Mårten Segelmark

Background: Although all-cause and cause-specific mortality trends are well studied in the general population, these trends were less explored in kidney transplant recipients with and without diabetes. Our aim was to examine time trends in (cause-specific) mortality in adult first kidney transplant recipients with and without diabetes as the cause of kidney failure in European countries. Methods: We included adult patients who received a first kidney transplant between 2005 and 2022 from 12 European countries contributing data to the European Renal Association Registry. We followed patients for a maximum of 5 years. We calculated age- and sex-standardized mortality rates, and the absolute and relative mortality differences between those with and without diabetes. Time trends were analysed using Joinpoint regression. Results: In total, 134 231 adults received a kidney transplant between 2005 and 2022, and 20 753 (15.5%) of them had diabetes as the cause of kidney failure. Mortality rates for kidney transplant recipients with diabetes were almost twice as high as for recipients without diabetes [45.5 deaths per 1000 person-years (py) and 24.9 per 1000 py, respectively]. The higher mortality of recipients with diabetes was mainly due to excess cardiovascular mortality and infection-related mortality. Trends in all-cause and cause-specific mortality remained stable over time up to the COVID-19 pandemic for recipients with and without diabetes. During the COVID-19 pandemic, both groups experienced an increase in mortality rates, mainly driven by an increase in infection-related mortality. Conclusions: Contrary to trends observed in the general population, age- and sex-standardized all-cause and cardiovascular mortality rates among kidney transplant recipients, irrespective of diabetes status, did not improve over time. In addition, in contrast to the general population, the cardiovascular mortality gap in kidney transplant recipients with and without diabetes did not narrow over time.

Key Points: Adverse muscle composition is common in CKD; affected individuals face a higher risk of premature death. Adverse muscle composition is an independent and strong predictor of all-cause mortality in CKD. Muscle health evaluation can identify patients at high risk and support targeted prevention strategies. Background: Adverse muscle composition (AMC), defined by low muscle volume and increased muscle fat infiltration (MFI), has been associated with comorbidity and poor function in CKD, and increased mortality in metabolic disorders and the general population. We investigated whether magnetic resonance imaging-derived muscle composition is associated with all-cause mortality in a UK Biobank (UKB) imaging study among participants with CKD. Methods: UKB participants with CKD (eGFR _CystatinC 2 ) were identified. Thigh fat-free muscle volume and MFI were quantified using magnetic resonance imaging and AMRA Researcher. Muscle volume was expressed as a sex-invariant and BMI (body mass index)-invariant z -score. AMC was defined as the coexistence of low muscle volume (z-score 75th percentile; >7.69% in men and >8.82% in women), on the basis of published UKB imaging thresholds. The mortality data were obtained through the UKB's linkage to national death registries. All-cause mortality was investigated using Kaplan–Meier curves and Cox regression. Models were adjusted for sex, age, BMI, proteinuria, low hand grip strength, physical activity, smoking, alcohol, previous diagnosis of cancer, prevalent cardiovascular heart diseases, and type 2 diabetes. Results: A total of 894 participants with CKD and available mortality data were included (52.5% male, mean±SD age 72.2±5.8 years, BMI 29±5.3 kg/m ² , eGFR 53.5±6.4 ml/min per 1.73 m ² ). Prevalence of AMC was 32.3%. During a mean follow-up of 3.6 years, 50 participants died. AMC was significantly associated with higher all-cause mortality compared with normal muscle composition in unadjusted analyses (hazard ratio, 6.17; 95% confidence interval, 2.36 to 16.15, P < 0.001) and remained significant after adjustment for demographic, lifestyle factors, proteinuria, and clinical factors (hazard ratio, 4.21; 95% confidence interval, 1.49 to 11.84; P = 0.007). Conclusion: AMC is associated with greater risk of all-cause mortality in participants with CKD, identifying a high-risk population. Preservation of muscle composition may represent an important therapeutic consideration and potential target for future interventions in CKD management.

Background: The involvement of the complement system in anti-glomerular basement membrane (GBM) disease is well known but incompletely characterized. The ability of autoantibodies to trigger the classical pathway is evident, while the lectin and alternative pathways also seem to be of importance. We studied complement activation in patients treated with imlifidase, which leads to rapid IgG depletion, to elucidate the role of complement in anti-GBM disease. Methods: The GOOD-IDES-01 trial included 15 anti-GBM disease patients treated with one dose of imlifidase in addition to standard therapy with 6 months of follow-up. Plasma samples were analyzed for C3, C4 and complement activation products [C4d, C3bBbP and soluble terminal complement complexes (sTCC)]. Ratios of C4d/C4 and C3bBbP/C3 were calculated to correct for plasmapheresis. Serum samples were analyzed for anti-drug antibodies (ADA) directed against imlifidase. Results: The C4d/C4 ratio decreased rapidly from its pre-dose level, while sTCC decreased more slowly. sTCC and C3bBbP/C3 were above the reference level throughout the trial. We observed a transient increase in C4d/C4 and C3bBbP/C3, but not sTCC, immediately following treatment with imlifidase, which tended to be more pronounced in patients with more pre-existing ADA. Conclusions: Classical pathway activation decreased rapidly after autoantibody removal by imlifidase and increased again in most of those that experienced a rebound, but terminal complement activation remained elevated throughout the trial. However, due to the small sample size our results must be interpreted with caution.

