Environmental exposures are increasingly associated with kidney and cardiometabolic disease in children. This review summarizes current understanding of the potentially hazardous effects of air pollution, chemical toxicants, and heavy metal contamination on pediatric kidney health and cardiometabolic risk factors for chronic kidney disease (CKD), as well as the potentially protective effect of green space. We highlight the critical windows of childhood development, during which the kidneys may have varying susceptibility to environmental exposures. We also discuss challenges and possible solutions to adequately powered studies at the intersection of environmental health and pediatric kidney disease. Environmental exposures are both ubiquitous and modifiable. Therefore, elucidating the contribution of environmental exposures to the increasing global burden of CKD will be crucial to informing strategies for kidney disease prevention, starting in childhood. IMPACT: We summarize current evidence on the associations between environmental exposures-including air pollution, chemical toxicants, and heavy metal contamination-and pediatric kidney disease and related cardiometabolic risk factors, as well as the potentially protective effect of green space. We highlight how the impact of environmental exposures on the kidneys may vary during different critical windows of childhood development. Lastly, we discuss methodological challenges and potential solutions, such as using novel technologies and approaches to adequately power studies toward the goal of environmental intervention for chronic kidney disease (CKD) prevention.

KEY POINTS:In adults with diabetes, native kidney biopsy complications were uncommon across multiple US centers. Most events were minor; major bleeding was rare, but clinically meaningful. Obtaining an additional (research) core does not significantly increase the risk. BACKGROUND:Percutaneous kidney biopsy is essential for diagnosing kidney disease, but carries a risk of bleeding and other complications. Reported complication rates vary widely because of heterogeneity in outcome definitions. Patients with diabetes frequently have hypertension, vascular stiffness, and altered hemostasis, which may further influence biopsy safety. The multicenter Transformative Research in Diabetic Nephropathy study prospectively evaluated biopsy complications in adults with diabetes using standardized definitions across 21 sites from the United States. METHODS:We analyzed 408 native kidney biopsies from participants with diabetes enrolled in Transformative Research in Diabetic Nephropathy (2017-2025). Complications were classified as minor (hematoma, biopsy site pain, or hemoglobin drop), resource-intense (transfusion, radiologic or surgical intervention, or prolonged hospitalization), and major bleeding (≥2 g/dl hemoglobin decline, transfusion, or intervention). Logistic regression with site clustered robust errors was used to identify clinical and procedural associations with outcomes. RESULTS:Among 408 biopsies, 81 complications (20%) occurred, most commonly hematoma (15%); resource-intense events were infrequent (5%). Use of an 18-gauge (versus 16-gauge) needle was associated with lower odds of resource intense events (odds ratio [OR], 0.32; 95% confidence interval [CI], 0.17 to 0.60). Procedures by fellows, hybrid teams, or interventional radiologists had higher odds than those by attendings (OR, 3.12-13.4). Renin-angiotensin system inhibitors use was independently associated with lower odds (OR, 0.13; 95% CI, 0.02 to 0.73). Female sex (OR, 4.88; 95% CI, 1.02-45.3) and postbiopsy hematoma (OR, 14.3; 95% CI, 3.66 to 74.5) were associated with major bleeding, whereas the number of passes correlated with hematoma formation, but not with adjusted major bleeding risk. CONCLUSIONS:In adults with diabetes, clinically significant biopsy complications were uncommon and were associated with procedural and operator factors rather than diabetes. Smaller gauge needles and experienced operators were associated with lower risk, whereas female sex and hematoma were associated with major bleeding. The higher overall complication rate mainly reflected comprehensive, prospective ascertainment of minor events, and supports standardized definitions and procedures to improve biopsy safety in diabetic kidney disease.

