In CKD, empagliflozin reduced kidney disease progression at a median 2 y, regardless of primary kidney disease type.

SOURCE CITATION: EMPA-KIDNEY Collaborative Group. Impact of primary kidney disease on the effects of empagliflozin in patients with chronic kidney disease: secondary analyses of the EMPA-KIDNEY trial. Lancet Diabetes Endocrinol. 2024;12:51-60. 38061372.

Race, Genetic Ancestry, and Estimating Kidney Function in CKD.

BACKGROUND: The inclusion of race in equations to estimate the glomerular filtration rate (GFR) has become controversial. Alternative equations that can be used to achieve similar accuracy without the use of race are needed. METHODS: In a large national study involving adults with chronic kidney disease, we conducted cross-sectional analyses of baseline data from 1248 participants for whom data, including the following, had been collected: race as reported by the participant, genetic ancestry markers, and the serum creatinine, serum cystatin C, and 24-hour urinary creatinine levels. RESULTS: Using current formulations of GFR estimating equations, we found that in participants who identified as Black, a model that omitted race resulted in more underestimation of the GFR (median difference between measured and estimated GFR, 3.99 ml per minute per 1.73 m2 of body-surface area; 95% confidence interval [CI], 2.17 to 5.62) and lower accuracy (percent of estimated GFR within 10% of measured GFR [P10], 31%; 95% CI, 24 to 39) than models that included race (median difference, 1.11 ml per minute per 1.73 m2; 95% CI, -0.29 to 2.54; P10, 42%; 95% CI, 34 to 50). The incorporation of genetic ancestry data instead of race resulted in similar estimates of the GFR (median difference, 1.33 ml per minute per 1.73 m2; 95% CI, -0.12 to 2.33; P10, 42%; 95% CI, 34 to 50). The inclusion of non-GFR determinants of the serum creatinine level (e.g., body-composition metrics and urinary excretion of creatinine) that differed according to race reported by the participants and genetic ancestry did not eliminate the misclassification introduced by removing race (or ancestry) from serum creatinine-based GFR estimating equations. In contrast, the incorporation of race or ancestry was not necessary to achieve similarly statistically unbiased (median difference, 0.33 ml per minute per 1.73 m2; 95% CI, -1.43 to 1.92) and accurate (P10, 41%; 95% CI, 34 to 49) estimates in Black participants when GFR was estimated with the use of cystatin C. CONCLUSIONS: The use of the serum creatinine level to estimate the GFR without race (or genetic ancestry) introduced systematic misclassification that could not be eliminated even when numerous non-GFR determinants of the serum creatinine level were accounted for. The estimation of GFR with the use of cystatin C generated similar results while eliminating the negative consequences of the current race-based approaches. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others.).

Metabolites Associated With Uremic Symptoms in Patients With CKD: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study.

RATIONALE & OBJECTIVE: The toxins that contribute to uremic symptoms in patients with chronic kidney disease (CKD) are unknown. We sought to apply complementary statistical modeling approaches to data from untargeted plasma metabolomic profiling to identify solutes associated with uremic symptoms in patients with CKD. STUDY DESIGN: Cross-sectional. SETTING & PARTICIPANTS: 1,761 Chronic Renal Insufficiency Cohort (CRIC) participants with CKD not treated with dialysis. PREDICTORS: Measurement of 448 known plasma metabolites. OUTCOMES: The uremic symptoms of fatigue, anorexia, pruritus, nausea, paresthesia, and pain were assessed by single items on the Kidney Disease Quality of Life-36 instrument. ANALYTICAL APPROACH: Multivariable adjusted linear regression, least absolute shrinkage and selection operator linear regression, and random forest models were used to identify metabolites associated with symptom severity. After adjustment for multiple comparisons, metabolites selected in at least 2 of the 3 modeling approaches were deemed "overall significant." RESULTS: Participant mean estimated glomerular filtration rate was 43mL/min/1.73m2, with 44% self-identifying as female and 41% as non-Hispanic Black. The prevalence of uremic symptoms ranged from 22% to 55%. We identified 17 metabolites for which a higher level was associated with greater severity of at least one uremic symptom and 9 metabolites inversely associated with uremic symptom severity. Many of these metabolites exhibited at least a moderate correlation with estimated glomerular filtration rate (Pearson's r≥0.5), and some were also associated with the risk of developing kidney failure or death in multivariable adjusted Cox regression models. LIMITATIONS: Lack of a second independent cohort for external validation of our findings. CONCLUSIONS: Metabolomic profiling was used to identify multiple solutes associated with uremic symptoms in adults with CKD, but future validation and mechanistic studies are needed. PLAIN-LANGUAGE SUMMARY: Individuals living with chronic kidney disease (CKD) often experience symptoms related to CKD, traditionally called uremic symptoms. It is likely that CKD results in alterations in the levels of numerous circulating substances that, in turn, cause uremic symptoms; however, the identity of these solutes is not known. In this study, we used metabolomic profiling in patients with CKD to gain insights into the pathophysiology of uremic symptoms. We identified 26 metabolites whose levels were significantly associated with at least one of the symptoms of fatigue, anorexia, itchiness, nausea, paresthesia, and pain. The results of this study lay the groundwork for future research into the biological causes of symptoms in patients with CKD.

