Clinical Kidney Journal最新文献

Background: Frameshift variants in the variable number tandem repeat region of mucin-1 (MUC1) cause autosomal dominant tubulointerstitial kidney disease (ADTKD-MUC1) but are challenging to detect. We investigated the prevalence in patients with kidney failure of undetermined aetiology and compared Danish families with ADTKD-MUC1.

Methods: We recruited patients with suspected kidney failure of undetermined aetiology at ≤50 years and excluded those with a clear-cut clinical or histopathological kidney diagnoses or established genetic kidney diseases identified thorough medical record review. MUC1 genotyping was performed by SNaPshot analysis, detecting the most common pathogenic cytosine duplication, followed by bioinformatics pipeline VNtyper analysis of short-read sequencing data.

Results: Of 172 recruited patients, 123 underwent SNaPshot analyses, which were abnormal in 5/123 patients (4%). Next, VNtyper genotyping was performed in all patients, including the five with abnormal SNaPshot analysis. VNtyper re-identified the common cytosine duplication in all five patients and revealed novel frameshift variants in two additional patients, while the analyses were normal in the remaining 116 patients. All patients carrying frameshift variants in MUC1 fulfilled ADTKD criteria and had a family history of kidney failure. A considerable inter- and intrafamilial variability of chronic kidney disease stage relative to age was observed in families with ADTKD-MUC1.

Conclusions: ADTKD-MUC1 was identified in 7/123 patients (6%) in a selected cohort of kidney failure of undetermined aetiology ≤50 years, and VNtyper effectively identified all pathogenic MUC1 variants.

Background: Amino acid (AA) depletion during dialysis deteriorates the protein-energy status of haemodialysis (HD) patients. This study aimed to determine whether intradialytic amino acid (IDAA) replacement by continuous infusion versus acute load could provide better nutritional outcomes.

Methods: HD patients with mild protein-energy wasting, defined as a serum albumin level of 3.5-3.9 mg/dl despite 7-point subjective global assessment in category A or a malnutrition inflammation score ≤5, were randomly assigned to receive IDAA by continuous infusion or acute load for 3 months. In continuous infusion (n = 24), 50% glucose followed by 7.2% branched-chain enriched AA solution were instilled in the first 15 minutes after HD initiation with high-flux dialyser through the end of the session. Similar parenteral nutrition compositions containing the same total amount of glucose and AA were rapidly added into the venous drip chamber within the last hour of HD in the acute load group (n = 24). The primary outcome was the change in serum albumin level. Secondary outcomes were changes in muscle parameters and plasma as well as dialysate AA concentrations.

Results: The mean age of patients was 68.9 ± 12.7 years and the average body mass index was 22.8 ± 4.4 kg/m² with 45.8% being men. After 3 months, serum albumin levels were significantly elevated in continuous infusion (P = .001) whereas it was unchanged in the acute load (P = .13). Despite comparable energy and protein intake, total body muscle mass was also increased in the continuous infusion group at 3 months (P = .03) compared with no significant change in the acute load group (P = .45). The amount of AA loss into the dialysate was similar between the two groups (P = .17). At post-dialysis, most plasma essential and non-essential AA levels were significantly lower in patients receiving continuous infusion than acute load, while branched-chain AA concentrations including leucine (P = .61) and valine (P = .09) were comparable between the two groups. Despite enhancing muscle mass in continuous infusion, handgrip strength and gait speed were unaltered in both techniques of IDAA replacement.

Conclusions: IDAA using continuous infusion appears to be superior to acute load in terms of serum albumin and muscle mass improvement. The impact of IDAA on hard clinical outcomes may require larger scale with a longer period of study (TCTR20230401003).

Background: Peripheral arterial disease (PAD) occurs frequently in patients undergoing dialysis, but early intervention for PAD may not be fully implemented. We evaluated the effects of financially incentivising dialysis facilities that provided early detection and management of PAD on outcomes of PAD care.

Methods: This retrospective cohort study identified patients aged 18-74 years who received maintenance haemodialysis between April 2016 and March 2021 from the JMDC Claims Database. The (time-dependent) exposure was claim for incentives for early detection and management of PAD. The outcomes were PAD screening tests (process indicator) and infections, revascularisation procedures, and amputations in the lower extremities (outcome indicators). We used Poisson regression models with generalised estimation equations for the number of screening tests and Cox proportional hazards models for the first incidence of the outcome indicator.

