Evaluation of novel candidate filtration markers from a global metabolomic discovery for glomerular filtration rate estimation.

Creatinine and cystatin-C are recommended for estimating glomerular filtration rate (eGFR) but accuracy is suboptimal. Here, using untargeted metabolomics data, we sought to identify candidate filtration markers for a new targeted assay using a novel approach based on their maximal joint association with measured GFR (mGFR) and with flexibility to consider their biological properties. We analyzed metabolites measured in seven diverse studies encompasing 2,851 participants on the Metabolon H4 platform that had Pearson correlations with log mGFR and used a stepwise approach to develop models to < -0.5 estimate mGFR with and without inclusion of creatinine that enabled selection of candidate markers. In total, 456 identified metabolites were present in all studies, and 36 had correlations with mGFR < -0.5. A total of 2,225 models were developed that included these metabolites; all with lower root mean square errors and smaller coefficients for demographic variables compared to estimates using untargeted creatinine. Seventeen metabolites were chosen, including 12 new candidate filtration markers. The selected metabolites had strong associations with mGFR and little dependence on demographic factors. Candidate metabolites were identified with maximal joint association with mGFR and minimal dependence on demographic variables across many varied clinical settings. These metabolites are excreted in urine and represent diverse metabolic pathways and tubular handling. Thus, our data can be used to select metabolites for a multi-analyte eGFR determination assay using mass spectrometry that potentially offers better accuracy and is less prone to non-GFR determinants than the current eGFR biomarkers.

New Creatinine- and Cystatin C-Based Equations to Estimate GFR without Race.

BACKGROUND: Current equations for estimated glomerular filtration rate (eGFR) that use serum creatinine or cystatin C incorporate age, sex, and race to estimate measured GFR. However, race in eGFR equations is a social and not a biologic construct. METHODS: We developed new eGFR equations without race using data from two development data sets: 10 studies (8254 participants, 31.5% Black) for serum creatinine and 13 studies (5352 participants, 39.7% Black) for both serum creatinine and cystatin C. In a validation data set of 12 studies (4050 participants, 14.3% Black), we compared the accuracy of new eGFR equations to measured GFR. We projected the prevalence of chronic kidney disease (CKD) and GFR stages in a sample of U.S. adults, using current and new equations. RESULTS: In the validation data set, the current creatinine equation that uses age, sex, and race overestimated measured GFR in Blacks (median, 3.7 ml per minute per 1.73 m2 of body-surface area; 95% confidence interval [CI], 1.8 to 5.4) and to a lesser degree in non-Blacks (median, 0.5 ml per minute per 1.73 m2; 95% CI, 0.0 to 0.9). When the adjustment for Black race was omitted from the current eGFR equation, measured GFR in Blacks was underestimated (median, 7.1 ml per minute per 1.73 m2; 95% CI, 5.9 to 8.8). A new equation using age and sex and omitting race underestimated measured GFR in Blacks (median, 3.6 ml per minute per 1.73 m2; 95% CI, 1.8 to 5.5) and overestimated measured GFR in non-Blacks (median, 3.9 ml per minute per 1.73 m2; 95% CI, 3.4 to 4.4). For all equations, 85% or more of the eGFRs for Blacks and non-Blacks were within 30% of measured GFR. New creatinine-cystatin C equations without race were more accurate than new creatinine equations, with smaller differences between race groups. As compared with the current creatinine equation, the new creatinine equations, but not the new creatinine-cystatin C equations, increased population estimates of CKD prevalence among Blacks and yielded similar or lower prevalence among non-Blacks. CONCLUSIONS: New eGFR equations that incorporate creatinine and cystatin C but omit race are more accurate and led to smaller differences between Black participants and non-Black participants than new equations without race with either creatinine or cystatin C alone. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases.).

Psychosocial evaluation of living liver donors-State of current practices in the United States.

