Anti-Tumor Necrosis Factor Therapy and Risk of Kidney Function Decline and Mortality in Inflammatory Bowel Disease.

Importance: Inflammatory bowel disease (IBD) is associated with adverse clinical outcomes, including chronic kidney disease and mortality, due in part to chronic inflammation. Little is known about the effects of anti-tumor necrosis factor (TNF) therapy on kidney disease progression and mortality among patients with new-onset IBD. Objective: To examine the association of incident use of TNF inhibitors with subsequent decline in kidney function and risk of all-cause mortality. Design, Setting, and Participants: This retrospective cohort study used data from the US Department of Veterans Affairs health care system. Participants were US veterans with new-onset IBD enrolled from October 1, 2004, through September 30, 2019. Data were analyzed from December 2022 to February 2024. Exposures: Incident use of TNF inhibitors. Main Outcomes and Measures: The main outcomes were at least 30% decline in estimated glomerular filtration rate (eGFR) and all-cause mortality. Results: Among 10 689 patients (mean [SD] age, 67.4 [12.3] years; 9999 [93.5%] male) with incident IBD, 3353 (31.4%) had diabetes, the mean (SD) baseline eGFR was 77.2 (19.2) mL/min/1.73 m2, and 1515 (14.2%) were newly initiated on anti-TNF therapy. During a median (IQR) follow-up of 4.1 (1.9-7.0) years, 3367 patients experienced at least 30% decline in eGFR, and over a median (IQR) follow-up of 5.0 (2.5-8.0) years, 2502 patients died. After multivariable adjustments, incident use (vs nonuse) of TNF inhibitors was significantly associated with higher risk of decline in eGFR (adjusted hazard ratio [HR], 1.34 [95% CI, 1.18-1.52]) but was not associated with risk of all-cause mortality (adjusted HR, 1.02 [95% CI, 0.86-1.21]). Similar results were observed in sensitivity analyses. Conclusions and Relevance: In this cohort study of US veterans with incident IBD, incident use (vs nonuse) of TNF inhibitors was independently associated with higher risk of progressive eGFR decline but was not associated with risk of all-cause mortality. Further studies are needed to elucidate potentially distinct pathophysiologic contributions of TNF inhibitor use to kidney and nonkidney outcomes in patients with IBD.

Incident Diuretic Use and Subsequent Risk of Bone Fractures: A Large Nationwide Observational Study of US Veterans.

OBJECTIVE: To investigate the association of incident use of diuretics with subsequent risk of incident bone fractures. PATIENTS AND METHODS: In a nationwide cohort of 863,339 US veterans receiving care from the VA health care system between October 1, 2004, and September 30, 2006, with follow-up through June 30, 2018, we examined the association of incident diuretic use (overall, and separately by thiazide, loop, and potassium-sparing diuretics) with subsequent risk of incident bone fractures using multivariable Cox regression models while minimizing confounding by indication using a target trial emulation approach. RESULTS: Patients were 63.3±12.9 years old; 93.5% (n=807,180) were male; and 27.1% (n=233,996) were diabetic. Their baseline estimated glomerular filtration rate was 84.4±16.5 mL/min per 1.73 m2. Among 863,339 patients, 424,386 (49.2%) newly initiated diuretics, of which 77.4% (n=328,524), 22.5% (n=95,457), and 0.1% (n=405) were thiazide, loop, and potassium-sparing diuretic users, respectively. After multivariable adjustments, incident diuretic use (vs non-use) was significantly associated with higher risk of incident fracture (adjusted HR [aHR], 1.14; 95% CI, 1.11 to 1.16). The association was most pronounced for loop diuretics (aHR, 1.39; 95% CI, 1.35 to 1.44) but less evident for thiazide diuretics (aHR, 1.08; 95% CI, 1.06 to 1.10) and was not significant for potassium-sparing diuretics (aHR, 0.97; 95% CI, 0.62 to 1.52). The diuretic-fracture association was more evident in younger (vs older) patients, those with (vs without) corticosteroid use, and those with lower (vs higher) serum sodium levels. CONCLUSION: Incident use of diuretics, particularly loop diuretics, was independently associated with higher risk of incident bone fractures. Our findings suggest distinct pathophysiologic contributions of diuretics to bone metabolism and the need for careful attention to skeletal outcomes when initiating diuretics.

Change Over Time in Pre-End-Stage Renal Disease 24-Hour Urine Creatinine as Muscle Mass Surrogate and Post-End-Stage Renal Disease Mortality.

