Nephrology Dialysis Transplantation最新文献

Inhibitors of the sodium-glucose cotransporter 2 (SGLT2i) were originally developed to treat diabetes mellitus but have shown important renoprotective benefits independently from blood glucose levels. SGLT2i have thus become an important addition to the therapeutic armamentarium to treat patients with chronic kidney disease. However, specific patient populations were excluded from the pivotal trials, for instance patients with very low eGFR, patients on dialysis, kidney transplant recipients and patients with autosomal dominant polycystic kidney disease (ADPKD), the most common genetic kidney disorder. Considering the lack of potent treatment modalities in ADPKD, the use of SGLT2i in this patient population would be of major interest. However, the combination of inconclusive results from preclinical models with the lack of clinical efficacy data and potential disease-specific safety concerns currently exclude patients with ADPKD from this promising therapeutic opportunity. This results in an urgent need for adequately powered clinical trials examining SGLT2i in ADPKD. This review summarizes the current knowledge on SGLT2i in this specific patient population and outlines running and upcoming clinical trial programs in different geographic regions aiming to make SGLT2i accessible to patients with ADPKD.

Background: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) and finerenone each improve kidney and cardiovascular outcomes in patients with chronic kidney disease (CKD). This study compares the association between combined therapy versus monotherapy with SGLT2i or finerenone and the kidney, cardiovascular, and mortality outcomes in CKD patients.

Methods: This retrospective cohort study included adults ≥18 years with CKD between July 9, 2021, and November 30, 2023 from multiple centers in the United States, utilizing the TriNetX database. Exposures included treatment with finerenone, SGLT2i, or a combination of both. The primary outcome was major adverse kidney events (MAKE). Secondary outcomes included all-cause mortality, major adverse cardiac events (MACE), and end stage renal disease (ESRD).

Results: 853 patients were included in the combined group [mean (±SD) age, 66.7±11.4 years; 34.9% female), 942 in the finerenone group (mean age, 68.2±11.4 years; 45.8% female), and 45,948 in the SGLT2i group (mean age, 70.2±11.8 years; 41.4% female). After matching, the combined group had less MAKE compared to finerenone monotherapy [adjusted hazard ratio (aHR)=0.20; 95% CI, 0.09-0.45] or SGLT2i monotherapy (aHR=0.44; 95% CI, 0.22-0.89). The hazards of all-cause mortality and ESRD were also lower in the combined group compared to either finerenone or SGLT2i alone, while hazard of MACE was similar between the combined and monotherapy groups. The combined group had higher risk of hyperkalemia compared to SGLT2i monotherapy (aHR=1.36; 95% CI, 1.08-1.71).

Conclusion: Combined therapy with finerenone and SGLT2i is associated with less MAKE and all-cause mortality in CKD patients compared to monotherapy. However, the risk of hyperkalemia with finerenone warrants caution.

Background: Male patients with X-linked Alport syndrome (XLAS) generally develop end-stage kidney disease in early or middle adulthood and show distinct genotype-phenotype correlations. However, female patients show various phenotypes ranging from asymptomatic to severe with no genotype-phenotype correlations. The factors affecting the severity of XLAS in female patients are unclear. Since X-chromosome inactivation (XCI) affects the severity of certain female X-linked diseases, we investigated whether genotype and XCI were associated with XLAS severity in female patients in a large Japanese cohort.

Methods: Among 139 female patients with genetically diagnosed XLAS at our institution, we conducted XCI analysis on peripheral blood leucocytes using the human androgen receptor assay method and analysed two cohorts. In 74 adult female patients we evaluated the correlation between kidney function [creatinine estimated glomerular filtration rate (Cr-eGFR) optimized for Japanese individuals] and genotype/XCI using multivariable linear regression analysis and in 65 paediatric female patients we evaluated the correlation between kidney function (Cr-eGFR optimized for Japanese individuals) and genotype/XCI using multivariable linear regression analysis. We also investigated the correlation between the development of proteinuria (urine protein:creatinine ratio above normal for the patient's age) and genotype/XCI using multivariable Cox proportional hazards analysis.

Results: In adult female patients, the XCI pattern was significantly associated with Cr-eGFR (regression coefficient estimate -0.53, P = .004), whereas genotype was not (P = .892). In paediatric female patients, both genotype and XCI pattern were significant independent risk factors for the development of proteinuria {hazard ratio [HR] 3.702 [95% confidence interval (CI) 1.681-8.150], P = .001 and HR 1.043 [95% CI 1.061-1.070], P = .001, respectively}, whereas both genotype and XCI pattern were not associated with Cr-eGFR (P = .20 and P = .67, respectively).

Conclusion: Genotype and XCI are factors associated with severity in females with XLAS.

Background: Studies in patients with heart failure have indicated that sodium-glucose cotransporter 2 (SGLT2) inhibitors increase iron use and enhance erythropoiesis. In this post hoc analysis of the Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial, we evaluated the effects of canagliflozin on iron metabolism in patients with chronic kidney disease (CKD) and whether the effects of canagliflozin on hemoglobin and cardiorenal outcomes were modified by iron deficiency.

