Faculty Bibliography

BACKGROUND:Vitamin D inadequacy at or shortly after kidney transplantation is associated with poor outcomes. Circulating 25-hydroxyvitamin D [25(OH)D] levels generally increase over time after transplantation, but inadequacy remains common. Few studies have examined associations of later circulating 25(OH)D levels and long-term outcomes. METHODS:We analyzed data from the Wisconsin Allograft Recipient Database to assess the association of post-transplant 25(OH)D with overall graft failure, death-censored graft failure (DCGF), death with a functioning graft (DWFG), cause-specific mortality and eGFR trajectory over the next 4 years. RESULTS:A total of 2504 recipients who maintained a functioning graft for at least 13 months were included in our analysis. A total of 867 overall graft failures occurred during a median follow-up of 6.8 years. Vitamin D deficiency (≤20 ng/ml) was associated with a 43% higher hazard of overall graft failure (95% confidence interval [CI]: 1.16, 1.78), a 2.24-fold higher hazard of DCGF (95% CI: 1.60, 3.12) and a 2.10-fold higher hazard (95% CI: 1.37, 3.21) of infection-related mortality compared with sufficiency. It also was associated with a 1.38 ml/min/1.73m2/year faster (95% CI: -1.97, -0.79) annual eGFR decline compared with sufficiency. No association was detected for DWFG or other cause-specific mortality. CONCLUSIONS:In conclusion, post-transplant vitamin D deficiency is associated with a higher risk of DCGF, infection-related mortality and a faster decline of graft function in kidney transplant recipients.

BACKGROUND:The link between metabolic acidosis (MA) and cardiovascular disease (CVD) outcomes has been studied in adults but not in children with CKD where MA is a common and early finding. Using longitudinal blood pressure (BP) and cardiac measurement data, we evaluated whether low serum bicarbonate (a surrogate for MA) is associated with adverse CVD risk. METHODS:This study used data from children 1 year of age and older with estimated glomerular filtration rates (eGFR) between 30-90 ml/min per 1.73m2 at enrollment into the Chronic Kidney Disease in Children (CKiD) study. Linear regression models were used to characterize the association between serum bicarbonate, resting and ambulatory BP measurements (ABPM), and indexed left ventricular mass measurements (LVMI). To compare BPs across children of different age/sex/height, BPs were indexed by dividing their average BP by the appropriate hypertensive threshold. Analyses allowed serum bicarbonate to be time varying and were adjusted for relevant demographic and clinical covariates. RESULTS:The study population consisted of 936 children who contributed data from 2581 paired visits. All had resting BP, 674 had ABPM measurements, and 736 had LVMI measurements. In fully adjusted models, there was an association between lower serum bicarbonate and higher resting BP. Lower serum bicarbonate level was also associated with lower ABPM wake and sleep systolic indices, and a small but significant increase in LVMI, 0.02 (95% CI: 0.004, 0.05). CONCLUSIONS:We observed an association between MA and higher resting BP, lower ABPM, and higher LVMI. Future studies should address MA and CVD risk across the spectrum of CKD severity, incorporate additional assessments of CVD risk such as pulse wave velocity and carotid intima media thickness. Future studies should also test whether alkali therapy treatment, and the resolution of MA, mitigates these observed associations.

Nearly 14% of Americans have chronic kidney disease (CKD), which includes persistent decrements in glomerular filtration rate or the presence of albuminuria. Although CKD is commonly attributed to diabetes or hypertension, there is growing awareness of the interplay among cardiovascular, kidney, and metabolic health. Progression of CKD can result in metabolic abnormalities and end-stage kidney disease, but cardiovascular events are even more common. The main goals of CKD treatment include slowing the decline in kidney function, preventing cardiovascular disease, and treating metabolic complications. Recent pharmacologic advancements have yielded effective therapeutic agents capable of concurrently addressing all of these objectives.