We surveyed living donor liver transplant programs in the United States to describe practices in the psychosocial evaluation of living donors focused on (1) composition of psychosocial team; (2) domains, workflow, and tools of the psychosocial assessment; (3) absolute and relative mental health-related contraindications to donation; and (4) postdonation psychosocial follow-up. We received 52 unique responses, representing 33 of 50 (66%) of active living donor liver transplant programs. Thirty-one (93.9%) provider teams included social workers, 22 (66.7%) psychiatrists, and 14 (42.4%) psychologists. Validated tools were rarely used, but domains assessed were consistent. Respondents rated active alcohol (93.8%), cocaine (96.8%), and opioid (96.8%) use disorder, as absolute contraindications to donation. Active suicidality (97%), self-injurious behavior (90.9%), eating disorders (87.9%), psychosis (84.8%), nonadherence (71.9%), and inability to cooperate with the evaluation team (78.1%) were absolute contraindications to donation. There were no statistically significant differences in absolute psychosocial contraindications to liver donation between geographical areas or between large and small programs. Programs conduct postdonation psychosocial follow-up (57.6%) or screening (39.4%), but routine follow-up of declined donors is rarely conducted (15.8%). Psychosocial evaluation of donor candidates is a multidisciplinary process. The structure of the psychosocial evaluation of donors is not uniform among programs though the domains assessed are consistent. Psychosocial contraindications to living liver donation vary among the transplant programs. Mental health follow-up of donor candidates is not standardized.

CKD-EPI and EKFC GFR Estimating Equations: Performance and Other Considerations for Selecting Equations for Implementation in Adults.

SIGNIFICANCE STATEMENT: New eGFR equations from Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and European Kidney Function Consortium (EKFC) using creatinine (eGFRcr), cystatin C (eGFRcys), and both (eGFRcr-cys) have sufficient accuracy for use in clinical practice, leading to uncertainty in selecting equations for implementation. The authors evaluated performance of equations in an independent population of 4050 adults and evaluated other considerations important for implementation. They found that CKD-EPI and EKFC equations are approaching convergence, with better performance of eGFRcr-cys equations in the overall group and fewer differences among race, sex, and age subgroups than eGFRcr equations. Larger differences among eGFRcr equations reflect regional population differences in creatinine, forcing a trade-off between accuracy and uniformity in global implementation of eGFRcr equations. More widespread use of cystatin C could avoid this trade-off. BACKGROUND: New CKD-EPI and EKFC eGFR equations using eGFRcr, eGFRcys, and both (eGFRcr-cys) have sufficient accuracy for use in clinical practice. A better understanding of the equations, including their performance in race, sex and age subgroups, is important for selection of eGFR equations for global implementation. METHODS: We evaluated performance (bias and P 30 ) of equations and methods used for equation development in an independent study population comprising 4050 adults pooled from 12 studies. The mean (SD) measured GFR was 76.4 (29.6) ml/min per 1.73 m 2 and age 57.0 (17.4) years, with 1557 (38%) women and 579 (14%) Black participants. RESULTS: Coefficients for creatinine, cystatin C, age, and sex in the CKD-EPI and EKFC equations are similar. Performance of the eGFRcr-cys equations in the overall population (bias <±5 ml/min per 1.73 m 2 and P 30 >90%) was better than the eGFRcr or eGFRcys equations, with fewer differences among race, sex, and age subgroups. Differences in performance across subgroups reflected differences in diversity of source populations and use of variables for race and sex for equation development. Larger differences among eGFRcr equations reflected regional population differences in non-GFR determinants of creatinine. CONCLUSION: CKD-EPI and EKFC equations are approaching convergence. It is not possible to maximize both accuracy and uniformity in selecting one of the currently available eGFRcr equations for implementation across regions. Decisions should consider methods for equation development in addition to performance. Wider use of cystatin C with creatinine could maximize both accuracy and uniformity of GFR estimation using currently available equations.

Role of Sodium-Glucose Cotransporter 2 Inhibitors for Management of Diabetes Mellitus in Renal Transplant Recipients and Management Strategies for Posttransplant Hypertension.