OBJECTIVE: Loss of muscle mass and sarcopenia are common in chronic kidney disease (CKD) and end-stage renal disease (ESRD), and sarcopenia can worsen insidiously in patients with advancing CKD. The temporal dynamics of sarcopenia in patients with progressive loss of kidney function, and its association with future outcomes, is unclear. METHODS: In a contemporary national cohort of incident ESRD US veterans, we selected 661 patients who had at least 2 24-hour urine creatinine (24hrUC) measurements, a surrogate of muscle mass, performed during the 3-year prelude period prior to ESRD transition. We estimated 24hrUC slopes in mixed effects models. To assess the temporal dynamics of pre-ESRD changes in 24hrUC and its association with changing eGFR, we separately fitted in mixed effects models a penalized spline regression of 24hrUC on time and on eGFR. We examined the association of 24hrUC slopes with postdialysis all-cause mortality using Cox models adjusted for confounders. RESULTS: The mean slope of 24hrUC versus time was -78 mg/year (95% confidence interval: -102 to -54), with a steeper decline noted in the last year prior to ESRD. More severe decreases in 24hrUC were associated with higher all-cause mortality: a 100 mg/year decrease in 24hrUC was associated with a multivariable adjusted death hazard ratio of 1.41 (95% confidence interval: 1.00-1.98, P = .05). CONCLUSION: Patients with advanced CKD lose a substantial proportion of their muscle mass each year during pre-ESRD prelude. Loss of muscle mass accelerates near ESRD transition, and more loss of muscle mass is associated with higher mortality after ESRD transition.

Long-term Patiromer Use and Outcomes Among US Veterans With Hyperkalemia and CKD: A Propensity-Matched Cohort Study.

Rationale & Objective: Patiromer is a potassium binder approved for the long-term management of hyperkalemia. Although patiromer use among patients with advanced chronic kidney disease (CKD) has been shown to reduce the discontinuation of renin-angiotensin-aldosterone system inhibition therapy, it remains unclear whether patiromer can improve clinical outcomes. The aim of this study was to examine the association of long-term patiromer use with clinical outcomes among hyperkalemic patients with CKD. Study Design: This was a longitudinal observational study. Setting & Participants: We evaluated a national cohort of 854,217 US Veterans who had at least 1 serum potassium measurement of ≥5.1 mEq/L and were treated at US Department of Veterans Affairs health care facilities between January 2016 and September 2019. Exposure: The exposure was long-term patiromer use. Outcomes: The outcomes were as follows: (1) composite endpoint of kidney failure with replacement therapy (KFRT) or all-cause death and (2) all-cause death including the post-KFRT period. Analytical Approach: Cox proportional Fine-Gray subdistribution hazard models were used in a propensity-matched cohort. Results: Among 2,004 patients who ever used patiromer during the study period (0.2% of the cohort), 666 met the criteria for long-term patiromer use. We matched 308 long-term patiromer users to 308 nonusers based on propensity scores. The median estimated glomerular filtration rate was 23.5 mL/min/1.73m2, and the median potassium level was 5.2 mEq/L. Approximately 45% were on renin-angiotensin system inhibitor(s) at baseline. During follow-up, 93 patients developed KFRT, and 134 patients died. Long-term patiromer users, when compared to nonusers, experienced a 26% lower risk of the composite outcome (HR, 0.74; 95% CI, 0.53-1.01; P = 0.06) and a 41% lower risk of all-cause mortality (HR, 0.59; 95% CI, 0.41-0.84; P = 0.003). Limitations: The study cohort included mostly male veterans with relatively short follow-up periods. Conclusions: Long-term patiromer use was associated with a lower risk of all-cause mortality among patients with CKD and hyperkalemia. Long-term potassium binder use for hyperkalemia may improve clinical outcomes in CKD. Plain-Language Summary: Hyperkalemia is a common complication of chronic kidney disease (CKD) and can result in the discontinuation of renin-angiotensin-aldosterone system inhibition therapy, a cornerstone of CKD management. Patiromer is a new potassium binder approved for the long-term management of hyperkalemia, but it remains unclear whether patiromer can improve clinical outcomes. We examined a cohort of US Veterans with hyperkalemia between January 2016 and September 2019 and found that patiromer use was uncommon for treating hyperkalemia during this study period. We then matched 308 long-term patiromer users and 308 nonusers based on propensity scores. Long-term patiromer users, when compared to nonusers, experienced a 26% lower risk of the composite outcome and a 41% lower risk of all-cause mortality. These findings indicate that long-term potassium binder use for hyperkalemia may improve clinical outcomes in CKD.

Comparison of outcomes on hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) in anaemia associated with chronic kidney disease: network meta-analyses in dialysis and non-dialysis dependent populations.

