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Rationale & Objective Benefits of sodium-glucose co-transporter 2 inhibitors on kidney outcomes have been demonstrated in clinical trials. Among patients with type 2 diabetes and established cardiovascular (CV) disease enrolled in EMPA-REG Outcome Study (NCT01131676), empagliflozin added to standard of care (SoC) reduced the risk of incident or worsening nephropathy compared to SoC alone. This analysis evaluated the cost-effectiveness of empagliflozin versus SoC alone in the subpopulation with diabetic kidney disease (DKD) from the perspective of United States (US) commercial insurers and Medicare. Study Design Discrete event simulation model. Setting & Population Patients with DKD in a US healthcare system. Interventions Empagliflozin 10 or 25 mg with SoC versus SoC alone. SoC included glucose-lowering therapies and medications to treat CV risk factors. Outcomes Incremental cost-effectiveness ratios (ICERs, 2020 US dollars per quality-adjusted life-year [QALY] gained). Costs and QALYs were discounted 3.0%/year. Model, Perspective, & Timeframe: Cost-effectiveness analysis, commercial insurers and Medicare perspective, lifetime horizon. Results The ICER of empagliflozin with SoC versus SoC alone was $25,974/QALY. Empagliflozin added 0.67 QALYs and $17,322/patient over a lifetime horizon. Results were driven by fewer clinical events (including CV death, heart failure [HF] hospitalization, albuminuria progression, and a composite kidney outcome) experienced by patients receiving empagliflozin with SoC versus SoC alone. Results were sensitive to rates of CV death, non-fatal MI, and HF hospitalization, as well as to drug costs, and time horizon. Probabilistic sensitivity analyses indicated 91% of simulations falling below $50,000/QALY. Limitations The EMPA-REG Outcome Study was not powered to assess treatment benefits in a subgroup and excluded patients with estimated glomerular filtration rate Conclusion Based on EMPA-REG Outcome Study, this cost-effectiveness analysis suggests that for commercial insurers and Medicare, adding empagliflozin to SoC may be a cost-effective treatment option for patients with DKD.

The lungs and kidneys are cooperative and interdependent organs that secure the homeostasis of the body. Volume and acid-base disorders sit at the nexus between these two systems. However, lung-kidney interactions affect the management of many other conditions, especially among critically ill patients. Therefore, management of one system cannot proceed without a thorough understanding of the physiology of the other. This installment of AJKD's Core Curriculum in Nephrology discusses the complex decision-making required in treating concomitant respiratory and kidney disorders. We cover systemic diseases of the pulmonary and glomerular capillaries, acute decompensated heart failure, management of acid-base disorders in acute respiratory distress syndrome and chronic obstructive pulmonary disease, and venous thromboembolism. Through a case-based approach, we weigh the factors affecting the risks and benefits of therapies to enable the reader to individualize treatment decisions in these challenging scenarios.

RATIONALE & OBJECTIVE: The utility of conventional upper reference limits (URL) for N-terminal pro brain natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hsTnT) in chronic kidney disease (CKD) remains debated. We analyzed the distribution of hsTnT and NT-proBNP in people with CKD in ambulatory settings to examine the diagnostic value of conventional URL in this population. STUDY DESIGN: Observational study. SETTING & PARTICIPANTS: We studied participants of the Chronic Renal Insufficiency Cohort with CKD and no self-reported history of cardiovascular disease (CVD). EXPOSURE: Estimated glomerular filtration rate (eGFR). OUTCOMES: NT-proBNP and hsTnT at baseline. ANALYTICAL APPROACH:. We described the proportion of participants above the conventional URL for NT-proBNP (125 pg/ml) and hsTnT (14 ng/L) overall, and by eGFR. We then estimated 99(th) percentile URL for NT-proBNP and hsTnT. Using quantile regression of the 99(th) percentile, we modeled the association of eGFR with NT-proBNP and hsTnT. RESULTS: Among 2,312 CKD participants, 40% and 43% had levels of NT-proBNP and hsTnT above conventional URL, respectively. In those with eGFR

The optimal timing of kidney support therapy in critically ill patients with acute kidney injury (AKI) without life-threatening complications related to AKI is controversial. Recent multicenter, randomized, controlled studies have questioned the need for earlier initiation of therapy, despite one study showing a benefit in survival and others with no differences in mortality based on the timing of kidney support therapy initiation. These findings reflect the uncertainties in decisions to initiate kidney support therapy, which should ideally be individualized according to the patient's comorbidities, severity of illness, trajectory of kidney function, and urine output as well as requirements for fluid balance and solute removal. A delayed approach could translate into a potentially reduced burden of dialysis dependence in addition to saving health resources. However, we must ascertain what constitutes the waiting period and the benefits and risks associated with this approach. This article reviews the concept of timing of dialysis in AKI, performs a critical assessment of the most important clinical trials in this topic, discusses ongoing research and knowledge gaps, and defines key research issues to address in the future.

Rationale & objective High anion gap acidosis frequently develops in patients with advanced chronic kidney disease (CKD) and might be involved in kidney injury. Its impact on kidney outcomes, however, has not been well studied. We sought to examine the association between time-updated anion gap and the risk of kidney failure with replacement therapy (KFRT) among patients with advanced CKD. Study design Retrospective cohort study. Setting & participants 1,168 patients with CKD glomerular filtration rate categories 3b-5 (G3b-G5) who had available data on anion gap. Exposure High time-updated anion gap defined as values ≥ 9.2 (top 25th percentile). Outcome KFRT and death. Analytical approach Marginal structural models were fit to characterize the association between anion gap and study outcomes while accounting for potential time-dependent confounding. Results The mean baseline estimated glomerular filtration rate (eGFR) of the study participants was 28 mL/min/1.73 m2. Over a median follow-up period of 3.1 years, 317 patients progressed to KFRT (7.5 per 100 patient-years), and 146 died (3.5 per 100 patient-years). In the marginal structural models, a high anion gap was associated with a higher rate of KFRT (HR, 3.04 [95% CI, 1.94-4.75]; P Limitations Observational study design and selection bias due clinical indications for measuring anion gap. Conclusions Among patients with advanced CKD, high anion gap was associated with an increased risk of progression to KFRT and death.