BACKGROUND: Diabetes mellitus and hypertension are the leading causes of cardiovascular disease in the renal transplant recipients. This review looks at the potential role of sodium-glucose cotransporter 2 inhibitors (SGLT2is) and reviews the management strategies for hypertension in this population. SUMMARY: Large-scale clinical trials are needed to study the potential cardiorenal benefits and risks of complications in renal transplant recipients. Future clinical trials are also needed to define optimal blood pressure treatment goals and therapies and how they influence graft and patient survival. KEY MESSAGES: Multiple recent prospective randomized clinical trials have shown the benefits of using SGLT2is to improve the cardiorenal outcomes in patients with chronic kidney disease with or without diabetes mellitus. Renal transplant recipients were not included in these trials due to concerns about genitourinary complications; hence, the role of these agents in this population is unclear. A number of small studies have highlighted the safety of using these agents in renal transplant recipients. Posttransplant hypertension is a complex problem requiring individualized management. Recent guidelines recommend using a calcium channel blocker or angiotensin receptor blocker as the first-line antihypertensive agents in adult renal transplant recipients.

Psychosocial characteristics of patients evaluated for kidney transplant and associations with functional and frailty metrics at a veterans affairs hospital.

BACKGROUND: The effect of psychosocial problems on listing outcomes and potential interactions with functional metrics is not well-characterized among Veteran transplant candidates. METHODS: The results from psychosocial evaluations, frailty metrics, and biochemical markers were collected on 375 consecutive Veteran kidney transplant candidates. Psychosocial diagnoses were compared between patients listed or denied for transplant. Functional abilities were compared among patients with or without psychosocial diagnoses and then evaluated based on reason for denial. RESULTS: Eighty-four percent of patients had a psychosocial diagnosis. Common issues included substance or alcohol abuse (62%), psychiatric diagnoses (50%), and poor adherence (25%). Patients with psychiatric diagnoses, cognitive impairments, and poor adherence were more likely to be denied for transplant (P < .05). Patients with depression, PTSD, and anxiety did not have worse functional ability, but experienced more exhaustion than patients without these problems. Patients denied for medical but not purely psychosocial reasons had worse troponin and functional metrics compared with listed patients. CONCLUSION: Over 80% of patients with a psychosocial diagnosis were listed; however, poor adherence was a particularly important reason for denial for purely psychosocial reasons. Patients with psychosocial diagnoses generally were not more functionally limited than their counterparts without psychosocial diagnoses or those listed for transplant.

A prospective controlled study of metabolic and physiologic effects of kidney donation suggests that donors retain stable kidney function over the first nine years.

While there have been numerous studies of living kidney donors, most have been retrospective without suitable controls and have yielded conflicting results. To clarify this we studied 205 living donor candidates and 203 controls having no medical conditions precluding donation. Before and at six months, one, two, three, six, and nine years after donation we measured iohexol glomerular filtration rate, clinic blood pressure, urine protein excretion and metabolic parameters reported to be affected by kidney function. We measured 24 hour ambulatory blood pressure at three, six, and nine years and at six and nine years blood pressure after treadmill exercise, carotid-femoral pulse wave velocity and arterial elasticity. Between six months and nine years, the mean (95% confidence interval) change in glomerular filtration rate was significantly different among 133 donors 0·02 (-0·16-0·20) mL/min/1·73m2/year versus -1·26 (-1·52--1·00) mL/min/1·73m2/year in 113 healthy controls. Blood pressure, urine protein, urine albumin, glucose, hemoglobin A1c, insulin, and lipoproteins were not different in controls versus donors; but parathyroid hormone, homocysteine and uric acid remained higher at nine years. At six and nine years carotid-femoral pulse wave velocity was not different, but the mean small artery elasticity was significantly lower in 141 donors 6·1 mL/mmHg x100, versus 113 controls 7·1 mL/mmHg x100, and 6·1 mL/mmHg x100 in 137 donors versus 7·6 mL/mmHg x100 in 112 controls at six and nine years, respectively [significant adjusted difference of 1·1 mL/mmHg x100]. Thus, donors remain healthy with stable kidney function for the first nine years, but differences in metabolic and vascular parameters could be harbingers of adverse outcomes requiring future interventions.

Treatment for presumed BK polyomavirus nephropathy and risk of urinary tract cancers among kidney transplant recipients in the United States.

