Kidney360最新文献

Systemic lupus erythematosus is a chronic multisystem autoimmune disease that affects the kidneys in approximately 50% of patients, with prevalence rising to as high as 70% in certain populations, such as African Americans and Asians. Antimalarials -and particularly hydroxychloroquine- are currently considered a mainstay of therapy, together with immunosuppressants. Over the last decades, several studies have extensively investigated the mechanisms of action of antimalarial agents, and their potential beneficial properties in patients with SLE in general. However, the evidence for the therapeutic benefit of hydroxychloroquine in patients with lupus nephritis (LN) derives mainly from observational studies, conducted in an era prior to the refinement of induction and maintenance protocols for immunosuppressive therapy. Despite the paucity of high-quality evidence on its efficacy in LN, the nephrology community widely supports the universal use of hydroxychloroquine in LN patients, and recommendations for its use are firmly entrenched in various clinical practice guidelines. Nonetheless, the use of antimalarials may also carry inherent risks, underscoring the importance of personalized approaches in these patients. Herein, we comprehensively review the available literature on antimalarials in LN aiming to update the current evidence, limitations, and future perspectives for the use of antimalarials in adults.

Background: Maturational failure of dialysis arteriovenous fistulas (AVFs) not uncommonly occurs and is of considerable and timely importance. Our prior studies demonstrate that senescence, a phenotypic process that promotes vascular and other diseases, occurs in the murine AVF. In the present study, we examined whether senescence also occurs in the rat AVF model and the effect of compounds that inhibit or accelerate senescence.

Methods: The rat AVF was created in the femoral vessels by an end vein-side artery anastomosis. We assessed in the AVF the expression of critical drivers of senescence, specifically, the cell cycle inhibitors p16Ink4a and p21Cip1, and such indices of a senescence phenotype as senescence-associated β-galactosidase (SA-β-gal) activity, SA-β-gal staining, and a senescence-associated secretory phenotype (SASP). We examined the effects of compounds that retard or accelerate senescence on AVF blood flow.

Results: The AVF evinced upregulation of p16Ink4a and p21Cip1 when assessed 3 days after AVF creation. The AVF also demonstrated increased SA-β-gal activity in the artery and vein; staining for SA-β-gal in the AVF artery, anastomosis, and vein; and a prominent SASP. Fisetin, an established senolytic that is protective in other models of vascular injury, when administered for 3 weeks, increased AVF blood flow and outward remodeling. Hemin, when administered for 3 weeks, decreased AVF blood flow. We demonstrate that hemin is a novel inducer of a senescence phenotype in endothelial cells, as reflected by several senescence indices. However, when administered relatively acutely (for 5 days) hemin increased AVF blood flow via HO-dependent mechanisms, as the latter was entirely prevented by a competitive inhibitor of HO activity.

Conclusions: The rat AVF exhibits senescence within 3 days of its creation. Chronic administration of a senolytic compound (fisetin) increases AVF blood flow, whereas chronic administration of a pro-senescence compound (hemin) decreases AVF blood flow.

Background: The lack of a recognized risk evaluation for Contrast-associated acute kidney injury (CA-AKI) after contrast-enhanced computed tomography (CECT) makes it challenging to counsel patients before the procedure. This study aims to identify the incidence of CA-AKI post CECT, assess the associated risk factors, develop and validate a predictive score.

Methods: All adult patients who underwent CECT in 2018 to 2022 were included in the training cohort while those in 2023 formed the external validation cohort. Exclusions applied to patients with CKD stage 5, recent dialysis, or incomplete data. Multiple logistic regression was employed to identify risk factors. The area under the receiver operating characteristic curve (AUROC) was used to evaluate both internal and external validation.

Results: From 21,878 enrolled patients, 6,042 and 2,463 met the inclusion criteria for the training and validation cohorts with a mean eGFR of 86.0 (26.4) and 81.4 (27.6) mL/min/1.73 m2, respectively. In the training cohort, 492 patients (8.1%) developed CA-AKI, and 49 (0.8%) required dialysis. Independent risk factors for CA-AKI included male gender, clinical setting, hemoglobin levels of <10 g/dL, and baseline eGFR less than 90 mL/min/1.73 m2. The model, using a weighted integer score derived from these factors, exhibited an AUROC of 0.715 (95% CI: 0.692-0.743) in the training cohort and 0.706 (95% CI: 0.663-0.748) in the validation cohort.

Conclusions: CECT can lead to CA-AKI in specific populations. The Pre-CT AKI risk score for CA-AKI following CECT demonstrated good discriminative power and can be easily applied in clinical practice.

Background: Renal glucosuria is a rare inheritable trait caused by loss-of-function variants in the gene that encodes SGLT2 (i.e., SLC5A2). The genetics of renal glucosuria is poorly understood and even less is known on how loss-of-function variants in SLC5A2 may affect response to SGLT2 inhibitors, a new class of medication gaining popularity to treat diabetes by artificially inducing glucosuria.

