Epidemiology, Outcomes, and Complement Gene Variants in Secondary Thrombotic Microangiopathies.

BACKGROUND: The identification of complement defects as major drivers of primary atypical hemolytic uremic syndrome (HUS) has transformed the landscape of thrombotic microangiopathies (TMAs), leading to the development of targeted therapies and better patient outcomes. By contrast, little is known about the presentation, genetics, and outcomes of TMA associated with specific diseases or conditions, also referred to as secondary TMA. METHODS: In this study, we assessed the relative incidence, clinical and genetic spectra, and long-term outcomes of secondary TMA versus other TMAs in consecutive patients hospitalized with a first episode of TMA from 2009 to 2019 at two European reference centers. RESULTS: During the study period, 336 patients were hospitalized with a first episode of TMA. Etiologies included atypical HUS in 49 patients (15%), thrombotic thrombocytopenic purpura (TTP) in 29 (9%), shigatoxin-associated HUS in 70 (21%), and secondary TMA in 188 (56%). The main causes of secondary TMA were hematopoietic stem-cell transplantation ( n =56, 30%), solid-organ transplantation ( n =44, 23%), and malignant hypertension ( n =25, 13%). Rare variants in complement genes were identified in 32 of 49 patients (65%) with atypical HUS and eight of 64 patients (13%) with secondary TMA; pathogenic or likely pathogenic variants were found in 24 of 49 (49%) and two of 64 (3%) of them, respectively ( P < 0.001). After a median follow-up of 1157 days, death or kidney failure occurred in 14 (29%), eight (28%), five (7%), and 121 (64%) patients with atypical HUS, TTP, shigatoxin-associated HUS, and secondary TMA, respectively. Unadjusted and adjusted Cox regressions showed that patients with secondary TMA had the highest risk of death or kidney failure (unadjusted hazard ratio [HR], 3.35; 95% confidence interval [CI], 1.85 to 6.07; P < 0.001; adjusted HR, 4.11; 95% CI, 2.00 to 8.46; P < 0.001; considering atypical HUS as reference). CONCLUSIONS: Secondary TMAs represent the main cause of TMA and are independently associated with a high risk of death and progression to kidney failure.

Atypical Hemolytic Uremic Syndrome Occurring After Receipt of mRNA-1273 COVID-19 Vaccine Booster: A Case Report.

Atypical hemolytic uremic syndrome (aHUS) is a subtype of thrombotic microangiopathy (TMA) characterized by a dysregulation of the alternative complement pathway. Here, we report a previously healthy 38-year-old woman in whom aHUS developed after a COVID-19 vaccine booster. One day after receipt of a booster dose of mRNA-1273 vaccine, she felt ill. Because of persistent headache, nausea, and general malaise, she went to her general practitioner, who referred her to the hospital after detecting hypertension and acute kidney injury. A diagnosis of TMA was made. Her treatment consisted of blood pressure control, hemodialysis, plasma exchange, and respiratory support. Kidney biopsy confirmed the diagnosis of acute TMA. The patient was referred for treatment with eculizumab, and kidney function improved after initiation of this therapy. Genetic analysis revealed a pathogenic C3 variant. SARS-CoV-2 infection as a trigger for complement activation and development of aHUS has been described previously. In addition, there is one reported case of aHUS occurring after receipt of the adenovirus-based COVID-19 vaccine ChAdOx1 nCoV-19, but, to our knowledge, this is the first case of aHUS occurring after a booster dose of an mRNA COVID-19 vaccine in a patient with an underlying pathogenic variant in complement C3. Given the time frame, we hypothesize that the vaccine probably was the trigger for development of aHUS in this patient.

Renal progression factors in young patients with tuberous sclerosis complex: a retrospective cohort study.

BACKGROUND: Renal pathology in tuberous sclerosis complex (TSC) is characterized by the growth of angiomyolipoma and renal cysts, and in rare cases renal cell carcinoma. Other consequences of renal involvement in TSC, including hypertension, proteinuria, and hyperfiltration, are not well studied. We aimed to analyze the early manifestations of the renal TSC phenotype in a young TSC cohort and to explore common, modifiable risk factors. METHODS: In this retrospective cohort study, TSC patients attending the TSC clinics of two tertiary hospitals were included. Data on demographics, history, genotype, kidney function, hematuria, proteinuria, blood pressure, and renal imaging were collected. RESULTS: Eighty patients were included, with a median age of 0.8 years (0.0-63.0) at first presentation, and a median follow-up time of 10.2 (0.4-41.0) years. Mutation analysis was available in 64 patients (80%). Renal lesions (cysts or angiomyolipoma) were observed in 55/73 (75%). Thirty-two percent (19/60) were hypertensive, 8/51 (16%) had proteinuria, and 18/71 (25%) had hyperfiltration (median eGFR 154 ml/min/m2). Six (7.5%) patients had developed end stage renal disease at the last follow-up. No association was found between hyperfiltration, hypertension, or proteinuria and CKD ≥ 3. Cox regression showed a significant positive association between the presence of a renal intervention and CKD ≥ 3 (Hazard-Ratio 3.91, P < 0.05). CONCLUSIONS: Besides renal cysts and angiomyolipoma, the modifiable progression factors hypertension, proteinuria, and hyperfiltration occur frequently and early in TSC patients. This represents a preventive treatment target.

Management dilemmas in pediatric nephrology: Cystinosis.