Comparative CKD risk prediction using homocitrulline and carbamylated albumin: two circulating markers of protein carbamylation.

BACKGROUND: Protein carbamylation, a post-translational protein modification primarily driven by urea, independently associates with adverse clinical outcomes in patients with CKD. Biomarkers used to quantify carbamylation burden have mainly included carbamylated albumin (C-Alb) and homocitrulline (HCit, carbamylated lysine). In this study, we aimed to compare the prognostic utility of these two markers in order to facilitate comparisons of existing studies employing either marker alone, and to inform future carbamylation studies. METHODS: Both serum C-Alb and free HCit levels were assayed from the same timepoint in 1632 individuals with CKD stages 2-4 enrolled in the prospective Chronic Renal Insufficiency Cohort (CRIC) study. Adjusted Cox proportional hazard models were used to assess risks for the outcomes of death (primary) and end stage kidney disease (ESKD) using each marker. C-statistics, net reclassification improvement, and integrated discrimination improvement were used to compare the prognostic value of each marker. RESULTS: Participant demographics included mean (SD) age 59 (11) years; 702 (43%) females; 700 (43%) white. C-Alb and HCit levels were positively correlated with one another (Pearson correlation coefficient 0.64). Higher C-Alb and HCit levels showed similar increased risk of death (e.g., the adjusted hazard ratio [HR] for death in the 4th carbamylation quartile compared to the 1st was 1.90 (95% confidence interval [CI] 1.35-2.66) for C-Alb, and 1.89 [1.27-2.81] for HCit; and on a continuous scale, the adjusted HR for death using C-Alb was 1.24 [1.11 to 1.39] per standard deviation increase, and 1.27 [1.10-1.46] using HCit). Both biomarkers also had similar HRs for ESKD. The C-statistics were similar when adding each carbamylation biomarker to base models (e.g., for mortality models, the C-statistic was 0.725 [0.707-0.743] with C-Alb and 0.725 [0.707-0.743] with HCit, both compared to a base model 0.723). Similarities were also observed for the net reclassification improvement and integrated discrimination improvement metrics. CONCLUSIONS: C-Alb and HCit had similar performance across multiple prognostic assessments. The markers appear readily comparable in CKD epidemiological studies.

In CKD, once-daily empagliflozin reduced progression of kidney disease or CV death at 2 y.

SOURCE CITATION: EMPA-KIDNEY Collaborative Group; Herrington WG, Staplin N, Wanner C, et al. Empagliflozin in patients with chronic kidney disease. N Engl J Med. 2023;388:117-27. 36331190.

Risk for Chronic Kidney Disease Progression After Acute Kidney Injury: Findings From the Chronic Renal Insufficiency Cohort Study.