BACKGROUND:Diet affects inflammation and kidney health, but few studies have investigated dietary inflammatory potential in CKD progression, particularly in women. We aim to examine this association in the Women's Health Initiative (WHI). METHODS:We conducted a non-concurrent prospective cohort study among WHI participants enrolled in the clinical trials and observational study (1993-1998) without baseline CKD and with available dietary intake assessments, Medicare data, and creatinine measurements at enrollment. The inflammatory potential of diets was assessed using the dietary inflammatory index (DII®), an acultural tool that quantifies diets from anti-inflammatory to pro-inflammatory. Scores were categorized into quartiles, with Q1 (reference group) and Q4 indicating the least and most inflammatory diets, respectively. Incident kidney failure (CKD stage G5, ESKD, or transplantation) was identified using diagnosis codes in Medicare claims from enrollment through 12/31/2019. We performed multivariable Cox proportional hazards regression and modeled death as a competing risk to determine the risk of incident kidney failure. RESULTS:Among the 17,334 women included in our study, the baseline mean age was 64.9 years (standard deviation 7.1); 33.5% self-identified as Black, 8.8% as Hispanic, 38% had hypertension, and 6.8% had diabetes mellitus. Baseline mean estimated glomerular filtration rate (eGFR) was 87.2 ml/min/1.73m2. Over a mean follow-up of 11.2 years, 1852 women (10.7%) developed kidney failure. Compared to Q1, women with dietary patterns in Q4 had a 18% higher risk (95% confidence interval 1.03-1.37; p-trend=0.01) of developing kidney failure after adjusting for age, race/ethnicity, education, region, comorbidities, medications, smoking, energy intake, physical activity, eGFR, and body mass index. Competing risk models yielded similar results. CONCLUSIONS:A pro-inflammatory diet (e.g., enriched in processed foods, refined sugars, and red meat) was associated with incident kidney failure in postmenopausal women without baseline CKD. Clinical trials are needed to assess the impact of an anti-inflammatory dietary pattern on CKD risk and progression.

INTRODUCTION/BACKGROUND:Late-onset infection occurring more than 6 months after transplantation is a major threat to the long-term survival of kidney transplant recipients (KTRs). Accumulating evidence indicates a potential role for vitamin D in host resistance to infections. While vitamin D inadequacy is common among KTRs, the association of posttransplant circulating 25-hydroxyvitamin D [25(OH)D] and late-onset infection remains uncertain. METHODS:We analyzed data from adult kidney-only transplant recipients at our center from 2005 to 2020 who had at least one valid posttransplant circulating 25(OH)D measurement from 5 to 13 months posttransplant. Survival analyses were conducted using marginal proportional rates models with late-onset infection within 1 year following the 25(OH)D measurement as the event of interest. Additional analyses used time-varying 25(OH)D measurements. RESULTS:Of 2207 KTRs included, 642 recipients had a total of 1448 late-onset infection episodes. Each 5 ng/mL lower serum 25(OH)D was associated with a 5% higher risk of late-onset infection (adjusted rate ratio [aRR] = 1.05; 95% confidence interval [CI]: 1.03, 1.07; p < 0.01). Vitamin D deficiency (≤ 20 ng/mL) was associated with a 1.22-fold higher incidence of late-onset infection (aRR = 1.22; 95% CI: 1.03-1.43; p = 0.02) compared with vitamin D sufficiency (≥30 ng/mL). The association was strongest for urinary tract infection among male recipients (aRR = 2.20; 95% CI: 1.57-3.08; p < 0.01). CONCLUSION/CONCLUSIONS:Vitamin D deficiency is significantly associated with a higher incidence of late-onset infection among KTRs, especially urinary tract infections in male recipients. Further research, including clinical trials, is needed to determine the causal relationship.