Rationale & Objective Deceased donor acute kidney injury (AKI) frequently leads to kidney discards, but its impact on long-term graft survival in kidney transplant recipients remains unclear. We investigated the association between deceased donor AKI assessed using back-estimation of baseline serum creatinine (Scr) and graft survival. Study Design Observational cohort study. Setting & Participants Adult patients represented within the French CRISTAL registry who received a single kidney allograft from brain-dead deceased donors between January 2006 and December 2017. Exposure A back-estimated Scr baseline value was derived for an assumed glomerular filtration rate at 75 mL/min/1.73 m2, using the MDRD Study equation. A refined classification system for donor AKI was implemented as follows: no AKI, undetermined AKI/chronic kidney disease (CKD), recovery from AKI, and ongoing AKI. Outcome Death-censored graft survival. Analytical Approach Multivariable Cox models using a robust variance estimator for paired kidneys from the same donor. Results We classified 26,786 recipients as follows: no AKI (n = 19,276); undetermined AKI/CKD (n = 1,745); recovery from AKI (n = 2,392); and ongoing AKI (n = 3,373). We observed 4,458 kidney graft losses during a median follow-up period of 5.7 years. Compared with no AKI, ongoing AKI was associated with an increased risk of graft failure (hazard ratio [HR], 1.24 [95% CI, 1.13-1.35]). The HRs for graft failure in the undetermined AKI/CKD and recovery from AKI groups (1.22 [95% CI, 1.07-1.38] and 1.18 [95% CI, 1.06-1.31], respectively) were similar to those observed in the ongoing AKI group. The adverse effect of deceased donor AKI was no longer evident when relying either on the admission or the lowest Scr throughout the procurement procedure as baseline Scr. Limitations No measurement of urine output in donors. Conclusions Deceased donor ongoing AKI, undetermined AKI/CKD, and recovery from AKI according to back-estimated baseline Scr are associated with decreased graft survival. The definition of baseline Scr as the first value measured on admission would have led to a misclassification bias and erroneous estimates.

We present a case of pseudo–acute kidney injury (AKI) following capmatinib therapy in an 84-year-old man with combined non–small cell (adenocarcinoma) and small cell lung cancer with MET exon 14–skipping mutation. His past medical history was significant for chronic kidney disease stage 3 with a baseline serum creatinine (Scr) of 1.6 mg/dL rising to 2.44 mg/dL (estimated glomerular filtration rate [GFR] 24 mL/min/1.73 m2) while on capmatinib. Scr improved to 1.84 mg/dL with the cessation of capmatinib but rose again to 2.22 mg/dL upon resumption of therapy. Further investigation with cystatin C and renal iothalamate clearance showed that despite fluctuation in Scr levels, there was not much variation in GFR calculated using these methods. Urinalysis and urinary protein-creatinine ratio were unremarkable. Treatment with capmatinib was continued at reduced dose and a third instance of rise in Scr was observed, followed by a spontaneous return to baseline. Thus, MET inhibitor therapy can result in an asymptomatic rise in Scr, and it must be distinguished from AKI with more accurate non–creatinine-based methods to evaluate GFR. This could spare such patients from invasive diagnostic tests, such as a kidney biopsy, and premature cessation of prognostically important cancer therapies.

Chikungunya nephropathy is an uncommon etiology of acute kidney injury, associated with the mosquito-borne chikungunya arbovirus (CHIKV). The very limited number of pathologic reports to date have only involved postmortem analyses. We here report 5 cases of acute kidney injury for which kidney biopsies were performed in patients with confirmed acute CHIKV infection, during the recent outbreak of chikungunya disease in the French West Indies. The patients ranged from 42 to 76 years of age. All of the patients developed kidney injury, 3 of whom required short-term dialysis and underwent a kidney biopsy. Analysis of kidney biopsies revealed 2 main histopathologic patterns: acute interstitial nephritis with predominant lymphoid inflammation and acute tubular injury. Epithelioid granulomas were observed in 2 cases. There were no glomerular lesions, except in biopsies from 2 patients, including 1 with a previous known primary focal segmental glomerulosclerosis. CHIKV antigen immunofluorescence microscopy revealed staining in tubular cells. In all of the cases, the short-term outcome was favorable, with recovery of kidney function.

International audience; Primary focal and segmental glomerulosclerosis (FSGS) frequently recurs after transplantation and is associated with a poor prognosis. We describe here the successful kidney graft reuse in an adult recipient, 8 months after early primary FSGS recurrence resistant to all available therapeutics. Patient 1, a 23-year-old man, followed for kidney failure secondary to primary FSGS, was first transplanted in 2018 with a deceased donor graft. Unfortunately, we observed an immediate recurrence of biopsy-proven primary FSGS. After 4 lines of treatment (intravenous cyclosporine + corticosteroids, plasma exchanges, immunoadsorption, and rituximab), the patient was still highly nephrotic and kidney function was slowly deteriorating. After approval from both the patient and the health authority (Biomedicine Agency), the graft was detransplanted 8 months after transplantation and reimplanted in patient 2, a 78-year-old nonimmunized and anephric recipient (bi-nephrectomy 2 years previously for bilateral renal carcinoma). We observed immediate kidney function and progressive resolution of proteinuria (serum creatinine of 1.2 mg/dL and proteinuria of 0.1 g/d 1 year later). Biopsies performed after surgery showed persistent FSGS lesions with a decrease in overall foot-process effacement. To our knowledge, this is the first reported case showing that kidney graft transfer may still be a viable option for refractory primary FSGS several months after transplantation.

