Background Dent disease is an X-linked disorder characterized by low molecular weight proteinuria (LMWP), hypercalciuria, nephrolithiasis and chronic kidney disease (CKD). It is caused by mutations in the chloride voltage-gated channel 5 (CLCN5) gene (Dent disease-1), or in the OCRL gene (Dent disease-2). It is associated with chronic metabolic acidosis; however metabolic alkalosis has rarely been reported. Case presentation We present a family with Dent-2 disease and a Bartter-like phenotype. The main clinical problems observed in the proband included a) primary phosphaturia leading to osteomalacia and stunted growth; b) elevated serum calcitriol levels, leading to hypercalcemia, hypercalciuria, nephrolithiasis and nephrocalcinosis; c) severe salt wasting causing hypotension, hyperaldosteronism, hypokalemia and metabolic alkalosis; d) partial nephrogenic diabetes insipidus attributed to hypercalcemia, hypokalemia and nephrocalcinosis; e) albuminuria, LMWP. Phosphorous repletion resulted in abrupt cessation of hypercalciuria and significant improvement of hypophosphatemia, physical stamina and bone histology. Years later, he presented progressive CKD with nephrotic range proteinuria attributed to focal segmental glomerulosclerosis (FSGS). Targeted genetic analysis for several phosphaturic diseases was unsuccessful. Whole Exome Sequencing (WES) revealed a c.1893C > A variant (Asp631Glu) in the OCRL gene which was co-segregated with the disease in male family members. Conclusions We present the clinical characteristics of the Asp631Glu mutation in the OCRL gene, presenting as Dent-2 disease with Bartter-like features. Phosphorous repletion resulted in significant improvement of all clinical features except for progressive CKD. Angiotensin blockade improved proteinuria and stabilized kidney function for several years. Graphical abstract
Renal hypomagnesemia syndromes involving CNNM2 protein pathogenic variants are associated with variable degrees of neurocognitive dysfunction and hypomagnesemia. Here, we report a family with a novel CNNM2 p.Pro482Ala variant, presenting with overt hypomagnesemia and mild neurological involvement (autosomal dominant renal hypomagnesemia 6, HOMG6, MIM# 613882). Using a bioinformatics approach, we showed that the p.Pro482Ala amino acid substitution causes a 3D conformational change in CNNM2 structure in the cystathionin beta synthase (CBS) domain and the carboxy-terminal protein segment. A novel finding was that aldosterone inhibition with spironolactone helped to alleviate hypomagnesemia and symptoms in the proband.
Under the term cardiorenal syndrome (CRS) falls an increasing number of patients who present with combined heart and kidney dysfunction. Despite the increasing knowledge concerning CRS pathophysiology, diagnosis, and treatment, many of the aforementioned aspects remain obscure in everyday clinical practice. Some of the challenges that clinicians face when they treat CRS nowadays is the need for a patient-centered management with early diagnosis, early intervention, the distinction of true kidney injury from permissive renal function deterioration during decongestion therapy, and the development of therapeutic algorithms to guide therapy.
Background and Aims Tubulointerstitial nephritis with uveitis (TINU) syndrome is a rare, but probably under-diagnosed, immune-mediated clinical entity, characterized by simultaneous renal and ocular manifestations Diagnosis requires exclusion of all other causes of tubulointerstitial nephritis (TIN). We present six patients with clinical, laboratory and renal biopsy findings consistent with TINU syndrome Method Medical records review. All patients underwent renal biopsy. Histochemical (pas, masson, silver, Congo-red) and immunohistochemical stains for immune cell populations (CD3, CD20, CD4, CD8, PGM1, CD138) and for the assessment of β2-microglobulin were conducted. Electron microscopy (ΕΜ) was also performed. Results All our patients experienced ocular and renal manifestations, defined by bilateral uveitis, photosensitivity, and decline of renal function. In some patients, increased serum creatinine was accompanied by non-nephrotic range proteinuria, glucosuria or “full blown” Fanconi syndrome. The rest of the laboratory evaluation was normal apart from the presence of elevated erythrocyte sedimentation rate and urine β2-microglobulin. Follow-up, ranged from 18 months to 10 years. Histological evaluation revealed interstitial inflammatory infiltration consisting of lymphocytes, with a T-cell predominance, along with several macrophages. Inflammation severity varied, with some showing scarce foci of immune cell clusters, while others demonstrated a dense, diffuse interstitial infiltration. Interestingly, in two cases, non-necrotic, ill-defined granulomas were detected. Tubulitis was also encountered in some patients. A divergence was noted regarding chronicity index, with different levels of tubular atrophy, interstitial fibrosis and global glomerulosclerosis among different cases. β2-Microglobulin immunohistochemical evaluation revealed diminution of cytoplasmic staining in tubular epithelial cells compared to control kidneys. A notable finding derived from ΕΜ was the presence, in one patient, of scattered granular electron-dense-deposits along tubular basement membranes. First-line treatment included steroids, supplemented in some cases by additional immunosuppressive agents. Three patients experienced partial or complete response. Progressive renal damage was observed in a case with severe chronic lesions and persistence of inflammation-triggering factor (illicit substance). Conclusion Our cases seem to represent progressive stages within the continuum of disease evolution. Patients with more prominent inflammation might represent a more initial state, while those with more severe chronicity index, probably depict more advanced stages. While the predominance of T-cells predicates a cell-mediated autoimmune mechanism, as the driving force of the disease occurrence, the presence of immune-complexes in more advanced stages might indicate the involvement of humoral immunity as a late event during disease course.
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