Calcium isotopes as a biomarker for vascular calcification in chronic kidney disease.

Calcium balance is abnormal in adults with chronic kidney disease (CKD) and is associated with the development of vascular calcification. It is currently not routine to screen for vascular calcification in CKD patients. In this cross-sectional study, we investigate whether the ratio of naturally occurring calcium (Ca) isotopes, 44Ca and 42Ca, in serum could be used as a noninvasive marker of vascular calcification in CKD. We recruited 78 participants from a tertiary hospital renal center: 28 controls, 9 subjects with mild-moderate CKD, 22 undertaking dialysis and 19 who received a kidney transplant. For each participant, systolic blood pressure, ankle brachial index, pulse wave velocity, and estimated glomerular filtration rate were measured, along with serum markers. Calcium concentrations and isotope ratios were measured in urine and serum. While we found no significant association between urine Ca isotope composition (noted δ44/42Ca) between the different groups, δ44/42Ca values in serum were significantly different between healthy controls, subjects with mild-moderate CKD and those undertaking dialysis (P < 0.01). Receiver operative characteristic curve analysis shows that the diagnostic utility of serum δ44/42Ca for detecting medial artery calcification is very good (AUC = 0.818, sensitivity 81.8% and specificity 77.3%, P < 0.01), and performs better than existing biomarkers. Although our results will need to be verified in prospective studies across different institutions, serum δ44/42Ca has the potential to be used as an early screening test for vascular calcification.

Acute kidney injury increases risk of kidney stones-a retrospective propensity score matched cohort study.

BACKGROUND: Acute kidney injury (AKI) is common. An episode of AKI may modify the risk of developing kidney stones by potential long-term effects on urine composition. We aimed to investigate the association between AKI and the risk of kidney stone presentations. METHODS: The retrospective cohort study used patient data (1 January 2008-31 December 2017), from an Australian Local Health District, which included AKI diagnosis, demographics, comorbidities and kidney stone admissions. Time-varying Cox proportional hazards and propensity-matched analysis were used to determine the impact of AKI on the risk of kidney stones. To address possible population inhomogeneity in comparisons between no AKI and hospitalized AKI, sub-group analysis was done comparing inpatient and outpatient AKI versus no AKI, to assess consistency of association with future stones. Sensitivity analysis was undertaken to capture the impact of a known AKI status and AKI severity. RESULTS: Out of 137 635 patients, 23 001 (17%) had an AKI diagnosis and 2295 (2%) had kidney stone presentations. In the unadjusted analysis, AKI was associated with kidney stones, with AKI used as a time-varying exposure, [hazard ratio (HR) 1.32, 95% confidence interval (CI) 1.16-1.50)]. Both inpatient-AKI (HR 1.19, 95% CI 1.01-1.39) and outpatient-AKI (HR 1.59, 95% CI 1.30-1.94) were significantly associated with future stones compared to no AKI subjects. This association persisted in the adjusted analysis (HR 1.45, 95% CI 1.26-1.66), propensity-matched dataset (HR 1.67, 95% CI 1.40-1.99) and sensitivity analysis. There was a dose-response relationship with higher stages of AKI being associated with a greater risk of kidney stones. CONCLUSIONS: In a large cohort of patients, AKI is associated with a greater risk of kidney stones, which increases with higher stages of AKI. This association should be examined in other cohorts and populations for verification.

Association of Peritonitis With Cardiovascular Mortality Over Time in the Peritoneal Dialysis Population: An Australia and New Zealand Dialysis and Transplant Registry Study.