Assessment of glomerular filtration rate (GFR) is fundamental to clinical practice, public health, and research. The kidney has several critical functions; GFR is used as an overall assessment of these kidney functions. GFR is used to diagnose, stage, and manage chronic kidney disease (CKD); ascertain the prognosis for chronic kidney disease-related events and mortality; and determine drug dosages. GFR is the rate at which the glomerulus filters plasma to produce an ultrafiltrate and can be assessed from clearance or serum levels of filtration markers. Clearance measurements using exogenous filtration markers are difficult to perform in routine clinical practice, so GFR is more commonly estimated through equations based on serum concentrations of endogenous filtration markers, most commonly creatinine. These GFR estimates are reasonably accurate, but optimal care for patients may require a confirmatory test for a more accurate GFR assessment. Confirmatory tests currently available include cystatin C-based equations, urinary or plasma clearance of exogenous filtration markers, or urinary clearance of creatinine. Appreciation of the concept of GFR and methods for optimal assessment in routine practice or special circumstances, and their strengths and limitations, are critical in making judicious use of the available tools.

Medications are an important part of the management of patients with kidney disease. When used appropriately, pharmacotherapy can slow disease progression and reduce morbidity and mortality. Unfortunately, reduced kidney function can significantly alter the pharmacokinetics and pharmacodynamics of many medications, putting patients at risk for drug toxicity if modifications to therapy are not appropriately managed. Adding complexity to the appropriateness of medication and dosage selection is the difficulty in estimating kidney function and the discordance between the Cockcroft-Gault-derived dosing cut points in most medication package inserts and the estimations of glomerular filtration rate by newer and generally more accurate guideline-recommended equations. This installment of the AJKD Core Curriculum in Nephrology provides recent updates and practical considerations for designing optimal medication regimens. Given the prevalence of abnormal kidney function and its importance in medication selection and dose adjustment, additional focus and specific recommendations are provided for anticoagulant, anti-infective, analgesic, antidiabetic, and antihypertensive agents.

Optimal glycemic control in kidney transplant recipients with diabetes is associated with improved morbidity and better patient and allograft survival. Transplant options for patients with diabetes requiring insulin therapy and chronic kidney disease who are suitable candidates for kidney transplantation should include consideration of beta-cell replacement therapy: pancreas or islet transplantation. International variation related to national regulatory policies exists in offering one or both options to suitable candidates and is further affected by pancreas/islet allocation policies and transplant waiting list dynamics. The selection of appropriate candidates depends on patient age, coexistent morbidities, the timing of referral to the transplant center (predialysis versus on dialysis) and availability of living kidney donors. Therefore, early referral (estimated glomerular filtration rate < 30 mL/min/1.73 m(2)) is of the utmost importance to ensure adequate time for informed decision making and thorough pretransplant evaluation. Obesity, cardiovascular disease, peripheral vascular disease, smoking, and frailty are some of the conditions that need to be addressed before acceptance on the transplant list, and ideally before dialysis becoming imminent. This review offers insights into selection of pancreas/islet transplant candidates by transplant centers and an update on posttransplant outcomes, which may have practice implications for referring nephrologists.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited cause of kidney failure, accounting for 5%-10% of cases. Predicting which patients with ADPKD will progress rapidly to kidney failure is critical to assess the risk-benefit ratio of any intervention and to consider early initiation of long-term kidney protective measures that will maximize the cumulative benefit of slowing disease progression. Surrogate prognostic biomarkers are required to predict future decline in kidney function. Clinical, genetic, environmental, epigenetic, and radiologic factors have been studied as predictors of progression to kidney failure in ADPKD. A complex interaction of these prognostic factors determines the number of kidney cysts and their growth rates, which affect total kidney volume (TKV). Age-adjusted TKV, represented by the Mayo imaging classification, estimates each patient's unique rate of kidney growth and provides the most individualized approach available clinically so far. Tolvaptan has been approved to slow disease progression in patients at risk of rapidly progressive disease. Several other disease-modifying treatments are being studied in clinical trials. Selection criteria for patients at risk of rapid progression vary widely among countries and are based on a combination of age, baseline glomerular filtration rate (GFR), GFR slope, baseline TKV, and TKV rate of growth. This review details the approach in assessing the risk of disease progression in ADPKD and identifying patients who would benefit from long-term therapy with disease-modifying agents.

We report on the development of minimal change disease (MCD) with nephrotic syndrome and acute kidney injury (AKI), shortly after first injection of the BNT162b2 COVID-19 vaccine (Pfizer-BioNTech). A 50-year-old previously healthy man was admitted to our hospital following the appearance of peripheral edema. Ten days earlier, he had received the first injection of the vaccine. Four days after injection, he developed lower leg edema, which rapidly progressed to anasarca. On admission, serum creatinine was 2.31 mg/dL and 24-hour urinary protein excretion was 6.9 grams. As kidney function continued to decline over the next days, empirical treatment was initiated with prednisone 80 mg/d. A kidney biopsy was performed and the findings were consistent with MCD. Ten days later, kidney function began to improve, gradually returning to normal. The clinical triad of MCD, nephrotic syndrome, and AKI has been previously described under a variety of circumstances, but not following the Pfizer-BioNTech COVID-19 vaccine. The association between the vaccination and MCD is at this time temporal and by exclusion, and by no means firmly established. We await further reports of similar cases to evaluate the true incidence of this possible vaccine side effect.