BACKGROUND/UNASSIGNED:Recurrence of glomerulonephritis (GN) is a significant contributor to long-term allograft failure among kidney transplant recipients (KTRs) with kidney failure because of GN. Accumulating evidence has revealed the role of vitamin D in both innate and adaptive immunity. Although vitamin D deficiency is common among KTRs, the association between 25-hydroxyvitamin D (25[OH]D) and GN recurrence in KTRs remains unclear. METHODS/UNASSIGNED:We analyzed data from KTRs with kidney failure caused by GN who received a transplant at our center from 2000 to 2019 and had at least 1 valid posttransplant serum 25(OH)D measurement. Survival analyses were performed using a competing risk regression model considering other causes of allograft failure, including death, as competing risk events. RESULTS/UNASSIGNED:A total of 67 cases of GN recurrence were identified in 947 recipients with GN followed for a median of 7.0 y after transplant. Each 1 ng/mL lower serum 25(OH)D was associated with a 4% higher hazard of recurrence (subdistribution hazard ratio [HR]: 1.04; 95% confidence interval [CI], 1.01-1.06). Vitamin D deficiency (≤20 ng/mL) was associated with a 2.99-fold (subdistribution HR: 2.99; 95% CI, 1.56-5.73) higher hazard of recurrence compared with vitamin D sufficiency (≥30 ng/mL). Results were similar after further adjusting for concurrent urine protein-creatinine ratio, serum albumin, and estimated glomerular filtration rate (eGFR). CONCLUSIONS/UNASSIGNED:Posttransplant vitamin D deficiency is associated with a higher hazard of GN recurrence in KTRs. Further prospective observational studies and clinical trials are needed to determine any causal role of vitamin D in the recurrence of GN after kidney transplantation. More in vitro and in vivo experiments would be helpful to understand its effects on autoimmune and inflammation processes.

BACKGROUND:Collagen X biomarker (CXM) is a novel biomarker of linear growth velocity. We investigated whether CXM correlated with measured growth velocity in children with impaired kidney function. METHODS:We used data from children aged 2 through 16 years old enrolled in the Chronic Kidney Disease in Children (CKiD) study. We assessed the association between CXM level and growth velocity based on height measurements obtained at study visits using linear regression models constructed separately by sex, with and without adjustment for CKD covariates. Linear mixed-effects models were used to capture the between-individual and within-individual CXM changes over time associated with concomitant changes in growth velocity from baseline through follow-up. RESULTS:A total of 967 serum samples from 209 participants were assayed for CXM. CXM correlated more strongly in females compared to male participants. After adjustment for growth velocity and CKD covariates, only proteinuria in male participants affected CXM levels. Finally, we quantified the between- and within-participant associations between CXM level and growth velocity. A between-participant increase of 24% and 15% in CXM level in females and males, respectively, correlated with a 1 cm/year higher growth velocity. Within an individual participant, on average, 28% and 13% increases in CXM values in females and males, respectively, correlated with a 1 cm/year change in measured growth. CONCLUSIONS:CXM measurement is potentially a valuable aid for monitoring growth in pediatric CKD. However, future research, including studies of CXM metabolism, is needed to clarify whether CXM can be a surrogate of growth in children with CKD. A higher resolution version of the Graphical abstract is available as Supplementary information.

PURPOSE:Urge urinary incontinence is the involuntary leakage of urine associated with a sudden compelling urge to void. A previous study found an association between urge urinary incontinence and household income, indicating that social determinants of health may influence urge urinary incontinence. Food insecurity is a relevant social determinant of health, as a diet with bladder irritants may worsen urge urinary incontinence symptoms. This study aimed to investigate the association between urge urinary incontinence and food insecurity. MATERIALS AND METHODS:We collected data from the 2005-2010 cycles of the National Health and Nutrition Examination Survey, a nationally representative health survey administered by the Centers for Disease Control and Prevention. The association between urge urinary incontinence and food insecurity was analyzed using survey-weighed logistic regression with adjustments for demographic, socioeconomic status, behavioral, and medical comorbidities covariates. RESULTS:< .001). When comparing diets, food-insecure participants reported significantly less intake of bladder irritants (caffeine and alcohol) compared to food-secure participants. When the sample was stratified by food insecurity status (yes vs no), consumption of caffeine did not differ by urge urinary incontinence status and consumption of alcohol was lower among participants with vs without urge urinary incontinence. CONCLUSIONS:Adults reporting food insecurity in the past year are significantly more likely to experience urge urinary incontinence than those who did not. Consumption of bladder irritants including caffeine and alcohol was significantly less in food-insecure compared to food-secure participants. When the sample was stratified by food insecurity status (yes vs no), consumption of caffeine did not differ by urge urinary incontinence status and consumption of alcohol was lower among participants with vs without urge urinary incontinence. These data indicate that diet alone does not drive the association between urge urinary incontinence and food insecurity. Instead, food insecurity may be a proxy for social inequity, perhaps the greatest driver of disease.