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• W1986607500 abstract "The patient is an 18-month-old boy from Romania, whose parents are healthy and non-consanguineous. In October 2005, periorbital and lower extremities edema were first noted while the child was in general good conditions and without any sign of acute infectious problem. For generalized edema, he was admitted at a pediatric nephrology unit where heavy proteinuria (>10 g day−1), with serum high cholesterol levels (>500 mg per 100 ml) and hypoalbuminemia (<1.5 g per 100 ml) were rapidly discovered. The urine microscopic analysis showed moderate microscopic hematuria, epithelial cells, and granular casts. Serum creatinine was normal. Serology was negative for hepatitis B, hepatitis C, EBV, HIV, and parvovirus B19. Complement profile was normal and tests for autoimmunity (ANA, nDNA, and ANCA) were negative. No focal neurological defects were observed. He was immediately treated with diuretics and infusions of albumin and soon started prednisone 2.3 mg kg−1 day−1. After the first 4 weeks of therapy, his edema increased and he developed anasarca. ACE inhibitors (5 mg per 1.73 m2) were added to the therapy, and a genetic approach considering major inherited diseases was adopted that excluded mutations relative to NPHS1 and NPHS2. Then, a renal biopsy was performed. As the clinical features did not improve, the patient underwent a unilateral nephrectomy and started a peritoneal dialysis program. Part of the clinical history of this patient has been described in detail elsewhere,1.Diomedi-Camassei F. Di Giandomenico S. Santorelli F.M. et al.COQ2 nephropathy: a newly described inherited mitochondriopathy with primary renal involvement.J Am Soc Nephrol. 2007; 18: 2773-2780Crossref PubMed Scopus (252) Google Scholar while the findings on renal biopsy and nephrectomy that are crucial for a correct differential diagnosis are described together in the next paragraph. Sections from the needle biopsy (Figure 1) showed a fragment of skeletal muscle as well as renal cortex with 19 glomeruli, some of which revealed collapsing features of glomerular damage. Sections from the nephrectomy (Figure 1) showed a more advanced disease with 25% globally sclerotic glomeruli, 25% of the glomeruli having global collapse, and 50% with segmental collapse. No mesangial sclerosis was identified. Marked podocyte hypertrophy and hyperplasia with either a foamy appearance or large vacuoles, and protein reabsorption droplets were present. In addition, PAS and silver-positive small inclusion in perinuclear location, probably representing accumulation of mitochondria, were seen in podocytes and other cell types. Proximal tubules contained numerous PAS-positive vacuoles as well as optically clear vacuoles. Large microcysts, and patchy interstitial fibrosis and tubular atrophy were noted, and were also more pronounced in the nephrectomy specimen compared with the biopsy, indicating progression of the disease. Mild inflammation of lymphocytes, monocytes, and plasma cells accompanied the areas of fibrosis. Arterioles and arteries were unremarkable. Immunohistochemical analysis was performed with selected antibodies and main results are reported in Figures 2 and 3 and Table 1. Glomeruli revealed segmentally reduced synaptopodin expression and positive staining for Ki-67 in the areas of pseudocrescents formation. Contrariwise, synaptopodin expression was well preserved in the areas where podocytes were markedly hypertrophic but not hyperplastic. Podocin and β-dystroglycan expression were also preserved. Podocytes were not dysregulated in their phenotype as the expression of WT-1 was maintained and PAX2 expression, normally regulated by WT-1, was absent in podocyte but positive in parietal cells nuclei. CK 17 staining was very focally and segmentally weakly positive in parietal cells, and podocytes with a perinuclear pattern. CK 7, 8, and 19 were strongly positive, in few hyperplastic and hypertrophic podocytes and in parietal cells (1% of glomeruli). CK 20 was negative (not shown).Figure 3CKs expression in NFK, NAK, and CoQ2 CG. CK 7 is negative in S-shape body stage in NFK and mature podocyte in NAK. CK 7 is positive in some of the cells forming pseudocrescents. CK 8 is positive in some podocytes at the capillary loop stage in NFK (arrow), but it is negative in podocytes in NAK. Rare parietal cells are positive in NAK. Cells forming pseudocrescents are strongly positive for CK 8 in CoQ2 CG, indicating dedifferentiation. Parietal cells are also focally positive in CoQ2 CG. CK 17 is negative in NFK and NAK, and only weakly positive in podocytes in CoQ2 CG. CAM 5.2 is positive in some podocytes at the capillary loop stage in NFK (arrow), but it is negative in podocytes in NAK. Rare parietal cells are positive in NAK. Cells forming pseudocrescents are strongly positive for CAM 5.2 in CoQ2 CG, indicating dedifferentiation. CK 19 is positive in some podocytes at the capillary loop stage in NFK (arrow), but it is negative in podocytes in NAK. Rare parietal cells are positive in NAK. Cells forming pseudocrescents are strongly positive for CK 19 in CoQ2 CG, indicating dedifferentiation. Images of CK staining from NFK and NAK are at original magnification × 40, and images of CoQ2 CG are at original magnification × 60.View Large Image Figure ViewerDownload (PPT)Table 1Podocytes and parietal cell phenotype in normal fetal and adult kidney, and CGPodocyte phenotypeParietal cell phenotypeAbsNormal fetal kidneyNormal adult kidneyHIV- associated CGCoQ2 NP-associated CGNormal fetal kidneyNormal adult kidneyHIV-associated CGCoQ2 NP-associated CGSynaptopodin−+−−−−−−Podocin−+−+−−−−β-dystroglycan++++++++PAX2+−+−++++WT-1++−++−−−Ki-67+−+++−−−CK 7−−+ (only in pseudocrescents)+ (very focal in pseudocrescents)−+(very focal and segmental)+ (diffuse and segmental)−CK 8+ (very focal and segmental, S-shape bodies and capillary loop stage)−+ (only in pseudocrescents)+ (very focal in pseudocrescents)+ (very focal and segmental, S-shape bodies and capillary loop stage)+ (very focal and segmental)+ (diffuse and segmental)+ (very focal and segmental)CK 17−−- (?)