BACKGROUND: Prior studies associating acute kidney injury (AKI) with more rapid subsequent loss of kidney function had methodological limitations, including inadequate control for differences between patients who had AKI and those who did not. OBJECTIVE: To determine whether AKI is independently associated with subsequent kidney function trajectory among patients with chronic kidney disease (CKD). DESIGN: Multicenter prospective cohort study. SETTING: United States. PARTICIPANTS: Patients with CKD (n = 3150). MEASUREMENTS: Hospitalized AKI was defined by a 50% or greater increase in inpatient serum creatinine (SCr) level from nadir to peak. Kidney function trajectory was assessed using estimated glomerular filtration rate (eGFR) based on SCr level (eGFRcr) or cystatin C level (eGFRcys) measured at annual study visits. RESULTS: During a median follow-up of 3.9 years, 433 participants had at least 1 AKI episode. Most episodes (92%) had stage 1 or 2 severity. There were decreases in eGFRcr (-2.30 [95% CI, -3.70 to -0.86] mL/min/1.73 m2) and eGFRcys (-3.61 [CI, -6.39 to -0.82] mL/min/1.73 m2) after AKI. However, in fully adjusted models, the decreases were attenuated to -0.38 (CI, -1.35 to 0.59) mL/min/1.73 m2 for eGFRcr and -0.15 (CI, -2.16 to 1.86) mL/min/1.73 m2 for eGFRcys, and the CI bounds included the possibility of no effect. Estimates of changes in eGFR slope after AKI determined by either SCr level (0.04 [CI, -0.30 to 0.38] mL/min/1.73 m2 per year) or cystatin C level (-0.56 [CI, -1.28 to 0.17] mL/min/1.73 m2 per year) also had CI bounds that included the possibility of no effect. LIMITATIONS: Few cases of severe AKI, no adjudication of AKI cause, and lack of information about nephrotoxic exposures after hospital discharge. CONCLUSION: After pre-AKI eGFR, proteinuria, and other covariables were accounted for, the association between mild to moderate AKI and worsening subsequent kidney function in patients with CKD was small. PRIMARY FUNDING SOURCE: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health.

Initial Management and Potential Opportunities to Deprescribe Dialysis among Patients with AKI-D Patients after Hospital Discharge.

SIGNIFICANCE STATEMENT: Dialysis-requiring AKI (AKI-D) now accounts for more than 15% of outpatient hemodialysis initiations; over 30% of these patients with AKI-D may have potential to recover. However, little is known about strategies currently used to treat outpatient AKI-D and screen for recovery. In this study of 1754 patients with AKI-D, we found that ( 1 ) the initial dialysis orders were similar to those of patients with contemporary incident ESKD, despite different treatment goals; ( 2 ) timed urine collections were completed in only a minority of patients; and ( 3 ) most patients with AKI-D who recovered discontinued dialysis without ever having been weaned from their initial dialysis prescription, suggesting there may be substantial opportunity to wean dialysis sooner.

A generalized covariate-adjusted top-scoring pair algorithm with applications to diabetic kidney disease stage classification in the Chronic Renal Insufficiency Cohort (CRIC) Study.

BACKGROUND: The growing amount of high dimensional biomolecular data has spawned new statistical and computational models for risk prediction and disease classification. Yet, many of these methods do not yield biologically interpretable models, despite offering high classification accuracy. An exception, the top-scoring pair (TSP) algorithm derives parameter-free, biologically interpretable single pair decision rules that are accurate and robust in disease classification. However, standard TSP methods do not accommodate covariates that could heavily influence feature selection for the top-scoring pair. Herein, we propose a covariate-adjusted TSP method, which uses residuals from a regression of features on the covariates for identifying top scoring pairs. We conduct simulations and a data application to investigate our method, and compare it to existing classifiers, LASSO and random forests. RESULTS: Our simulations found that features that were highly correlated with clinical variables had high likelihood of being selected as top scoring pairs in the standard TSP setting. However, through residualization, our covariate-adjusted TSP was able to identify new top scoring pairs, that were largely uncorrelated with clinical variables. In the data application, using patients with diabetes (n = 977) selected for metabolomic profiling in the Chronic Renal Insufficiency Cohort (CRIC) study, the standard TSP algorithm identified (valine-betaine, dimethyl-arg) as the top-scoring metabolite pair for classifying diabetic kidney disease (DKD) severity, whereas the covariate-adjusted TSP method identified the pair (pipazethate, octaethylene glycol) as top-scoring. Valine-betaine and dimethyl-arg had, respectively, ≥ 0.4 absolute correlation with urine albumin and serum creatinine, known prognosticators of DKD. Thus without covariate-adjustment the top-scoring pair largely reflected known markers of disease severity, whereas covariate-adjusted TSP uncovered features liberated from confounding, and identified independent prognostic markers of DKD severity. Furthermore, TSP-based methods achieved competitive classification accuracy in DKD to LASSO and random forests, while providing more parsimonious models. CONCLUSIONS: We extended TSP-based methods to account for covariates, via a simple, easy to implement residualizing process. Our covariate-adjusted TSP method identified metabolite features, uncorrelated from clinical covariates, that discriminate DKD severity stage based on the relative ordering between two features, and thus provide insights into future studies on the order reversals in early vs advanced disease states.