For almost 2 decades, equations that use serum creatinine, age, sex, and race to estimate glomerular filtration rate (GFR) have included "race" as Black or non-Black. Given considerable evidence of disparities in health and health care delivery in African American communities, some regard keeping a race term in GFR equations as a practice that differentially influences access to care and kidney transplantation. Others assert that race captures important non-GFR determinants of serum creatinine and its removal from the calculation may perpetuate other disparities. The National Kidney Foundation (NKF) and American Society of Nephrology (ASN) established a task force in 2020 to reassess the inclusion of race in the estimation of GFR in the United States and its implications for diagnosis and subsequent management of patients with, or at risk for, kidney diseases. This interim report details the process, initial assessment of evidence, and values defined regarding the use of race to estimate GFR. We organized activities in phases: (1) clarify the problem and examine evidence, (2) evaluate different approaches to address use of race in GFR estimation, and (3) make recommendations. In phase 1, we constructed statements about the evidence and defined values regarding equity and disparities; race and racism; GFR measurement, estimation, and equation performance; laboratory standardization; and patient perspectives. We also identified several approaches to estimate GFR and a set of attributes to evaluate these approaches. Building on evidence and values, the attributes of alternative approaches to estimate GFR will be evaluated in the next phases and recommendations will be made.

Rationale & Objective: Chronic kidney disease (CKD) has a heritable component. We aimed to quantify familial aggregation of CKD in the general population and assess the extent to which kidney traits could be explained by genetic and environmental factors.Study Design: Cross-sectional 3-generation family study.Setting & Participants: Data were collected at entry into the Lifelines Cohort Study from a sample of the general population of the northern Netherlands, composed predominantly of individuals of European ancestry.Exposure: Family history of CKD.Outcomes: The primary outcome was CKD, defined as estimated glomerular filtration rate (eGFR)Analytical Approach: Familial aggregation of CKD was assessed by calculating the recurrence risk ratio (RRR), using adapted Cox proportional hazards models. Heritability of continuous kidney-related traits was estimated using linear mixed models and defined as the ratio of the additive genetic variance to total phenotypic variance. All models were adjusted for age, sex, and known risk factors for kidney disease.Results: Among 155,911 participants with available eGFR data, the prevalence of CKD was 1.19% (1,862 cases per 155,911). The risk of CKD in those with an affected first-degree relative was 3 times higher than the risk in the total sample ( RRR, 3.04 [95% CI, 2.26-4.09). In those with an affected spouse, risk of CKD was also higher (RRR, 1.56 [95% CI, 1.20-1.96]), indicative of shared environmental factors and/or assortative mating. Heritability estimates of eGFR, UAE, and UACR were 44%, 20%, and 18%, respectively. For serum urea, creatinine, and uric acid, estimates were 31%, 37%, and 48%, respectively, whereas estimates for serum electrolytes ranged from 22% to 28%.Limitations: Use of estimated rather than measured GFR. UAE data only available in a subsample.Conclusions: In this large population-based family study, a positive family history was strongly associated with increased risk of CKD. We observed moderate to high heritability of kidney traits and related biomarkers. These results indicate an important role of genetic factors in CKD risk.

Rationale & Objective Hyperuricemia has been implicated in the development and progression of chronic kidney disease. Verinurad is a novel, potent, specific urate reabsorption inhibitor. We evaluated the effects on albuminuria of intensive urate-lowering therapy with verinurad combined with the xanthine oxidase inhibitor febuxostat in patients with hyperuricemia and type 2 diabetes mellitus (T2DM). Study Design Phase 2, multicenter, prospective, randomized, double-blind, parallel-group, placebo-controlled trial. Setting & Participants Patients 18 years or older with hyperuricemia, albuminuria, and T2DM. Intervention Patients randomly assigned 1:1 to verinurad (9mg) plus febuxostat (80mg) or matched placebo once daily for 24 weeks. Outcomes The primary end point was change in urinary albumin-creatinine ratio (UACR) from baseline after 12 weeks' treatment. Secondary end points included safety and tolerability and effect on glomerular filtration. Results 60 patients were enrolled (n=32, verinurad and febuxostat; n=28, placebo). UACRs after treatment with verinurad plus febuxostat were lower than after placebo at 1, 12, and 24 weeks: −38.6% (90% CI, −60.9% to−3.6%), −39.4% (90% CI, −61.8% to−3.8%), and−49.3% (90% CI, −68.2% to−19.0%), respectively. Serum urate levels after treatment with verinurad plus febuxostat were 59.6% and 63.7% lower than after placebo at 12 and 24 weeks, respectively. No clinically meaningful changes were observed in estimated glomerular filtration rate or serum creatinine or serum cystatin C concentrations. Verinurad plus febuxostat was well tolerated. Limitations Sample size and study duration were insufficient to evaluate definitive effects of verinurad plus febuxostat on UACR and glomerular filtration. Generalizability was limited by exclusion of patients with stages 4 and 5 chronic kidney disease. Conclusions Verinurad plus febuxostat reduced albuminuria and lowered serum urate concentrations in patients with T2DM, albuminuria, and hyperuricemia. Definitive assessment of their combined impact on preservation of kidney function awaits larger clinical studies. Funding This study was supported by AstraZeneca. Trial Registration Registered at ClinicalTrials.gov with study number NCT03118739.

Obesity prevalence continues to increase worldwide, accompanied by a rising tide of hypertension, diabetes, and chronic kidney disease (CKD). Although body mass index is typically used to assess obesity in clinical practice, altered body composition (eg, reduced muscle mass and increased visceral adiposity) are common among patients with CKD. Weight loss achieved through behavioral modification or medications reduces albuminuria and in some cases slows the decline in estimated glomerular filtration rate. Use of medications that promote weight loss with favorable cardiovascular risk profiles should be promoted, particularly in patients with type 2 diabetes, obesity, and CKD. For those who fail to achieve weight loss through lifestyle modification, bariatric surgery should be considered because observational studies have shown reductions in risk for estimated glomerular filtration rate decline and kidney failure. Uncertainty persists on the risk to benefit ratio of intentional weight loss in patients with kidney failure due to the lack of prospective trials and limitations of observational data. Regardless, sleeve gastrectomy is increasingly being used for patients with kidney failure and severe obesity, with success in achieving sustained weight loss, improved access to kidney transplantation, and favorable posttransplantation outcomes. More research is needed assessing long-term cardiovascular and kidney outcomes of most weight loss medications.