Results: Overall, 5850 patients on haemodialysis were identified: 5183 and 667 with and without claims for the incentive, respectively; the numbers of screening tests were 9070 and 776, respectively (adjusted ratio of the frequency, 1.89 [95% confidence interval 1.70-2.10]). Among patients with and without claims for the incentive, infections occurred in 479 and 109 (adjusted hazard ratio [HR], 0.99 [0.80-1.23]), revascularisations were performed in 192 and 29 (adjusted HR, 1.11 [0.75-1.66]), and amputations were conducted in 72 and 9 patients, respectively (adjusted HR, 1.35 [0.66-2.75]).

Conclusion: The financial incentive for early detection and management of PAD was associated with a higher frequency of PAD screening tests, but not with improved outcome indicators.

Background: Arteriovenous fistulas (AVFs) in kidney transplant recipients are sometimes closed, either as a policy or due to complications. We collected data on the incidence of complications after AVF closure in a national cohort of transplanted patients.

Methods: Patients who received a kidney transplant between 2000 and 2015 and had a functional AVF that was later ligated or extirpated were included. Medical records were searched for arterial complications on the arm with the closed AVF. Furthermore, all patients who were still alive in January 2023 were invited for a follow-up arterial ultrasound exam.

Results: Sixty patients were included; mean follow-up was 9.3 ± 3.8 years. There were five (8% cumulative incidence) patients with symptomatic arterial thrombosis and three (5% incidence) with a symptomatic feeding artery aneurysm. Prospective ultrasound exams were performed in 50 patients; the mean diameter of the brachial artery was almost doubled on the arm with the closed AVF (8.1 ± 3.2 versus 4.7 ± 0.7 mm; P < .001). Additional asymptomatic complications were found in nine patients (18% incidence): seven cases (14% incidence) of arterial thrombosis, some extending up to the axillary artery, and three (6% incidence) brachial artery aneurysms. All patients in whom the thrombosis spread to the brachial artery had large brachial arteries (>10 mm) or an aneurysm.

Conclusion: We observed a high cumulative incidence of arterial thrombosis (20%) and brachial artery aneurysms (10%), sometimes developing several years after AVF closure. These complications should be taken into account when contemplating closure of a well-developed AVF and an AVF-preserving approach with flow reduction surgery might be preferred in some cases.

Background: Patients with kidney failure on maintenance dialysis have a high stroke and bleeding risk. Multivariable prediction models can be used to estimate the risk of ischemic stroke and bleeding. A systematic review and meta-analysis was performed to determine the performance of the existing models in patients on dialysis.

Methods: MEDLINE and Embase databases were searched, from inception through 12 January 2024, for studies of prediction models for stroke or bleeding, derived or validated in dialysis cohorts. Discrimination measures for models with c-statistic data from three or more cohorts were pooled by random effects meta-analysis and a 95% prediction interval (PI) was calculated. Risk of bias was assessed using PROBAST. The review was conducted according to the PRISMA statement and the CHARMS checklist.

Results: Eight studies were included in this systematic review. All the included studies validated pre-existing models that were derived in cohorts from the general population. None of the identified studies reported the development of a new dialysis specific prediction model for stroke, while dialysis specific risk scores for bleeding were proposed by two studies. In meta-analysis of c-statistics, the CHA₂DS₂-VASc, CHADS₂, ATRIA, HEMORR(2)HAGES and HAS-BLED scores showed very poor discriminative ability in the dialysis population. Six of the eight included studies were at low or unclear risk of bias and certainty of evidence was moderate.

Conclusions: The existing prediction models for stroke and bleeding have very poor performance in the dialysis population. New dialysis-specific risk scores should be developed to guide clinical decision making in these patients.