INTRODUCTION:Diabetic nephropathy (DN) remains the leading cause of kidney failure worldwide. Histopathologic assessment is the diagnostic standard, and the Renal Pathology Society (RPS) classification system is widely used in clinical practice and research. However, its prognostic performance is limited, particularly in advanced disease. METHODS:To examine this, we used TRIDENT, a multicenter, prospective observational cohort of patients with diabetes undergoing clinically indicated kidney biopsy (176 individuals). Light-microscopy features were scored and analyzed by unsupervised k-means clustering to derive the RPS-TRIDENT modification (RPS-TM) classification. Associations between RPS-TM classes and kidney outcomes: death, dialysis initiation or 40% or more decline in estimated glomerular filtration rate were evaluated with Kaplan-Meier curves and Cox proportional hazards models. Clinical utility was assessed by decision-curve analysis. An external cohort of 101 individuals was used for validation. RESULTS:The RPS classification showed only modest prognostic discrimination, with no significant survival difference between classes 3 and 4. The RPS-TM classification introduced an additional high-risk category (Class 5) defined by visceral epithelial hyperplasia, which more clearly separated risk groups, modestly improved prediction at one year (area under the curve 0.68 vs. 0.65) and two years (0.75 vs. 0.71), and demonstrated higher net benefit in decision curve analysis. RPS-TM Class 5 had the most rapid progression to kidney failure. CONCLUSIONS:The RPS-TM classification enhances prognostication in DN by identifying a morphologic subgroup characterized by visceral epithelial hyperplasia with aggressive clinical course. This framework offers more precise risk stratification and could guide targeted management and trial design in DN.

BACKGROUND:Clinical guidelines recommend that patients with diabetes mellitus (DM) are screened annually for kidney disease with estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR). To improve screening, we implemented clinical decision support (CDS) at UVA Health in April 2022. This included: (1) auto-enrollment of primary care patients with DM in an electronic health record (EHR)-based health maintenance plan; and (2) prompting one-click ordering of the Kidney Profile (KP; panel including UACR and eGFR) or UACR alone, as needed. METHODS:We assessed effectiveness of the CDS using an interrupted time series approach across 3 periods (pre-COVID-19 control: January 2019-February 2020; post-COVID-19 control: March 2021-April 2022; post-CDS: May 2022 to April 2023). All non-acute office and telehealth encounters in primary care for patients aged ≥22 years with DM, no coded diagnosis of CKD in the prior 4 years, and due for screening (i.e., not screened for CKD in past 365 days). Screening was assessed as orders placed for UACR within 30 days of the encounter and aggregated by calendar months. RESULTS:There were 66,388 encounters (23,419 pre-COVID-19 control; 22,611 post-COVID-19 control; 20,358 post-CDS). The screening trend in both control periods was similar, therefore only the post-COVID-19 control was considered further. Demographics, encounter types, and clinic distribution were similar in the control and post-CDS periods. There was an immediate screening difference of 3.02% (95% CI, 0.37- 5.68; p=0.03) after the CDS, and screening acceleration with a difference in screening rate of 0.57% each month compared to 0.06% per month prior to the CDS (p<0.01). Results were similar if encounters for patients with prior CKD by laboratory criteria were removed. CONCLUSIONS:Roll out of CDS coincided with immediate and ongoing improvement in annual screening for CKD among adult patients with DM. These results suggest that simple CDS may be an effective intervention to promote CKD screening.

PURPOSE OF REVIEW:The purpose of this review is to: evaluate the clinical trial evidence base for the treatment of chronic kidney disease mineral and bone disorder (CKD-MBD) in patients with kidney failure as it relates to highly prioritized clinical outcomes; and discuss approaches and principles to develop needed trials in CKD-MBD. RECENT FINDING:Most clinical trials in CKD-MBD focus on biochemical outcomes, with few trials of surrogate outcomes (e.g., vascular calcification, left ventricular hypertrophy, bone mineral density), and even fewer of highly prioritized clinically important outcomes, such as mortality, cardiovascular disease events, or hospitalization. Within phosphate management, the recent LANDMARK trial did not detect a difference in a cardiovascular composite outcome between patients randomized to lanthanum carbonate vs. a calcium-based phosphate binder strategy over 3 years. The ongoing PHOSPHATE trial will provide needed evidence on phosphate treatment targets. There are no comparable, large trials of parathyroid hormone (PTH) targets. Observational approaches using clinical trial emulation suggest the potential for reduced cardiovascular disease and mortality with an 'emulated' low PTH target, but trials must be designed to confirm this. To ensure success, these trials must focus on practical treatment approaches, leveraging areas of practice variation and recognizing the dynamic nature of longitudinal CKD-MBD care. SUMMARY:More intensive treatment of CKD-MBD remains a promising approach to improve clinical outcomes in patients with kidney failure and should prompt ongoing efforts to obtain needed trials.

Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) is a complex condition impacting patients with kidney failure and characterized by inter-related features such as hyperparathyroidism, hyperphosphatemia, and hypocalcemia. Current treatments include active vitamin D sterols, calcimimetics, and phosphate binders alone and in combination. However, identifying optimal treatment is challenged by interdependency among CKD-MBD features, requiring new approaches to understand dynamic systems. In this review, we discuss challenges and opportunities for a more integrated view of CKD-MBD care. Few clinical studies in CKD-MBD care have incorporated a dynamic understanding of the disorder and its treatment. Dynamic treatment regime methods are an evolving area of artificial intelligence (AI) that offer a promising approach for modeling and understanding CKD-MBD care. Efforts to date have included dynamic systems and quantitative systems pharmacology-based models to simulate the impact of alternative treatment regimes. Additional studies utilizing dynamic treatment regime approaches may help improve knowledge gaps in CKD-MBD care. Although preliminary research highlights the potential of dynamic treatment regime approaches in optimizing CKD-MBD management, further investigation and clinical validation are necessary to fully harness this approach for improving patient outcomes.

Background:Pulmonary microvascular dysfunction has been suggested to be an early feature of interstitial lung changes, which may precede interstitial lung disease. The prospective association of albuminuria, a marker of endothelial dysfunction, with interstitial lung abnormalities (ILA) and high-attenuation areas (HAA) remains unexplored. Methods:The study included participants with available spot urinary albumin-creatinine ratio (UACR) and computed tomography data for ILA and HAA enrolled in two independent cohorts, Multi-Ethnic Study of Atherosclerosis (MESA; n=2248) and Age Gene/Environment Susceptibility (AGES)-Reykjavik (n=3509). HAA were defined as the percentage of imaged lungs with attenuation between -600 and -250 HU (MESA only). Regression modelling was performed to assess the associations of UACR with ILA and HAA, adjusted for anthropometric and demographic variables and kidney function. Cox proportional-hazard models were used to examine whether ILA modified the association between albuminuria and all-cause mortality. Results:Log-transformed UACR was significantly associated with ILA, with an OR 1.21 (95% CI 1.12-1.30) in MESA and OR 1.13 (95% CI 1.06-1.21) in AGES-Reykjavik. In multivariable-adjusted models incorporating age, albuminuria was no longer associated with ILA, nor with ILA progression in AGES-Reykjavik. In MESA, higher levels of albuminuria were associated with greater HAA (mean increase of 1.01% per 1-unit increment in log-transformed UACR, 95% CI 1.01-1.02%), even after adjusting for covariates including age. Albuminuria was more strongly associated with death among those with ILA in MESA, but not in AGES-Reykjavik. Conclusions:Albuminuria was not associated with ILA after accounting for chronological age. Our findings suggest that there may be a common systemic pathology of ageing that underlies albuminuria and interstitial lung changes.