Recent case series describe detection of BK polyomavirus (BKV) in urinary tract cancers in kidney transplant recipients, suggesting that BKV could contribute to the development of these cancers. We assessed risk for urinary tract cancers in kidney recipients with or without treatment for presumed BKV nephropathy (tBKVN) using data from the United States Transplant Cancer Match Study (2003-2013). Among 55 697 included recipients, 2015 (3.6%) were reported with tBKVN. Relative to the general population, incidence was similarly elevated (approximately 4.5-fold) for kidney cancer in recipients with or without tBKVN, and incidence was not increased in either group for prostate cancer. In contrast, for invasive bladder cancer, incidence was more strongly elevated in recipients with versus without tBKVN (standardized incidence ratios 4.5 vs. 1.7; N = 48 cases), corresponding to an incidence rate ratio (IRR) of 2.9 (95% confidence interval [CI] 1.0-8.2), adjusted for sex, age, transplant year, and use of polyclonal antibody induction. As a result, recipients with tBKVN had borderline increased incidence for all urothelial cancers combined (renal pelvis, ureter, and bladder cancers: adjusted IRR 2.2, 95% CI 0.9-5.4; N = 89 cases). Together with reports describing BKV detection in tumor tissues, these results support an association between BKV and urothelial carcinogenesis among kidney transplant recipients.

Impact of Hyperuricemia on Long-term Outcomes of Kidney Transplantation: Analysis of the FAVORIT Study.

BACKGROUND: Elevated uric acid concentration is associated with higher rates of cardiovascular (CV) morbidity and mortality in the general population. It is not known whether hyperuricemia increases the risk for CV death or transplant failure in kidney transplant recipients. STUDY DESIGN: Post hoc cohort analysis of the FAVORIT Study, a randomized controlled trial that examined the effect of homocysteine-lowering vitamins on CV disease in kidney transplantation. SETTING & PARTICIPANTS: Adult recipients of kidney transplants in the United States, Canada, or Brazil participating in the FAVORIT Study, with hyperhomocysteinemia, stable kidney function, and no known history of CV disease. PREDICTOR: Uric acid concentration. OUTCOMES: The primary end point was a composite of CV events. Secondary end points were all-cause mortality and transplant failure. Risk factors included in statistical models were age, sex, race, country, treatment assignment, smoking history, body mass index, presence of diabetes mellitus, history of CV disease, blood pressure, estimated glomerular filtration rate (eGFR), donor type, transplant vintage, lipid concentrations, albumin-creatinine ratio, and uric acid concentration. Cox proportional hazards models were fit to examine the association of uric acid concentration with study end points after risk adjustment. RESULTS: 3,512 of 4,110 FAVORIT participants with baseline uric acid concentrations were studied. Median follow-up was 3.9 (IQR, 3.0-5.3) years. 503 patients had a primary CV event, 401 died, and 287 had transplant failure. In unadjusted analyses, uric acid concentration was significantly related to each outcome. Uric acid concentration was also strongly associated with eGFR. The relationship between uric acid concentration and study end points was no longer significant in fully adjusted multivariable models (P=0.5 for CV events; P=0.09 for death, and P=0.1 for transplant failure). LIMITATIONS: Unknown use of uric acid-lowering agents among study participants. CONCLUSIONS: Following kidney transplantation, uric acid concentrations are not independently associated with CV events, mortality, or transplant failure. The strong association between uric acid concentrations with traditional risk factors and eGFR is a possible explanation.

Abnormalities in biomarkers of mineral and bone metabolism in kidney donors.

Previous studies have suggested that kidney donors may have abnormalities of mineral and bone metabolism typically seen in chronic kidney disease. This may have important implications for the skeletal health of living kidney donors and for our understanding of the pathogenesis of long-term mineral and bone disorders in chronic kidney disease. In this prospective study, 182 of 203 kidney donors and 173 of 201 paired normal controls had markers of mineral and bone metabolism measured before and at 6 and 36 months after donation (ALTOLD Study). Donors had significantly higher serum concentrations of intact parathyroid hormone (24.6% and 19.5%) and fibroblast growth factor-23 (9.5% and 8.4%) at 6 and 36 months, respectively, as compared to healthy controls, and significantly reduced tubular phosphate reabsorption (-7.0% and -5.0%) and serum phosphate concentrations (-6.4% and -2.3%). Serum 1,25-dihydroxyvitamin D3 concentrations were significantly lower (-17.1% and -12.6%), while 25-hydroxyvitamin D (21.4% and 19.4%) concentrations were significantly higher in donors compared to controls. Moreover, significantly higher concentrations of the bone resorption markers, carboxyterminal cross-linking telopeptide of bone collagen (30.1% and 13.8%) and aminoterminal cross-linking telopeptide of bone collagen (14.2% and 13.0%), and the bone formation markers, osteocalcin (26.3% and 2.7%) and procollagen type I N-terminal propeptide (24.3% and 8.9%), were observed in donors. Thus, kidney donation alters serum markers of bone metabolism that could reflect impaired bone health. Additional long-term studies that include assessment of skeletal architecture and integrity are warranted in kidney donors.