Chimeric antigen receptor T (CAR-T) cell therapy, an emerging personalized immunotherapy for various haematologic malignancies, autoimmune diseases and other conditions, involves the modification of patients' T cells to express a chimeric antigen receptor that recognizes tumour or autoimmune cell antigens, allowing CAR-T cells to destroy cancerous and other target cells selectively. Despite remarkable clinical improvements in patients, multiple adverse effects have been associated with CAR-T cell therapy. Among the most recognized adverse effects are cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome and tumour lysis syndrome. Even though less recognized, the incidence of acute kidney injury (AKI) ranges from 5 to 33%. The wide range of reported AKI incidence rates might depend on patient population characteristics and comorbidities and specific CAR-T cell therapy features. Even though the exact pathophysiology remains unknown, several key mechanisms, including cytokine release syndrome, tumour lysis syndrome and other factors such as direct renal toxicity of CAR-T cell therapy, conditioning regimens or other medications (e.g. antibiotics), and infectious complications (e.g. sepsis) have been proposed. Risk factors for CAR-T-related AKI include lower baseline glomerular filtration rate, higher rates of allopurinol or rasburicase use, intravenous contrast material exposure, elevated baseline lactate dehydrogenase and grade 3 or higher cytokine release syndrome. Future prospective studies with larger patient populations are needed to gain insights into the pathophysiology of CAR-T-related AKI and, more importantly, to be able to prevent as well as to develop novel and more efficient treatment modalities. In this narrative review, we discuss the underlying pathophysiology, risk factors, potential interventions and future directions related to AKI following CAR-T cell therapy.

Background: Prior nonrandomized studies have suggested nephroprotective effects of arteriovenous fistula (AVF) formation, but these are plausibly susceptible to immortal time and selection biases.

Methods: We studied patients attending nephrology clinics in the West of Scotland during 2010-22 with an estimated glomerular filtration rate (eGFR) ≤15 mL/min/1.73 m² and no prior AVF. Using target trial emulation and a sequential trial design, we simulated a hypothetical trial that would randomize patients to either undergo AVF formation immediately or not to undergo AVF formation. The primary outcome was the difference in eGFR slope for the first 6 months of follow-up, estimated using a mixed-effects model. The secondary outcomes were 5-year absolute risks of dialysis and death, estimated using the Aalen-Johansen and Kaplan-Meier estimators respectively.

Results: A total of 1364 unique patients (mean age 51.1 years, 55.7% male) contributed 3125 person-trials, with 561 in the AVF and 2564 in the no AVF group. Mean eGFR was 12.6 mL/min/1.73 m² and the median number of eGFR measurements per person-trial was 7 (interquartile range 4-12). Slope of eGFR decline did not differ significantly between the AVF and no AVF groups (between-group difference -0.67 mL/min/1.73 m²/year, 95% CI -1.43, 0.10). The 5-year absolute risk of dialysis was 87% (95% CI 84, 91) in the AVF group and 75% (95% CI 73, 77) in the no AVF group, and the 5-year survival probability was 77% (95% CI 70, 83) in the AVF group and 67% (95% CI 64, 69) in the no AVF group.

Conclusions: In this study of patients with advanced chronic kidney disease, there was no evidence of a nephroprotective effect of AVF formation.

Background: Ageing often affects biomarker production. Yet, clinical/optimal thresholds to guide clinical decisions do not consider this. Serum albumin decreases with age, but hypoalbuminaemia is defined as serum albumin <4.0 g/dl. This study explores whether age might affect serum albumin levels and its association with mortality in haemodialysis patients.

Methods: COSMOS (Current Management of Secondary Hyperparathyroidism: a Multicentre Observational Study) is a prospective, open-cohort, observational study of haemodialysis patients followed for 3 years. Binary logistic and linear regression were used to analyse the association between age and hypoalbuminaemia or serum albumin (continuous). Cox proportional hazard multivariate regression was used to examine the relationship between hypoalbuminaemia and mortality in patients younger and older than 65 years. Time-dependent receiver operating characteristic (ROC) curves were used to assess the discriminatory ability of serum albumin and optimal thresholds for predicting mortality.

Results: The present analysis included 5585 patients. The odds of experiencing hypoalbuminaemia increased with age [adjusted odds ratios = 1.56(95%CI: 1.31-1.86), 1.89(95%CI: 1.59-2.24), 2.68(95%CI: 2.22-3.23) for 56-65, 66-75, and >75 years, respectively (reference ≤55 years; P value for trend: <0.001)]. Survival analysis showed that the association between hypoalbuminaemia and mortality was weaker in patients aged ≥65 compared to <65 years [hazard ratios: 1.36(95%CI: 1.17-1.57) and 1.81(95%CI:1.42-2.31) respectively; P value for interaction 0.004]. The ability of albumin levels to predict mortality was consistently higher in younger patients. Optimal albumin thresholds for predicting mortality were 3.7 g/dl in patients younger than 65 years and 3.5 g/dl in patients 65 years and older.