RATIONALE & OBJECTIVE:Prescribing psychoactive medications for patients with kidney disease is common, but for patients receiving dialysis some medications may be inappropriate. We evaluated the association of coprescribing gabapentinoids and other psychoactive potentially inappropriate medications (PPIMs) (eg, sedatives or opioids) with altered mental status (AMS) and falls and whether the associations are modified by frailty. STUDY DESIGN:Observational cohort study. SETTING & PARTICIPANTS:Adults receiving dialysis represented in the US Renal Data System who had an active gabapentinoid prescription and no other PPIM prescriptions in the prior 6 months. EXPOSURE:PPIM coprescribing, or the presence of overlapping prescriptions of a gabapentinoid and≥1 additional PPIM. OUTCOME:Acute care visits for AMS and injurious falls. ANALYTICAL APPROACH:Prentice-Williams-Petersen Gap Time models estimated the association between PPIM coprescribing and each outcome, adjusting for demographics, comorbidities, and frailty, as assessed by a validated frailty index (FI). Each model tested for interaction between PPIM coprescribing and frailty. RESULTS:Overall, PPIM coprescribing was associated with increased hazard of AMS (HR, 1.66 [95% CI, 1.44-1.92]) and falls (HR, 1.55 [95% CI, 1.36-1.77]). Frailty significantly modified the effect of PPIM coprescribing on the hazard of AMS (interaction P=0.01) but not falls. Among individuals with low frailty (FI=0.15), the HR for AMS with PPIM coprescribing was 2.14 (95% CI, 1.69-2.71); for individuals with severe frailty (FI=0.34), the hazard ratio for AMS with PPIM coprescribing was 1.64 (95% CI, 1.42-1.89). Individuals with PPIM coprescribing and severe frailty (FI=0.34) had the highest hazard of AMS (HR, 3.22 [95% CI, 2.55-4.06]) and falls (HR, 2.77 [95% CI, 2.27-3.38]) compared with nonfrail individuals without PPIM coprescribing. LIMITATIONS:Outcome ascertainment bias; residual confounding. CONCLUSIONS:Compared with gabapentinoid prescriptions alone, PPIM coprescribing was associated with an increased risk of AMS and falls. Clinicians should consider these risks when coprescribing PPIMs to patients receiving dialysis. PLAIN-LANGUAGE SUMMARY:Among people on dialysis, gabapentinoids may lead to confusion and falls. Often they are prescribed with other sedatives drugs or opioids, which can increase these risks. This study of adults with kidney failure receiving maintenance dialysis in the United States found that those who were prescribed both gabapentinoids and other psychoactive drugs were more likely to have confusion and falls compared with those who only took gabapentinoids. These relationships were seen at all levels of frailty although the relative risk of confusion related to an additional psychoactive drug was somewhat lower in the setting of greater frailty. Clinicians should consider elevated risks of confusion and falls when prescribing psychoactive drugs to patients receiving dialysis who are also prescribed gabapentinoids.

Rationale & Objective: Coronary artery calcifi cation (CAC) progresses rapidly in people with chronic kidney disease (CKD) compared with the general population. We studied the association between CAC progression and higher risks of atherosclerotic cardiovascular disease (CVD), congestive heart failure, and all-cause mortality among adults with CKD. Study Design: Prospective cohort study. Setting & Participants: 1,310 participants in the Chronic Renal Insufficiency Cohort (CRIC) Study who had at least 1 CAC scan with no prior history of CVD and with observed or imputed data on changes in CAC over time. Exposure: Observed or imputed CAC progression, categorized as incident CAC among participants with 0 CAC on the baseline scan or progressive CAC when the baseline scan demonstrated CAC and there was an increase in CAC >= 50 Agatston units per year. Outcome: Atherosclerotic CVD (myocardial infarction or stroke), congestive heart failure, and all-cause mortality. Analytical Approach: Cause-specific Cox proportional hazards regression, stratified by presence of CAC at baseline. Results: A total of 545 participants without and 765 with prevalent CAC at baseline were included. During a mean 3.3 years between CAC assessments, 177 participants (32.5%) without baseline CAC developed incident CAC while 270 participants (35.3%) with baseline CAC developed a >= 50 Agatston units per year increase in CAC. After multivariable adjustment, incident CAC was associated with 2.42-fold higher rate of atherosclerotic CVD (95% CI, 1.23-4.79) and 1.82-fold higher rate of all-cause mortality (95% CI, 1.03-3.22). Progressive CAC (>= 50 units per year) was not associated with atherosclerotic CVD (HR, 1.42 [95% CI, 0.85-2.35]) but was associated with a 1.73-fold higher rate of all- cause mortality (95% CI, 1.31-2.28). Progressive CAC was not associated with incident heart failure. Limitations: Residual confounding and limited statistical power for some outcomes. Conclusions: Among adults with CKD stages 2-4, CAC progression over a mean 3.3 years was associated with higher risk of atherosclerotic CVD and all- cause mortality. The associations were strongest among participants without CAC at baseline.

