Epimeric vitamin D and cardiovascular structure and function in advanced CKD and after kidney transplantation.

BACKGROUND: 25-hydroxyvitamin D can undergo C-3 epimerization to produce 3-epi-25(OH)D3. 3-epi-25(OH)D3 levels decline in chronic kidney disease (CKD), but its role in regulating the cardiovascular system is unknown. Herein, we examined the relationship between 3-epi-25(OH)D3, and cardiovascular functional and structural endpoints in patients with CKD. METHODS: We examined n = 165 patients with advanced CKD from the Cardiopulmonary Exercise Testing in Renal Failure and After Kidney Transplantation (CAPER) study cohort, including those who underwent kidney transplant (KTR, n = 76) and waitlisted patients who did not (NTWC, n = 89). All patients underwent cardiopulmonary exercise testing and echocardiography at baseline, 2 months and 12 months. Serum 3-epi-25(OH)D3 was analyzed by liquid chromatography-tandem mass spectrometry. RESULTS: Patients were stratified into quartiles of baseline 3-epi-25(OH)D3 (Q1: <0.4 ng/mL, n = 51; Q2: 0.4 ng/mL, n = 26; Q3: 0.5-0.7 ng/mL, n = 47; Q4: ≥0.8 ng/mL, n = 41). Patients in Q1 exhibited lower peak oxygen uptake [VO2Peak = 18.4 (16.2-20.8) mL/min/kg] compared with Q4 [20.8 (18.6-23.2) mL/min/kg; P = .009]. Linear mixed regression model showed that 3-epi-25(OH)D3 levels increased in KTR [from 0.47 (0.30) ng/mL to 0.90 (0.45) ng/mL] and declined in NTWC [from 0.61 (0.32) ng/mL to 0.45 (0.29) ng/mL; P < .001]. Serum 3-epi-25(OH)D3 was associated with VO2Peak longitudinally in both groups [KTR: ß (standard error) = 2.53 (0.56), P < .001; NTWC: 2.73 (0.70), P < .001], but was not with left ventricular mass or arterial stiffness. Non-epimeric 25(OH)D3, 24,25(OH)2D3 and the 25(OH)D3:24,25(OH)2D3 ratio were not associated with any cardiovascular outcome (all P > .05). CONCLUSIONS: Changes in 3-epi-25(OH)D3 levels may regulate cardiovascular functional capacity in patients with advanced CKD.

Metformin for preventing the progression of chronic kidney disease.

BACKGROUND: Metformin has been used in the management of diabetes for decades. It is an effective, low-cost intervention with a well-established safety profile. Emerging evidence suggests that metformin targets a number of pathways that lead to chronic kidney damage, and long-term use may, therefore, slow the rate of kidney function decline and chronic kidney disease (CKD) progression. OBJECTIVES: To evaluate the effect of metformin therapy on kidney function decline in patients with CKD with or without diabetes mellitus and assess the safety and dose tolerability in this population. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 19 July 2023 with assistance from an Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that reported kidney-related outcomes with a minimum duration of 12 months delivery of the metformin intervention and whose eligibility criteria included adult participants with either i) a diagnosis of CKD of any aetiology and/or ii) those with a diagnosis of diabetes mellitus. Comparisons included placebo, no intervention, non-pharmacological interventions, other antidiabetic medications or any other active control. Studies that included patients on any modality of kidney replacement therapy were excluded. DATA COLLECTION AND ANALYSIS: Two authors independently carried out data extraction using a standard data extraction form. The methodological quality of the included studies was assessed using the Cochrane risk of bias tool. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes and mean difference (MD) and 95% CI for continuous outcomes. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: This review included 11 studies reporting on 8449 randomised participants. Studies were conducted in patient populations with Autosomal Dominant Polycystic Kidney Disease (ADPKD) (four studies) or diabetes mellitus (seven studies). Six studies compared metformin with no active control, four studies compared metformin with active controls (rosiglitazone, glyburide, pioglitazone, or glipizide), and one study included treatment arms that randomised to either metformin, diet and lifestyle modifications, or other antidiabetic therapies. The risk of bias in included studies varied; two studies were abstract-only publications and were judged to have a high risk of bias in most domains. Other included publications were judged to have a low risk of bias in most domains. Across comparisons, GRADE evaluations for most outcomes were judged as low or very low certainty, except for those relating to side effects, tolerance, and withdrawals, which were judged as moderate certainty. The evidence suggests that compared to placebo, metformin may result in i) a slightly smaller decline in kidney function (3 studies, 505 participants: MD 1.92 mL/min, 95% CI 0.33 to 3.51; I2 = 0%; low certainty), ii) very uncertain effects on the incidence of kidney failure (1 study, 753 participants: RR 1.20, 95% CI 0.17 to 8.49), iii) little or no effect on death (3 studies, 865 participants: RR 1.00, 95% CI 0.76 to 1.32; I2 = 0%; moderate certainty), iv) little or no effect on the incidence of serious adverse events (3 studies, 576 participants: RR 1.15, 95% CI 0.76 to 1.72; I2 = 0%; moderate certainty), and v) likely higher incidence of intolerance leading to study withdrawal than placebo (4 studies, 646 participants: RR 2.19, 95% CI 1.46 to 3.27; I2 = 0%; moderate certainty). The certainty of the evidence for proteinuria was very uncertain. Compared to other active controls (rosiglitazone, glyburide, pioglitazone, or glipizide), metformin i) demonstrated very uncertain effects on kidney function decline, ii) may result in little or no difference in death (3 studies, 5608 participants: RR 0.95 95% CI 0.63 to 1.43; I2 = 0%; low certainty), iii) probably results in little or no difference in intolerance leading to study withdrawal (3 studies, 5593 participants: RR 0.92, 95% CI, 0.79 to 1.08; I2 = 0%; moderate certainty), iv) probably results in little or no difference in the incidence of serious adverse events (2 studies, 5545 participants: RR 1.16, 95% CI 0.79 to 1.71; I2 = 0%; moderate certainty), and v) may increase the urinary albumin-creatinine ratio (2 studies, 3836 participants: MD 14.61, 95% CI 8.17 to 21.05; I2 = 0%; low certainty). No studies reported the incidence of kidney failure. AUTHORS' CONCLUSIONS: This review highlights the lack of RCTs reporting on the effects of metformin on kidney function, particularly in patients with CKD. Future research in this field requires adequately powered RCTs comparing metformin to placebo or standard care in those with CKD. Seven ongoing studies were identified in this review, and future updates, including their findings, may further inform the results of this review.