Background: Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are oral alternatives to current standard-of-care treatments for anaemia in chronic kidney disease (CKD). We conducted network meta-analyses to indirectly compare clinical outcomes for three HIF-PHIs in dialysis and non-dialysis populations with anaemia in CKD. Methods: The evidence base comprised phase III, randomised, controlled trials evaluating daprodustat, roxadustat, or vadadustat. Three outcomes were evaluated: efficacy [change from baseline in haemoglobin (Hgb)], cardiovascular safety [time to first major adverse cardiovascular event (MACE)] and quality of life [change from baseline in 36-Item Short Form Health Survey (SF-36) Vitality score]. Analyses were performed separately for all patients and for erythropoiesis-stimulating agent (ESA) non-users at baseline (non-dialysis population) or prevalent dialysis patients (dialysis population). Bayesian Markov Chain Monte Carlo methods with non-informative priors were used to estimate the posterior probability distribution and generate pairwise treatment comparisons. Point estimates (medians of posterior distributions) and 95% credible intervals (CrI) were calculated. Results: Seventeen trials were included. In non-dialysis patients, there were no clinically meaningful differences between the three HIF-PHIs with respect to Hgb change from baseline [all patients analysis (total n = 7907): daprodustat vs. roxadustat, 0.09 g/dL (95% CrI -0.14, 0.31); daprodustat vs. vadadustat, 0.09 g/dL (-0.04, 0.21); roxadustat vs. vadadustat, 0.00 g/dL (-0.22, 0.22)] or risk of MACE [all patients analysis (total n = 7959): daprodustat vs. roxadustat, hazard ratio (HR) 1.16 (95% CrI 0.76, 1.77); daprodustat vs. vadadustat, 0.88 (0.71, 1.09); roxadustat vs. vadadustat, 0.76 (0.50, 1.16)]. Daprodustat showed a greater increase in SF-36 Vitality compared with roxadustat [total n = 4880; treatment difference 4.70 points (95% CrI 0.08, 9.31)]. In dialysis patients, Hgb change from baseline was higher with daprodustat and roxadustat compared with vadadustat [all patients analysis (total n = 11 124): daprodustat, 0.34 g/dL (0.22, 0.45); roxadustat, 0.38 g/dL (0.27, 0.49)], while there were no clinically meaningful differences in the risk of MACE between the HIF-PHIs [all patients analysis (total n = 12 320): daprodustat vs. roxadustat, HR 0.89 (0.73, 1.08); daprodustat vs. vadadustat, HR 0.99 (0.82, 1.21); roxadustat vs. vadadustat, HR 1.12 (0.92, 1.37)]. Results were similar in analyses of ESA non-users and prevalent dialysis patients. Conclusions: In the setting of anaemia in CKD, indirect treatment comparisons suggest that daprodustat, roxadustat, and vadadustat are broadly clinically comparable in terms of efficacy and cardiovascular safety (precision was low for the latter), while daprodustat may be associated with reduction in fatigue to a greater extent than roxadustat.

Impact of Thyroid Status on Incident Kidney Dysfunction and Chronic Kidney Disease Progression in a Nationally Representative Cohort.

OBJECTIVE: To examine the relationship between thyroid status and incident kidney dysfunction/chronic kidney disease (CKD) progression. PATIENTS AND METHODS: We examined incident thyroid status, ascertained by serum thyrotropin (TSH) levels measured from January 1, 2007, through December 31, 2018, among 4,152,830 patients from the Optum Labs Data Warehouse, containing deidentified retrospective administrative claims data from a large national health insurance plan and electronic health record data from a nationwide network of provider groups. Associations of thyroid status, categorized as hypothyroidism, euthyroidism, or hyperthyroidism (TSH levels >5.0, 0.5-5.0, and <0.5 mIU/L, respectively), with the composite end point of incident kidney dysfunction in patients without baseline kidney dysfunction and CKD progression in those with baseline CKD were examined using Cox models. RESULTS: Patients with hypothyroidism and hyperthyroidism had higher risk of incident kidney dysfunction/CKD progression in expanded case-mix analyses (reference: euthyroidism): adjusted hazard ratios (aHRs) (95% CIs) were 1.37 (1.34 to 1.40) and 1.42 (1.39 to 1.45), respectively. Incrementally higher TSH levels in the upper reference range and TSH ranges for subclinical, mild overt, and overt hypothyroidism (≥3.0-5.0, >5.0-10.0, >10.0-20.0, and >20.0 mIU/L, respectively) were associated with increasingly higher risk of the composite end point (reference: TSH level, 0.5 to <3.0 mIU/L): aHRs (95% CIs) were 1.10 (1.09 to 1.11), 1.37 (1.34 to 1.40), 1.70 (1.59 to 1.83), and 1.70 (1.50 to 1.93), respectively. Incrementally lower TSH levels in the subclinical (<0.5 mIU/L) and overt (<0.1 mIU/L) hyperthyroid ranges were also associated with the composite end point: aHRs (95% CIs) were 1.44 (1.41 to 1.47) and 1.48 (1.39 to 1.59), respectively. CONCLUSION: In a national cohort, TSH levels in the upper reference range or higher (≥3.0 mIU/L) and below the reference range (<0.5 mIU/L) were associated with incident kidney dysfunction/CKD progression.

Determinants of the serum phosphate concentration in chronic kidney disease.