Blood Pressure, Incident Cognitive Impairment, and Severity of CKD: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study.

RATIONALE & OBJECTIVE: Hypertension is a known risk factor for dementia and cognitive impairment. There are limited data on the relation of systolic blood pressure (SBP) and diastolic blood pressure (DBP) with incident cognitive impairment in adults with chronic kidney disease. We sought to identify and characterize the relationship among blood pressure, cognitive impairment, and severity of decreased kidney function in adults with chronic kidney disease. STUDY DESIGN: Longitudinal cohort study. SETTING & PARTICIPANTS: 3,768 participants in the Chronic Renal Insufficiency Cohort (CRIC) Study. EXPOSURE: Baseline SBP and DBP were examined as exposure variables, using continuous (linear, per 10-mm Hg higher), categorical (SBP<120 [reference], 120 to 140,>140mm Hg; DBP<70 (reference), 70 to 80, > 80mm Hg) and nonlinear terms (splines). OUTCOME: Incident cognitive impairment defined as a decline in Modified Mini-Mental State Examination (3MS) score to greater than 1 standard deviation below the cohort mean. ANALYTICAL APPROACH: Cox proportional hazard models adjusted for demographics as well as kidney disease and cardiovascular disease risk factors. RESULTS: The mean age of participants was 58±11 (SD) years, estimated glomerular filtration rate (eGFR) was 44mL/min/1.73m2 ± 15 (SD), and the median follow-up time was 11 (IQR, 7-13) years. In 3,048 participants without cognitive impairment at baseline and with at least 1 follow-up 3MS test, a higher baseline SBP was significantly associated with incident cognitive impairment only in the eGFR>45mL/min/1.73m2 subgroup (adjusted hazard ratio [AHR], 1.13 [95% CI, 1.05-1.22] per 10mm Hg higher SBP]. Spline analyses, aimed at exploring nonlinearity, showed that the relationship between baseline SBP and incident cognitive impairment was J-shaped and significant only in the eGFR>45mL/min/1.73m2 subgroup (P=0.02). Baseline DBP was not associated with incident cognitive impairment in any analyses. LIMITATIONS: 3MS test as the primary measure of cognitive function. CONCLUSIONS: Among patients with chronic kidney disease, higher baseline SBP was associated with higher risk of incident cognitive impairment specifically in those individuals with eGFR>45mL/min/1.73m2. PLAIN-LANGUAGE SUMMARY: High blood pressure is a strong risk factor for dementia and cognitive impairment in studies of adults without kidney disease. High blood pressure and cognitive impairment are common in adults with chronic kidney disease (CKD). The impact of blood pressure on the development of future cognitive impairment in patients with CKD remains unclear. We identified the relationship between blood pressure and cognitive impairment in 3,076 adults with CKD. Baseline blood pressure was measured, after which serial cognitive testing was performed over 11 years. Fourteen percent of participants developed cognitive impairment. We found that a higher baseline systolic blood pressure was associated with an increased risk of cognitive impairment. We found that this association was stronger in adults with mild-to-moderate CKD compared with those with advanced CKD.

Plasma Soluble Tumor Necrosis Factor Receptor Concentrations and Clinical Events After Hospitalization: Findings From the ASSESS-AKI and ARID Studies.