Kidney Function and Cardiovascular Events in Postmenopausal Women: The Impact of Race and Ethnicity in the Women's Health Initiative.

BACKGROUND: Kidney disease disproportionately affects minority populations, including African Americans and Hispanics; therefore, understanding the relationship of kidney function to cardiovascular (CV) outcomes within different racial/ethnic groups is of considerable interest. We investigated the relationship between kidney function and CV events and assessed effect modification by race/ethnicity in the Women's Health Initiative. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: Baseline serum creatinine concentrations (assay traceable to isotope-dilution mass spectrometry standard) of 19,411 postmenopausal women aged 50 to 79 years who self-identified as either non-Hispanic white (n=8,921), African American (n=7,436), or Hispanic (n=3,054) were used to calculate estimated glomerular filtration rates (eGFRs). PREDICTORS: Categories of eGFR (exposure); race/ethnicity (effect modifier). OUTCOMES: The primary outcome was the composite of 3 physician-adjudicated CV events: myocardial infarction, stroke, or CV-related death. MEASUREMENTS: We evaluated the multivariable-adjusted associations between categories of eGFR and CV events using proportional hazards regression and formally tested for effect modification by race/ethnicity. RESULTS: During a mean follow-up of 7.6 years, 1,424 CV events (653 myocardial infarctions, 627 strokes, and 297 CV-related deaths) were observed. The association between eGFR and CV events was curvilinear; however, the association of eGFR with CV outcomes differed by race (P=0.006). In stratified analyses, we observed that the U-shaped association was present in non-Hispanic whites, whereas African American participants had a rather curvilinear relationship, with lower eGFR being associated with higher CV risk, and higher eGFR, with reduced CV risk. Analyses among Hispanic women were inconclusive owing to few Hispanic women having very low or high eGFRs and very few events occurring in these categories. LIMITATIONS: Lack of urinary albumin measurements; residual confounding by unmeasured or imprecisely measured characteristics. CONCLUSIONS: In postmenopausal women, the patterns of association between eGFR and CV risk differed between non-Hispanic whites and African American women.

Association between Renal Function and Bleeding Risk for Dabigatran after Switching from Warfarin.

BACKGROUND: There is a higher risk of gastrointestinal (GI) bleeding in patients treated with dabigatran versus warfarin. We analyzed the impact of renal function on the relative risk of bleeding in patients converted to dabigatran. METHODS: Patients aged ≥65 years who received anticoagulation with warfarin for a minimum of 6 months and subsequently converted to dabigatran or remained on warfarin were studied. Data sources included VA National Patient Care, and VA Decision Support System National Pharmacy and Laboratory. Each patient who converted to dabigatran 150 mg twice daily was matched by propensity score with 2 patients on warfarin who did not convert. Outcomes included rates of hospital admission for GI or other major bleeding and mortality, stratified by estimated glomerular filtration rate (eGFR). RESULTS: Study population included 864 patients who converted and 1,710 patients who did not convert to dabigatran. In patients with eGFR 50-80 ml/min/1.73 m², the hazard of GI bleeding in patients who initiated dabigatran was nearly 3 times higher, (4.1 vs. 1.3 per 100 patient years; hazards ratio 2.94; 95% CI 1.24-7.02; p = 0.015), compared to patients who remained on warfarin. There were relatively few patients with eGFR <50 or >80 ml/min/1.73 m2, and relatively few bleeding events outside the GI tract. CONCLUSIONS: Prescribing healthcare providers should exercise caution and close monitoring for bleeding complications when converting from warfarin to dabigatran, even in patients with renal function in the range considered safe for dabigatran use as per current recommendations.