Rationale & Objective Existing data sets correlating kidney histopathologic findings with kidney function have low proportions of elderly patients (and those with a family history of kidney failure are over-represented), which limits their generalizability. Our objective was to use non-neoplastic tissue from nephrectomy specimens to examine the association between degree of histopathologic changes and estimated glomerular filtration rate (eGFR) and determine whether the association differed by age. Study Design Cross-sectional study. Exposures Glomerulosclerosis (GS), interstitial fibrosis/tubular atrophy (IFTA), and arterial sclerosis/arteriosclerosis (AS). Outcome eGFR. Analytical Approach We retrospectively reviewed kidney pathology reports (of non-neoplastic tissue) from 1,347 patients who underwent nephrectomy (1999-2018) for any indication but most commonly due to kidney cancer. We evaluated the association between degree of GS, IFTA, and AS with eGFR at the time of nephrectomy and whether this was modified by age. Results Among the participants (aged 17-91 years), 42% and 57.8% had >10% GS and IFTA, respectively, and 81.8% had moderate or severe AS. We found that greater degrees of GS, IFTA, and AS were associated with lower eGFR after multivariable adjustment. Although there was a greater prevalence of more severe degrees of GS and IFTA in older individuals, the association between various histopathologic features and eGFR was not modified by age. Limitations Retrospective cross-sectional study. Conclusions Our study demonstrates differences in the histologic appearance of the kidneys across levels of eGFR. Although the prevalence of advanced changes was higher in the oldest group of patients, a subset had excellent kidney function and limited histologic changes.

Rationale & Objective Obesity has been related to risk for chronic kidney disease. However, the associations of different measures of midlife obesity with long-term kidney function trajectories and whether they differ by sex and race are unknown. Study Design Observational study. Setting & Participants 13,496 participants from the Atherosclerosis Risk in Communities (ARIC) Study. Predictors Midlife obesity status as measured by body mass index (BMI), waist-to-hip ratio, and predicted percent fat at baseline. Outcomes Estimated glomerular filtration rate (eGFR) calculated using serum creatinine level measured at 5 study visits, and incident kidney failure with replacement therapy (KFRT). Analytical Approach Mixed models with random intercepts and random slopes for eGFR. Cox proportional hazards models for KFRT. Results Baseline mean age was 54 years, median eGFR was 103 mL/min/1.73 m2, and median BMI was 27 kg/m2. Over 30 years of follow-up, midlife obesity measures were associated with eGFR decline in White and Black women but not consistently in men. Adjusted for age, center, smoking, and coronary heart disease, the differences in eGFR slope per 1-SD higher BMI, waist-to-hip ratio, and predicted percent fat were 0.09 (95% CI, −0.18 to 0.36), −0.25 (95% CI, −0.50 to 0.01), and −0.14 (95% CI, −0.41 to 0.13) mL/min/1.73 m2 per decade for White men; −0.91 (95% CI, −1.15 to −0.67), −0.82 (95% CI, −1.06 to −0.58), and −1.02 (95% CI, −1.26 to −0.78) mL/min/1.73 m2 per decade for White women; −0.70 (95% CI, −1.54 to 0.14), −1.60 (95% CI, −2.42 to −0.78), and −1.24 (95% CI, −2.08 to −0.40) mL/min/1.73 m2 per decade for Black men; and −1.24 (95% CI, −2.08 to −0.40), −1.50 (95% CI, −2.05 to −0.95), and −1.43 (95% CI, −2.00 to −0.86) mL/min/1.73 m2 per decade for Black women. Obesity indicators were independently associated with risk for KFRT for all sex-race groups except White men. Limitations Loss to follow-up during 3 decades of follow-up with 5 eGFR assessments. Conclusions Obesity status is a risk factor for future decline in kidney function and development of KFRT in Black and White women, with less consistent associations among men.

Studies showing an association between lower bicarbonate levels and worse kidney disease prognosis have not accounted for the influence of pH. It remains unknown whether this association is consistent across a wide range of blood pH values. This study sought to assess how pH modifies the relationship between hypobicarbonatemia and incident kidney failure requiring kidney replacement therapy (KFRT).Retrospective cohort study.1,058 Japanese patients with estimated glomerular filtration rates60mL/min/1.73mBaseline venous bicarbonate levels and venous pH.KFRT defined as initiation of kidney replacement therapy (hemodialysis, peritoneal dialysis, and kidney transplantation).Cox proportional hazards model assessing the interaction between baseline bicarbonate levels and venous pH on incident KFRT.In the lowest bicarbonate quartile (≤21.5 mEq/L), 59% of patients had acidemia (pH7.32), whereas 38% had venous pH within the normal range and 3% had alkalemia (pH7.42). During a median follow-up of 3.0 years, 374 patients developed KFRT. Venous pH modified the association between bicarbonate level and rate of KFRT (P for interaction=0.04). After adjustment for potential confounders, including capacity for respiratory compensation, the lowest (vs the highest) bicarbonate quartile was associated with a 2.29-fold (95% CI, 1.10-4.77; P=0.03) higher rate of KFRT among patients with acidemia (pH7.32). In contrast, among patients without acidemia (pH≥7.32), no significant association was found between bicarbonate level and KFRT. In an exploratory analysis, patients with higher respiratory compensation capacity had a lower rate of KFRT (HR per 0.1 increase in respiratory compensation capacity, 0.90; 95% CI, 0.87-0.94; P0.001).Observational study design; blood gas measurements were performed in a select patient population.Venous pH modified the association of hypobicarbonatemia with progression of chronic kidney disease to KFRT. Measurement of venous pH may be valuable for identifying patients with chronic kidney disease and hypobicarbonatemia and may inform treatment.