RATIONALE & OBJECTIVE: The role of plasma soluble tumor necrosis factor receptor 1 (sTNFR1) and sTNFR2 in the prognosis of clinical events after hospitalization with or without acute kidney injury (AKI) is unknown. STUDY DESIGN: Prospective cohort. SETTING & PARTICIPANTS: Hospital survivors from the ASSESS-AKI (Assessment, Serial Evaluation, and Subsequent Sequelae of Acute Kidney Injury) and ARID (AKI Risk in Derby) studies with and without AKI during the index hospitalization who had baseline serum samples for biomarker measurements. PREDICTORS: We measured sTNFR1 and sTNFR2 from plasma samples obtained 3 months after discharge. OUTCOMES: The associations of biomarkers with longitudinal kidney disease incidence and progression, heart failure, and death were evaluated. ANALYTICAL APPROACH: Cox proportional hazard models. RESULTS: Among 1,474 participants with plasma biomarker measurements, 19% had kidney disease progression, 14% had later heart failure, and 21% died during a median follow-up of 4.4 years. For the kidney outcome, the adjusted HRs (AHRs) per doubling in concentration were 2.9 (95% CI, 2.2-3.9) for sTNFR1 and 1.9 (95% CI, 1.5-2.5) for sTNFR2. AKI during the index hospitalization did not modify the association between biomarkers and kidney events. For heart failure, the AHRs per doubling in concentration were 1.9 (95% CI, 1.4-2.5) for sTNFR1 and 1.5 (95% CI, 1.2-2.0) for sTNFR2. For mortality, the AHRs were 3.3 (95% CI, 2.5-4.3) for sTNFR1 and 2.5 (95% CI, 2.0-3.1) for sTNFR2. The findings in ARID were qualitatively similar in terms of the magnitude of association between biomarkers and outcomes. LIMITATIONS: Different biomarker platforms and AKI definitions; limited generalizability to other ethnic groups. CONCLUSIONS: Plasma sTNFR1 and sTNFR2 measured 3 months after hospital discharge were independently associated with clinical events regardless of AKI status during the index admission. sTNFR1 and sTNFR2 may assist with the risk stratification of patients during follow-up.

Variability in serum creatinine is associated with waitlist and post-liver transplant mortality in patients with cirrhosis.

BACKGROUND AND AIMS: Kidney function in patients with cirrhosis is dynamic. After controlling for the presence of chronic kidney disease (CKD) and acute kidney injury (AKI), we investigated the impact of variation in clinical function on pre-liver transplantation (LT) and post-LT outcomes. APPROACH AND RESULTS: We included adults listed for LT from 2011 through 2018. We excluded those with any exceptions, those on hemodialysis at listing, and those with fewer than three clinical updates in the United Network for Organ Sharing database. Our primary exposure was the serum creatinine coefficient of variation (sCr CoV). Logistic regression determined the associations between our exposures and higher sCr CoV. Competing risk regression determined the associations between our exposures and waitlist mortality, accounting for LT as a competing risk. Cox regression determined the associations between our exposures and either listing for kidney transplant or death. We divided our cohort into tertiles of sCr CoV: low variability, 8.8% (interquartile range [IQR], 6.6%-10.8%); intermediate variability, 17.4% (IQR, 14.8%-20.4%); high variability, 36.8% (IQR, 29.5%-48.8%). We demonstrate that women, those with CKD, and those with advanced liver disease were more likely to have a greater sCr CoV. Compared to those with low variability, those with high variability had significantly higher waitlist mortality (34.7% vs. 19.6% vs. 11.7%, p < 0.001). We highlight that the sCr CoV was associated with higher waitlist and post-LT mortality-an association independent of baseline sCr, the degree of underlying liver disease, the presence of AKI, or the presence of CKD. CONCLUSION: This study informs the long-term impact of the variation in kidney function we all see in clinical practice. These data highlight that all fluctuations in sCr are associated with worse pre-LT and post-LT outcomes.

Association of urine and plasma ADMA with atherosclerotic risk in DKD cardiovascular disease risk in diabetic kidney disease: findings from the Chronic Renal Insufficiency Cohort (CRIC) study.