If Ccr is creatinine clearance and EP and TRP are rates of phosphate excretion and reabsorption, the serum phosphate concentration (Ps) is the sum of EP/Ccr and TRP/Ccr, i.e., the amounts of phosphate excreted and reabsorbed per volume of filtrate. At equilibrium, influx of phosphate into plasma determines EP, and EP/Ccr quantifies the contribution of phosphate influx to Ps. We used data obtained at 688 clinic visits of 387 patients to analyze the evolution of Ps in chronic kidney disease (CKD) stages G1 - 5 (dialysis excluded). EP/Ccr was calculated as (Pu×crs)/cru and TRP/Ccr as Ps-EP/Ccr (where u is urine, s is serum, and cr is creatinine). Means of these parameters were plotted against CKD stages, and correlations among variables were determined with regression analyses. In comparison to values in CKD stages G1 - 2, EP/Ccr rose and TRP/Ccr fell by the same amount in CKD G3a and G3b, and Ps did not change. In stages G4 and G5, EP/Ccr increased sharply, TRP/Ccr fell minimally, and Ps rose significantly. At estimated glomerular filtration rate (eGFR) ≥45 mL/min/1.73m2, TRP/Ccr was the principal determinant of Ps at eGFR < 45 mL/min/1.73m2, contributions of EP/Ccr and TRP/Ccr to Ps were comparable. Taken together, our results show that in CKD stages G4 and G5, the effect of phosphate reabsorption on Ps changes negligibly while that of phosphate influx increases dramatically. Because the tubular response to rising EP/Ccr is limited, maintenance of stable Ps in advanced CKD requires extreme reduction of phosphate influx into plasma. TRP/Ccr may define the lowest attainable Ps.

Development and Validation of the American Heart Association's PREVENT Equations.

BACKGROUND: Multivariable equations are recommended by primary prevention guidelines to assess absolute risk of cardiovascular disease (CVD). However, current equations have several limitations. Therefore, we developed and validated the American Heart Association Predicting Risk of CVD EVENTs (PREVENT) equations among US adults 30 to 79 years of age without known CVD. METHODS: The derivation sample included individual-level participant data from 25 data sets (N=3 281 919) between 1992 and 2017. The primary outcome was CVD (atherosclerotic CVD and heart failure). Predictors included traditional risk factors (smoking status, systolic blood pressure, cholesterol, antihypertensive or statin use, and diabetes) and estimated glomerular filtration rate. Models were sex-specific, race-free, developed on the age scale, and adjusted for competing risk of non-CVD death. Analyses were conducted in each data set and meta-analyzed. Discrimination was assessed using the Harrell C-statistic. Calibration was calculated as the slope of the observed versus predicted risk by decile. Additional equations to predict each CVD subtype (atherosclerotic CVD and heart failure) and include optional predictors (urine albumin-to-creatinine ratio and hemoglobin A1c), and social deprivation index were also developed. External validation was performed in 3 330 085 participants from 21 additional data sets. RESULTS: Among 6 612 004 adults included, mean±SD age was 53±12 years, and 56% were women. Over a mean±SD follow-up of 4.8±3.1 years, there were 211 515 incident total CVD events. The median C-statistics in external validation for CVD were 0.794 (interquartile interval, 0.763-0.809) in female and 0.757 (0.727-0.778) in male participants. The calibration slopes were 1.03 (interquartile interval, 0.81-1.16) and 0.94 (0.81-1.13) among female and male participants, respectively. Similar estimates for discrimination and calibration were observed for atherosclerotic CVD- and heart failure-specific models. The improvement in discrimination was small but statistically significant when urine albumin-to-creatinine ratio, hemoglobin A1c, and social deprivation index were added together to the base model to total CVD (ΔC-statistic [interquartile interval] 0.004 [0.004-0.005] and 0.005 [0.004-0.007] among female and male participants, respectively). Calibration improved significantly when the urine albumin-to-creatinine ratio was added to the base model among those with marked albuminuria (>300 mg/g; 1.05 [0.84-1.20] versus 1.39 [1.14-1.65]; P=0.01). CONCLUSIONS: PREVENT equations accurately and precisely predicted risk for incident CVD and CVD subtypes in a large, diverse, and contemporary sample of US adults by using routinely available clinical variables.

Association of long-term aspirin use with kidney disease progression.