Effect of extended-release niacin on cardiovascular events and kidney function in chronic kidney disease: a post hoc analysis of the AIM-HIGH trial.

Chronic kidney disease (CKD) in patients is strongly associated with cardiovascular morbidity and mortality, and prevalent abnormal lipid metabolism. The AIM-HIGH trial examined the benefits of adding extended-release niacin (ERN) to simvastatin in patients with established coronary heart disease. Here we conducted a post hoc analysis of the AIM-HIGH trial examining whether participants derived cardiovascular or renal benefits when stratified by renal function. Of 3414 participants, 505 had stage 3 CKD at baseline. Among the CKD subset, demographics and cardiovascular disease (CVD) risk factors were well balanced in the ERN and placebo arms. Compared with placebo, CKD participants receiving ERN had a significant decrease in triglycerides by a median of 59.0 mg/dl, and high-density lipoprotein cholesterol significantly increased by a mean of 11.3 mg/dl over a mean follow-up of 3 years. CVD events were similar between CKD participants in both arms. However, all-cause mortality was significantly higher in the ERN group (hazard ratio of 1.73). Mean change in eGFR among ERN-treated CKD participants was not significantly different between study arms. Thus, among AIM-HIGH participants with CKD, the addition of ERN to simvastatin for secondary prevention of CVD improved triglyceride and high-density lipoprotein-cholesterol concentrations but did not improve cardiovascular outcomes or kidney function, and was associated with higher all-cause mortality.

A prospective controlled study of living kidney donors: three-year follow-up.

BACKGROUND: There have been few prospective controlled studies of kidney donors. Understanding the pathophysiologic effects of kidney donation is important for judging donor safety and improving our understanding of the consequences of reduced kidney function in chronic kidney disease. STUDY DESIGN: Prospective, controlled, observational cohort study. SETTING & PARTICIPANTS: 3-year follow-up of kidney donors and paired controls suitable for donation at their donor's center. PREDICTOR: Kidney donation. OUTCOMES: Medical history, vital signs, glomerular filtration rate, and other measurements at 6, 12, 24, and 36 months after donation. RESULTS: At 36 months, 182 of 203 (89.7%) original donors and 173 of 201 (86.1%) original controls continue to participate in follow-up visits. The linear slope of the glomerular filtration rate measured by plasma iohexol clearance declined 0.36±7.55mL/min per year in 194 controls, but increased 1.47±5.02mL/min per year in 198 donors (P=0.005) between 6 and 36 months. Blood pressure was not different between donors and controls at any visit, and at 36 months, all 24-hour ambulatory blood pressure parameters were similar in 126 controls and 135 donors (mean systolic blood pressure, 120.0±11.2 [SD] vs 120.7±9.7mmHg [P=0.6]; mean diastolic blood pressure, 73.4±7.0 vs 74.5±6.5mmHg [P=0.2]). Mean arterial pressure nocturnal dipping was manifest in 11.2% ± 6.6% of controls and 11.3% ± 6.1% of donors (P=0.9). Urinary protein-creatinine and albumin-creatinine ratios were not increased in donors compared with controls. From 6 to 36 months postdonation, serum parathyroid hormone, uric acid, homocysteine, and potassium levels were higher, whereas hemoglobin levels were lower, in donors compared with controls. LIMITATIONS: Possible bias resulting from an inability to select controls screened to be as healthy as donors, short follow-up duration, and dropouts. CONCLUSIONS: Kidney donors manifest several of the findings of mild chronic kidney disease. However, at 36 months after donation, kidney function continues to improve in donors, whereas controls have expected age-related declines in function.

Risk of cancer in retransplants compared to primary kidney transplants in the United States.

