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IgA nephropathy (IgAN) is a progressive form of kidney disease defined by glomerular deposition of IgA. We performed a genome-wide association study involving 10,146 kidney biopsy-diagnosed IgAN cases and 28,751 matched controls across 17 international cohorts. We defined 30 independent genome-wide significant risk loci jointly explaining 11% of disease risk. A total of 16 loci were novel, including TNFSF4, REL, CD28, CXCL8/PF4V1, LY86, LYN, ANXA3, TNFSF8/15, REEP3, ZMIZ1, RELA, ETS1, IGH, IRF8, TNFRSF13B and FCAR. The SNP-based heritability of IgAN was estimated at 23%. We observed a positive genetic correlation between IgAN and total serum IgA levels, allergy, tonsillectomy, and several infections, and a negative correlation with inflammatory bowel disease. All significant non-HLA loci shared with serum IgA levels had a concordant effect on the risk of IgAN. Moreover, IgAN loci were globally enriched in gene orthologs causing abnormal IgA levels when genetically manipulated in mice. The explained heritability was enriched in the regulatory elements of cells from the immune and hematopoietic systems and intestinal mucosa, providing support for the pathogenic role of extra-renal tissues. The polygenic risk of IgAN was associated with early disease onset, increased lifetime risk of kidney failure, as well as hematuria and several other traits in a phenome-wide association study of 590,515 individuals. In the comprehensive functional annotation analysis of candidate causal genes across genome-wide significant loci, we observed the convergence of biological candidates on a common set of inflammatory signaling pathways and cytokine ligand-receptor pairs, prioritizing potential new drug targets.

Dear Editor: Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common inherited kidney disorder and affects up to 12 million individuals worldwide. Radiologic imaging is critical for successful management. Until recently, the treatments were only symptomatic but EMA in 2017 and FDA in 2018 approved Tolvaptan for ADPKD therapy. Renal imaging provide important diagnostic and management guidance in the monitoring of disease progression. In the past, standard radiographic imaging has not provided the accuracy necessary to reliably measure renal [...]

Purpose: Calciphylaxis or Calcific Uraemic Arteriolopathy (CUA) is a rare systemic disorder associated with endstage renal disease and carrying a very poor prognosis and high mortality. It is characterized by skin necrosis and gangrene secondary to thrombosis and calcification of dermo-epidermal arterioles. Pathogenetic mechanisms inducing calciphylaxis are for the most part unknown. Methods: We report a case of calciphylaxis in a patient on long-term haemodialysis with severe secondary hyperparathyroidism. Despite therapies for hyperparathyroidism, the injury healed only after parathyroidectomy. Results: Calciphylaxis is an obliterative vasculopathy. The role of severe hyperparathyroidism in the pathogenesis of calciphylaxis is not well understood. A unique feature is the phenotypic differentiation of smooth muscle cells into osteoid-like cells. The vascular smooth muscle cells, exposed to high inorganic phosphate levels, could be transformed into osteoblast-like cells in patients undergoing haemodialysis with a poor control of phosphate intake. Conclusions: The uraemic condition contributes to vascular smooth muscle cell apoptosis and differentiation into bone forming osteoblast-like cells resulting in medial calcification. Nowadays no effective treatments are available for the successful management of calciphylaxis.

PurposeCalciphylaxis or Calcific Uraemic Arteriolopathy (CUA) is a rare systemic disorder associated with endstage renal disease and carrying a very poor prognosis and high mortality. It is characterized by skin necrosis and gangrene secondary to thrombosis and calcification of dermo-epidermal arterioles. Pathogenetic mechanisms inducing calciphylaxis are for the most part unknown.MethodsWe report a case of calciphylaxis in a patient on long-term haemodialysis with severe secondary hyperparathyroidism. Despite therapies for hyperparathyroidism, the injury healed only after parathyroidectomy.ResultsCalciphylaxis is an obliterative vasculopathy. The role of severe hyperparathyroidism in the pathogenesis of calciphylaxis is not well understood. A unique feature is the phenotypic differentiation of smooth muscle cells into osteoid-like cells. The vascular smooth muscle cells, exposed to high inorganic phosphate levels, could be transformed into osteoblast-like cells in patients undergoing haemodialysis with a...

Leptospirosis is an emerging worldwide zoonotic disease. Renal involvement is common; it may vary from sub-clinical course with mild proteinuria and urinary sediment changes to severe renal failure. Leptospirosis-induced acute kidney injury is usually non oliguric and hypokalaemic. Renal impairment is mainly characterized by an association of interstitial and tubular damages. The most severe form of Leptospirosis, characterized by jaundice, acute kidney injury and haemorrhagic diathesis, is referred as Weil's disease. We describe a Weil's disease case with oliguric and hypokalaemic acute renal failure, hypotension, jaundice and lung haemorrhage. We performed haemodialysis treatment, steroid and antibiotic therapy with complete recovery of renal function.

To the Editor: Today in developed countries, infection-related glomerulonephritides are incommon and often associated with debilitating diseases. Legionnaires’ disease (LD) is one of the most common causes of severe community-acquired acute pneumonia in Europe and in up to 40% of cases of hospital-acquired pneumonia. The acute kidney injury (AKI) in LD is a well described complication but the renal morphology has only been reported in a few cases. The Tubulointerstitial Nephritis (TIN) is the most diagnosed histological change; instead, there [...]

Wegener Granulomatosis is a systemic Anti-Neutrophil Cytoplasmic Autoantibody-associated Vasculitis, affecting small-to-medium vessels. Clinical presentation with simultaneous involvement of kidney and upper and lower respiratory tract is unusual. We report an instructive case of WG, analyzing clinical course, laboratory, and radiological features, kidney, lung, and larynx histological pictures. Besides renal biopsy, nephrology team performed larynx and lung biopsies because of unusual clinical presentation, computed tomography chest examination, and relevant malignancy risk regarding following immunosuppressant therapy.

Sir, We read with interest the recent case report ‘Minimal change disease with interferon-β therapy for relapsing remitting multiple sclerosis’ [1]. In this paper, the authors include renal thrombotic microangiopathy (TMA) among rare side effects of interferon (IFN) therapy, more frequently described with IFN-α [2]. We report here our experience about this topic. A 36-year-old white female with a 3-year history of multiple sclerosis and normal blood pressure and renal function was admitted for acute renal failure and pulmonary oedema. Three months previously, she started subcutaneous IFN-β-1a treatment of 22 μg thrice weekly. On admission, physical examination showed high blood pressure and severe pleuropericarditis without neurological or dermatological findings. Laboratory tests revealed microangiopathic haemolytic anaemia. Other immunological and microbiological laboratory tests were unremarkable. A renal biopsy disclosed signs of TMA; among 43 glomeruli, light microscopy revealed focal ischaemic signs and mild mesangial cell proliferation; vessel narrowing with thrombi and thickening of arteriolar walls and intimal onion skin-like swelling; light interstitial lymphomonocytic infiltration and focal tubular atrophy. Immunofluorescence showed mesangial IgM, C1q and fibrinogen staining. A diagnosis of haemolytic–uraemic syndrome was made. She was treated with transfusions, haemodialysis, plasma exchange and methylprednisolone i.v. followed by oral prednisone. Her cardiac function improved, and haematological signs progressively disappeared, but renal function did not recover. IFN-β treatment was discontinued. She is now receiving peritoneal dialysis treatment. IFN-α is known to cause a variety of renal lesions, including TMA [3,4], but to our knowledge, our observation is the first report of TMA induced by INF-β. Editorial note: This letter had been sent to Aravindan A. et al., but we did not receive a response. Conflict of interest statement. None declared.