Background: Chronic microinflammation contributes to the progression of chronic kidney disease (CKD). Aspirin (ASA) has been used to treat inflammation for centuries. The effects of long-term low-dose ASA on CKD progression are unclear. Methods: We examined the association of long-term use of newly initiated low-dose ASA (50-200 mg/day) with all-cause mortality using Cox proportional hazard models; with cardiovascular/cerebrovascular (CV) mortality and with end stage kidney disease (ESKD) using Fine and Gray competing risk regression models; with progression of CKD defined as patients' eGFR slopes steeper than -5 mL/min/1.73m2/year using logistic regression models in a nationwide cohort of US Veterans with incident CKD. Among 831,963 patients, we identified 385,457 who either initiated ASA (N = 21,228) within 1 year of CKD diagnosis or never received ASA (N = 364,229). We used propensity score matching to account for differences in key characteristics, yielding 29,480 patients (14,740 in each group). Results: In the matched cohort, over a 4.9-year median follow-up period, 11,846 (40.2%) patients (6,017 vs. 5,829 ASA users vs. non-users) died with 25.8% CV deaths, and 934 (3.2%) patients (476 vs. 458) reached ESKD. ASA users had a higher risk of faster decline of kidney functions, i.e., steeper slopes (OR 1.30 [95%CI: 1.18, 1.44], p < 0.01), but did not have apparent benefits on mortality (HR 0.97 [95%CI: 0.94, 1.01], p = 0.17), CV mortality (Sub-Hazard Ratio [SHR]1.06 [95%CI: 0.99-1.14], p = 0.11), or ESKD (SHR1.00 [95%CI: 0.88, 1.13], p = 0.95). Conclusion: Chronic low-dose ASA use was associated with faster kidney function deterioration, and no association was observed with mortality or risk of ESKD.

Association of oral iron replacement therapy with kidney failure and mortality in CKD patients.

Background: Oral iron is the predominant route of iron replacement (IRT) but its benefits and safety are unclear in patients with chronic kidney disease (CKD). Methods: We examined the association of oral IRT vs no IRT with end-stage kidney disease (ESKD) and mortality in a national cohort of US Veterans. We identified 17 413 incident new users of oral IRT with estimated glomerular filtration rates <60 mL/min/1.73 m2 and 32 530 controls who did not receive any IRT during 2004-18. We used propensity score-overlap weighting to account for differences in key baseline characteristics associated with the use of oral IRT. We examined associations using competing risk regression and Cox models. Results: In the cohort of 49 943 patients, 1616 (3.2%) patients experienced ESKD and 28 711 (57%) patients died during a median follow-up of 1.9 years. Oral IRT was not associated with ESKD [subhazard ratio (HR) (95% confidence interval, CI) 1.00 (0.84-1.19), P = .9] and was associated with higher risk of all-cause mortality [HR (95% CI) 1.06 (1.01-1.11), P = .01]. There was significant heterogeneity of treatment effect for mortality, with oral IRT associated with higher mortality in the subgroups of patients without congestive heart failure (CHF), anemia or iron deficiency. In patient with blood hemoglobin <10 g/dL oral IRT was associated with significantly lower mortality. Conclusion: Oral IRT was associated with lower mortality only in patients with anemia. In patients without anemia, iron deficiency or CHF, the risk-benefit ratio of oral IRT should be further examined.

Hypoglycemia and Mortality Risk in Incident Hemodialysis Patients.

OBJECTIVE: Hypoglycemia is a frequent occurrence in chronic kidney disease patients due to alterations in glucose and insulin metabolism. However, there are sparse data examining the predictors and clinical implications of hypoglycemia including mortality risk among incident hemodialysis patients. DESIGN AND METHODS: Among 58,304 incident hemodialysis patients receiving care from a large national dialysis organization over 2007-2011, we examined clinical characteristics associated with risk of hypoglycemia, defined as a blood glucose concentration <70 mg/dL, in the first year of dialysis using expanded case-mix + laboratory logistic regression models. We then examined the association between hypoglycemia during the first year of dialysis with all-cause mortality using expanded case-mix + laboratory Cox models. RESULTS: In the first year of dialysis, hypoglycemia was observed among 16.8% of diabetic and 6.9% of nondiabetic incident hemodialysis patients. In adjusted logistic regression models, clinical characteristics associated with hypoglycemia included younger age, female sex, African-American race, presence of a central venous catheter, lower residual renal function, and longer dialysis session length. In the overall cohort, patients who experienced hypoglycemia had a higher risk of all-cause mortality risk (reference: absence of hypoglycemia): adjusted hazard ratio (95% confidence interval) 1.08 (1.04, 1.13). In stratified analyses, hypoglycemia was also associated with higher mortality risk in the diabetic and nondiabetic subgroups: adjusted hazard ratios (95% confidence interval's) 1.08 (1.04-1.13), and 1.17 (0.94-1.45), respectively. CONCLUSIONS: Hypoglycemia was a frequent occurrence among both diabetic and nondiabetic hemodialysis patients and was associated with a higher mortality risk. Further studies are needed to identify approaches that reduce hypoglycemia risk in the hemodialysis population.

Residual Kidney Function and Cause-Specific Mortality Among Incident Hemodialysis Patients.

Introduction: The survival benefit of residual kidney function (RKF) in patients on hemodialysis is presumably due to enhanced fluid management and solute clearance. However, data are lacking on the association of renal urea clearance (CLurea) with specific causes of death. Methods: We conducted a longitudinal cohort study of 39,623 adults initiating thrice-weekly in-center hemodialysis from 2007 to 2011 and had data on renal CLurea and urine volume. Multivariable cause-specific proportional hazards model was used to examine the associations between baseline RKF and cause-specific mortality, including sudden cardiac death (SCD), non-SCD cardiovascular death (CVD), and non-CVD. Restricted cubic splines were fitted for change in RKF over 6 months after initiating hemodialysis. Results: Among 39,623 patients with data on baseline renal CLurea and urine volume, there was a significant trend toward a higher mortality risk across lower RKF levels, irrespective of cause of death in a case-mix adjustment model (Ptrend < 0.05). Adjustment for ultrafiltration rate (UFR) slightly attenuated the association between low renal CLurea and high cause-specific mortality, whereas adjustment for highest potassium did not have substantial effect. Among 12,169 patients with data on change in RKF, a 6-month decline in renal CLurea showed graded associations with SCD, non-SCD CVD, and non-CVD risk, whereas the graded associations between faster 6-month decline in urine output and higher death risk were clear only for SCD and non-CVD. Conclusion: Lower RKF and loss of RKF were associated with higher cause-specific mortality among patients initiating thrice-weekly in-center hemodialysis.

Association of iron therapy with incidence of chronic kidney disease.

OBJECTIVE: We investigated the association of oral iron replacement with the incidence of chronic kidney disease (CKD) in a population with normal kidney function to study the effects of iron replacement on the development of new onset CKD. METHODS: In a national cohort of US Veterans with no pre-existing CKD, we identified 33 894 incident new users of oral iron replacement and a comparable group of 112 780 patients who did not receive any iron replacement during 2004-2018. We examined the association of oral iron replacement versus no iron replacement with the incidence of eGFR <60 mL/min/1.73 m2 and the incidence of urine albumin creatinine ratio (UACR) ≥30 mg/g in competing risk regressions and in Cox models. We used propensity score weighing to account for differences in key baseline characteristics associated with the use of oral iron replacement. RESULTS: In the cohort of 146 674 patients, a total of 18 547 (13%) patients experienced incident eGFR <60 mL/min/1.73 m2 , and 16 117 patients (11%) experienced new onset UACR ≥30 mg/g. Oral iron replacement was associated with significantly higher risk of incident eGFR <60 mL/min/1.73 m2 (subhazard ratio, 95% confidence interval [CI]: 1.3 [1.22-1.38], p < .001) and incident albuminuria (subhazard ratio, 95% CI: 1.14 [1.07-1.22], p < .001). CONCLUSION: Oral iron replacement is associated with higher risk of new onset CKD. The long-term kidney safety of oral iron replacement should be tested in clinical trials.

New Insights Into Dietary Approaches to Potassium Management in Chronic Kidney Disease.

Potassium disorders are one of the most common electrolyte abnormalities in patients with chronic kidney disease (CKD), contributing to poor clinical outcomes. Maintaining serum potassium levels within the physiologically normal range is critically important in these patients. Dietary potassium restriction has long been considered a core strategy for the management of chronic hyperkalemia in patients with CKD. However, this has been challenged by recent evidence suggesting a paradigm shift toward fostering more liberalized, plant-based dietary patterns. The advent of novel potassium binders and an improved understanding of gastrointestinal processes involved in potassium homeostasis (e.g., gastrointestinal potassium wasting) may facilitate a paradigm shift and incorporation of heart-healthy potassium-enriched food sources. Nevertheless, uncertainty regarding the risk-benefit of plant-based diets in the context of potassium management in CKD remains, requiring well-designed clinical trials to determine the efficacy of dietary potassium manipulation toward improvement of clinical outcomes in patients with CKD.

Gut Microbiota-Targeted Interventions in the Management of Chronic Kidney Disease.

Recent advances in microbiome research have informed the potential role of the gut microbiota in the regulation of metabolic, cardiovascular, and renal systems, and, when altered, in the pathogenesis of various cardiometabolic disorders, including chronic kidney disease (CKD). The improved understanding of gut dysbiosis in cardiometabolic pathologies in turn has led to a vigorous quest for developing therapeutic strategies. These therapeutic strategies aim to investigate whether interventions targeting gut dysbiosis can shift the microbiota toward eubiosis and if these shifts, in turn, translate into improvements in (or prevention of) CKD and its related complications, such as premature cardiovascular disease. Existing evidence suggests that multiple interventions (eg, plant-based diets; prebiotic, probiotic, and synbiotic supplementation; constipation treatment; fecal microbiota transplantation; and intestinal dialysis) might result in favorable modulation of the gut microbiota in patients with CKD, and thereby potentially contribute to improving clinical outcomes in these patients. In this review, we summarize the current understanding of the characteristics and roles of the gut microbiota in CKD and discuss the potential of emerging gut microbiota-targeted interventions in the management of CKD.