BACKGROUND: Cystinosis is a rare, inherited autosomal recessive disease caused by the accumulation of free cystine in lysosomes. It is treated by the administration of cysteamine, which should be monitored by trough white blood cell (WBC) cystine measurements to ensure effective treatment. CASE-DIAGNOSIS/TREATMENT: The index case had an older brother who had previously been diagnosed with cystinosis, allowing early diagnosis of the index case at the age of 5 months. Cysteamine therapy was started at the age of 3 years; however, monitoring of WBC cystine levels did not occur on a regular basis during most of his life. Growth retardation improved after correction of electrolyte disturbances, the initiation of cysteamine therapy and treatment with recombinant human growth hormone. Renal replacement therapy was started at the age of 11 years, and renal transplantation was performed at the age of 12 years. Extra-renal cystine accumulation caused multiple endocrinopathies (including adrenal insufficiency, hypothyroidism and primary hypogonadism), neurological symptoms, pancytopenia owing to splenomegaly and portal hypertension due to nodular regenerative hyperplasia, aggravated by splenic vein thrombosis and partial portal vein thrombosis. The patient died of diffuse intra-abdominal bleeding caused by severe portal hypertension. CONCLUSION: Cysteamine treatment should be started as early as possible, and dosage should be monitored and adapted based on trough WBC cystine levels. RELEVANT INTERNATIONAL GUIDELINE: Emma F et al. (2014) Nephropathic cystinosis: an international consensus document. Nephrol Dial Transplant 29:iv87-iv94.

Postimplantation X-ray parameters predict functional catheter problems in peritoneal dialysis.

Functional catheter problems are a major challenge for peritoneal dialysis (PD) programs. Here we performed a retrospective single-center study of 110 consecutive patients receiving a first PD catheter (swan neck double-cuff Missouri curled catheters, open surgical technique). Using postimplantation X-ray, the following categories were defined: swan neck angle (posterioanterio view (PA): under 45°, 45-90°, over 90°), inclination (angle between intramural part of catheter and horizontal line; lateral view: greater than/equal to 30°, under 30°), and the position of silicone bead relative to spine (PA view: L1-2, L3-4, lower) and catheter tip (PA view: hypogastric, umbilical, subcostal). Covariates included demographics, body size, previous abdominal surgery, and abdominal wall hernias. During a mean follow-up of 36 months, the time to first functional catheter problem was significantly associated with both the swan neck angle and inclination. The need for surgical intervention was significantly associated with inclination only. Technique failure was not associated with any parameter. In multivariate analysis, inclination was the sole variable significantly associated with functional catheter problems (hazard ratio 3.65 [1.98-6.72]) and the need for surgical intervention (hazard ratio 2.86 [1.19-6.88]). Thus, our study defines a set of X-ray variables that predict functional PD catheter problems and can be used for troubleshooting in individual cases as well as for education and internal audit purposes.

Aortic calcifications and arterial stiffness as predictors of cardiovascular events in incident renal transplant recipients.

Renal transplant recipients have an increased risk of cardiovascular (CV) disease. Arterial stiffness (AS) and aortic calcifications (ACs) are well-known CV risk factors in patients with chronic kidney disease. We aimed to determine the prognostic value of AS and AC in incident renal transplant recipients (RTRs). We conducted a prospective study in 253 single RTR. AC were scored by means of lumbar X-ray. Carotid-femoral pulse wave velocity (PWV) was assessed in a subgroup of 115 patients. AC were present in 61% of patients. After a mean follow-up of 36 months, 32 CV events occurred in the overall group and 13 events in the PWV subgroup. When we accounted for age, gender, and CV history, AC score (HR, hazard ratio 1.09 per 1 unit increase; 95% CI 1.02-1.17) and PWV (HR 1.45 per 1 m/s; 95% CI 1.16-1.8) remained an independent predictor of CV events in Cox-regression analyses. Using receiver operating characteristics, the area under the curve for predicting CV events amounted to 0.80 and 0.72 for sum AC and PWV, respectively. Both AS and AC are strong predictors of future CV events in an incident RTR population. These vascular assessments are readily available and easy to perform, making them ideal tools for further risk stratification. (ClinicalTrials.gov number: NCT00547040).

Reasons for dose reduction of mycophenolate mofetil during the first year after renal transplantation and its impact on graft outcome.

UNLABELLED: Mycophenolate mofetil (MMF) decreases the risk of acute rejection and is associated with improved graft survival in renal transplant recipients. However, MMF-related side effects often necessitate dose reduction, which may expose patients to a higher risk of acute rejection and graft loss. This study's aim was to examine the reasons for MMF dose reduction during the first post-transplant year and its impact on acute rejection, overall and death-censored graft loss. METHODS: Single-center retrospective analysis of 749 renal transplant recipients treated with MMF in their initial maintenance immunosuppressive protocol. RESULTS: In 365 patients (48.7%) a total of 530 MMF dose reductions were done. Reasons for reduction were hematologic toxicity (46.5%), infection (16.1%), gastrointestinal side effects (12.3%), malignancy (2.1%), study protocol (14.6%), and unknown (13.5%). MMF dose reduction as such was not an independent predictor of acute rejection or graft survival, although reductions in ≥ 50% of initial dose were significantly associated with acute rejection. CONCLUSIONS: In this retrospective cohort, by far the most important reason for MMF dose reduction during the first post-transplantation year was hematologic. MMF dose reductions in ≥ 50% increased the risk of acute rejection but did not compromise graft survival.