SARS-CoV-2 Causes a Specific Dysfunction of the Kidney Proximal Tubule

Coronavirus disease 2019 (COVID-19) is commonly associated with kidney damage, and the angiotensin converting enzyme 2 (ACE2) receptor for SARS-CoV-2 is highly expressed in the proximal tubule cells. Whether patients with COVID-19 present specific manifestations of proximal tubule dysfunction remains unknown. To test this, we examined a cohort of 49 patients requiring hospitalization in a large academic hospital in Brussels, Belgium. There was evidence of proximal tubule dysfunction in a subset of patients with COVID-19, as attested by low-molecular-weight proteinuria (70-80%), neutral aminoaciduria (46%), and defective handling of uric acid (46%) or phosphate (19%). None of the patients had normoglycemic glucosuria. Proximal tubule dysfunction was independent of pre-existing comorbidities, glomerular proteinuria, nephrotoxic medications or viral load. At the structural level, kidneys from patients with COVID-19 showed prominent tubular injury, including in the initial part of the proximal tubule, with brush border loss, acute tubular necrosis, intraluminal debris, and a marked decrease in the expression of megalin in the brush border. Transmission electron microscopy identified particles resembling coronaviruses in vacuoles or cisternae of the endoplasmic reticulum in proximal tubule cells. Among features of proximal tubule dysfunction, hypouricemia with inappropriate uricosuria was independently associated with disease severity and with a significant increase in the risk of respiratory failure requiring invasive mechanical ventilation using Cox (adjusted hazard ratio 6.2, 95% CI 1.9-20.1) or competing risks (adjusted sub-distribution hazard ratio 12.1, 95% CI 2.7-55.4) survival models. Thus, our data establish that SARS-CoV-2 causes specific manifestations of proximal tubule dysfunction and provide novel insights into COVID-19 severity and outcome

Application of C5 inhibitors in glomerular diseases in 2021

The complement pathway is an essential mechanism in innate immunity, but it is also involved in multiple pathologies. For kidney diseases, strong evidence of a dysregulation in the alternative pathway in atypical hemolytic uremic syndrome (aHUS) led to the use of eculizumab, the first anti-C5 inhibitor available in clinical practice. Intensive fundamental research resulted in the development of subsequent new drugs, such as long-acting C5 inhibitors, oral medications, or antagonists of C5aR, the receptor for C5a. New data in the domain of C5-inhibition in glomerular diseases are still limited and mainly focus on 1) the efficacy of ravulizumab, a long-acting C5 inhibitor in aHUS, and 2) the use of avacopan, a C5aR antagonist, in antineutrophil cytoplasmic antibody vasculitis. Several new studies ongoing or planned for the next few years will evaluate the efficacy of C5 inhibition in secondary thrombotic microangiopathy, C3 glomerulopathy, membranous nephropathy, or immunoglobulin A nephropathy

Statins and Clarithromycin : a dangerous combination. Case report and review of the literature.

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Defects in complement and "secondary" hemolytic uremic syndrome

The thrombotic microangiopathy syndromes are extraordinarily diverse. Most thrombotic microangiopathy syndromes, ∼90%, occur in the setting of coexisting diseases and have been termed secondary hemolytic uremic syndrome (HUS), while a subset of thrombotic microangiopathy syndromes occur on the background of complement gene variants and are termed primary atypical HUS. 1 Le Clech et al.2 recently reported the low prevalence of such variants in patients with secondary HUS and poor clinical outcomes. [...

Streptococcus Pneumoniae Bacteremia with Acute Kidney Injury and Transient ADAMTS13 Deficiency

A 43-year-old woman with a medical history of splenectomy for immune thrombocytopenic purpura was diagnosed with Streptococcus pneumoniae bacteremia. Her initial complaints were fever and more importantly painful extremities that appeared cyanotic. During her hospitalisation, she never developed cardiocirculatory failure but presented acute kidney injury (AKI) with oliguria. Laboratory investigations confirmed AKI with serum creatinine 2.55 mg/dL which peaked at 6.49 mg/dL. There was also evidence for disseminated intravascular coagulation (DIC) with decreased platelet count, low fibrinogen levels, and high D-dimer levels. There were no signs of haemolytic anaemia. The initial ADAMTS13 activity was low (17%) but slowly recovered. Renal function progressively improved with supportive therapy, as opposed to the progressing skin necrosis. The association of DIC and low ADAMTS13 activity may have contributed to the severity of microthrombotic complications, even in the absence of thrombotic microangiopathy as thrombotic thrombocytopenic purpura (TTP) or pneumococcal-associated haemolytic uremic syndrome (pa-HUS)

The natural course of pregnancies in women with primary atypical haemolytic uraemic syndrome and asymptomatic relatives

Pregnancy has been linked to various microangiopathies, including primary atypical haemolytic uraemic syndrome (aHUS). Complement dysregulation, often linked to rare variants in complement genes, is key for primary aHUS to manifest and may play a role in pregnancy complications of the mother and fetus. The burden of such complications is unknown, making counselling of women with primary aHUS and asymptomatic relatives difficult. We analyzed the maternal and fetal outcomes of 39 pregnancies from 17 women with primary aHUS and two asymptomatic relatives. Seven out of 39 pregnancies were complicated by pregnancy-associated aHUS. Five out of 32 pregnancies not linked to pregnancy-associated aHUS were complicated by pre-eclampsia or HELLP. Rare genetic variants were identified in 10 women (asymptomatic relatives, n = 2) who had a total of 14 pregnancies, including 10 uncomplicated pregnancies. Thirty-five out of 39 pregnancies resulted in live birth. Eight out of 19 women had progressed to end-stage kidney disease, with an incidence of 2·95 (95% confidence interval, 1·37-5·61) per 100 person-years after the first pregnancy. Thus, we emphasized the frequency of successful pregnancies in women with primary aHUS and asymptomatic relatives. Pregnancies should be monitored closely. Rare genetic variants cannot predict the risk of a given pregnancy