Significance Statement Black adults in the United States have 2–4 times higher incidence of kidney failure than White adults. Yet, the reasons underlying this disparity remain poorly understood. Among 547,188 US veterans with new-onset CKD, according to a new race-free GFR equation, Black veterans had a 2.5-fold higher cumulative incidence of kidney failure, compared with White veterans, in any follow-up period from CKD onset. This disparity resulted from a combination of higher hazards of progression to kidney failure and lower hazards of competing-risk death in Black veterans. Both, in turn, were largely explained by the younger age at CKD onset in Black veterans, underscoring an urgent need to prevent early onset and slow progression of CKD in younger Black adults. Background The Black adult population is well known to have higher incidence of kidney failure than their White counterpart in the United States, but the reasons underlying this disparity are unclear. We assessed the racial differences in kidney failure and death from onset of CKD on the basis of the race-free 2021 CKD Epidemiology Collaboration equation and examined the extent to which these differences could be explained by factors at the time of CKD onset. Methods We analyzed a national cohort consisting of 547,188 US veterans (103,821 non-Hispanic Black and 443,367 non-Hispanic White), aged 18–85 years, with new-onset CKD between 2005 and 2016 who were followed through 10 years or May 2018 for incident kidney failure with replacement therapy (KFRT) and pre-KFRT death. Results At CKD onset, Black veterans were, on average, 7.8 years younger than White veterans. In any time period from CKD onset, the cumulative incidence of KFRT was 2.5-fold higher for Black versus White veterans. Meanwhile, Black veterans had persistently >2-fold higher hazards of KFRT throughout follow-up (overall hazard ratio [95% confidence interval], 2.38 [2.31 to 2.45]) and conversely had 17%–48% decreased hazards of pre-KFRT death. These differences were reduced after accounting for the racial difference in age at CKD onset. Conclusions The 2.5-fold higher cumulative incidence of kidney failure in Black adults resulted from a combination of higher hazards of progression to kidney failure and lower hazards of the competing risk of death, both of which can be largely explained by the younger age at CKD onset in Black compared with White adults.

Rationale & ObjectiveLife expectancy of patients treated with maintenance hemodialysis (MHD) is heterogeneous. Knowledge of life-expectancy may focus care decisions on near-term vs. long-term goals. Current tools are limited and focus on near-term mortality. Here, we develop and assess potential utility for predicting near-term mortality and long-term survival on MHD.Study DesignPredictive modelling study.Setting & Participants42,351 patients contributing 997,381 patient months over 11 years, abstracted from the EHR system of mid-size, non-profit dialysis providers.New Predictors & Established PredictorsDemographics, laboratory results, vital signs, and service utilization data available within dialysis EHR.OutcomesFor each patient month, we ascertained death within the next 6-months (i.e., near-term mortality) and survival over more than 5-years during receipt of MHD or following kidney transplantation (i.e., long-term survival).Analytical ApproachWe used LASSO logistic regression and gradient-boosting machines to predict each outcome. We compared these to time-to-event models spanning both time horizons. We explored the performance of decision rules at different cut-points.ResultsAll models achieved AUROC ≥ 0.80 and optimal calibration metrics in the test set. Long-term survival models had significantly better performance than near-term mortality models. Time-to-event models performed similarly to binary models. Applying different cutpoints spanning from the 1st to 90th percentile of the predictions, a positive predictive value (PPV) of 54% could be achieved for near-term mortality, but with poor sensitivity of 6%. A PPV of 71% could be achieved for long-term survival with a sensitivity of 67%.LimitationsThe retrospective models would need to be prospectively validated before they could be appropriately used as clinical decision aids.ConclusionsA model built with readily available clinical variables to support easy implementation, can predict clinically important life expectancy thresholds and shows promise as a clinical decision support tool for patients on MHD. Predicting long-term survival has better decision rule performance than predicting near-term mortality.

Key PointsWe found poor ability to distinguish among different causes of death using clinical information in the 30 days before death for patients on hemodialysis.We found that models of different causes of death identified similar associated clinical factors.Given the lack of clear phenotypic differences, this study questions the usefulness of cause of death in research in dialysis.BackgroundPatients treated with maintenance hemodialysis are at high risk of death from a variety of causes.MethodsTo identify markers (i.e., risk phenotypes) that distinguish among causes of death, we used dialysis electronic health record data for a cohort of adults treated with maintenance in-center hemodialysis who died between 2003 and 2016 (n=19,793). Patients were linked to the United States Renal Data System (USRDS) Files. We classified USRDS-reported causes of death into five categories: sudden cardiac death, nonsudden cardiac death cardiovascular death, infection, others, and unknown. A subcohort was linked to the National Death Index with similar categories defined. We used ensemble classification trees to discriminate among causes using demographics, vital signs, laboratory measures, health service utilization, and comorbidity claims from 30 days before death. We then created nested case-control populations for each cause of death and used ridge logistic regression to evaluate clinical risk markers that associate with distinct causes.ResultsThe area under the receiver operating characteristic curves from ensemble classification trees were all between 0.59 and 0.70, suggesting minimal ability to distinguish among causes using clinical risk markers. Model coefficients were similar and highly correlated across different cause of death models (i.e., 0.87-0.94). This suggests that most clinical risk markers are shared across causes without distinct risk phenotypes.ConclusionsWe conclude that different causes of death may share similar clinical risk markers in the setting of kidney failure or that the causes of death attributed on USRDS or National Death Index forms are not precise.