Methods: We measured serum iron, total iron binding capacity (TIBC), transferrin saturation (TSAT) and ferritin at baseline and 12 months. The effects of canagliflozin, relative to placebo, on iron markers were assessed with analysis of covariance. Interactions between baseline iron deficiency, defined as TSAT <20%, and the effects of canagliflozin on hemoglobin and cardiorenal outcomes were evaluated with mixed effect models and Cox regression models, respectively.

Results: Of 4401 participants randomized in CREDENCE, 2416 (54.9%) had iron markers measured at baseline, of whom 924 (38.2%) were iron deficient. Canagliflozin, compared with placebo, increased TIBC by 2.1% [95% confidence interval (CI) 0.4, 3.8; P = .014] and decreased ferritin by 11.5% (95% CI 7.1, 15.7; P < .001) with no clear effect on serum iron or TSAT. Canagliflozin increased hemoglobin over the trial duration by 7.3 g/L (95% CI 6.2, 8.5; P < .001) and 6.7 g/L (95% CI 5.2, 8.2; P < .001) in patients with and without iron deficiency, respectively (P for interaction = .38). The relative effect of canagliflozin on the primary outcome of doubling of serum creatinine, kidney failure or death due to cardiovascular disease or kidney failure (hazard ratio 0.70, 95% CI 0.56, 0.87) was consistent regardless of iron deficiency (P for interaction = .83), as were effects on other cardiovascular and mortality outcomes (all P for interactions ≥0.10).

Conclusion: Iron deficiency is highly prevalent in patients with type 2 diabetes and CKD. Canagliflozin increased TIBC and decreased ferritin in patients with type 2 diabetes and CKD, suggesting increased iron utilization, and improved hemoglobin levels and clinical outcomes regardless of iron deficiency.

Background: Early steroid withdrawal (ESW) is often preferred over conventional steroid maintenance (CSM) therapy for kidney transplant recipients with low immunological risks because it may minimize immunosuppression-related adverse events while achieving similar transplant outcomes. However, the risk-benefit balance of ESW could be less favorable in retransplant recipients given their unique immunological risk profile. We hypothesized that the association of ESW with transplant outcomes would differ between first-transplant and retransplant recipients.

Methods: To assess whether the impact of ESW differs between first and retransplant recipients, we studied 210 086 adult deceased-donor kidney transplant recipients using the Scientific Registry of Transplant Recipients. Recipients who discontinued maintenance steroids before discharge from transplant admission were classified with ESW; all others were classified with CSM. We quantified the association of ESW (vs CSM) with acute rejection, death-censored graft failure and death, addressing retransplant as an effect modifier, using logistic/Cox regression with inverse probability weights to control for confounders.

Results: In our cohort, 26 248 (12%) were retransplant recipients. ESW was used in 30% of first-transplant and 20% of retransplant recipients. Among first-transplant recipients, ESW was associated with no significant difference in acute rejection {adjusted odds ratio (aOR) = 1.04 [95% confidence interval (CI) = 1.00-1.09]}, slightly higher hazard of graft failure [hazard ratio (HR) = 1.09 (95% CI = 1.05-1.12)] and slightly lower mortality [HR = 0.93 (95% CI = 0.91-0.95)] compared with CSM. Nonetheless, among retransplant recipients, ESW was associated with notably higher risk of acute rejection [OR = 1.42 (95% CI = 1.29-1.57); interaction P < .001] and graft failure [HR = 1.24 (95% CI = 1.14-1.34); interaction P = .003], and similar mortality [HR = 1.01 (95% CI = 0.94-1.08); interaction P = .04].

Conclusions: In retransplant recipients, the negative impacts of ESW on transplant outcomes appear to be non-negligible. A more conservatively tailored approach to ESW might be necessary for retransplant recipients.

BK polyomavirus (BKPyV) is recognized as a significant viral complication of kidney transplantation. Prompt immunosuppression reduction reduces early graft failure rates due to BK polyomavirus-associated nephropathy (BKPyVAN), however, modulation of immunosuppression can lead to acute rejection. Medium-to-long-term graft outcomes are negatively affected by BKPyVAN, probably due to a combination of virus-induced graft damage and host immune responses against graft alloantigens potentiated by immunosuppression reduction. Kidney biopsy remains the gold-standard diagnostic test, however, false-negative findings are common due to the focal nature of BKPyVAN. BKPyV DNAemia, as measured by quantitative polymerase chain reaction, is established as a screening test but there is at present no (inter)national standardization of these assays to allow collation and comparison of data between centres. Randomized controlled trials are lacking both in terms of optimal immunosuppression reduction strategies, and for the medications variably used to attempt treatment in clinical practice. Much of the fundamental biology of BKPyV is not yet understood, and further elucidation is required to promote rational direct-acting antiviral drug design. Insights into the role of adaptive immunity in control of BKPyV have informed the design of novel treatments such as adoptive immunotherapies and neutralizing antibodies that require evaluation in clinical studies. Here, we review the current standards of diagnosis and treatment of BKPyVAN and discuss novel developments in the pathophysiology, diagnosis, outcome prediction, and management.