Rationale & Objective Most adults with chronic kidney disease (CKD) in the United States are cared for by primary care providers (PCPs). We evaluated the feasibility and preliminary effectiveness of an electronic clinical decision support system (eCDSS) within the electronic health record with or without pharmacist follow-up to improve the management of CKD in primary care. Study Design Pragmatic cluster-randomized trial. Setting & Participants 524 adults with confirmed creatinine-based estimated glomerular filtration rates of 30 to 59 mL/min/1.73 m2 cared for by 80 PCPs at the University of California San Francisco. Electronic health record data were used for patient identification, intervention deployment, and outcomes ascertainment. Interventions Each PCP’s eligible patients were randomly assigned as a group into 1 of 3 treatment arms: (1) usual care; (2) eCDSS: testing of creatinine, cystatin C, and urinary albumin-creatinine ratio with individually tailored guidance for PCPs on blood pressure, potassium, and proteinuria management, cardiovascular risk reduction, and patient education; or (3) eCDSS plus pharmacist counseling (eCDSS-PLUS). Outcomes The primary clinical outcome was change in blood pressure over 12 months. Secondary outcomes were PCP awareness of CKD and use of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker and statin therapy. Results All 80 eligible PCPs participated. Mean patient age was 70 years, 47% were nonwhite, and mean estimated glomerular filtration rate was 56 ± 0.6 mL/min/1.73 m2. Among patients receiving eCDSS with or without pharmacist counseling (n = 336), 178 (53%) completed laboratory measurements and 138 (41%) had laboratory measurements followed by a PCP visit with eCDSS deployment. eCDSS was opened by the PCP for 102 (74%) patients, with at least 1 suggested order signed for 83 of these 102 (81%). Changes in systolic blood pressure were −2.1 ± 1.5 mm Hg with usual care, −2.8 ± 1.8 mm Hg with eCDSS, and −1.1 ± 1.1 with eCDSS-PLUS (P = 0.7). PCP awareness of CKD was 16% with usual care, 26% with eCDSS, and 32% for eCDSS-PLUS (P = 0.09). In as-treated analyses, PCP awareness of CKD was significantly greater with eCDSS and eCDSS-PLUS (73% and 69%) versus usual care (47%; P = 0.002). Limitations Recruitment of smaller than intended sample size and limited uptake of the testing component of the intervention. Conclusions Although we were unable to demonstrate the effectiveness of eCDSS to lower blood pressure and uptake of the eCDSS was limited by low testing rates, eCDSS use was high when laboratory measurements were available and was associated with higher PCP awareness of CKD. Funding Grants from government (National Institutes of Health) and not-for-profit (American Heart Association) entities. Trial Registration Registered at ClinicalTrials.gov with study number NCT02925962 .

Rationale & Objective Disordered mineral metabolism complicates chronic kidney disease (CKD), but the effect of reduced kidney function on fracture risk has not been fully established. We conducted a systematic review and meta-analysis of the risks for hip and nonvertebral fractures in people with CKD. We also investigated the effects of age, sex, and CKD stage. Study Design Systematic review and meta-analysis. Study Population Adults with CKD glomerular filtration rate (GFR) categories 3a-5D (G3a-G5D) compared with adults without CKD G3a-G5D. Selection Criteria for Studies Observational studies. Data Extraction Data extraction was conducted by 1 reviewer and checked by a second reviewer. Analytical Approach MEDLINE, EMBASE, and Cochrane databases were searched in March 2018 and an update was conducted in November 2019. We used random-effects models to calculate pooled risk estimates and 95% CIs. Results 17 studies met the inclusion criteria. We included 13 studies in the hip fracture systematic review and 10 studies in the meta-analysis. Studies reported data from 250,440,035 participants; 5,798,566 with CKD G3a-G5D and 363,410 with hip fractures. 4 studies were included in the nonvertebral fracture analysis, reporting data from 1,396,976 participants; 464,978 with CKD G3a-G5D and 115,284 fractures. Studies reported data from participants aged 18 to older than 90 years. We found a significant increase in fracture risk both for hip (relative risk [RR], 2.36; 95% CI, 1.64-3.39) and nonvertebral fractures (RR, 1.47; 95% CI, 1.15-1.88). For hip fractures, younger patients ( 65 years; RR, 2.11; 95% CI, 1.41-3.16). Greater GFR loss was associated with higher relative risk for fractures. Limitations We could not assess the effects of bone mineral density, biochemical abnormalities, renal osteodystrophy, frailty, falls, or medications on risk for fractures. Conclusions Risks for hip and nonvertebral fractures are increased in CKD G3a-G5D. The relative risk of hip fracture is greater in the younger than the older population and increases progressively with loss of GFR. We suggest that fracture prevention should be a consideration in CKD at any age.

The management of pain in patients with chronic kidney disease (CKD) is challenging for many reasons. These patients have increased susceptibility to adverse drug effects due to altered drug metabolism and excretion, and there are limited safety data for use in this population despite a high pain burden. Nonsteroidal anti-inflammatory drugs (NSAIDs) have long been regarded as dangerous for use in patients with CKD because of their risk for nephrotoxicity and thus alternative classes of analgesics, including opioids, have become more commonly used for pain control in this population. Given the well-established risks that opioids and other analgesics pose, further characterization of the risk posed by NSAIDs in patients with CKD is warranted. NSAID use has been associated with acute kidney injury, progressive loss of glomerular filtration rate in CKD, electrolyte derangements, and hypervolemia with worsening of heart failure and hypertension. The risk for these nephrotoxicity syndromes is modified by many comorbid conditions, risk factors, and characteristics of use, and in patients with CKD, the risk differs between levels of glomerular filtration rate. In this review, we offer recommendations for the cautious use of NSAIDs in the CKD population after careful consideration of these risk factors on an individualized basis.

Rationale and Objective: Glomerular filtration rate (GFR) estimation based on creatinine and cystatin C (eGFRcr-cys) is more accurate than estimated GFR (eGFR) based on creatinine or cystatin C alone (eGFRcr or eGFRcys, respectively), but the inclusion of creatinine in eGFRcr-cys requires specification of a person's race. beta 2-Microglobulin (B2M) and beta-trace protein (BTP) are alternative filtration markers that appear to be less influenced by race than creatinine is.Study Design: Study of diagnostic test accuracy.Setting and Participants: Development in a pooled population of 7 studies with 5,017 participants with and without chronic kidney disease. External validation in a pooled population of 7 other studies with 2,245 participants. Tests Compared: Panel eGFR using B2M and BTP in addition to cystatin C (3-marker panel) or creatinine and cystatin C (4-marker panel) with and without age and sex or race. Outcomes: GFRmeasured as the urinary clearance of iothalamate, plasmaclearanceof iohexol, orplasma clearance of [Cr-51]EDTA.Results: Mean measured GFRs were 58.1 and 83.2 mL/min/1.73 m(2), and the proportions of Black participants were 38.6% and 24.0%, in the development and validation populations, respectively. In development, addition of age and sex improved the performance of all equations compared with equations without age and sex, but addition of race did not further improve the performance. In validation, the 4-marker panels were more accurate than the 3-marker panels (P < 0.001). The 3-marker panel without race was more accurate than eGFRcys (percentage of estimates greater than 30% different from measured GFR [1-P30] of 15.6% vs 17.4%; P = 0.01), and the 4-marker panel without race was as accurate as eGFRcr-cys (1-P-30 of 8.6% vs 9.4%; P = 0.2). Results were generally consistent across subgroups.Limitations: No representation of participants with severe comorbid illness and from geographic areas outside of North America and Europe.Conclusions: The 4-marker panel eGFR is as accurate as eGFRcr-cys without requiring specification of race. A more accurate race-free eGFR could be an important advance.

RATIONALE AND OBJECTIVE: GFR estimation based on creatinine and cystatin C (eGFR(cr-cys)) is more accurate than eGFR based on either creatinine or cystatin C alone (eGFR(cr) or eGFR(cys)), but the inclusion of creatinine in eGFR(cr-cys) requires specification of a person’s race. Beta-2-microglobulin (B2M) and beta-trace protein (BTP) are alternative filtration markers that appear to be less influenced by race than creatinine. STUDY DESIGN: Study of diagnostic test accuracy. SETTING AND PARTICIPANTS: Development in pooled population of seven studies with 5017 participants with and without chronic kidney disease. External validation in a pooled population of seven other studies with 2245 participants. TESTS COMPARED: Panel eGFR using B2M and BTP in addition to cystatin C (three-marker panel) or creatinine and cystatin C (four-marker panel) with and without age and sex or race. OUTCOMES: GFR measured as the urinary clearance of iothalamate, plasma clearance of iohexol, or plasma clearance of Cr-EDTA RESULTS: Mean measured GFR was 58.1 and 83.2 ml/min/1.73m(2) and the proportion of blacks was 38.6% and 24.0%, in the development and validation populations, respectively. In development, addition of age and sex improved the performance of all equations compared to equations without age and sex, but addition of race did not further improve the performance. In validation, the four-marker panels were more accurate than the three-marker panels (p

RATIONALE AND OBJECTIVE: The use of kidney histopathology for predicting kidney failure is not established. We hypothesized that use of histopathological features of kidney biopsy specimens would improve prediction of clinical outcomes made using demographic and clinical variables alone. STUDY DESIGN: Retrospective cohort study and development of a clinical prediction model. SETTING AND PARTICIPANTS: All 2720 individuals from the Biopsy Biobank Cohort of Indiana who underwent a kidney biopsy between 2002 and 2015 and had at least two years of follow-up. NEW PREDICTORS & ESTABLISHED PREDICTORS: Demographic variables, comorbidities, baseline clinical characteristics, and histopathological features. OUTCOMES: Time to kidney failure, defined as sustained estimated glomerular filtration rate

Clinical practice guidelines recommend a target blood pressure (BP)130/80 mm Hg to reduce cardiovascular risk. However, the optimal BP to prevent chronic kidney disease (CKD) is unknown.Population-based retrospective cohort study.10.5 million adults who participated in the National Health Insurance Service National Health Checkup Program in South Korea between 2009 and 2015 and had an estimated glomerular filtration rate (GFR) ≥ 60 mL/min/1.73 mBaseline and time-updated systolic BP (SBP) as a continuous variable and categorized as110, 110 to 119, 120 to 129, 130 to 139, or≥140 mm Hg.Incident CKD GFR categories 3 to 5 (CKD G3-G5), defined as de novo development of estimated GFR60 mL/min/1.73 mCox proportional hazards regression for baseline BP and marginal structural analysis for time-updated BP.During 49,169,311 person-years of follow-up, incident CKD G3-G5 developed in 172,423 (1.64%) individuals with a crude event rate of 3.51 (95% CI, 3.49-3.52) per 1,000 person-years. Compared to a baseline SBP of 120 to 129 mm Hg, HRs for incident CKD G3-G5 for the110, 110 to 119, 130 to 139, and≥140 mm Hg categories were 0.84 (95% CI, 0.82-0.85), 0.92 (95% CI, 0.91-0.94), 1.11 (95% CI, 1.09-1.12), and 1.30 (95% CI, 1.28-1.31), respectively. For time-updated SBPs, corresponding HRs were 0.57 (95% CI, 0.56-0.59), 0.79 (95% CI, 0.78-0.80), 1.58 (95% CI, 1.55-1.60), and 2.49 (95% CI, 2.45-2.53), respectively. Treated as a continuous exposure, each 10-mm Hg higher SBP was associated with 35% higher risk for incident CKD G3-G5 (95% CI, 1.35-1.36).Use of International Classification of Diseases codes to assess comorbid condition burden; residual confounding, and potential selection bias cannot be excluded.In this large national cohort study, higher SBPs were associated with higher risk for incident CKD G3-G5. These findings support evaluation of SBP-lowering strategies to reduce the development of CKD.