Circulating microRNA Profiles for Premature Cardiovascular Death in Patients with Kidney Failure with Replacement Therapy.

INTRODUCTION: Patients with kidney failure with replacement therapy (KFRT) suffer from a disproportionately high cardiovascular disease burden. Circulating small non-coding RNAs (c-sncRNAs) have emerged as novel epigenetic regulators and are suggested as novel biomarkers and therapeutic targets for cardiovascular disease; however, little is known about the associations of c-sncRNAs with premature cardiovascular death in KFRT. METHODS: In a pilot case-control study of 50 hemodialysis patients who died of cardiovascular events as cases, and 50 matched hemodialysis controls who remained alive during a median follow-up of 2.0 years, we performed c-sncRNAs profiles using next-generation sequencing to identify differentially expressed circulating microRNAs (c-miRNAs) between the plasma of cases and that of controls. mRNA target prediction and pathway enrichment analysis were performed to examine the functional relevance of differentially expressed c-miRNAs to cardiovascular pathophysiology. The association of differentially expressed c-miRNAs with cardiovascular mortality was examined using multivariable conditional logistic regression. RESULTS: The patient characteristics were similar between cases and controls, with a mean age of 63 years, 48% male, and 54% African American in both groups. We detected a total of 613 miRNAs in the plasma, among which five miRNAs (i.e., miR-129-1-5p, miR-500b-3p, miR-125b-1-3p, miR-3648-2-5p, and miR-3150b-3p) were identified to be differentially expressed between cases and controls with cut-offs of p < 0.05 and log2 fold-change (log2FC) > 1. When using more stringent cut-offs of p-adjusted < 0.05 and log2FC > 1, only miR-129-1-5p remained significantly differentially expressed, with higher levels of miR-129-1-5p in the cases than in the controls. The pathway enrichment analysis using predicted miR-129-1-5p mRNA targets demonstrated enrichment in adrenergic signaling in cardiomyocytes, arrhythmogenic right ventricular cardiomyopathy, and oxytocin signaling pathways. In parallel, the circulating miR-129-1-5p levels were significantly associated with the risk of cardiovascular death (adjusted OR [95% CI], 1.68 [1.01-2.81] for one increase in log-transformed miR-129-1-5p counts), independent of potential confounders. CONCLUSIONS: Circulating miR-129-1-5p may serve as a novel biomarker for premature cardiovascular death in KFRT.

Nutritional and Dietary Management of Chronic Kidney Disease Under Conservative and Preservative Kidney Care Without Dialysis.

While dialysis has been the prevailing treatment paradigm for patients with advanced chronic kidney disease (CKD), emphasis on conservative and preservative management in which dietary interventions are a major cornerstone have emerged. Based on high-quality evidence, international guidelines support the utilization of low-protein diets as an intervention to reduce CKD progression and mortality risk, although the precise thresholds (if any) for dietary protein intake vary across recommendations. There is also increasing evidence demonstrating that plant-dominant low-protein diets reduce the risk of developing incident CKD, CKD progression, and its related complications including cardiometabolic disease, metabolic acidosis, mineral and bone disorders, and uremic toxin generation. In this review, we discuss the premise for conservative and preservative dietary interventions, specific dietary approaches used in conservative and preservative care, potential benefits of a plant-dominant low-protein diet, and practical implementation of these nutritional strategies without dialysis.

Comorbidities and neighborhood factors associated with prescription of sodium-glucose cotransporter protein-2 inhibitors and glucagon-like peptide-1 receptor agonists among medically underserved populations.