BACKGROUND: Chronic kidney disease (CKD) is associated with atherosclerotic cardiovascular disease (ASCVD) risk, especially among those with diabetes. Altered metabolism of solutes that accumulate in CKD [asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA) and trimethylamine N-oxide (TMAO)] may reflect pathways linking CKD with ASCVD. METHODS: This case-cohort study included Chronic Renal Insufficiency Cohort participants with baseline diabetes, estimated glomerular filtration rate <60 mL/min/1.73 m2, and without prior history for each outcome. The primary outcome was incident ASCVD (time to first myocardial infarction, stroke or peripheral artery disease event) and secondary outcome was incident heart failure. The subcohort comprised randomly selected participants meeting entry criteria. Plasma and urine ADMA, SDMA and TMAO concentrations were determined by liquid chromatography-tandem mass spectrometry. Associations of uremic solute plasma concentrations and urinary fractional excretions with outcomes were evaluated by weighted multivariable Cox regression models, adjusted for confounding covariables. RESULTS: Higher plasma ADMA concentrations (per standard deviation) were associated with ASCVD risk [hazard ratio (HR) 1.30, 95% confidence interval (CI) 1.01-1.68]. Lower fractional excretion of ADMA (per standard deviation) was associated with ASCVD risk (HR 1.42, 95% CI 1.07-1.89). The lowest quartile of ADMA fractional excretion was associated with greater ASCVD risk (HR 2.25, 95% CI 1.08-4.69) compared with the highest quartile. Plasma SDMA and TMAO concentration and fractional excretion were not associated with ASCVD. Neither plasma nor fractional excretion of ADMA, SDMA and TMAO were associated with incident heart failure. CONCLUSION: These data suggest that decreased kidney excretion of ADMA leads to increased plasma concentrations and ASCVD risk.

ELIMINATING THE RACE COEFFICIENT IN KIDNEY FUNCTION ESTIMATING EQUATIONS: THE CENTER DID HOLD.

Dr. Chi-yuan Hsu describes controversies surrounding the race coefficient ("if African American") in widely used kidney function estimating equations. He outlines recent research results on this topic by himself and others and comments on the relationship between activists and the academic medical community.

Associations between abrupt transition, dialysis-requiring AKI, and early mortality in ESKD among U.S. veterans.

BACKGROUND: Mortality is high within the first few months of starting chronic dialysis. Pre-ESKD trajectory of kidney function has been shown to be predictive of early death after dialysis initiation. We aim to better understand how two key aspects of pre-dialysis kidney function-an abrupt transition pattern and an episode of dialysis-requiring AKI (AKI-D) leading directly to ESKD-are associated with early mortality after dialysis initiation. METHODS: We extracted national data from U.S. Veterans Health Administration cross-linked with the United States Renal Data System (USRDS) to identify patients who initiated hemodialysis during 2009-2013. We defined abrupt transition as having a mean outpatient eGFR ≥ 30 ml/min/1.73m2 within 1 year prior to ESKD. AKI-D was identified using inpatient serum creatinine measurements (serum Cr increase by at least 50% from baseline) along with billing codes for inpatient receipt of dialysis for AKI within 30 days prior to the ESKD start date. We used multivariable proportional hazards models to examine the association between patterns of kidney function prior to ESKD and all-cause mortality within 90 days after ESKD. RESULTS: Twenty-two thousand eight hundred fifteen patients were identified in the final analytic cohort of Veterans who initiated hemodialysis and entered the USRDS. We defined five patterns of kidney function decline. Most (68%) patients (N = 15,484) did not have abrupt transition and did not suffer an episode of AKI-D prior to ESKD (reference group). The remaining groups had abrupt transition, AKI-D, or both. Patients who had an abrupt transition with (N = 503) or without (N = 3611) AKI-D had the highest risk of early mortality after ESKD onset after adjustment for demographics and comorbidities (adjusted HR 2.10, 95% CI 1.66-2.65 for abrupt transition with AKI-D; adjusted HR 2.10, 95% CI 1.90-2.33 for abrupt transition without AKI-D). In contrast, patients who experienced AKI-D without an abrupt transition pattern (N = 2141 had only a modestly higher risk of early death (adjusted HR 1.19, 95% CI 1.01-1.40). CONCLUSIONS: An abrupt decline in kidney function within 1 year prior to ESKD occurred in nearly 1 in 5 incident hemodialysis patients (18%) in this national cohort of Veterans and was strongly associated with higher early mortality after ESKD onset.

In IgA nephropathy, oral methylprednisolone reduced adverse kidney outcomes but increased adverse events.

SOURCE CITATION: Lv J, Wong MG, Hladunewich MA, et al. Effect of oral methylprednisolone on decline in kidney function or kidney failure in patients with IgA nephropathy: the TESTING randomized clinical trial. JAMA. 2022;327:1888-98. 35579642.

Systematic integrated analysis of genetic and epigenetic variation in diabetic kidney disease.