Methods: We used two biobanks that link genomic with electronic health record data to study the genetics of renal glucosuria. This included 245,394 participants enrolled in the All of Us (AoU) Research Program and 11,011 enrolled in Marshfield Clinic's Personalized Research Project (PMRP). Association studies in AoU and PMRP identified 10 variants that reached an experiment-wise Bonferroni threshold in either cohort, nine were novel. PMRP was further used as a recruitment source for a prospective SGLT2 pharmacogenetic trial. During a glucose tolerance test, the trial measured urine glucose concentrations in 15 SLC5A2 variant-positive individuals and 15 matched wild types with and without an SGLT2 inhibitor.

Results: This trial demonstrated that carriers of SLC5A2 risk variants may be more sensitive to SGLT2 inhibitors compared to wild types (P=0.075). Based on population data, 2% of an ethnically diverse population carry rare variants in SLC5A2 and are at risk for renal glucosuria.

Conclusions: As a result, 2% of individuals being treated with SGLT2 inhibitors may respond differently to this new class of medication compared to the general population suggesting a larger investigation into SLC5A2 variants and SGLT2 inhibitors is needed.

Background: Currently there are limited methods to link disease severity and risk of disease progression in Chronic Kidney Disease (CKD). To better understand this potential relationship, we interrogated the renal transcriptomic profile of individuals with CKD with measures of CKD severity and identified FERM-domain containing protein 3 (FRMD3) as a candidate gene for follow-up study.

Methods: RNA-seq was used to profile the transcriptome of CKD biopsies from the North Dublin Renal BioBank the results of which were correlated with clinical parameters. The potential function of FRMD3 was explored by interrogating the FRMD3 interactome and assessing the impact of lentiviral mediated FRMD3 knock down on human renal proximal tubule epithelial cells by assessing cell viability, metabolic activity, and structural markers.

Results: We identified a subset of 93 genes which are significantly correlated with estimated glomerular filtration rate and percentage tubulointerstitial fibrosis at time of biopsy and with CKD progression 5 years post-biopsy. These results were validated against transcriptomic data from an external cohort of 432 nephrectomy samples. One of the top-ranking genes from this subset, FRMD3, has previously been associated with the risk of developing diabetic kidney disease. Interrogating the interactome of FRMD3 in tubule epithelial cells revealed interactions with cytoskeletal components of cell-cell junctions. Knockdown of FRMD3 expression in tubule epithelial cells resulted in increased pro-apoptotic activity within the cells as well as dysregulation of E-Cadherin.

Conclusions: We have identified a panel of kidney-specific transcripts correlated with severity and progression of kidney disease, and from this have identified a possible role for FRMD3 in tubule cell structure and health.

Background: Pruritus is common in dialysis patients and associated with impaired health-related quality of life (HRQoL) and sleep disturbances. Its pathophysiology remains unclear resulting in limited treatment options and lack of treatment guidelines. The exact trajectory of pruritus after dialysis initiation nor the state of current medical treatment has been studied.

Methods: Incident dialysis patients (n=1438), included in the Dutch nOcturnal and hoME dialysis Study To Improve Clinical Outcomes (DOMESTICO), were studied. Outcome parameters were prevalence of pruritus, severity of pruritus and the use of antipruritic medication, repeatedly measured during the first year of dialysis. Associations between treatment, pruritus and quality of life were longitudinally studied using linear mixed models.

Results: The prevalence of pruritus ranged from 50.5% to 56.6% during the first year of dialysis. Throughout the year approximately 35% experienced persistent pruritus and 40% fluctuating pruritus. During follow-up 21.5% to 26.5% received medical treatment for pruritus. Emollients were associated with more severe pruritus (adjusted β = 0.31, 95% CI 0.15; 0.48), the remaining treatments did not show any association. Pruritus was significantly associated with lower physical and mental HRQoL (adjusted β = -2.04, 95% CI -2.78; -1.30 and β = -1.73, 95% CI -2.51; -0.94, respectively), irrespective of treatment.

Conclusions: During the first year of dialysis, pruritus is highly prevalent, predominantly fluctuating, and associated with impaired HRQoL. The minority of patients received medical treatment; in our study current treatment was not associated with an improvement of pruritus. These results highlight the need for more awareness among clinicians and for the development of effective treatment options.

Background: Hyperphosphatemia is associated with poor outcome and is still very common in peritoneal dialysis (PD) patients. Since peritoneal phosphate clearance is closer to peritoneal creatinine clearance than urea clearance, we hypothesized that weekly creatinine clearance (CrCl) could be a better marker of serum phosphate in PD.