Introduction: Though peritonitis is associated with increased mortality in patients receiving peritoneal dialysis (PD), its association with cardiovascular mortality remains uncertain. Methods: The study participants included adult patients (≥18 years old) commencing PD in Australia (from October 2003 to December 2019) using the Australia and New Zealand Dialysis and Transplant (ANZDATA) registry. Association between peritonitis and cardiovascular mortality was evaluated using Cox proportional hazards analysis and competing risks analysis. Associations between peritonitis rates between different eras and cardiovascular mortality were also compared using Jointpoint regression model to determine the time point when a significant change in peritonitis trend occurred to define the era for cardiovascular mortality. Subgroup analysis dividing the groups into 0, 1 and ≥2 episodes of peritonitis and sensitivity analysis censoring at 90 days post-transfer to hemodialysis (HD) were performed. Results: The study included 9699 incident PD patients. The overall peritonitis rate was 0.37 episodes per patient-year and declined by 4.7% (95% confidence interval [CI] 3.6-5.8%) during the study period. Peritonitis was associated with increased cardiovascular mortality risk (subdistribution hazard ratio [SHR] 1.53, 95% CI 1.39-1.69, P < 0.001) with increasing peritonitis episodes associated with higher risk (1 episode of peritonitis SHR 1.41, 95%CI 1.24-1.61; ≥2 episodes of peritonitis SHR 1.69, 95% CI 1.47-1.93, P < 0.001). Patients who commenced PD between 2012 and 2019 had a lower risk of cardiovascular mortality (SHR 0.60, 95% CI 0.50-0.72, P < 0.001), compared to patients who commenced between 2003 and 2011. Results were consistent in the sensitivity analysis. Conclusion: Peritonitis is independently associated with an increased risk of cardiovascular mortality, and the association is episode-dependent. Prevention and adequate treatment of PD peritonitis may improve cardiovascular outcomes among patients receiving PD.

Exploring the Agreement Between Self-Reported Medication Adherence and Pharmacy Refill-Based Measures in Patients with Kidney Disease.

Aim: To assess the quantitative and categorical agreement between two methods of measuring medication adherence: pharmacy refill-based medication possession rates and self-reported medication adherence scale. Background: Categorisation of adherence metrics using empirical cut-off scores can lead to misclassification, which can be overcome by expressing adherence as a continuous variable. Pharmacy refill-based adherence can be reported as actual rates, but the validity of expressing self-reported medication adherence scores as a continuous variable to reflect adherence is unknown and its quantitative agreement with refill-based adherence rates untested. Methods: Patients with kidney disease, including dialysis patients, from Illawarra Shoalhaven region of New South Wales, Australia were recruited between January 2015 and June 2016 to this cross-sectional study. Medication adherence was assessed using the self-reported Morisky Medication Adherence Scale (MMAS) and two pharmacy refill-based measures, Medication Possession Ratio (MPR) and Proportion of Days Covered (PDC) for antihypertensives and cardiometabolic drugs. Categorical and quantitative agreement between self-reported adherence and pharmacy refill-based adherence were assessed using tests of trend, analysis of covariance (ANCOVA), Cohen's kappa and Bland-Altman analysis. Results: We recruited 113 patients. There was a significant declining trend of MPR (p < 0.001) and PDC (<0.001 for antihypertensives, p = 0.004 for cardiometabolic) scores among categories with worsening MMAS adherence. Adjusted ANCOVA showed significant association between self-report and pharmacy refill-based adherence (p < 0.001). Weighted Cohen's kappa statistics showed fair agreement between the self-report and pharmacy refill-based categories. Bland-Altman's analysis showed less than 5% of cases were outside the limits of agreement (-0.36 to 0.27) and the bias for MMAS was negative (-0.05 to -0.09), indicating MMAS did not overestimate adherence. Conclusion: There is modest agreement between pharmacy refill-based measures and self-report MMAS measures when assessed categorically or quantitatively. Assessing adherence as a continuous variable should be considered to overcome the challenges associated with categorization of adherence based on arbitrary thresholds.

Systematic Review and Meta-analysis of Herpes Zoster Vaccine in Patients With CKD.

INTRODUCTION: Chronic kidney disease (CKD) is a risk factor for herpes zoster (HZ) infection. Few studies have examined HZ vaccine (HZV) in this population. We conducted a systematic review and meta-analysis investigating the efficacy and safety of HZV in patients with renal disease (CKD, dialysis, and transplant). METHODS: MEDLINE, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) databases (up to May 2020) were searched for randomized controlled trials and nonrandomized controlled studies evaluating HZV in patients with CKD for effectiveness and adverse event risks. Studies without a control group (placebo or no vaccine) were excluded. Extraction of prespecified data and risk of bias assessments using the Newcastle-Ottawa scale for cohort studies and the Cochrane Risk of Bias Tool for randomized controlled trials were done by 3 authors. Random-effects meta-analysis was used to generate pooled treatment effects and 95% confidence intervals. RESULTS: Included were 404,561 individuals from 8 studies (3 randomized controlled trials and 5 nonrandomized). All 8 studies examined HZ as an outcome, with 3 reporting adverse events. Risk of HZ was lower in patients who received HZV compared with controls (hazard ratio, 0.55; 95% confidence interval, 0.37-0.82; P < 0.01); however, heterogeneity was high (I 2 = 88%, P < 0.01). There was no significant difference in adverse events associated with HZV (hazard ratio, 1.03; 95% confidence interval, 0.54-1.28; P = 0.8). CONCLUSIONS: HZV compared with control significantly lowers the risk of HZ without an increase in adverse events in CKD patients. However, significant heterogeneity was present. HZV should be actively considered in CKD patients because the prevalence of HZ is higher in this population.

Changes in measures of cognitive function in patients with end-stage kidney disease on dialysis and the effect of dialysis vintage: A longitudinal cohort study.

INTRODUCTION: Prevalence of cognitive impairment increases with worsening severity of chronic kidney disease (CKD) and majority of end-stage kidney disease (ESKD) patients on dialysis have cognitive impairment. Trends of cognitive function (CF) in this population are less well known with published studies reporting conflicting results. METHODS: We assessed CF in a cohort of non-dialysis CKD and ESKD patients undergoing dialysis using modified mini-mental state examination (3MS), trail-making test (TMT-A & B) scores and Stroop task, and evaluated demographics, comorbidities and depression using Beck depression inventory at baseline. We repeated tests of CF and depression ≥ 1-year after baseline in both groups and compared change scores in CF and depression between ESKD/ CKD sub-groups. Among ESKD patients we compared change scores between patients with dialysis vintage of <1-year and >1-year. Analysis of covariance was used to adjust for the effect of age on these change scores. RESULTS: At baseline (N = 211), compared to CKD (N = 108), ESKD (N = 103) patients had significantly worse CF based on 3MS and TMT-A & B scores, and depression scores. On follow-up (N = 160) 3MS scores, especially the memory subscale significantly improved in ESKD, but worsened in CKD, with no significant changes in TMT A /TMT-B, or depression scores after adjusting for age. Among ESKD patients, 3MS, especially memory subscale improved in patients with dialysis vintage <1-year compared to >1-year. The 51 patients who discontinued after baseline assessment had worse baseline CF scores suggesting differential attrition. CONCLUSION: Though baseline cognitive scores were worse in ESKD patients on dialysis, compared to CKD, their 3MS, especially memory subscale improved on follow-up. Among ESKD patients, the improvement was significant only in patients who have been on dialysis for less than one-year which may indicate a beneficial effect of clearance of uraemic toxins. Differential attrition of study subjects may have impacted the observed results.

Peritoneal dialysis-related peritonitis as a risk factor for cardiovascular events.

BACKGROUND: Cardiovascular disease is the leading cause of mortality in peritoneal dialysis (PD) patients. Infection is known to increase the risk of cardiovascular events (CVE); however, no studies have examined the association between PD peritonitis and CVE. AIM: To examine peritonitis as a risk factor for CVE in PD patients. METHODS: This retrospective cohort study included all adults undertaking PD for ≥3 months in one Australian health district from 2001 to 2015. Baseline characteristics and peritonitis event information was obtained from the Australian and New Zealand Dialysis and Transplant registry. The Centre for Health Research Illawarra Shoalhaven Population facilitated data linkage using ICD10 coding to capture CVE information. RESULTS: A total of 211 patients was included, with median age of 66 years (interquartile range 54.49-74.45); 64% were male. Peritonitis occurred in 114 (54%) patients and 65 (30.8%) patients experienced a CVE. Identified risk factors for CVE included: cerebrovascular disease (hazard ratio (HR) 2.72, 95% confidence interval (CI) 1.36-5.47), diabetes (HR 2.41, 95% CI 1.47-3.96), coronary artery disease (HR 1.67, 95% CI 1.01-2.77) and age (HR 1.03, 95% CI 1.01-1.06). There was no significant increase in risk of CVE following peritonitis (HR 1.37, 95% CI 0.81-2.32, P = 0.24), even when accounting for age, cerebrovascular disease, diabetes and existing coronary artery disease (HR 1.32, 95% CI 0.78-2.23, P = 0.30). CONCLUSIONS: We did not find an increase in the risk of CVE following a peritonitis episode in PD patients. This result may be due to small sample size or rapid peritonitis treatment mitigating cardiovascular risk.

Incidence and factors associated with geographical relocation in patients receiving renal replacement therapy.

BACKGROUND: Renal replacement therapy (RRT) places a burden on patients, and geographical relocation for easier access to healthcare facilities is a necessity for some. Incidence and factors associated with relocation has not been comprehensively examined at a national level. We aimed to determine proportion, incidence, characteristics of RRT patients who relocate and relocation rate by remoteness of residence and dialysis modality. METHODS: Retrospective cohort analysis using Australian and New Zealand Dialysis and Transplant Registry to examine RRT patients in Australia from January 2005 to December 2015. Relocation incidence was calculated for remoteness of residence and RRT modality as rate per 100 patient years. Factors associated with relocation were examined using competing risk regression models with death as a competing event. RESULTS: Of 24,676 incident patients on RRT, 5888 (23.9%) relocated with a median time of 1.6 years [IQR 0.7-3.4] years. Relocation incidence was 7.9 per 100 patient years and increased from major cities to very remote regions (7.2 to 48.8 per 100 patient years respectively, p < 0.001). Remoteness of residence was associated with geographical relocation in competing risk analysis especially in remote (SHR 1.20, 95%CI 1.01, 1.41 p = 0.034) and very remote regions (SHR 3.51 95% 3.05, 4.04 p < 0.001). Aboriginal or Torres Strait Islander ethnicity, compared to Caucasian, was independently associated with relocation (SHR 1.18, 95% CI 1.06,1.31, p = 0.002) while transplant patients were less likely to relocate compared to haemodialysis patients (HR 0.37, 95%CI 0.34, 0.39, p < 0.001). CONCLUSIONS: Relocation in patients receiving RRT is associated with remoteness of residence, RRT modality and ethnicity. Reasons for relocation and its impact on patient wellbeing and outcome should be further explored.

The Association between Biomarker Profiles, Etiology of Chronic Kidney Disease, and Mortality.

BACKGROUND: Prognosis in chronic kidney disease (CKD) for adverse outcomes differs substantially based on the etiology of CKD. We examined whether the biomarker profile differed based on CKD etiology and whether they were associated with mortality. METHODS: Prospective observational study of 1,157 patients, 663 with diabetic kidney disease (DKD), 273 with glomerulonephritis (GN), and 221 with cystic/interstitial disease (polycystic kidney disease, pyelonephritis or chronic tubulointerstitial nephritis [PCK/TIN]) were identified in the Canadian Study of Prediction of Dialysis, Death and Interim Cardiovascular events over Time cohort. The outcome of interest was mortality before commencing dialysis. The biomarker profile consisted of N-terminal pro-brain natriuretic peptide (NT-proBNP), troponin I (TnI), asymmetric dimethylarginine (ADMA), interleukin (IL)-6, high sensitivity C-reactive protein, fibroblast growth factor-23 (FGF23), transforming growth factor-beta, 25-hydroxylvitamin D, and cystatin C (CysC). RESULTS: The mean estimated glomerular filtration rate was 27 mL/min/1.73 m2 and median follow-up time was 44 months. Mortality before dialysis commencement was the greatest in DKD (20%), followed by PCK/TIN (13%), and was least in those GN (8%). The majority of deaths were cardiovascular in nature, 17, 9, and 5.5% for DKD, PCK/TIN, GN, respectively. Those with DKD had higher hazard for mortality, unadjusted (hazard ratio [HR] 2.7, 95% CI 1.7-4.3) and adjusted (HR 1.7, 95% CI 1.1-2.8). The biomarker profiles associated with mortality differed significantly by CKD etiology as follows: DKD was associated with CysC (HR 1.3, 95% CI 1.0-1.6), ADMA (HR 1.3, 95% CI 1.1-1.6), and NT-proBNP (HR 1.7, 95% CI 1.4-2.1), GN was associated with FGF23 (HR 1.8, 95% CI 1.1-2.8), TnI (HR 3.6, 95% CI 1.3-9.5), and transforming growth factor-beta (HR 0.6, 95% CI 0.4-0.9) and PCK/TIN was associated with ADMA (HR 1.5, 95% CI 1.3-1.8) and IL-6 (HR 2.1, 95% CI 1.5-3.1). CONCLUSIONS: Biomarkers profiles differ according to the etiology of CKD and are associated with mortality.

Infection in advanced chronic kidney disease leads to increased risk of cardiovascular events, end-stage kidney disease and mortality.

The risk of infection in advanced chronic kidney disease (CKD) and its subsequent impact on adverse outcomes are not well established. Therefore, we determined the association of an infectious episode with the subsequent risk of cardiovascular ischemia, congestive heart failure, end-stage kidney disease or mortality in a Canadian prospective cohort (CanPREDDICT) of patients with advanced CKD (eGFR: 15-45 ml/min/1.73m(2)) followed by nephrologists for up to 5 years. Infectious episodes were classified by anatomic location and identified by positive culture, hospital admission, or use of antibiotics. Competing risk models were used to examine the time-varying risk of infection and the risk of cardiovascular ischemia, congestive heart failure, or end-stage kidney disease accounting for the competing risk of mortality. All outcomes were independently adjudicated. Of 2370 patients (mean age, 68 years; mean baseline eGFR, 28.2 mL/min/1.73m(2)), 575 patients (24.3%) had recorded infections; 378 had 1 infection episode, whereas 197 had 2 or more episodes, the most common being urinary and respiratory. An infectious episode was independently associated with an increased risk of cardiovascular ischemia (hazard ratio 1.80, 95% confidence interval 1.24-2.60), congestive heart failure (hazard ratio, 3.2; confidence interval, 2.25-4.61), end-stage kidney disease (hazard ratio, 1.58; confidence interval, 1.22-2.05) or mortality (hazard ratio, 3.39; confidence interval, 2.65-4.33). Thus, there is a high risk of infection in advanced CKD being associated with subsequent adverse outcomes.

Efficacy and safety of gabapentin for uremic pruritus and restless legs syndrome in conservatively managed patients with chronic kidney disease.

CONTEXT: Pruritus and restless legs syndrome (RLS) frequently affect patients with chronic kidney disease (CKD) and end-stage kidney disease (ESKD), impacting the quality of life. Gabapentin (1-aminomethyl cyclohexane acetic acid) alleviates these symptoms in hemodialysis (HD) patients, but data are lacking for patients on the conservative pathway. OBJECTIVES: To determine the safety and effectiveness of gabapentin for pruritus or RLS in conservatively managed patients (n = 34) with CKD and ESKD. METHODS: This was a single-center retrospective cohort study. We compared dosing and side effects in 34 CKD/ESKD patients with similar patients receiving HD (n = 15). RESULTS: Forty-four percent of conservatively managed patients complained of RLS and/or pruritus; 18% were excluded for a nonuremic cause of symptom. Thirty-four patients were included in the final analysis. The most common starting daily dose of gabapentin was the equivalent of 50 mg (44.1%) or 100 mg (38.2%) daily, with the median daily dose of 100 mg (range 39-455 mg). Side effects occurred in 47% of patients, with 17% discontinuing gabapentin. Gabapentin reduced symptoms of pruritus (P < 0.001) and RLS (P < 0.05). There was no statistical difference when comparing HD and conservatively managed patients for daily starting dose (P = 0.88), median dose (P = 0.84), and final dose (P = 0.18). Patients conservatively managed were more likely to manifest side effects compared with HD patients (47.1% vs. 14.3%, P = 0.023). Dose was not found to be a factor associated with side effects in univariate analysis. CONCLUSION: Gabapentin is a viable treatment for conservatively managed CKD and ESKD patients with pruritus and/or RLS, but side effects are common. Gabapentin should be used with caution although higher doses do not appear to be a factor associated with side effects.