Poor metabolic control and host genetic predisposition are critical for diabetic kidney disease (DKD) development. The epigenome integrates information from sequence variations and metabolic alterations. Here, we performed a genome-wide methylome association analysis in 500 subjects with DKD from the Chronic Renal Insufficiency Cohort for DKD phenotypes, including glycemic control, albuminuria, kidney function, and kidney function decline. We show distinct methylation patterns associated with each phenotype. We define methylation variations that are associated with underlying nucleotide variations (methylation quantitative trait loci) and show that underlying genetic variations are important drivers of methylation changes. We implemented Bayesian multitrait colocalization analysis (moloc) and summary data-based Mendelian randomization to systematically annotate genomic regions that show association with kidney function, methylation, and gene expression. We prioritized 40 loci, where methylation and gene-expression changes likely mediate the genotype effect on kidney disease development. Functional annotation suggested the role of inflammation, specifically, apoptotic cell clearance and complement activation in kidney disease development. Our study defines methylation changes associated with DKD phenotypes, the key role of underlying genetic variations driving methylation variations, and prioritizes methylome and gene-expression changes that likely mediate the genotype effect on kidney disease pathogenesis.

Acute Kidney Injury Associates with Long-Term Increases in Plasma TNFR1, TNFR2, and KIM-1: Findings from the CRIC Study.

BACKGROUND: Some markers of inflammation-TNF receptors 1 and 2 (TNFR1 and TNFR2)-are independently associated with progressive CKD, as is a marker of proximal tubule injury, kidney injury molecule 1 (KIM-1). However, whether an episode of hospitalized AKI may cause long-term changes in these biomarkers is unknown. METHODS: Among adult participants in the Chronic Renal Insufficiency Cohort (CRIC) study, we identified 198 episodes of hospitalized AKI (defined as peak/nadir inpatient serum creatinine values ≥1.5). For each AKI hospitalization, we found the best matched non-AKI hospitalization (unique patients), using prehospitalization characteristics, including eGFR and urine protein/creatinine ratio. We measured TNFR1, TNFR2, and KIM-1 in banked plasma samples collected at annual CRIC study visits before and after the hospitalization (a median of 7 months before and 5 months after hospitalization). RESULTS: In the AKI and non-AKI groups, we found similar prehospitalization median levels of TNFR1 (1373 pg/ml versus 1371 pg/ml, for AKI and non-AKI, respectively), TNFR2 (47,141 pg/ml versus 46,135 pg/ml, respectively), and KIM-1 (857 pg/ml versus 719 pg/ml, respectively). Compared with matched study participants who did not experience AKI, study participants who did experience AKI had greater increases in TNFR1 (23% versus 10%, P<0.01), TNFR2 (10% versus 3%, P<0.01), and KIM-1 (13% versus -2%, P<0.01). CONCLUSIONS: Among patients with CKD, AKI during hospitalization was associated with increases in plasma TNFR1, TNFR2, and KIM-1 several months after their hospitalization. These results highlight a potential mechanism by which AKI may contribute to more rapid loss of kidney function months to years after the acute insult.

Angiopoietins as Prognostic Markers for Future Kidney Disease and Heart Failure Events after Acute Kidney Injury.

BACKGROUND: The mechanisms underlying long-term sequelae after AKI remain unclear. Vessel instability, an early response to endothelial injury, may reflect a shared mechanism and early trigger for CKD and heart failure. METHODS: To investigate whether plasma angiopoietins, markers of vessel homeostasis, are associated with CKD progression and heart failure admissions after hospitalization in patients with and without AKI, we conducted a prospective cohort study to analyze the balance between angiopoietin-1 (Angpt-1), which maintains vessel stability, and angiopoietin-2 (Angpt-2), which increases vessel destabilization. Three months after discharge, we evaluated the associations between angiopoietins and development of the primary outcomes of CKD progression and heart failure and the secondary outcome of all-cause mortality 3 months after discharge or later. RESULTS: Median age for the 1503 participants was 65.8 years; 746 (50%) had AKI. Compared with the lowest quartile, the highest quartile of the Angpt-1:Angpt-2 ratio was associated with 72% lower risk of CKD progression (adjusted hazard ratio [aHR], 0.28; 95% confidence interval [CI], 0.15 to 0.51), 94% lower risk of heart failure (aHR, 0.06; 95% CI, 0.02 to 0.15), and 82% lower risk of mortality (aHR, 0.18; 95% CI, 0.09 to 0.35) for those with AKI. Among those without AKI, the highest quartile of Angpt-1:Angpt-2 ratio was associated with 71% lower risk of heart failure (aHR, 0.29; 95% CI, 0.12 to 0.69) and 68% less mortality (aHR, 0.32; 95% CI, 0.15 to 0.68). There were no associations with CKD progression. CONCLUSIONS: A higher Angpt-1:Angpt-2 ratio was strongly associated with less CKD progression, heart failure, and mortality in the setting of AKI.

