence about its impact on physical activity, symptoms, and surrogates of cardiovascular risk. Study Design Pilot randomized controlled trial. Setting & Participants 60 dialysis patients from San Francisco dialysis clinics. Intervention Participants were randomly assigned 1:1 to receiving pedometers with weekly step goals or usual care for 3 months. Outcomes The primary outcome was step counts, measured using pedometers. Secondary outcomes included physical performance using the Short Physical Performance Battery, the Physical Function and Vitality scales of the 36-Item Short Form Health Survey, the Dialysis Symptoms Index, and the Center for Epidemiologic Studies–Depression Scale, with endothelial function as a secondary and heart rate variability as an exploratory surrogate measure of cardiovascular risk. Targeted enrollment was 50% and targeted completion was 85%. Results 49% of approached patients were enrolled, and 92% completed the study. After 3 months, patients randomly assigned to the intervention (n = 30) increased their average daily steps by 2,256 (95% CI, 978-3,537) more than the 30 controls (P < 0.001). Heart rate variability (standard deviation of N-N intervals) increased by 14.94 (95% CI, 0.31-33.56) milliseconds in the intervention group as compared with controls (P = 0.05). There were no statistically significant differences across intervention groups in symptoms, physical performance, or endothelial function. Participants in the intervention group reverted to baseline steps during the postintervention follow-up. Limitations The Northern California study setting may limit generalizability. Walking does not capture the full spectrum of physical activity. Conclusions A short-term pedometer-based intervention led to increased step counts in dialysis patients, but the increase was not sustained. Pedometer-based interventions are feasible for dialysis patients, but future studies are needed to address whether more prolonged interventions can improve physical function or symptoms. Funding Supported by grants from the American Kidney Fund, National Institutes of Health-National Institute of Diabetes and Digestive and Kidney Diseases, and International Society of Nephrology. Trial Registration Registered at ClinicalTrials.gov with study identifier NCT02623348.

Rationale & Objective Elicitation and documentation of patient preferences is at the core of shared decision making and is particularly important among patients with high anticipated mortality. The extent to which older patients with incident kidney failure undertake such discussions with their providers is unknown and its characterization was the focus of this study. Study Design Retrospective cohort study. Setting & Participants A random sample of veterans 67 years and older with incident kidney failure receiving care from the US Veterans Health Administration between 2005 and 2010. Exposures Demographic and facility characteristics, as well as predicted 6-month mortality risk after dialysis initiation and documentation of resuscitation preferences. Outcomes Documented discussions of dialysis treatment and supportive care. Analytical Approach We reviewed medical records over the 2 years before incident kidney failure and up to 1 year afterward to ascertain the frequency and timing of documented discussions about dialysis treatment, supportive care, and resuscitation. Logistic regression was used to identify factors associated with these documented discussions. Results The cohort of 821 veterans had a mean age of 80.9 ± 7.2 years, and 37.2% had a predicted 6-month mortality risk > 20% with dialysis. Documented discussions addressing dialysis treatment and resuscitation were present in 55.6% and 77.1% of patients, respectively. Those addressing supportive care were present in 32.4%. The frequency of documentation varied by mortality risk and whether the patient ultimately started dialysis. In adjusted analyses, the frequency and pattern of documentation were more strongly associated with geographic location and receipt of outpatient nephrology care than with patient demographic or clinical characteristics. Limitations Documentation may not fully reflect the quality and content of discussions, and generalizability to nonveteran patients is limited. Conclusions Among older veterans with incident kidney failure, discussions of dialysis treatment are decoupled from other aspects of advance care planning and are suboptimally documented, even among patients at high risk for mortality.

Rationale & Objective The Centers for Medicare & Medicaid Services introduced the Quality Incentive Program (QIP) along with the bundled payment reform to improve the quality of dialysis care in the United States. The QIP has been criticized for using easily obtained laboratory indicators without patient-centered measures and for a lack of evidence for an association between QIP indicators and patient outcomes. This study examined the association between dialysis facility QIP performance scores and survival among patients after initiation of dialysis. Study Design Retrospective cohort study. Setting & Participants Study participants included 84,493 patients represented in the US Renal Disease System’s patient-level data who had initiated dialysis between January 1, 2013, and December 1, 2013, and who did not, during the first 90 days after dialysis initiation, die, receive a transplant, or become lost to follow-up. Patients were followed up for the study outcome through March 31, 2014. Predictor Dialysis facility QIP scores. Outcome Mortality. Analytical Approach Using a unique facility identifier, we linked Medicare freestanding dialysis facility data from 2015 with US Renal Disease System patient-level data. Kaplan-Meier product limit estimator was used to describe the survival of study participants. Cox proportional hazards regression was used to assess the multivariable association between facility performance scores and patient survival. Results Excluding patients who died during the first 90 days of dialysis, 11.8% of patients died during an average follow-up of 5 months. Facilities with QIP scores < 45 (HR, 1.39; 95% CI, 1.15-1.68) and 45 to <60 (HR, 1.21; 95% CI, 1.10-1.33) had higher patient mortality rates than facilities with scores ≥ 90. Limitations Because the Centers for Medicare & Medicaid Services have revised QIP criteria each year, the findings may not relate to years other than those studied. Conclusions Dialysis facilities characterized by lower QIP scores were associated with higher rates of patient mortality. These findings need to be replicated to assess their consistency over time.

Rationale & Objective The pathogenesis of disordered mineral metabolism in chronic kidney disease (CKD) is largely informed by cross-sectional studies of humans and longitudinal animal studies. We sought to characterize the longitudinal evolution of disordered mineral metabolism during the course of CKD. Study Design Retrospective analysis nested in a cohort study. Setting & Participants Participants in the Chronic Renal Insufficiency Cohort (CRIC) Study who had up to 5 serial annual measurements of estimated glomerular filtration rate, fibroblast growth factor 23 (FGF-23), parathyroid hormone (PTH), serum phosphate, and serum calcium and who subsequently reached end-stage kidney disease (ESKD) during follow-up (n = 847). Exposure Years before ESKD. Outcomes Serial FGF-23, PTH, serum phosphate, and serum calcium levels. Analytical Approach To assess longitudinal dynamics of disordered mineral metabolism in human CKD, we used “ESKD-anchored longitudinal analyses” to express time as years before ESKD, enabling assessments of mineral metabolites spanning 8 years of CKD progression before ESKD. Results Mean FGF-23 levels increased markedly as time before ESKD decreased, while PTH and phosphate levels increased modestly and calcium levels declined minimally. Compared with other mineral metabolites, FGF-23 levels demonstrated the highest rate of change (velocity: first derivative of the function of concentration over time) and magnitude of acceleration (second derivative). These changes became evident approximately 5 years before ESKD and persisted without deceleration through ESKD onset. Rates of changes in PTH and phosphate levels increased modestly and without marked acceleration around the same time, with modest deceleration immediately before ESKD, when use of active vitamin D and phosphate binders increased. Limitations Individuals who entered the CRIC Study at early stages of CKD and who did not progress to ESKD were not studied. Conclusions Among patients with progressive CKD, FGF-23 levels begin to increase 5 years before ESKD and continue to rapidly accelerate until transition to ESKD.

Rationale & Objective In populations with folic acid fortification or supplementation, the main nutritional determinant of total homocysteine levels is vitamin B12 (B12) status. We aimed to evaluate the modifying effect of B12 levels on the association between folic acid treatment and chronic kidney disease (CKD) progression. Study Design A post hoc analysis of an interventional trial. Setting & Participants This is a post hoc analysis of 1,374 hypertensive adults with mild to moderate CKD and B12 measurements at baseline from the kidney disease substudy of the China Stroke Primary Prevention Trial (CSPPT), conducted in 20 communities in Jiangsu province in China, a region with low folate consumption. Interventions Assignments to a double-blinded daily treatment of enalapril, 10 mg, and folic acid, 0.8 mg; or enalapril, 10 mg, alone. Outcomes The primary outcome was progression of CKD (defined as a decrease in estimated glomerular filtration rate [eGFR] ≥ 30% and to a level of <60 mL/min/1.73 m2 if baseline eGFR was ≥60 mL/min/1.73 m2; or a decrease in eGFR ≥ 50% if baseline eGFR was <60 mL/min/1.73 m2; or kidney failure). Results Mean baseline eGFR in this study was 86.1 ± 20.5 (SD) mL/min/1.73 m2. Median treatment duration was 4.4 years. Among participants with higher baseline B12 levels (≥248 pmol/L), compared to enalapril alone, enalapril–folic acid treatment was associated with an 83% reduction in the odds of the primary outcome (OR, 0.17; 95% CI, 0.07-0.40). However, among those with baseline B12 levels < 248 pmol/L (metabolic B12 deficiency), there was no significant group difference in the primary outcome (OR, 1.21; 95% CI, 0.51-2.85). The interaction between B12 level and folic acid treatment was significant (P = 0.001). Limitations The analysis is post hoc and event rate is low. Conclusions Folic acid treatment was associated with a greater reduction in the odds of CKD progression among patients with mild to moderate CKD and higher B12 levels. Funding Government funding (National Key Research and Development Program of China).

Rationale & Objective Although multiple lines of evidence suggest a negative impact of secondary hyperparathyroidism on patients with kidney failure treated by hemodialysis, it is uncertain whether patients can detect associated symptoms. The objective was to determine whether changes in parathyroid hormone (PTH) levels are associated with changes in symptoms within this patient population. Study Design Prospective cohort. Setting & Participants 165 adults with hyperparathyroidism secondary to kidney failure diagnosed, a range of dialysis vintages, and receiving regular hemodialysis from a US single-provider organization. Exposure Change in PTH levels over 24 weeks. Outcomes 19 putative symptoms of secondary hyperparathyroidism measured up to 4 times using a self-administered questionnaire that assessed severity on a 5-level ordinal scale. Analytical Approach Longitudinal associations between changes in PTH levels and symptom severity were assessed using generalized additive models. Results The 165 participants studied represented 81% of enrollees (N = 204) who had sufficiently complete data for analysis. Mean age was 56 years and 54% were women. Increases in PTH levels over time were associated (P < 0.1) with worsening of bone aches and stiffness, joint aches, muscle soreness, overall pain, itchy skin, and tiredness, and the effects were more pronounced with larger changes in PTH levels. Limitations Findings may have been influenced by confounding by unmeasured comorbid conditions, concomitant medications, and multiple testing coupled with a P value threshold of 0.10. Conclusions In this exploratory study, we observed that among patients with secondary hyperparathyroidism, increases in PTH levels over time were associated with worsening of 1 or more cluster of symptoms. Replication of these findings in other populations is needed before concluding about the magnitude and shape of these associations. If replicated, these findings could inform clinically useful approaches for measuring patient-reported outcomes related to secondary hyperparathyroidism.

African Americans have a 2- to 4-fold greater incidence of end-stage kidney disease (ESKD) than whites, which has long raised the possibility of a genetic cause for this disparity. Recent advances in genetic studies have shown a causal association of polymorphisms at the apolipoprotein L1 gene (APOL1) with the markedly increased risk for the nondiabetic component of the overall disparity in ESKD in African Americans. Although APOL1-associated kidney disease is thought to account for a substantial proportion of ESKD in African Americans, not all the increased risk for ESKD is accounted for, and a complete cataloging of disparities in genetic causes of ESKD eludes our current understanding of genetic-associated kidney disease. Genetic testing aids the screening, diagnosis, prognosis, and treatment of diseases with a genetic basis. Widespread use of genetic testing in clinical practice is limited by the small number of actionable genetic variants, limited health literacy of providers and patients, and underlying complex ethical, legal, and social issues. This perspective reviews racial and ethnic differences associated with genetic diseases and the development of ESKD in African Americans and discusses potential uncertainties associated with our current understanding of penetrance of genetically linked kidney disease and population-attributable risk percent.

Proton pump inhibitors (PPIs), long thought to be safe, are associated with a number of nonkidney adverse health outcomes and several untoward kidney outcomes, including hypomagnesemia, acute kidney injury, acute interstitial nephritis, incident chronic kidney disease, kidney disease progression, kidney failure, and increased risk for all-cause mortality and mortality due to chronic kidney disease. PPIs are abundantly prescribed, rarely deprescribed, and frequently purchased over the counter. They are frequently used without medical indication, and when medically indicated, they are often used for much longer than needed. In this In Practice review, we summarize evidence linking PPI use with adverse events in general and adverse kidney outcomes in particular. We review the literature on the association of PPI use and risk for hypomagnesemia, acute kidney injury, acute interstitial nephritis, incident chronic kidney disease, kidney disease progression, end-stage kidney disease, and death. We provide an assessment of how this evidence should inform clinical practice. We review the impact of this evidence on patients’ perception of risk, synthesize PPI deprescription literature, and provide our recommendations on how to approach PPI use and deprescription.