Background: National registries which capture patients with chronic kidney disease (CKD) across all stages are scarce. We present here the Swedish Renal Registry (SRR), a nationwide prospective register covering the whole spectrum of CKD. Methods: Created in 1991, SRR enrolls CKD patients referred to adult nephrologist care (non-dialysis CKD [ND-CKD], kidney transplantation, maintenance dialysis), with an overall coverage of nearly all nephrology clinics in Sweden. SRR encompasses several interconnected databases in which longitudinal clinical, biological, kidney-related, patient-reported data, as well as provider-level information are collected. This report presents the design of the registry, as well as patients characteristics and temporal trends between 2008 and 2021. Results: A total of 45,590 new ND-CKD patients (72 years, 16,656 [36%] women, eGFR 26 mL/min per 1.73m²), and 8829 incident kidney transplant recipients (51 years, 35% women) were enrolled in SRR between 2008-2021. SRR also included 16,034 new patients (68 years, 5420 [34%] women) on maintenance dialysis (70% Hemodialysis [HD], 30% Peritoneal dialysis [PD]). Between 2015 and 2021, 4753 patients (59 years, 1884 [40%] women, eGFR 37 mL/min per 1.73m²) had a registered kidney biopsy. We observed a decrease in HD incidence (69% to 60%, P for trend <0.01) and an increase in PD incidence (26% to 32%, P<0.01) and preemptive transplantation (4.7 to 7.5%, P<0.01). The prevalence of comorbidities is high in all CKD stages and increase as eGFR declines. While nephroangiosclerosis and diabetic kidney disease are the most common etiologies, glomerulonephritis are the most frequent diagnoses in biopsied and transplanted patients. Conclusion: The SRR is a nationwide register which aims to contribute to address gaps in our understanding of CKD, to identify important challenges and health priorities, to evaluate real-life clinical management, and to analyze international variations, to improve health outcomes, quality of life, and reduce the burden of CKD.

Background and hypothesis: Knowledge regarding access to first kidney transplantation (KT) and subsequent KT in patients commencing kidney replacement therapy (KRT) in childhood is limited. Methods: Using European Renal Association (ERA) Registry data, we investigated European patients who started KRT below 20 years of age between 1978 and 2019. Access and determinants to first, second, and third KT were assessed using multivariable Cox regression. Results: Totals of 12 623, 4077, and 1186 patients were included while awaiting first, second, and third KT, at median ages of 13.8 (IQR: 7.5–17.4), 20.9 (IQR: 16.5–26.1), and 26.6 (IQR: 20.3–32.8) years, respectively. During the study period, overall access was 87.8%, 72.7%, and 60.5% for first, second, and third KT, respectively, and median time to each KT was 0.9 (IQR: 0.2–2.1), 1.9 (0.6–4.5), and 2.6 (IQR: 1.0–5.3) years. Younger age at KRT initiation (aHR 0-4 vs. 10–14 years: 0.54; 95%CI: 0.51–0.57) and female sex (HR: 0.94; 95%CI: 0.90–0.98) were associated with lower access to first KT. KT candidates between 15 and 19 years had lower access to first and second KT (aHR: 0.69; 95%CI: 0.66–0.73, and aHR: 0.70; 95%CI: 0.61–0.81) compared to 10–14 year-olds. Compared to CAKUT, glomerulonephritis patients had lower access to KT (aHR: 0.75; 95%CI: 0.71–0.80 for first, aHR: 0.89; 95%CI: 0.81–0.98 for second, and aHR: 0.80; 95%CI: 0.66–0.97 for third KT). Similarly, patients with primary renal diseases with high risk of recurrence, had lower chances of receiving a first and second KT (aHR: 0.80; 95%CI: 0.76–0.85 for first, aHR: 0.86; 95%CI: 0.78–0.95 for second KT). Access to re-transplantation was also higher with previous pre-emptive KT and previous graft survival exceeding 5 years. Conclusion: Our study highlights KT access disparities particularly for females, the youngest recipients, high-risk age (15–19 years), and diseases with recurrence risk. Notably, pre-emptive transplants and enduring previous grafts offer advantages regarding re-transplantation.

Background: Current knowledge about risk factors for severe COVID-19 among kidney transplant recipients stem from meta-analyses of small or regional studies. Methods: All kidney transplant recipients in Sweden as of 1 January 2020 (n = 5824) were followed during the first 2 years of the pandemic. Data from the Swedish Renal Registry and linked health care registries were analyzed by multivariable adjusted logistic regression to identify risk factors for severe COVID-19, defined as hospitalization or death due to COVID-19. Results: Male sex increased the risk of severe COVID-19. While many comorbidities were associated with increased risk, their significance diminished after adjustment for other factors. Kidney transplant recipients of working age, 49–58 years adjusted odds ratio (aOR) 2.32 (95% CI 1.53–3.51) and 59–68 years aOR (1.92; 1.26–2.91) had the highest risk compared to the youngest age group (18–38 years). Compared to recently (5 years ago had a lower risk of severe COVID-19 (aOR 0.52; 0.36–0.75 for 6–10 years; aOR 0.57; 0.41–0.79 for >10 years). Longer pre-transplant dialysis vintage (aOR1-year 1.04; 1.01–1.06) and deceased donor kidneys (aOR 1.41; 1.09–1.84) increased the risk. Immunosuppression with mycophenolate mofetil (aOR 1.47, 95% CI 1.08–1.99) and proton pump inhibitor use (aOR 1.58, 95% CI 1.24–2.01) were strongly associated with severe COVID-19. Conclusions: While kidney transplant recipients share risk factors with the general population, working age groups were at the highest risk, unlike in the general population. These findings emphasize the need for targeted prevention and treatment strategies for kidney transplant recipients in future pandemics.