Rationale & Objective Persons with chronic kidney disease (CKD) are often unaware of their disease status. Efforts to improve CKD awareness may be most effective if focused on persons at highest risk for progression to kidney failure. Study Design Serial cross-sectional surveys. Setting & Participants Nonpregnant adults (aged ≥20 years) with CKD glomerular filtration rate categories 3-4 (G3-G4) who participated in the National Health and Nutrition Examination Survey from 1999 to 2016 (n = 3,713). Predictor 5-year kidney failure risk, estimated using the Kidney Failure Risk Equation. Predicted risk was categorized as minimal ( Outcome CKD awareness, defined by answering “yes” to the question “Have you ever been told by a doctor or other health professional that you had weak or failing kidneys?” Analytical Approach Prevalence of CKD awareness was estimated within each risk group using complex sample survey methods. Associations between Kidney Failure Risk Equation risk and CKD awareness were assessed using multivariable logistic regression. CKD awareness was compared with awareness of hypertension and diabetes during the same period. Results In 2011 to 2016, unadjusted CKD awareness was 9.6%, 22.6%, 44.7%, and 49.0% in the minimal-, low-, intermediate-, and high-risk groups, respectively. In adjusted analyses, these proportions did not change over time. Awareness of CKD, including among the highest risk group, remains consistently below that of hypertension and diabetes and awareness of these conditions increased over time. Limitations Imperfect sensitivity of the “weak or failing kidneys” question for ascertaining CKD awareness. Conclusions Among adults with CKD G3-G4 who have 5-year estimated risks for kidney failure of 5%

We report a case of a patient who developed dialysis-requiring acute kidney injury (AKI) after the use of canagliflozin. A 66-year-old man with type 2 diabetes who was recovering from left knee septic arthritis at a rehabilitation facility was admitted with oliguric AKI 5 days after starting treatment with canagliflozin, an inhibitor of sodium/glucose cotransporter 2 (SGLT2). The patient presented with hematuria, non-nephrotic-range proteinuria, and serum creatinine level of 6.8 (baseline, 1.1-1.3) mg/dL. There was no recent use of radiocontrast agents or exposure to other nephrotoxins. The patient subsequently required hemodialysis. Due to recent antibiotic use (ampicillin-sulbactam), acute interstitial nephritis was considered in the differential diagnosis. Kidney biopsy was performed, which showed the presence of osmotic nephropathy. The patient's kidney function returned to baseline after 2 weeks of hemodialysis. This case provides evidence of an association of osmotic nephropathy with the use of canagliflozin and discusses potential mechanisms. We recommend kidney biopsy for cases of severe AKI associated with SGLT2 inhibitors to better understand the relationship of this complication with the use of this class of medications.

Rationale & Objective The efficacy and safety of icodextrin versus glucose-only peritoneal dialysis (PD) regimens is unclear. The aim of this study was to compare once-daily long-dwell icodextrin versus glucose among patients with kidney failure undergoing PD. Study Design Systematic review of randomized controlled trials (RCTs), enriched with unpublished data from investigator-initiated and industry-sponsored studies. Setting & Study Populations Individuals with kidney failure receiving regular PD treatment enrolled in clinical trials of dialysate composition. Selection Criteria for Studies Medline, Embase, CENTRAL, Ichushi Web, 10 Chinese databases, clinical trials registries, conference proceedings, and citation lists from inception to November 2018. Further data were obtained from principal investigators and industry clinical study reports. Data Extraction 2 independent reviewers selected studies and extracted data using a prespecified extraction instrument. Analytic Approach Qualitative synthesis of demographics, measurement scales, and outcomes. Quantitative synthesis with Mantel-Haenszel risk ratios (RRs), Peto odds ratios (ORs), or (standardized) mean differences (MDs). Risk of bias of included studies at the outcome level was assessed using the Cochrane risk-of-bias tool for RCTs. Results 19 RCTs that enrolled 1,693 participants were meta-analyzed. Ultrafiltration was improved with icodextrin (medium-term MD, 208.92 [95% CI, 99.69-318.14] mL/24 h; high certainty of evidence), reflected also by fewer episodes of fluid overload (RR, 0.43 [95% CI, 0.24-0.78]; high certainty). Icodextrin-containing PD probably decreased mortality risk compared to glucose-only PD (Peto OR, 0.49 [95% CI, 0.24-1.00]; moderate certainty). Despite evidence of lower peritoneal glucose absorption with icodextrin-containing PD (medium-term MD, −40.84 [95% CI, −48.09 to −33.59] g/long dwell; high certainty), this did not directly translate to changes in fasting plasma glucose (−0.50 [95% CI, −1.19 to 0.18] mmol/L; low certainty) and hemoglobin A1c levels (−0.14% [95% CI, −0.34% to 0.05%]; high certainty). Safety outcomes and residual kidney function were similar in both groups; health-related quality-of-life and pain scores were inconclusive. Limitations Trial quality was variable. The follow-up period was heterogeneous, with a paucity of assessments over the long term. Mortality results are based on just 32 events and were not corroborated using time-to-event analysis of individual patient data. Conclusions Icodextrin for once-daily long-dwell PD has clinical benefit for some patients, including those not meeting ultrafiltration targets and at risk for fluid overload. Future research into patient-centered outcomes and cost-effectiveness associated with icodextrin is needed.

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 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 Limitations Possible unmeasured confounding. Conclusions Influenza vaccination was associated with lower risk for hospitalizations with pneumonia/influenza and major cardiac diseases in eGFR ≥ 30mL/min/1.73m2. Studies are needed to explore optimal vaccination strategies for eGFR

International audience; 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], 30-60mL/min/1.73m2) or advanced (stages 4-5, estimated glomerular filtration rate40% 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.