+ (very focal in pseudocrescents)−−- (?)+ (very focal and segmental)CAM 5.2 (CK 8+CK 18)+ (very focal and segmental, S-shape bodies and capillary loop stage)−- (?)+ (very focal in pseudocrescents)+ (very focal and segmental, S-shape bodies and capillary loop stage)+ (focal and segmental)+ (diffuse and segmental)+ (very focal and segmental)CK 19+ (very focal and segmental, S-shape bodies and capillary loop stage)−+ (focally in pseudocrescents)+ (very focal and segmental in pseudocrescents)+ (very focal and segmental, S-shape bodies and capillary loop stage)+ (diffuse and segmental)+ (diffuse and segmental)+ (focal and segmental)CK 20−−−−−−−−CG, collapsing glomerulopathy.Note: ‘diffuse’≥50% of glomeruli; ‘segmental’=only few podocytes or parietal cells are positive; ‘very focal’=only <5% of the glomeruli have positive staining in podocytes or parietal cells; ‘(?)’=is probably due to sampling error, since CK 17 and CAM 5.2 were only very rarely positive (<1%) in glomeruli from the patient's nephrectomy.In CoQ2 CG, synaptopodin expression is lost only in pseudocrescents; whereas, in other forms of CG, synaptopodin is generally not expressed in all podocytes. Open table in a new tab CG, collapsing glomerulopathy. Note: ‘diffuse’≥50% of glomeruli; ‘segmental’=only few podocytes or parietal cells are positive; ‘very focal’=only <5% of the glomeruli have positive staining in podocytes or parietal cells; ‘(?)’=is probably due to sampling error, since CK 17 and CAM 5.2 were only very rarely positive (<1%) in glomeruli from the patient's nephrectomy. In CoQ2 CG, synaptopodin expression is lost only in pseudocrescents; whereas, in other forms of CG, synaptopodin is generally not expressed in all podocytes. On ultrastructural analysis, the glomerular capillary walls were wrinkled and folded. Hypertrophic podocytes revealed focal loss of primary processes, extensive foot process effacement, and contained numerous vacuoles. Many of the intracytoplasmic vacuoles appeared to be dismorphic mitochondria, from 0.78 to 1.2 μm in diameter, with absent or truncated cristae. In addition, a central double membrane ring was occasionally noted, but no classic ‘parking lot inclusions’ (paracrystalline intramitochondrial inclusions) were identified. Abnormal mitochondria were also in parietal, endothelial, and mesangial cell cytoplasm in glomeruli and fibroblast, tubular cells, smooth muscle and endothelial cells of the tubulointerstitial compartment. No electron-dense deposits or tubuloreticular inclusions were present. The fragment of skeletal muscle revealed abnormal myocytes with loss of the typical striate appearance and formation of a reddish band at the border of the cells resembling ragged red fibers. On occasion, myocytes appeared filled with vacuolated PAS-positive granules, which also were fuschinophilic on trichrome staining, in the perinuclear areas and in the region underneath the sarcolemma. Collapsing glomerulopathy (CG) associated with mitochondrial abnormalities—consider inherited mitochondriopathy. After the results of the renal biopsy, additional studies on mitochondria functionality and genetic analysis were performed on the patient's DNA. The results of the molecular workup have been described in details elsewhere.1.Diomedi-Camassei F. Di Giandomenico S. Santorelli F.M. et al.COQ2 nephropathy: a newly described inherited mitochondriopathy with primary renal involvement.J Am Soc Nephrol. 2007; 18: 2773-2780Crossref PubMed Scopus (252) Google Scholar Briefly, genes involved in Mendelian forms of mitochondrial pathologies were analyzed. First, prenyltransferase-like mitochondrial protein, the human ortholog of the murine gene responsible for a spontaneous mouse model of CG was negative. Instead, the child was found to carry a compound heterozygous mutation in the gene encoding for CoQ2 (c.590G>A (p.Arg197His) and a c.683A>G (p.Asn228Ser), which was associated with markedly decreased CoQ10 levels and complex II+III activities in the renal cortex. The c.590G>A was also heterozygous in the mother, whereas the p.Asn228Ser mutation was also heterozygous in the father and in the healthy brother. Other family members showed no relevant renal symptoms. The final diagnosis was CoQ2-associated CG. At the last follow-up, nearly 2 years after the initial presentation, the patient is on chronic peritoneal dialysis and is growing well. He is currently awaiting a renal transplantation and is treated with oral ubiquinone supplementations. His neurological examination has been checked periodically and has always been found to remain normal." @default.
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• W1986607500 date "2008-07-01" @default.
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• W1986607500 title "Collapsing glomerulopathy associated with inherited mitochondrial injury" @default.
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• W1986607500 doi "https://doi.org/10.1038/sj.ki.5002767" @default.
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