Methods: In a retrospective observational study, data from adult PD patients were collected across five institutions in North and South America: LATAM, RRI, Mount Sinai Hospital, Hospital Civil de Guadalajara, and the BRAZPD cohort. All centers analyzed routinely available laboratory data, with exclusions for missing data on serum phosphate, CrCl, or urea Kt/V. A unified statistical protocol was employed across centers. Linear mixed-effect models examined associations between longitudinal serum phosphate levels, CrCl, and Kt/V. Adjustments were made for age, gender, and baseline phosphate binder usage. Mixed-effects meta-analysis determined the pooled effect size of CrCl and Kt/V on serum phosphate trajectories, adjusted for confounders.

Results: There were 16,796 incident PD patients analyzed. Age, BMI, gender, PD modality, Kt/V and CrCl as well as serum phosphate varied significantly across the different cohorts, but >70% had residual renal function. For most cohorts, both CrCltotal and urea Kt/V associated negatively with serum phosphorus levels, and log-likelihood ratio tests demonstrate that models including CrCltotal have more predictive information than those including only urea Kt/V for the largest cohorts. Models including CrCltotal increase information predicting longitudinal serum phosphate levels irrespective of baseline urea Kt/V, age, use of phosphorus binder, and gender.

Conclusions: CrCl was not more accurate in predicting serum phosphate than urea Kt/V, but its inclusion in multivariable models predicting serum phosphate added accuracy. In conclusion, both creatinine clearance and Kt/V are associated with phosphate levels, and using both biomarkers, instead of just one, may better assist in the optimization of serum phosphate levels.

Background: Preservation of residual kidney function (RKF) in dialysis patients has been associated with improved survival. RKF in the BISTRO trial was relatively well preserved and here we describe its association with survival during the trial and extended follow-up.

Methods: RKF, measured as the average urea and creatinine clearance (GFR) or 24-hour urine volume was assessed at baseline, one, two and three months and three-monthly up to 2 years in incident haemodialysis patients. Time to event survival data or competing events (transplantation, modality change) were obtained for 50 months post enrolment via data linkage with the UK Renal Registry. Cox proportional hazards regression survival models, including those incorporating change in GFR from baseline as a time-varying variable and joint regression models for longitudinal and survival data (longitudinal models for GFR or urine volume) were used to explore the relationship of RKF preservation with survival. Analyses were adjusted for age, sex, comorbidity and ethnicity.

Results: 2919 measures of RKF were made in 387 patients from 32 UK dialysis units. Higher age and comorbidity score associated with increased mortality in all models. Baseline GFR reduced the risk of death (Hazard Ratio: 0.918 95%CI: 0.844, 0.999) per ml/min/1.73m2. A greater fall in GFR and urine volume from baseline was associated with a non-significant increased risk of death as visualised on spline plots. In the joint survival models higher GFR (adjusted HR: 0.88 95%CI 0.80, 0.97) or urine volume (adjusted HR: 0.75 95%CI 0.57, 0.95 per L) at any time point associated with better survival.

Conclusions: Lower RKF during the first two years of haemodialysis is associated with an increased death risk for up to 50 months following dialysis initiation. This adds to a growing body of evidence that interventions to preserve RKF should be developed and tested in clinical trials.

Background: Immunoglobulin A nephropathy (IgAN), an immune-mediated kidney disease, is particularly prevalent among individuals of East Asian ancestry. Nefecon is a novel, oral, targeted-release budesonide formulation designed to inhibit galactose-deficient-IgA1 formation underlying IgAN pathophysiology. We present findings in patients with IgAN from mainland China participating in the 2-year, multicenter, randomized, double-blind, phase 3 NefIgArd trial of Nefecon.

Methods: Patients (aged ≥18 years) with primary IgAN (estimated glomerular filtration rate [eGFR] 35-90 ml/min per 1.73 m2, persistent proteinuria [urine protein-creatinine ratio ≥0.8 g/g or proteinuria ≥1 g/24 h] despite optimized renin-angiotensin system blockade) received Nefecon or placebo over 9 months, followed by a 15-month follow-up phase on supportive care alone. The primary efficacy end point was time-weighted average of eGFR over 2 years.

Results: Sixty-two patients from mainland China were included in this prespecified analysis. The primary efficacy end point was 9.6 ml/min per 1.73 m2 (95% confidence interval [CI], 2.0 to 19.8) in favor of Nefecon versus placebo. This was consistent with (and numerically greater than) that of the global study population. Time to confirmed 30% eGFR reduction or kidney failure from baseline was substantially delayed with Nefecon (patients with an event: 9%) versus placebo (30%; hazard ratio, 0.21; 95% CI, 0.04 to 0.73]). No deaths were reported in the China cohort. In the Nefecon group, treatment-emergent serious adverse events were reported by one patient during treatment and two patients during follow-up (versus no patients and seven patients, respectively, in the placebo group). No severe infections requiring hospitalization were reported.

Conclusions: Nefecon treatment for 9 months showed greater preservation of eGFR over 2 years compared with placebo. The efficacy outcomes were consistent with global study results, with a numerically greater treatment benefit observed in patients from China. Nefecon was well tolerated, with no unexpected safety signals.