Trans-ethnic genome-wide association study of blood metabolites in the Chronic Renal Insufficiency Cohort (CRIC) study.

Metabolomics genome wide association study (GWAS) help outline the genetic contribution to human metabolism. However, studies to date have focused on relatively healthy, population-based samples of White individuals. Here, we conducted a GWAS of 537 blood metabolites measured in the Chronic Renal Insufficiency Cohort (CRIC) Study, with separate analyses in 822 White and 687 Black study participants. Trans-ethnic meta-analysis was then applied to improve fine-mapping of potential causal variants. Mean estimated glomerular filtration rate was 44.4 and 41.5 mL/min/1.73m2 in the White and Black participants, respectively. There were 45 significant metabolite associations at 19 loci, including novel associations at PYROXD2, PHYHD1, FADS1-3, ACOT2, MYRF, FAAH, and LIPC. The strength of associations was unchanged in models additionally adjusted for estimated glomerular filtration rate and proteinuria, consistent with a direct biochemical effect of gene products on associated metabolites. At several loci, trans-ethnic meta-analysis, which leverages differences in linkage disequilibrium across populations, reduced the number and/or genomic interval spanned by potentially causal single nucleotide polymorphisms compared to fine-mapping in the White participant cohort alone. Across all validated associations, we found strong concordance in effect sizes of the potentially causal single nucleotide polymorphisms between White and Black study participants. Thus, our study identifies novel genetic determinants of blood metabolites in chronic kidney disease, demonstrates the value of diverse cohorts to improve causal inference in metabolomics GWAS, and underscores the shared genetic basis of metabolism across race.

The incidence of and risk factors for hospitalized acute kidney injury among people living with HIV on antiretroviral treatment.

OBJECTIVES: The epidemiology of hospitalized acute kidney injury (AKI) among people living with HIV (PLWH) in the era of modern antiretroviral therapy (ART) for all PLWH is not well characterized. We evaluated the incidence of and risk factors for hospitalized AKI from 2005 to 2015 among PLWH on ART. METHODS: We conducted a retrospective analysis of PLWH from the Johns Hopkins HIV Clinical Cohort. We defined hospitalized AKI as a rise of ≥ 0.3 mg/dL in serum creatinine (SCr) within any 48-h period or a 50% increase in SCr from baseline and assessed associations of risk factors with incident AKI using multivariate Cox regression models. RESULTS: Most participants (75%) were black, 34% were female, and the mean age was 43 years. The incidence of AKI fluctuated annually, peaking at 40 per 1000 person-years (PY) [95% confidence interval (CI) 22-69 per 1000 PY] in 2007, and reached a nadir of 20 per 1000 PY (95% CI 11-34 per 1000 PY) in 2010. There was no significant temporal trend (-3.3% change per year; 95% CI -8.6 to 2.3%; P = 0.24). After multivariable adjustment, characteristics independently associated with AKI included black race [hazard ratio (HR) 2.44; 95% CI 1.42-4.20], hypertension (HR 1.62; 95% CI 1.09-2.38), dipstick proteinuria > 1 (HR 1.86; 95% CI 1.07-3.23), a history of AIDS (HR 1.82; 95% CI 1.29-2.56), CD4 count < 200 cells/µL (HR 1.46; 95% CI 1.02-2.07), and lower serum albumin (HR 1.73 per 1 g/dL decrease; 95% CI 1.02-2.07). CONCLUSIONS: In this contemporary cohort of PLWH, the annual incidence of first AKI fluctuated during the study period. Attention to modifiable AKI risk factors and social determinants of health may further reduce AKI incidence among PLWH.