BACKGROUND:The Choosing Wisely campaign suggests an individualized approach to cancer screening among patients receiving dialysis. We aimed to evaluate breast and prostate cancer screening among patients receiving maintenance hemodialysis (HD) by kidney transplant waitlist status and five-year survival probability. METHODS:We conducted a retrospective cohort study using a nationally representative population of HD patients. Patients receiving HD each calendar year from 2003-2018, ≥1 year of Medicare as the Primary Payer, and age 50-69 years were included. The cohort was split into prognosis and cancer screening sets. Models of five-year survival were built in the prognosis set using logistic regression. Five-year survival probabilities were generated in the cancer screening set, excluding patients with prior breast or prostate cancer, and screening over the next year was assessed. RESULTS:160,537 patients contributed 356,165 person-years to the cancer screening set (59% of the person-years were contributed by males, median age was 60 years). Compared to a benchmark rate of 50% (e.g., mammography every other year), 42% of waitlisted female-years were screened by mammography. Overall, 17% of non-waitlisted female-years were screened (20% among those with >50% probability of five-year survival and 8% among those with <10% probability of five-year survival). Compared to a benchmark rate of 20% [e.g., serum prostate-specific antigen (PSA) screening up to five years apart], 24% of waitlisted male-years were screened with serum PSA. Overall 15% of non-waitlisted male-years were screened (13% among those with >50% probability of five-year survival and 1% among those with <10% probability of five-year survival). Patterns were similar after age-standardization. CONCLUSION:Patients with higher predicted survival have higher rates of cancer screening, suggesting providers consider life expectancy. However, non-waitlisted patients with high probability of five-year survival were less likely to be screened compared to waitlisted patients. Interventions may be needed to close this screening gap.

Objective: The gut microbiota contributes to metabolic diseases, such as diabetes and hypertension, but is poorly characterized in chronic kidney disease (CKD). Design and Methods: We enrolled 24 adults within household pairs, in which at least one member had self-reported kidney disease, diabetes, or hypertension. CKD was classified based on estimated glomerular filtration rate < 60 mL/min/1.73 m(2) or urine-albumin-to-creatinine ratio of >= 30 mg/g. Participants collected stool and dietary recalls seasonally over a year. Gut microbiota was characterized using 16s rRNA and metagenomic sequencing. Results: Ten participants had CKD (42%) with a median (interquartile range) estimated glomerular filtration rate of 49 (44, 54) mL/min/1.73 m(2). By 16s rRNA sequencing, there was moderate to high intraclass correlation (ICC = 0.63) for seasonal alpha diversity (Shannon index) within individuals and modest differences by season (P < .01). ICC was lower with metagenomics, which has resolution at the species level (ICC = 0.26). There were no differences in alpha or beta diversity by CKD with either method. Among 79 genera, Frisingicoccus, Tuzzerella, Faecalitalea, and Lachnoclostridium had lower abundance in CKD, while Collinsella, Lachnospiraceae_ND3007, Veillonella, and Erysipelotrichaceae_UCG_003 were more abundant in CKD (each nominal P < .05) using 16s rRNA sequencing. Higher Collinsella and Veillonella and lower Lachnoclostridium in CKD were also identified by metagenomics. By metagenomics, Coprococcus catus and Bacteroides stercoris were more and less abundant in CKD, respectively, at false discovery rate corrected P = .02. Conclusions: We identified candidate taxa in the gut microbiota associated with CKD. High ICC in individuals with modest seasonal impacts implies that follow-up studies may use less frequent sampling. (c) 2024 Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc