BMC Nephrology

Cystinuria is caused by the defective renal reabsorption of cystine and dibasic amino acids, and results in cystine stone formation. So far, mutations in two genes have been identified as causative. The SLC3A1/rBAT gene encodes the heavy subunit of the heterodimeric rBAT-b0,+AT transporter, whereas the light chain is encoded by the SLC7A9/ b0,+AT gene. In nearly 85% of patients mutations in both genes are detectable, but a significant number of patients currently remains without a molecular diagnosis. Thus, the existence of a further cystinuria gene had been suggested, and the recently identified AGT1/SLC7A13 represents the long-postulated partner of rBAT and third cystinuria candidate gene. We screened a cohort of 17 cystinuria patients for SLC7A13 variants which were negative for SLC3A1 and SLC7A9 mutations. Despite strong evidences for an involvement of SLC7A13 mutations in cystinuria, we could not confirm a relevant role of SLC7A13 for the disease. With the exclusion of SLC7A13/AGT1 as the third cystinuria gene accounting for the SLC3A1 and SLC7A9 mutation negative cases, it becomes obvious that other genetic factors should be responsible for the cystinuria phenotype in nearly 15% of patients.

Diabetic nephropathy (DN) is one of the most common and serious complications of diabetes, which can lead to renal failure and fatality. miRNAs are an important class of endogenous non-coding RNAs implicated in a wide range of biological processes and pathological conditions. This study aims to investigate the potential functional roles of miR-543 in DN and its underlying mechanisms. qRT-PCR was performed to detect the expression levels of miR-543 and TSPAN8 in kidney tissues of mice with DN. Western blot (WB) was used to measure the protein levels. CCK8 assay was employed to evaluate the proliferation of HK2 cells. Dual luciferase reporter assay was conducted to verify the functional interaction between miR-543 and TSpan8. The downregulation of miR-543 and upregulation of TSPAN8 were observed in kidney tissues of mice with DN. miR-543 mimic significantly decreased cell proliferation and autophagy in high-glucose (HG)-induced HK2 cells, and promoted cell fibrosis. We further identified a putative binding site between miR-543 and TSPAN8, which was validated by Dual luciferase reporter assay. The treatment of miR-543 mimic and miR-543 inhibitor could reduce or increase TSPAN8 protein level respectively. We further showed that the overexpression of TSPAN8 could attenuate HG-induced cell injury by reducing fibrosis and increase autophagy. The effects of miR-543 mimic in proliferation, fibrosis, and autophagy were rescued by TSPAN8 overexpression. Our study indicate that miR-543 mediates high-glucose induced DN via targeting TSPAN8. Interfering miR-543/TSPAN8 axis could serve as potential approach to ameliorate DN.

TGF-β is induced in the vasculature with aging suggesting that high plasma TGF-β levels may be a risk factor for chronic kidney disease (CKD) in older adults. We conducted a cross-sectional analysis of the association between plasma TGF-β levels and CKD including data for 1722 older adults who had participated in the 1996/97 visit of the Cardiovascular Health Study (CHS). Prevalent CKD was defined as eGFR < 60 mL/min/1.73 m2 or urinary albumin/creatinine ratio (ACR) ≥30 mg/g. We also evaluated whether baseline TGF-β levels predicted change in eGFR, cardiovascular (CV) events, or mortality in longitudinal analysis. Plasma TGF-β levels were significantly and independently associated with lower eGFR in cross-sectional analysis. Doubling of TGF-β was significantly associated with lower eGFR (β estimate after adjusting for CV risk factors = −1.18, 95% CI −2.03, −0.32). We observed no association with albuminuria. There was no association between baseline TGF-β and change in eGFR, but each doubling of TGF-β at baseline was associated with increased risk of a composite outcome of CV events and mortality, adjusted HR 1.10 (95% C.I. 1.02– 1.20, p = 0.006). In this large cohort of community-dwelling older individuals, high plasma TGF-β levels are modestly, but independently associated with lower eGFR but not with albuminuria in cross-sectional analysis. In addition, TGF-β levels are associated with increased risk of CV events and mortality. Further research is needed to determine the direction of association between plasma TGF-β and the risk of CKD and CKD-associated morbidities in older adults.