Recipients of kidney transplantation have elevated risk of developing cancer. There are limited data on cancer risk in recipients of kidney retransplantation. We used data from the Transplant Cancer Match Study, which links the U.S. transplant registry with 15 cancer registries. Cancer incidence in recipients of kidney retransplantation and primary kidney transplants was compared utilizing Poisson regression, adjusting for demographic and medical characteristics. We assessed 109 224 primary recipients and 6621 retransplants. Compared to primary recipients, retransplants were younger (median age 40 vs. 46 yr), had higher PRA, and more often received induction with polyclonal antibodies (43% vs. 25%). A total of 5757 cancers were observed in primary recipients and 245 in retransplants. Overall cancer risk was similar in retransplants compared with primary recipients (incidence rate ratio [IRR] 1.06, 95% CI 0.93-1.20, adjusted for age, gender, race/ethnicity, PRA, and use of polyclonal induction). However, renal cell carcinoma (RCC) occurred in excess among retransplants (adjusted IRR 2.03, 95% CI 1.45-2.77), based on 514 cases in primary recipients and 43 cases in retransplants. Overall cancer risk did not differ in retransplants compared to primary recipients. Increased risk of RCC may be explained by the presence of acquired cystic kidney disease, which is more likely to develop with additional time with kidney disease and time spent on dialysis waiting for retransplantation.

Effects of cardiac resynchronization therapy on muscle sympathetic nerve activity.

INTRODUCTION: Muscle sympathetic nerve activity (MSNA) is an independent prognostic marker in patients with heart failure (HF). Therefore, its relevance to the treatment of HF patients is unquestionable. OBJECTIVES: In this study, we investigated the effects of cardiac resynchronization therapy (CRT) on MSNA response at rest and during exercise in patients with advanced HF. METHODS: We assessed 11 HF patients (51 ± 3.4 years; New York Heart Association class III-IV; left ventricular ejection fraction 27.8 ± 2.2%; optimal medical therapy) submitted to CRT. Evaluations were made prior to and 3 months after CRT. MSNA was performed at rest and during moderate static exercise (handgrip). Peak oxygen consumption (VO2 ) was evaluated by means of cardiopulmonary exercise test. HF patients with advanced NYHA class without CRT and healthy individuals were also studied. RESULTS: CRT reduced MSNA at rest (48.9 ± 11.1 bursts/min vs 33.7 ± 15.3 bursts/min, P < 0.05) and during handgrip exercise (MSNA 62.3 ± 13.1 bursts/min vs 46.9 ± 14.3 bursts/min, P < 0.05). Among HF patients submitted to CRT, the peak VO2 increased (12.9 ± 2.8 mL/kg/min vs 16.5 ± 3.9 mL/kg/min, P < 0.05) and an inverse correlation between peak VO2 and resting MSNA (r = -0.74, P = 0.01) was observed. CONCLUSIONS: In patients with advanced HF and severe systolic dysfunction: (1) a significant reduction of MSNA (at rest and during handgrip) occurred after CRT, and this behavior was significantly superior to HF patients receiving only medical therapy; (2) MSNA reduction after CRT had an inverse correlation with O2 consumption outcomes.

Psychosocial Evaluation of Living Kidney Donors: A Survey of Current Practices in the United States.

BACKGROUND: Best practices in psychosocial evaluation and care of living donor candidates and donors are not well established. METHODS: We surveyed 195 living kidney donor (LKD) transplant centers in United States from October 2021 to April 2022 querying (1) composition of psychosocial teams, (2) evaluation processes including clinical tools and domains assessed, (3) selection criteria, and (4) psychosocial follow-up post-donation. RESULTS: We received 161 responses from 104 programs, representing 53% of active LKD programs and 67% of LKD transplant volume in 2019. Most respondents (63%) were social workers/independent living donor advocates. Over 90% of respondents indicated donor candidates with known mental health or substance use disorders were initially evaluated by the psychosocial team. Validated psychometric or transplant-specific tools were rarely utilized but domains assessed were consistent. Active suicidality, self-harm, and psychosis were considered absolute contraindications in >90% of programs. Active depression was absolute contraindication in 50% of programs; active anxiety disorder was excluded 27%. Conditions not contraindicated to donation include those in remission: anxiety (56%), depression (53%), and posttraumatic stress disorder (41%). There was acceptance of donor candidates using alcohol, tobacco, or cannabis recreationally, but not if pattern met criteria for active use disorder. Seventy-one percent of programs conducted post-donation psychosocial assessment and use local resources to support donors. CONCLUSIONS: There was variation in acceptance of donor candidates with mental health or substance use disorders. Although most programs conducted psychosocial screening post-donation, support is not standardized and unclear if adequate. Future studies are needed for consensus building among transplant centers to form guidelines for donor evaluation, acceptance, and support.