Conclusions: Ageing is accompanied by lower albumin levels, and the association between hypoalbuminaemia and mortality may be modified by age. Different clinical thresholds that consider age may better discriminate risks associated with hypoalbuminaemia.

Background: The serum calcification propensity test (or T50 test) might become a standard tool for the assessment of vascular calcification risk and T50 might be a valuable biomarker in clinical trials of treatments intended to slow the progression of vascular calcification. Literature data suggest that non-calcium-containing phosphate binders can influence T50 in chronic dialysed patients. However, it is not clear whether similar interventions are effective in patients at earlier stages of chronic kidney disease (CKD).

Methods: The FGF23 Reduction: Efficacy of a New phosphate binder in CHronic kidney disease (FRENCH) trial was a multicentre, double-blind, placebo-controlled, randomized trial of sevelamer carbonate in participants with stage 3b/4 CKD. In this subanalysis of the FRENCH data, T50 and other laboratory variables (including fetuin-A and ionized and total magnesium) were measured centrally at baseline and after 12 weeks of treatment.

Results: A total of 96 patients were screened and 78 (55 men and 23 women) met the inclusion criteria and were randomized to receive placebo (n = 39) or sevelamer carbonate (n = 39). The median patient age was 66 years [interquartile range (IQR) 56-72], the median eGFR was 25 ml/min/1.73 m² (IQR 21-30) and the mean T50 was 335 minutes (standard deviation 82). In a linear regression model, T50 was independently associated with serum ionized magnesium, fetuin-A and bicarbonate levels and inversely associated with phosphate concentration. The within-group changes in the mean T50 between week 0 and week 12 were not significant in the sevelamer group or the placebo group {4.6 minutes [95% confidence interval (CI) -13.6-22.8; P = .61] and 7.8 minutes [95% CI -16.4-32.1; P = .51], respectively}. Furthermore, we did not observe significant changes in fetuin-A and magnesium levels.

Conclusion: A 12-week course of the non-calcium-containing phosphate binder sevelamer carbonate was not associated with a significant change in T50 in patients with stage 3b/4 CKD. Phosphate binders might not be an effective strategy for modifying serum calcification propensity in non-dialysis-dependent patients with CKD.

Background: The symptoms, comorbidities and treatment burden associated with chronic kidney disease (CKD) can be debilitating and limit life participation in patients with CKD not requiring kidney replacement therapy (KRT). The aim of this study was to identify the characteristics, content and psychometric properties of patient-reported outcome measures (PROMs) used to assess life participation in patients with CKD.

Methods: We searched MEDLINE, Embase, PsycINFO and CINAHL from database inception to February 2023 for all studies that reported life participation in patients with CKD (stages 1-5 not requiring kidney replacement therapy). We analysed the characteristics, dimensions of life participation and psychometric properties of the measures.

Results: From the 114 studies included, 20 (18%) were randomized trials, 3 (3%) were non-randomized trials and 91 (80%) were observational studies. Forty-one different measures were used to assess life participation, of which six (15%) were author-developed measures. Twelve (29%) measures assessed life participation specifically, while 29 (71%) measures assessed broader constructs such as quality of life, which included questions relevant to life participation. The 36-Item Short Form Health Survey (SF-36) and Kidney Disease Quality of Life Short Form (KDQOL-SF) were the most frequently used, in 39 (34%) and 24 (21%) studies, respectively. Many content domains for life participation were assessed, including physical activities (walking, running and sports), social activities, leisure activities, work or study and self-care. None of the measures for life participation were developed specifically for CKD. Four measures (EuroQol 5-dimension 3-level (EQ-5D-3L), Functional Assessment of Cancer Therapy - Anemia, Short Form 6-dimension and Short-From 36-dimension (SF-36)) had validation data collected in patients with CKD.

Conclusion: The measures for life participation used in patients with CKD vary in content, with few validated in the CKD population. There is a need for a validated measure to assess life participation in a meaningful and consistent way in all patients with CKD worldwide.