Health-Related Quality of Life (HRQoL) assessment after kidney transplantation has become an important tool in evaluating outcomes. This study aims to identify the associated factors with HRQoL among a representative sample size of Kidney Transplant Recipients (KTR) at the time of their inclusion in the study. Data of this cross-sectional design is retrieved from a longitudinal study conducted in five French kidney transplant centers in 2011, and included KTR aged 18 years with a functioning graft for at least 1 year. Measures include demographic, psycho-social and clinical characteristics. To evaluate HRQoL, the Short Form-36 Health Survey (SF-36) and a HRQoL instrument for KTR (ReTransQol) were administered. Multivariate linear regression models were performed. A total of 1424 patients were included, with 61.4% males, and a mean age of 55.7 years (±13.1). Demographic and clinical characteristics were associated with low HRQoL scores for both questionnaires. New variables were found in our study: perceived poor social support and being treated by antidepressants were associated with low scores of Quality of Life (QoL), while internet access was associated with high QoL scores. The originality of our study’s findings was that psycho-social variables, particularly KTR treated by antidepressants and having felt unmet needs for any social support, have a negative effect on their QoL. It may be useful to organize a psychological support specifically adapted for patients after kidney transplantation.

There are few studies assessing the quality of life of patients with chronic and end stage kidney disease in sub-Saharan Africa. We aimed to describe the health-related quality of life (HRQOL) of patients undergoing in-centre maintenance hemodialysis in Rwanda using the KDQOL™-36 and determine sociodemographic and clinical factors associated with their quality of life. We conducted a multicenter, cross-sectional study between September 2020 and July 2021. Patients over the age of 18 receiving maintenance in-centre hemodialysis for at least three months at the Rwandan tertiary hospitals were administered the KDQOL™-36 questionnaire to assess physical and mental health functioning, the effect, burden and symptoms and problem of kidney disease. Sociodemographic and clinical information was collected for all eligible patients. Using mixed effects linear regression models, we explored factors associated with overall KDQOL and its domains, while accounting for clustering of patients within hemodialysis centres. Eighty-nine eligible patients were included in the study. The majority of participants were younger than 60 years old (69.7%), male (66.3%), had comorbidities (91%), and 71.6% were categorized as level 3 on a 4 tier in-country poverty scale. All participants had health insurance coverage, with 67.4% bearing no out of pocket payments for hemodialysis. The median (IQR) quality of life score was 45.1 (29.4) for overall HRQOL, 35.0 (17.9) for PCS and 41.7 (17.7) for MCS. Symptoms and problem of kidney disease, effect of kidney disease, and burden of kidney disease scored 58.3 (43.8), 56.3 (18.8) and 18.8 (37.5), respectively. A notable difference of KDQOL scores between hemodialysis centres was observed. Overall KDQOL was associated with male sex (adjusted ß coefficient [aß]: 8.5, 95% confidence interval [CI]: 2.8, 14.3); being employed (aß: 8.2, 95% CI: 2.2, 14.3); dialysis vintage of 13–24 months (aß: 10.5, 95% CI: 3.6, 17.6), hemoglobin of 10-11 g/dl (aß: 7.3, 95% CI: 0.7, 13.7) and comorbidities (e.g., ≥ 3 comorbidities vs. none) (aß: -29.8, 95% CI: -41.5, -18.3). Patients on in-centre hemodialysis in Rwanda have reduced KDQOL scores, particularly in the burden of kidney disease and physical composite summary domains. Higher overall KDQOL mean score was associated with male sex, being employed, and dialysis vintage of 13–24 months, hemoglobin of 10-11 g/dl and absence of comorbidities. The majority of patients receiving in-centre hemodialysis have higher socioeconomic status reflecting the social and financial constraints to access and maintain dialysis in resource limited settings.