Legal and ethical framework for global health information and biospecimen exchange - an international perspective.

BACKGROUND: The progress of electronic health technologies and biobanks holds enormous promise for efficient research. Evidence shows that studies based on sharing and secondary use of data/samples have the potential to significantly advance medical knowledge. However, sharing of such resources for international collaboration is hampered by the lack of clarity about ethical and legal requirements for transfer of data and samples across international borders. MAIN TEXT: Here, the International Clinical Trial Center Network (ICN) reports the legal and ethical requirements governing data and sample exchange (DSE) across four continents. The most recurring requirement is ethical approval, whereas only in specific conditions approval of national health authorities is required. Informed consent is not required in all sharing situations. However, waiver of informed consent is only allowed in certain countries/regions and under certain circumstances. The current legal and ethical landscape appears to be very complex and under constant evolution. Regulations differ between countries/regions and are often incomplete, leading to uncertainty. CONCLUSION: With this work, ICN illuminates the unmet need for a single international collaborative framework to facilitate DSE. Harmonising requirements for global DSE will reduce inefficiency and waste in research. There are many challenges to realising this ambitious vision, including inconsistent terminology and definitions, and heterogeneous and dynamic legal constraints. Here, we identify areas of agreement and significant difference as a necessary first step towards facilitating international collaboration. We propose the establishment of a working group to continue the comparison across jurisdictions, create a standardised glossary and define a set of basic principles and fundamental requirements for DSE.

Mycophenolate mofetil versus cyclophosphamide for remission induction in ANCA-associated vasculitis: a randomised, non-inferiority trial.

OBJECTIVES: Cyclophosphamide induction regimens are effective for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), but are associated with infections, malignancies and infertility. Mycophenolate mofetil (MMF) has shown high remission rates in small studies of AAV. METHODS: We conducted a randomised controlled trial to investigate whether MMF was non-inferior to cyclophosphamide for remission induction in AAV. 140 newly diagnosed patients were randomly assigned to MMF or pulsed cyclophosphamide. All patients received the same oral glucocorticoid regimen and were switched to azathioprine following remission. The primary endpoint was remission by 6 months requiring compliance with the tapering glucocorticoid regimen. Patients with an eGFR <15 mL/min were excluded from the study. RESULTS: At baseline, ANCA subtype, disease activity and organ involvement were similar between groups. Non-inferiority was demonstrated for the primary remission endpoint, which occurred in 47 patients (67%) in the MMF group and 43 patients (61%) in the cyclophosphamide group (risk difference 5.7%, 90% CI -7.5% to 19%). Following remission, more relapses occurred in the MMF group (23 patients, 33%) compared with the cyclophosphamide group (13 patients, 19%) (incidence rate ratio 1.97, 95% CI 0.96 to 4.23, p=0.049). In MPO-ANCA patients, relapses occurred in 12% of the cyclophosphamide group and 15% of the MMF group. In PR3-ANCA patients, relapses occurred in 24% of the cyclophosphamide group and 48% of the MMF group. Serious infections were similar between groups (26% MMF group, 17% cyclophosphamide group) (OR 1.67, 95% CI 0.68 to 4.19, p=0.3). CONCLUSION: MMF was non-inferior to cyclophosphamide for remission induction in AAV, but resulted in higher relapse rate. TRIAL REGISTRATION NUMBER: NCT00414128.

Hyperphosphataemia in 2019: have we made progress?

PURPOSE OF REVIEW: This review describes recent developments in the management of serum phosphate in dialysis patients, with a focus on the development of recent trials which randomize patients to different levels of control. RECENT FINDINGS: We review the uncertainties around clinical benefits of serum phosphate control and alternative approaches to current management, as well as a multinational attempt to conduct randomized controlled trials in this area. We discuss novel methods of limiting oral phosphate absorption. SUMMARY: Although numerous guidelines and target ranges for serum phosphate management exist, they are largely based on observational data and there is no definitive evidence that good control improves the length or quality of life of dialysis patients. New phosphate binders continue to appear on the market with increasing financial cost but without additional meaningful outcome data. Two recently published trials have demonstrated the feasibility of a large-scale study of differing phosphate levels to test the hypothesis that reduction of serum phosphate is beneficial to dialysis patients. Restriction of oral phosphate intake should not be overlooked.

A randomized, multicenter, open-label, blinded end point trial comparing the effects of spironolactone to chlorthalidone on left ventricular mass in patients with early-stage chronic kidney disease: Rationale and design of the SPIRO-CKD trial.

BACKGROUND: Chronic kidney disease (CKD) is associated with increased left ventricular (LV) mass and arterial stiffness. In a previous trial, spironolactone improved these end points compared with placebo in subjects with early-stage CKD, but it is not known whether these effects were specific to the drug or secondary to blood pressure lowering. AIM: The aim was to investigate the hypothesis that spironolactone is superior to chlorthalidone in the reduction of LV mass while exerting similar effects on blood pressure. DESIGN: This is a multicenter, prospective, randomized, open-label, blinded end point clinical trial initially designed to compare the effects of 40weeks of treatment with spironolactone 25mg once daily to chlorthalidone 25mg once daily on the co-primary end points of change in pulse wave velocity and change in LV mass in 350 patients with stages 2 and 3 CKD on established treatment with an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Because of slow recruitment rates, it became apparent that it would not be possible to recruit this sample size within the funded time period. The study design was therefore changed to one with a single primary end point of LV mass requiring 150 patients. Recruitment was completed on 31 December 2016, at which time 154 patients had been recruited. Investigations included cardiac magnetic resonance imaging, applanation tonometry, 24-hour ambulatory blood pressure monitoring, and laboratory tests. Subjects are assessed before and after 40weeks of randomly allocated drug therapy and at 46weeks after discontinuation of the study drug.

Long term azathioprine maintenance therapy in ANCA-associated vasculitis: combined results of long-term follow-up data.

Objective: We studied whether in ANCA-associated vasculitis patients, duration of AZA maintenance influenced relapse rate during long-term follow-up. Methods: Three hundred and eighty newly diagnosed ANCA-associated vasculitis patients from six European multicentre studies treated with AZA maintenance were included; 58% were male, median age at diagnosis 59.4 years (interquartile range: 48.3-68.2 years); granulomatosis with polyangiitis, n = 236; microscopic polyangiitis, n = 132; or renal limited vasculitis, n = 12. Patients were grouped according to the duration of AZA maintenance after remission induction: ⩽18 months, ⩽24 months, ⩽36 months, ⩽48 months or > 48 months. Primary outcome was relapse-free survival at 60 months. Results: During follow-up, 84 first relapses occurred during AZA-maintenance therapy (1 relapse per 117 patient months) and 71 after withdrawal of AZA (1 relapse/113 months). During the first 12 months after withdrawal, 20 relapses occurred (1 relapse/119 months) and 29 relapses >12 months after withdrawal (1 relapse/186 months). Relapse-free survival at 60 months was 65.3% for patients receiving AZA maintenance >18 months after diagnosis vs 55% for those who discontinued maintenance ⩽18 months (P = 0.11). Relapse-free survival was associated with induction therapy (i.v. vs oral) and ANCA specificity (PR3-ANCA vs MPO-ANCA/negative). Conclusion: Post hoc analysis of combined trial data suggest that stopping AZA maintenance therapy does not lead to a significant increase in relapse rate and AZA maintenance for more than 18 months after diagnosis does not significantly influence relapse-free survival. ANCA specificity has more effect on relapse-free survival than duration of maintenance therapy and should be used to tailor therapy individually.

Human urinary exosomes as innate immune effectors.

Exosomes are small extracellular vesicles, approximately 50 nm in diameter, derived from the endocytic pathway and released by a variety of cell types. Recent data indicate a spectrum of exosomal functions, including RNA transfer, antigen presentation, modulation of apoptosis, and shedding of obsolete protein. Exosomes derived from all nephron segments are also present in human urine, where their function is unknown. Although one report suggested in vitro uptake of exosomes by renal cortical collecting duct cells, most studies of human urinary exosomes have focused on biomarker discovery rather than exosome function. Here, we report results from in-depth proteomic analyses and EM showing that normal human urinary exosomes are significantly enriched for innate immune proteins that include antimicrobial proteins and peptides and bacterial and viral receptors. Urinary exosomes, but not the prevalent soluble urinary protein uromodulin (Tamm-Horsfall protein), potently inhibited growth of pathogenic and commensal Escherichia coli and induced bacterial lysis. Bacterial killing depended on exosome structural integrity and occurred optimally at the acidic pH typical of urine from omnivorous humans. Thus, exosomes are innate immune effectors that contribute to host defense within the urinary tract.

Impairment of Cardiovascular Functional Capacity in Mild to Moderate Kidney Dysfunction.

BACKGROUND: Traditional diagnostic tools that assess resting cardiac function and structure fail to accurately reflect cardiovascular alterations in patients with chronic kidney disease (CKD). This study sought to determine whether multidimensional exercise response patterns related to cardiovascular functional capacity can detect abnormalities in mild-to-moderate CKD. METHODS: In a cross-sectional study, we examined 3,075 participants from the Framingham Heart Study (FHS) and 451 participants from the Massachusetts General Hospital Exercise Study (MGH-ExS) who underwent cardiopulmonary exercise testing (CPET). Participants were stratified by estimated glomerular filtration rate (eGFR): eGFR ≥90; eGFR 60-89; eGFR 30-59. Our primary outcomes of interest were peak oxygen uptake (VO 2 Peak),VO 2 at anaerobic threshold (VO 2 AT), and the ratio of minute ventilation to carbon dioxide production (VE/VCO 2 ). Multiple linear regression models were fitted to evaluate the associations between eGFR group and each outcome variable adjusted for covariates. RESULTS: In the FHS cohort, N=1,712 (56%) had an eGFR ≥90 ml/min/1.73m 2 , N=1,271 (41%) had an eGFR 60-89 ml/min/1.73m 2 , and N=92 (3%) had an eGFR 30-59 ml/min/1.73m 2 . In the MGH-ExS cohort, N=247 (55%) had an eGFR ≥90 ml/min/1.73m 2 , N=154 (34%) had an eGFR 60-89 ml/min/1.73m 2 , and N=50 (11%) had an eGFR 30-59 ml/min/1.73m 2 . In FHS, VO 2 Peak and VO 2 AT were incrementally impaired with declining kidney function ( p <0.001); however this pattern was attenuated following adjustment for age. Percent-predicted VO 2 Peak at AT was higher in the lower eGFR groups ( p <0.001). In MGH-ExS, VO 2 Peak and VO 2 AT were incrementally impaired with declining kidney function in unadjusted and adjusted models ( p <0.05). VO 2 Peak was associated with eGFR ( p <0.05) in all models even after adjusting for age. On further mechanistic analysis, we directly measured cardiac output (CO) at peak exercise via right heart catheterization and found impaired CO in the lower eGFR groups ( p ≤0.007). CONCLUSION: CPET-derived indices may detect impairment in cardiovascular functional capacity and track cardiac output declines in mild to moderate CKD.

Association of calcium, phosphate and parathyroid hormone with renal allograft function: a retrospective cohort study.

BACKGROUND: Significant variations in postoperative levels of parathyroid hormone (PTH), calcium and phosphate exist after renal transplantation, but whether they affect allograft function is unknown. We investigated the association between early post-transplant levels of PTH, calcium and phosphate and graft function. METHODS: We performed a single-centre cohort study of renal transplant recipients from Addenbrooke's Hospital, Cambridge, between April 1997 and March 2007, evaluating the association between plasma calcium, phosphate and PTH 1 month after transplantation and change in epidermal growth factor receptor (eGFR) in the first 12 months after transplantation (estimated using the Modification of Diet in Renal Disease Study equation). Differences in eGFR between 26 and 52 weeks after transplantation were computed using mixed effects linear regression models for repeated measures of eGFR, while adjusting for sociodemographic and biochemical variables. RESULTS: Three hundred and forty-three patients were eligible for study. The mean age (standard deviation) at transplant was 43 years (13 years). Between 30 and 90 days after transplantation, the median (25th-75th percentile) eGFR was 33 (26-50) ml/min/1.73 m(2), the mean calcium level was 2.4 (0.17) mmol/l and the mean phosphate level was 0.78 (0.23) mmol/l. There was a significant interaction between calcium and phosphate levels (p = 0.006). In patients with low levels of phosphate, higher levels of calcium were associated with declining eGFR over time. However, in patients with a high phosphate level, higher calcium was associated with improved eGFR. CONCLUSIONS: Higher serum calcium in patients with low serum phosphate after transplantation is associated with a decline in graft function during the first year after transplantation. Disorders of mineral metabolism after transplant may represent an important therapeutic target to preserve allograft function.

PROphylaxis for paTiEnts at risk of COVID-19 infecTion (PROTECT-V).

BACKGROUND: Despite the introduction of vaccination, there remains a need for pre-exposure prophylactic agents against SARS-CoV-2. Several patient groups are more vulnerable to SARS-CoV-2 infection by virtue of underlying health conditions, treatments received or suboptimal responses to vaccination. METHODS: PROTECT-V is a platform trial testing pre-exposure prophylactic interventions against SARS-CoV-2 infection in vulnerable patient populations (organ transplant recipients; individuals with oncological/haematological diagnoses, immune deficiency or autoimmune diseases requiring immunosuppression or on dialysis). Multiple agents can be evaluated across multiple vulnerable populations sharing placebo groups, with the option of adding additional treatments at later time points as these become available. The primary endpoint is symptomatic SARS-CoV-2 infection, and each agent will be independently evaluated in real time when the required number of events occurs. Presently, three agents are approved in the platform: intranasal niclosamide, nasal and inhaled ciclesonide and intravenous sotrovimab. DISCUSSION: Despite the introduction of vaccination, there remains a need for pre-exposure prophylactic agents against SARS-CoV-2. Several patient groups are more vulnerable to COVID-19 disease by virtue of underlying health conditions, treatments received or suboptimal responses to vaccination. TRIAL REGISTRATION: ClinicalTrials.gov NCT04870333. EudraCT 2020-004144-28.

Clinical utility of PKD2 mutation testing in a polycystic kidney disease cohort attending a specialist nephrology out-patient clinic.

BACKGROUND: ADPKD affects approximately 1:1000 of the worldwide population. It is caused by mutations in two genes, PKD1 and PKD2. Although allelic variation has some influence on disease severity, genic effects are strong, with PKD2 mutations predicting later onset of ESRF by up to 20 years. We therefore screened a cohort of ADPKD patients attending a nephrology out-patient clinic for PKD2 mutations, to identify factors that can be used to offer targeted gene testing and to provide patients with improved prognostic information. METHODS: 142 consecutive individuals presenting to a hospital nephrology out-patient service with a diagnosis of ADPKD and CKD stage 4 or less were screened for mutations in PKD2, following clinical evaluation and provision of a detailed family history (FH). RESULTS: PKD2 mutations were identified in one fifth of cases. 12% of non-PKD2 patients progressed to ESRF during this study whilst none with a PKD2 mutation did (median 38.5 months of follow-up, range 16-88 months, p < 0.03). A significant difference was found in age at ESRF of affected family members (non-PKD2 vs. PKD2, 54 yrs vs. 65 yrs; p < 0.0001). No PKD2 mutations were identified in patients with a FH of ESRF occurring before age 50 yrs, whereas a PKD2 mutation was predicted by a positive FH without ESRF. CONCLUSIONS: PKD2 testing has a clinically significant detection rate in the pre-ESRF population. It did not accurately distinguish those individuals with milder renal disease defined by stage of CKD but did identify a group less likely to progress to ESRF. When used with detailed FH, it offers useful prognostic information for individuals and their families. It can therefore be offered to all but those whose relatives have developed ESRF before age 50.

Clinical outcomes associated with the emergency treatment of hyperkalaemia with intravenous insulin-dextrose.

BACKGROUND: Hyperkalaemia occurs in up to 10% of hospital admissions but its treatment in the emergency setting is inconsistent. OBJECTIVES: To describe the emergency management of hyperkalaemia in adults with insulin-dextrose (IDex) and to explore clinical outcomes associated with IDex treatment. DESIGN AND SETTING: Cohort study using comprehensive electronic health records of all emergency admissions to a large university hospital in the United Kingdom between April 2015 and August 2018. PARTICIPANTS: Adult patients aged ≥16 years with at least one emergency admission and one blood potassium result during the study period. MAIN OUTCOMES AND MEASURES: Emergency hyperkalaemia treatment was evaluated including the requirement for re-treatment with IDex, episodes of glucose dysregulation, intensive care (ICU) admission and length of hospital stay. Associations with hyperkalaemia, adverse events and IDex treatment were explored by logistic regression. RESULTS: Amongst 211,993 patients attending the Emergency Department (ED) we identified 11,107 hyperkalaemic adult patients, of whom 1,284 were treated with IDex. Multiple doses were required in 542 patients (42.2%). Hypoglycaemia (plasma glucose < 4 mmol/L) occurred in 249 patients (19.4%) within 6 hours of IDex. Repeated doses were associated with an increased risk of hypoglycaemia (OR 2.94, 95% CI 2.20 to 3.93) compared to patients receiving a single dose, which, after adjustment was also associated with an increased risk of death (OR 1.56, 95% CI 1.16 to 2.09) during the study period. Patients who received multiple doses of IDex (OR 2.2, 95% CI 1.6-3.1) and those who received a dose of insulin above the guideline recommended limit (OR 5.6 3.1-10.3) were more likely to be admitted to ICU following IDex than those who received a single dose or the guideline recommended dose of insulin. CONCLUSIONS AND RELEVANCE: This study provides novel insight into the emergency management of hyperkalaemia in a large population, demonstrates the high risk of hypoglycaemia and highlights the urgent need for an improved, evidence-based approach to the emergency management of hyperkalaemia.

FGF23 and Cardiovascular Structure and Function in Advanced Chronic Kidney Disease.

Background: Fibroblast growth factor 23 (FGF23) is a bone-derived phosphatonin that is elevated in chronic kidney disease (CKD) and has been implicated in the development of cardiovascular disease. It is unknown whether elevated FGF23 in CKD is associated with impaired cardiovascular functional capacity, as assessed by maximum exercise oxygen consumption (VO2Max). We sought to determine whether FGF23 is associated with cardiovascular functional capacity in patients with advanced CKD and after improvement of VO2Max by kidney transplantation. Methods: We performed secondary analysis of 235 patients from the Cardiopulmonary Exercise Testing in Renal Failure and After Kidney Transplantation (CAPER) cohort, which recruited patients with stage 5 CKD who underwent kidney transplantation or were waitlisted and hypertensive controls. All patients underwent cardiopulmonary exercise testing (CPET) and echocardiography and were followed longitudinally for 1 year after study enrollment. Results: Patients across FGF23 quartiles differed in BMI (P=0.004) and mean arterial pressure (P<0.001) but did not significantly differ in sex (P=0.5) or age (P=0.08) compared with patients with lower levels of FGF23. Patients with higher FGF23 levels had impaired VO2Max (Q1: 24.2±4.8 ml/min per kilogram; Q4: 18.6±5.2 ml/min per kilogram; P<0.001), greater left ventricular mass index (LVMI; P<0.001), reduced HR at peak exercise (P<0.001), and maximal workload (P<0.001). Kidney transplantation conferred a significant decline in FGF23 at 2 months (P<0.001) before improvement in VO2Max at 1 year (P=0.008). Multivariable regression modeling revealed that changes in FGF23 was significantly associated with VO2Max in advanced CKD (P<0.001) and after improvement after kidney transplantation (P=0.006). FGF23 was associated with LVMI before kidney transplantation (P=0.003), however this association was lost after adjustment for dialysis status (P=0.4). FGF23 was not associated with LVMI after kidney transplantation in all models. Conclusions: FGF23 levels are associated with alterations in cardiovascular functional capacity in advanced CKD and after kidney transplantation. FGF23 is only associated with structural cardiac adaptations in advanced CKD but this was modified by dialysis status, and was not associated after kidney transplantation.

Initiation of Dialysis Is Associated With Impaired Cardiovascular Functional Capacity.

Background The transition to dialysis period carries a substantial increased cardiovascular risk in patients with chronic kidney disease. Despite this, alterations in cardiovascular functional capacity during this transition are largely unknown. The present study therefore sought to assess ventilatory exercise response measures in patients within 1 year of initiating dialysis. Methods and Results We conducted a cross-sectional study of 241 patients with chronic kidney disease stage 5 from the CAPER (Cardiopulmonary Exercise Testing in Renal Failure) study and from the intradialytic low-frequency electrical muscle stimulation pilot randomized controlled trial cohorts. Patients underwent cardiopulmonary exercise testing and echocardiography. Of the 241 patients (age, 48.9 [15.0] years; 154 [63.9%] men), 42 were predialytic (mean estimated glomerular filtration rate, 14 mL·min-1·1.73 m-2), 54 had a dialysis vintage ≤12 months, and 145 had a dialysis vintage >12 months. Dialysis vintage ≤12 months exhibited a significantly impaired cardiovascular functional capacity, as assessed by oxygen uptake at peak exercise (18.7 [5.8] mL·min-1·kg-1) compared with predialysis (22.7 [5.2] mL·min-1·kg-1; P<0.001). Dialysis vintage ≤12 months also exhibited reduced peak workload, impaired peak heart rate, reduced circulatory power, and increased left ventricular mass index (P<0.05 for all) compared with predialysis. After excluding those with prior kidney transplant, dialysis vintage >12 months exhibited a lower oxygen uptake at peak exercise (17.0 [4.9] mL·min-1·kg-1) compared with dialysis vintage ≤12 months (18.9 [5.9] mL·min-1·kg-1; P=0.033). Conclusions Initiating dialysis is associated with a significant impairment in oxygen uptake at peak exercise and overall decrements in ventilatory and hemodynamic exercise responses that predispose patients to functional dependence. The magnitude of these changes is comparable to the differences between low-risk New York Heart Association class I and higher-risk New York Heart Association class II to IV heart failure.

Myocardial Cytoskeletal Adaptations in Advanced Kidney Disease.

Background The myocardial cytoskeleton functions as the fundamental framework critical for organelle function, bioenergetics and myocardial remodeling. To date, impairment of the myocardial cytoskeleton occurring in the failing heart in patients with advanced chronic kidney disease has been largely undescribed. Methods and Results We conducted a 3-arm cross-sectional cohort study of explanted human heart tissues from patients who are dependent on hemodialysis (n=19), hypertension (n=10) with preserved renal function, and healthy controls (n=21). Left ventricular tissues were subjected to pathologic examination and next-generation RNA sequencing. Mechanistic and interference RNA studies utilizing in vitro human cardiac fibroblast models were performed. Left ventricular tissues from patients undergoing hemodialysis exhibited increased myocardial wall thickness and significantly greater fibrosis compared with hypertension patients (P<0.05) and control (P<0.01). Transcriptomic analysis revealed that the focal adhesion pathway was significantly enriched in hearts from patients undergoing hemodialysis. Hearts from patients undergoing hemodialysis exhibited dysregulated components of the focal adhesion pathway including reduced ß-actin (P<0.01), ß-tubulin (P<0.01), vimentin (P<0.05), and increased expression of vinculin (P<0.05) compared with controls. Cytoskeletal adaptations in hearts from the hemodialysis group were associated with impaired mitochondrial bioenergetics, including dysregulated mitochondrial dynamics and fusion, and loss of cell survival pathways. Mechanistic studies revealed that cytoskeletal changes can be driven by uremic and metabolic abnormalities of chronic kidney disease, in vitro. Furthermore, focal adhesion kinase silencing via interference RNA suppressed major cytoskeletal proteins synergistically with mineral stressors found in chronic kidney disease in vitro. Conclusions Myocardial failure in advanced chronic kidney disease is characterized by impairment of the cytoskeleton involving disruption of the focal adhesion pathway, mitochondrial failure, and loss of cell survival pathways.

Glyceraldehyde 3-phosphate dehydrogenase is required for band 3 (anion exchanger 1) membrane residency in the mammalian kidney.

The mammalian kidney isoform of the essential chloride-bicarbonate exchanger AE1 differs from its erythrocyte counterpart, being shorter at its N terminus. It has previously been reported that the glycolytic enzyme GAPDH interacts only with erythrocyte AE1, by binding to the portion not found in the kidney isoform. (Chu H, Low PS. Biochem J 400:143-151, 2006). We have identified GAPDH as a candidate binding partner for the C terminus of both AE1 and AE2. We show that full-length AE1 and GAPDH coimmunoprecipitated from both human and rat kidney as well as from Madin-Darby canine kidney (MDCK) cells stably expressing kidney AE1, while in human liver, AE2 coprecipitated with GAPDH. ELISA and glutathione S-transferase (GST) pull-down assays using GST-tagged C-terminal AE1 fusion protein confirmed that the interaction is direct; fluorescence titration revealed saturable binding kinetics with Kd 2.3±0.2 µM. Further GST precipitation assays demonstrated that the D902EY residues in the D902EYDE motif located within the C terminus of AE1 are important for GAPDH binding. In vitro GAPDH activity was unaffected by C-terminal AE1 binding, unlike in erythrocytes. Also, differently from red cell N-terminal binding, GAPDH-AE1 C-terminal binding was not disrupted by phosphorylation of AE1 in kidney AE1-expressing MDCK cells. Importantly, small interfering RNA knockdown of GAPDH in these cells resulted in significant intracellular retention of AE1, with a concomitant reduction in AE1 at the cell membrane. These results indicate differences between kidney and erythrocyte AE1/GAPDH behavior and show that in the kidney, GAPDH is required for kidney AE1 to achieve stable basolateral residency.

Adverse clinical outcomes associated with RAAS inhibitor discontinuation: analysis of over 400 000 patients from the UK Clinical Practice Research Datalink (CPRD).

BACKGROUND: Users of guideline-recommended renin-angiotensin-aldosterone system (RAAS) inhibitors may experience disruptions to their treatment, e.g. due to hyperkalaemia, hypotension or acute kidney injury. The risks associated with treatment disruption have not been comprehensively assessed; therefore, we evaluated the risk of adverse clinical outcomes in RAAS inhibitor users experiencing treatment disruptions in a large population-wide database. METHODS: This exploratory, retrospective analysis utilized data from the UK's Clinical Practice Research Datalink, linked to Hospital Episodes Statistics and the Office for National Statistics databases. Adults (≥18 years) with first RAAS inhibitor use (defined as angiotensin-converting enzyme inhibitors or angiotensin receptor blockers) between 1 January 2009 and 31 December 2014 were eligible for inclusion. Time to the first occurrence of adverse clinical outcomes [all-cause mortality, all-cause hospitalization, cardiac arrhythmia, heart failure hospitalization, cardiac arrest, advancement in chronic kidney disease (CKD) stage and acute kidney injury] was compared between RAAS inhibitor users with and without interruptions or cessations to treatment during follow-up. Associations between baseline characteristics and adverse clinical outcomes were also assessed. RESULTS: Among 434 027 RAAS inhibitor users, the risk of the first occurrence of all clinical outcomes, except advancement in CKD stage, was 8-75% lower in patients without interruptions or cessations versus patients with interruptions/cessations. Baseline characteristics independently associated with increased risk of clinical outcomes included increasing age, smoking, CKD, diabetes and heart failure. CONCLUSIONS: These findings highlight the need for effective management of factors associated with RAAS inhibitor interruptions or cessations in patients for whom guideline-recommended RAAS inhibitor treatment is indicated.

Per-Treatment Post Hoc Analysis of Clinical Trial Outcomes With Tolvaptan in ADPKD.

INTRODUCTION: In pivotal trials of patients with autosomal dominant polycystic kidney disease at risk of rapid progression, tolvaptan slowed estimated glomerular filtration rate (eGFR) decline in early-to-moderate (TEMPO 3:4 [NCT00428948]) and moderate- to late-stage (REPRISE [NCT02160145]) chronic kidney disease (CKD). Discontinuation was less frequent in REPRISE (15.0%) than TEMPO 3:4 (23.0%), given that in REPRISE, only subjects who tolerated tolvaptan 60/30 mg daily initiated the double-blind phase. We evaluated whether the greater treatment effect in REPRISE was attributable to different completion rates. METHODS: We conducted post hoc analyses of TEMPO 3:4 and REPRISE completers, defined as subjects who took trial drug to the end of the treatment period in TEMPO 3:4 (3 years) or REPRISE (1 year). Efficacy (rate of change in eGFR for tolvaptan vs. placebo) was analyzed as in each trial. Subjects from TEMPO 3:4 and REPRISE were also matched by propensity score for age, gender, and baseline eGFR to explore potential additional determinants of treatment effect. RESULTS: The annualized tolvaptan treatment effect in TEMPO 3:4 completers (difference vs. placebo of 0.98 ml/min per 1.73 m2/y) and REPRISE completers (difference of 1.23) was similar to that of the respective total trial populations (TEMPO 3:4: 0.94; REPRISE: 1.27). The treatment effect of tolvaptan was also similar between matched subjects. CONCLUSION: Greater treatment completion rate did not drive greater treatment effect in REPRISE. The more advanced CKD of REPRISE subjects may be more relevant. More rapid decline in kidney function in later-stage CKD enabled the effects of tolvaptan to be more easily discerned.