Thrombotic Microangiopathy as a Life-Threatening Complication of Long-Term Interferon Beta Therapy for Multiple Sclerosis: Clinical Phenotype and Response to Treatment-A Literature Review.

Thrombotic microangiopathy (TMA) has been observed in some patients receiving interferon beta (IFNß) therapy for relapsing-remitting multiple sclerosis, but little is known about its clinical features and outcomes. We searched the literature to identify cases with IFNß-related TMA and assessed their pattern of organ involvement, the presence of prodromal manifestations, the treatments used, and the outcomes. Thirty-five articles met the inclusion criteria, and data of 67 patients were collected. The median duration of IFNß therapy before the diagnosis of TMA was 8 years, and 56/67 (84%) presented with acute kidney injury (AKI), of which 33 required acute dialysis. All but three patients had manifestations during the four weeks before TMA onset, including flu-like symptoms, headache, and worsening blood pressure control. In only two patients, ADAMTS13 activity was reduced, while 27% had low C3 levels. However, none showed causative genetic mutations associated with development of atypical hemolytic uremic syndrome. All patients discontinued IFNß, 34 (55%) also received plasma exchange, and 12 (18%) received eculizumab. Complete renal recovery was achieved by 20 patients (30%), while 13 (20%) developed end-stage renal disease. Among those with AKI requiring dialysis, eculizumab therapy was associated with a significantly reduced risk of ESRD compared with plasma exchange. Therefore, TMA with features of aHUS mainly occurs after prolonged treatment with IFNß and is preceded by prodromes, which may lead to an early diagnosis before life-threatening complications occur. Eculizumab appears beneficial in cases with severe kidney involvement, which supports a role of the complement system in the pathogenesis of these forms.

A Clinical Workflow for Cost-Saving High-Rate Diagnosis of Genetic Kidney Diseases.

SIGNIFICANCE STATEMENT: To optimize the diagnosis of genetic kidney disorders in a cost-effective manner, we developed a workflow based on referral criteria for in-person evaluation at a tertiary center, whole-exome sequencing, reverse phenotyping, and multidisciplinary board analysis. This workflow reached a diagnostic rate of 67%, with 48% confirming and 19% modifying the suspected clinical diagnosis. We obtained a genetic diagnosis in 64% of children and 70% of adults. A modeled cost analysis demonstrated that early genetic testing saves 20% of costs per patient. Real cost analysis on a representative sample of 66 patients demonstrated an actual cost reduction of 41%. This workflow demonstrates feasibility, performance, and economic effect for the diagnosis of genetic kidney diseases in a real-world setting. BACKGROUND: Whole-exome sequencing (WES) increases the diagnostic rate of genetic kidney disorders, but accessibility, interpretation of results, and costs limit use in daily practice. METHODS: Univariable analysis of a historical cohort of 392 patients who underwent WES for kidney diseases showed that resistance to treatments, familial history of kidney disease, extrarenal involvement, congenital abnormalities of the kidney and urinary tract and CKD stage ≥G2, two or more cysts per kidney on ultrasound, persistent hyperechoic kidneys or nephrocalcinosis on ultrasound, and persistent metabolic abnormalities were most predictive for genetic diagnosis. We prospectively applied these criteria to select patients in a network of nephrology centers, followed by centralized genetic diagnosis by WES, reverse phenotyping, and multidisciplinary board discussion. RESULTS: We applied this multistep workflow to 476 patients with eight clinical categories (podocytopathies, collagenopathies, CKD of unknown origin, tubulopathies, ciliopathies, congenital anomalies of the kidney and urinary tract, syndromic CKD, metabolic kidney disorders), obtaining genetic diagnosis for 319 of 476 patients (67.0%) (95% in 21 patients with disease onset during the fetal period or at birth, 64% in 298 pediatric patients, and 70% in 156 adult patients). The suspected clinical diagnosis was confirmed in 48% of the 476 patients and modified in 19%. A modeled cost analysis showed that application of this workflow saved 20% of costs per patient when performed at the beginning of the diagnostic process. Real cost analysis of 66 patients randomly selected from all categories showed actual cost reduction of 41%. CONCLUSIONS: A diagnostic workflow for genetic kidney diseases that includes WES is cost-saving, especially if implemented early, and is feasible in a real-world setting.

Clinical features suggesting renal hypouricemia as the cause of acute kidney injury: a case report and review of the literature.

Hypouricemia is defined as a level of serum uric acid below 2 mg/dl. Renal hypouricemia is related to genetic defects of the uric acid tubular transporters urate transporter 1 and glucose transporter 9. Patients with renal hypouricemia can be completely asymptomatic or can develop uric acid kidney stones or acute kidney injury, particularly after exercise. Renal hypouricemia is especially challenging to diagnose in patients with acute kidney injury, due to the nonspecific clinical, hematochemical and histological features. No common features are reported in the literature that could help clinicians identify renal hypouricemia-acute kidney injury. Currently available guidelines on diagnosis and management of renal hypouricemia provide limited support in defining clues for the differential diagnosis of renal hypouricemia, which is usually suspected when hypouricemia is found in asymptomatic patients. In this paper we report a case of renal hypouricemia-acute kidney injury developing after exercise. We carried out a review of the literature spanning from the first clinical description of renal hypouricemia in 1974 until 2022. We selected a series of clinical features suggesting a diagnosis of renal hypouricemia-acute kidney injury. This may help clinicians to suspect renal hypouricemia in patients with acute kidney injury and to avoid invasive, costly and inconclusive exams such as renal biopsy. Considering the excellent outcome of the patients reported in the literature, we suggest a "wait-and-see" approach with supportive therapy and confirmation of the disease via genetic testing.

Drug-induced thrombotic microangiopathy: An updated review of causative drugs, pathophysiology, and management.

Drug-induced thrombotic microangiopathy (DITMA) represents 10%-13% of all thrombotic microangiopathy (TMA) cases and about 20%-30% of secondary TMAs, just behind pregnancy-related and infection-related forms. Although the list of drugs potentially involved as causative for TMA are rapidly increasing, the scientific literature on DITMA is quite scarce (mostly as individual case reports or little case series), leading to poor knowledge of pathophysiological mechanisms and clinical management. In this review, we focused on these critical aspects regarding DITMA. We provided an updated list of TMA-associated drugs that we selected from a scientific literature review, including only those drugs with a definite or probable causal association with TMA. The list of drugs is heterogeneous and could help physicians from several different areas to be familiar with DITMA. We describe the clinical features of DITMA, presenting the full spectrum of clinical manifestations, from systemic to kidney-limited forms. We also analyze the association between signs/symptoms (i.e., malignant hypertension, thrombocytopenia) and specific DITMA causative drugs (i.e., interferon, ticlopidine). We highlighted their multiple different pathophysiological mechanisms, being frequently classified as immune-mediated (idiosyncratic) and dose-related/toxic. In particular, to clarify the role of the complement system and genetic deregulation of the related genes, we conducted a revision of the scientific literature searching for DITMA cases who underwent renal biopsy and/or genetic analysis for complement genes. We identified a complement deposition in renal biopsies in half of the patients (37/66; 57%), with some drugs associated with major deposits (i.e., gemcitabine and ramucirumab), particularly in capillary vessels (24/27; 88%), and other with absent deposits (tyrosine kinase inhibitors and intraocular anti-VEGF). We also found out that, differently from other secondary TMAs (such as pregnancy-related-TMA and malignant hypertension TMA), complement genetic pathological mutations are rarely involved in DITMA (2/122, 1.6%). These data suggest a variable non-genetic complement hyperactivation in DITMA, which probably depends on the causative drug involved. Finally, based on recent literature data, we proposed a treatment approach for DITMA, highlighting the importance of drug withdrawal and the role of therapeutic plasma-exchange (TPE), rituximab, and anti-complementary therapy.