We developed machine learning models to understand the predictors of shorter-, intermediate-, and longer-term mortality among hemodialysis (HD) patients affected by COVID-19 in four countries in the Americas. We used data from adult HD patients treated at regional institutions of a global provider in Latin America (LatAm) and North America who contracted COVID-19 in 2020 before SARS-CoV-2 vaccines were available. Using 93 commonly captured variables, we developed machine learning models that predicted the likelihood of death overall, as well as during 0–14, 15–30, > 30 days after COVID-19 presentation and identified the importance of predictors. XGBoost models were built in parallel using the same programming with a 60%:20%:20% random split for training, validation, & testing data for the datasets from LatAm (Argentina, Columbia, Ecuador) and North America (United States) countries. Among HD patients with COVID-19, 28.8% (1,001/3,473) died in LatAm and 20.5% (4,426/21,624) died in North America. Mortality occurred earlier in LatAm versus North America; 15.0% and 7.3% of patients died within 0–14 days, 7.9% and 4.6% of patients died within 15–30 days, and 5.9% and 8.6% of patients died > 30 days after COVID-19 presentation, respectively. Area under curve ranged from 0.73 to 0.83 across prediction models in both regions. Top predictors of death after COVID-19 consistently included older age, longer vintage, markers of poor nutrition and more inflammation in both regions at all timepoints. Unique patient attributes (higher BMI, male sex) were top predictors of mortality during 0–14 and 15–30 days after COVID-19, yet not mortality > 30 days after presentation. Findings showed distinct profiles of mortality in COVID-19 in LatAm and North America throughout 2020. Mortality rate was higher within 0–14 and 15–30 days after COVID-19 in LatAm, while mortality rate was higher in North America > 30 days after presentation. Nonetheless, a remarkable proportion of HD patients died > 30 days after COVID-19 presentation in both regions. We were able to develop a series of suitable prognostic prediction models and establish the top predictors of death in COVID-19 during shorter-, intermediate-, and longer-term follow up periods.

The Clinical Frailty Scale (CFS) is a commonly utilised frailty screening tool that has been associated with hospitalisation and mortality in haemodialysis recipients, but is subject to heterogenous methodologies including subjective clinician opinion. The aims of this study were to (i) examine the accuracy of a subjective, multidisciplinary assessment of CFS at haemodialysis Quality Assurance (QA) meetings (CFS-MDT), compared with a standard CFS score via clinical interview, and (ii) ascertain the associations of these scores with hospitalisation and mortality. We performed a prospective cohort study of prevalent haemodialysis recipients linked to national datasets for outcomes including mortality and hospitalisation. Frailty was assessed using the CFS after structured clinical interview. The CFS-MDT was derived from consensus at haemodialysis QA meetings, involving dialysis nurses, dietitians, and nephrologists. 453 participants were followed-up for a median of 685 days (IQR 544–812), during which there were 96 (21.2%) deaths and 1136 hospitalisations shared between 327 (72.1%) participants. Frailty was identified in 246 (54.3%) participants via CFS, but only 120 (26.5%) via CFS-MDT. There was weak correlation (Spearman Rho 0.485, P < 0.001) on raw frailty scores and minimal agreement (Cohen’s κ = 0.274, P < 0.001) on categorisation of frail, vulnerable and robust between the CFS and CFS-MDT. Increasing frailty was associated with higher rates of hospitalisation for the CFS (IRR 1.26, 95% C.I. 1.17–1.36, P = 0.016) and CFS-MDT (IRR 1.10, 1.02–1.19, P = 0.02), but only the CFS-MDT was associated with nights spent in hospital (IRR 1.22, 95% C.I. 1.08–1.38, P = 0.001). Both scores were associated with mortality (CFS HR 1.31, 95% C.I. 1.09–1.57, P = 0.004; CFS-MDT HR 1.36, 95% C.I. 1.16–1.59, P < 0.001). Assessment of CFS is deeply affected by the underlying methodology, with the potential to profoundly affect decision-making. The CFS-MDT appears to be a weak alternative to conventional CFS. Standardisation of CFS use is of paramount importance in clinical and research practice in haemodialysis. Clinicaltrials.gov : NCT03071107 registered 06/03/2017.

Cardiovascular (CV) complications are the main cause of death in end-stage renal disease (ESRD) patients. The high CV risks are attributable to the additive effects of multiple factors. Endothelin (EDN) is a potent vasoconstrictor and plays a role in regulating vascular homeostasis. However, whether variants of the EDN gene are associated with risks of CV events is not known. We conducted a study to investigate associations of variants of the EDN gene with CV events in ESRD patients. A cohort of 190 ESRD patients was recruited, and 19 tagged single-nucleotide polymorphisms within the EDN gene family were selected for genotyping through a TaqMan assay. Data on clinical characteristics and hospitalizations for CV events were collected. Associations of genetic variants of the EDN gene with CV events were analyzed. In this cohort, 62% (n = 118) of patients were hospitalized for a CV event. The EDN1 rs4714384 (CC/TC vs. TT) polymorphism was associated with an increased risk of a CV event after multiple testing (p < 0.001). Further functional exploration showed that it was a quantitative trait locus which may significantly alter gene expression in the tibial artery. EDN1 rs4714384 is very likely an important biomarker of CV events in ESRD patients.