BACKGROUND: Evidence from clinical trials shows that newer second-line diabetes medications-glucagon-like peptide 1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is)-have cardio-renal protective effects in addition to their glucose-lowering properties. Despite strong evidence of benefits, there is limited evidence regarding prescribing patterns for these medications, especially among populations at high risk for disparities. OBJECTIVE: To examine the associations of cardio-renal and obesity comorbidities and neighborhood factors with the prescribing of GLP-1RAs or SGLT2is in comparison with dipeptidyl peptidase 4 inhibitors (DPP-4is) or sulfonylureas (SFUs) and for each of the newer second-line diabetes medications (GLP-1RA vs DPP-4i, SGLT2i vs DPP-4i, GLP-1RA vs SFU, and SGLT2i vs SFU) in medically underserved populations. METHODS: A retrospective cohort study was conducted using electronic medical records from a health care delivery system that serves medically underserved populations in the Mid-South region of the United States. Metformin-treated adult patients with type 2 diabetes, and at least 1 prescription for GLP-1RA, SGLT2i, DPP-4i, or SFU class medications, were identified between April 2016 and August 2021. Neighborhood factors were assessed at the census tract level by geocoding and linking patient addresses to neighborhood-level risk factors. Using multilevel logistic regression models, we examined the associations of comorbidities and neighborhood factors with the prescription of newer second-line diabetes medications. RESULTS: 7,723 patients received newer second-line diabetes medications, with 16% prescribed GLP-1RAs, 11% prescribed SGLT2is, 28% prescribed DPP-4is, and 45% prescribed SFUs. Patients with cerebrovascular disease were significantly less likely to receive newer second-line diabetes medications (odds ratio [OR] = 0.65, 95% CI = 0.52-0.80). Patients with obesity were more likely to receive newer second-line diabetes medications (OR = 1.68, 95% CI = 1.48-1.90). Living in neighborhoods with higher proportions of college graduates was associated with a higher likelihood of receiving newer second-line diabetes medications (quartile 3 vs 1: OR = 1.30, 95% CI = 1.06-1.59; and quartile 4 vs 1: OR = 1.46, 95% CI = 1.13-1.88). CONCLUSIONS: Our findings demonstrate substantial underprescribing and significant clinical and neighborhood variations in the use of newer second-line diabetes medications. We found lower use of newer second-line diabetes medications among patients with cerebrovascular disease and higher use in those with obesity. Our findings also suggest that newer second-line diabetes medications are first adopted by those in higher socioeconomic groups, thus increasing disparities in care. DISCLOSURES: Dr Surbhi reports grants or contracts from the Tennessee Department of Health, Agency for Healthcare Research and Quality, and PhRMA Foundation. Dr Bailey reports honoraria from the SouthEast Texas Chapter of the American College of Healthcare Executives, leadership or fiduciary role in the Coalition for Better Health and The Healthy City, Inc., and stock or stock options in Proctor and Gamble, Walmart, and Apple. Dr Kovesdy reports personal fees from Bayer, Abbott, AstraZeneca, Takeda, Tricida, Akebia, Cara Therapeutics, Vifor, Rockwell, CSL Behring, Boehringer Ingelheim, and GSK, outside the submitted work. The other authors report no conflicts of interest.

Modifiability of Composite Cardiovascular Risk Associated With Chronic Kidney Disease in Type 2 Diabetes With Finerenone.

Importance: It is currently unclear whether chronic kidney disease (CKD)-associated cardiovascular risk in type 2 diabetes (T2D) is modifiable. Objective: To examine whether cardiovascular risk can be modified with finerenone in patients with T2D and CKD. Design, Setting, and Participants: Incidence rates from Finerenone in Chronic Kidney Disease and Type 2 Diabetes: Combined FIDELIO-DKD and FIGARO-DKD Trial Programme Analysis (FIDELITY), a pooled analysis of 2 phase 3 trials (including patients with CKD and T2D randomly assigned to receive finerenone or placebo) were combined with National Health and Nutrition Examination Survey data to simulate the number of composite cardiovascular events that may be prevented per year with finerenone at a population level. Data were analyzed over 4 years of consecutive National Health and Nutrition Examination Survey data cycles (2015-2016 and 2017-2018). Main Outcomes and Measures: Incidence rates of cardiovascular events (composite of cardiovascular death, nonfatal stroke, nonfatal myocardial infarction, or hospitalization for heart failure) were estimated over a median of 3.0 years by estimated glomerular filtration rate (eGFR) and albuminuria categories. The outcome was analyzed using Cox proportional hazards models stratified by study, region, eGFR and albuminuria categories at screening, and cardiovascular disease history. Results: This subanalysis included a total of 13 026 participants (mean [SD] age, 64.8 [9.5] years; 9088 male [69.8%]). Lower eGFR and higher albuminuria were associated with higher incidences of cardiovascular events. For recipients in the placebo group with an eGFR of 90 or greater, incidence rates per 100 patient-years were 2.38 (95% CI, 1.03-4.29) in those with a urine albumin to creatinine ratio (UACR) less than 300 mg/g and 3.78 (95% CI, 2.91-4.75) in those with UACR of 300 mg/g or greater. In those with eGFR less than 30, incidence rates increased to 6.54 (95% CI, 4.19-9.40) vs 8.74 (95% CI, 6.78-10.93), respectively. In both continuous and categorical models, finerenone was associated with a reduction in composite cardiovascular risk (hazard ratio, 0.86; 95% CI, 0.78-0.95; P = .002) irrespective of eGFR and UACR (P value for interaction = .66). In 6.4 million treatment-eligible individuals (95% CI, 5.4-7.4 million), 1 year of finerenone treatment was simulated to prevent 38 359 cardiovascular events (95% CI, 31 741-44 852), including approximately 14 000 hospitalizations for heart failure, with 66% (25 357 of 38 360) prevented in patients with eGFR of 60 or greater. Conclusions and Relevance: Results of this subanalysis of the FIDELITY analysis suggest that CKD-associated composite cardiovascular risk may be modifiable with finerenone treatment in patients with T2D, those with eGFR of 25 or higher, and those with UACR of 30 mg/g or greater. UACR screening to identify patients with T2D and albuminuria with eGFR of 60 or greater may provide significant opportunities for population benefits.