CHronic use of Amiodarone aGAinSt Implantable cardioverter-defibrillator therapy for primary prevention of death in patients with Chagas cardiomyopathy Study: rationale and design of a randomized clinical trial.

BACKGROUND: The implantable cardioverter defibrillator (ICD) is better than antiarrhythmic drug therapy for the primary and secondary prevention of all-cause mortality and sudden cardiac death in patients with either coronary artery disease or idiopathic dilated cardiomyopathy. This study aims to assess whether the ICD also has this effect for primary prevention in chronic Chagas cardiomyopathy (CCC). METHODS: In this randomized (concealed allocation) open-label trial, we aim to enroll up to 1,100 patients with CCC, a Rassi risk score for death prediction of ≥10 points, and at least 1 episode of nonsustained ventricular tachycardia on a 24-hour Holter monitoring. Patients from 28 centers in Brazil will be randomly assigned in a 1:1 ratio to receive an ICD or amiodarone (600 mg/d for 10 days, then 200-400 mg/d until the end of the study). The randomization sequence will be generated by computer, and the members of the committees responsible for end point validation and data analysis will be blinded to study assignment. The primary end point is all-cause death, and enrolment will continue until 256 patients have reached this end point. Key secondary end points include cardiovascular death, sudden cardiac death, hospitalization for heart failure, and quality of life. We expect follow-up to last 3 to 6 years, and data analysis will be done on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov number NCT01722942. CONCLUSION: CHAGASICS is the first large-scale trial to assess the benefit of ICD therapy for the primary prevention of death in patients with CCC and nonsustained ventricular tachycardia, who have a moderate to high risk of death.

A prospective controlled study of kidney donors: baseline and 6-month follow-up.

BACKGROUND: Most previous studies of living kidney donors have been retrospective and have lacked suitable healthy controls. Needed are prospective controlled studies to better understand the effects of a mild reduction in kidney function from kidney donation in otherwise healthy individuals. STUDY DESIGN: Prospective, controlled, observational cohort study. SETTING & PARTICIPANTS: Consecutive patients approved for donation at 8 transplant centers in the United States were asked to participate. For every donor enrolled, an equally healthy control with 2 kidneys who theoretically would have been suitable to donate a kidney also was enrolled. PREDICTOR: Kidney donation. MEASUREMENTS: At baseline predonation and at 6 months after donation, medical history, vital signs, measured (iohexol) glomerular filtration rate, and other measurements were collected. There were 201 donors and 198 controls who completed both baseline and 6-month visits and form the basis of this report. RESULTS: Compared with controls, donors had 28% lower glomerular filtration rates at 6 months (94.6 ± 15.1 [SD] vs 67.6 ± 10.1 mL/min/1.73 m(2); P < 0.001), associated with 23% greater parathyroid hormone (42.8 ± 15.6 vs 52.7 ± 20.9 pg/mL; P < 0.001), 5.4% lower serum phosphate (3.5 ± 0.5 vs 3.3 ± 0.5 mg/dL; P < 0.001), 3.7% lower hemoglobin (13.6 ± 1.4 vs 13.1 ± 1.2 g/dL; P < 0.001), 8.2% greater uric acid (4.9 ± 1.2 vs 5.3 ± 1.1 mg/dL; P < 0.001), 24% greater homocysteine (1.2 ± 0.3 vs 1.5 ± 0.4 mg/L; P < 0.001), and 1.5% lower high-density lipoprotein cholesterol (54.9 ± 16.4 vs 54.1 ± 13.9 mg/dL; P = 0.03) levels. There were no differences in albumin-creatinine ratios (5.0 [IQR, 4.0-6.6] vs 5.0 [IQR, 3.3-5.4] mg/g; P = 0.5), office blood pressures, or glucose homeostasis. LIMITATIONS: Short duration of follow-up and possible bias resulting from an inability to screen controls with kidney and vascular imaging performed in donors. CONCLUSIONS: Kidney donors have some, but not all, abnormalities typically associated with mild chronic kidney disease 6 months after donation. Additional follow-up is warranted.