Dominique Nochy

Thrombotic Microangiopathy and Purtscher-Like Retinopathy Associated With Adult-Onset Still's Disease: A Role for Glomerular Vascular Endothelial Growth Factor?

Adult-onset Still’s disease (AOSD) is a rare systemic in-flammatory disorder of unknown etiology. It is character-ized by daily high spiking fevers associated with an eva-nescent rash, arthritis, and multiorgan involvement (1,2).HerewereportapatientwithAOSD-associatedthromboticmicroangiopathy (TMA) combining central nervous sys-tem and renal involvement, associated with 2 severe andunusual complications: Purtscher-like retinopathy and ex-tremity gangrene. Interestingly, renal biopsy showed de-creased expression of glomerular vascular endothelialgrowth factor (VEGF), which could have triggered theTMA and may represent a new pathophysiologic mecha-nism in human TMA.

Antineutrophil cytoplasmic antibody-associated vasculitides and IgG4-related disease: A new overlap syndrome

OBJECTIVE Atypical manifestations have been described in patients with ANCA-associated vasculitides (AAV), such as pachymeningitis, orbital mass or chronic periaortitis. Because these manifestations have been associated to the spectrum of IgG4-related disease (IgG4-RD), we hypothesized that both diseases could overlap. METHODS We conducted a European retrospective multicenter observational study including patients fulfilling ACR and Chapel Hill criteria for AAV and IgG4-RD Comprehensive Diagnostic Criteria. RESULTS Eighteen patients were included (median age 55.5years, 13 men). AAV and IgG4-RD were diagnosed concomitantly in 13/18 (72%) patients; AAV preceded IgG4-RD in 3/18 (17%) while IgG4-RD preceded AAV in 2/18 (11%). AAV diagnoses included granulomatosis with polyangiitis in 14 (78%), microscopic polyangiitis in 3 (17%), and eosinophilic granulomatosis with polyangiitis in one case. IgG4-RD diagnosis included definite IgG4-RD in 5 (28%) cases, probable IgG4-RD in 5 (28%) and possible IgG4-RD in 8 (44%). IgG4-RD manifestations were chronic periaortitis in 9/18 (50%) patients, orbital mass and tubulointerstitial nephritis in 4 (22%) cases, prevertebral fibrosis in 3 (17%), pachymeningitis and autoimmune pancreatitis in 2 (11%) cases. Patients required median number of 2 (range 0-4) lines of immunosuppressants in combination with glucocorticoids. During the follow-up (median 49,8months, range 17,25-108months), AAV manifestations relapsed in 10/18 (56%) cases and IgG4-RD lesions in 5/18 (28%). When used, mainly for relapses, rituximab showed response in all cases. CONCLUSION AAV and IgG4-RD may overlap. Clinicians should consider that atypical manifestations during AAV could be related to IgG4-RD rather than to refractory granulomatous or vasculitic lesions.

Comments on the Oxford classification of IgA nephropathy

We congratulate the authors of the recent articles on the Oxford classification of IgA nephropathy (IgAN) on their rigorous scientific approach. Our preliminary results in a study of IgAN broadly support their findings. However we would like to make two additional points. First, the rubric segmental glomerulosclerosis in the Oxford classification actually comprises at least two different lesions. First is focal segmental glomerulosclerosis (FSGS), a separate category in the Haas classification of IgAN. Second are the sequelae of segmental proliferative and necrotic lesions. Segmental lesions occurred in 66% of our patients. Of these, 47% had visible intracapillary hyalinosis lesions and, in our opinion, represent definite FSGS. The other 53% had only capsular adhesions and epithelial changes, and thus were indeterminate, possibly representing FSGS but also possibly other pathological processes. Those with frank FSGS had a poor prognosis, with 50% ending on dialysis, compared with 4.1% of patients without segmental lesions (P1⁄4 0.00001). Those with indeterminate segmental lesions had a course intermediate between the other two groups, with 36.1% ending on dialysis. Another lesion not included in the Oxford classification is thrombotic microangiopathy (TMA). TMA has been described in IgAN, usually associated with severe/malignant hypertension. TMA was present in 53% of our patients, including 26% of normotensive patients. It has a poor prognosis, with 47% of patients ending on dialysis, compared with 9% of patients without TMA (P1⁄4 0.000002). Thus, TMA must be considered with care in evaluating biopsies with IgAN, and should perhaps be added to the Oxford classification.

Genetic and pharmacological inhibition of microRNA-92a maintains podocyte cell cycle quiescence and limits crescentic glomerulonephritis

Crescentic rapidly progressive glomerulonephritis (RPGN) represents the most aggressive form of acquired glomerular disease. While most therapeutic approaches involve potentially toxic immunosuppressive strategies, the pathophysiology remains incompletely understood. Podocytes are glomerular epithelial cells that are normally growth-arrested because of the expression of cyclin-dependent kinase (CDK) inhibitors. An exception is in RPGN where podocytes undergo a deregulation of their differentiated phenotype and proliferate. Here we demonstrate that microRNA-92a (miR-92a) is enriched in podocytes of patients and mice with RPGN. The CDK inhibitor p57Kip2 is a major target of miR-92a that constitutively safeguards podocyte cell cycle quiescence. Podocyte-specific deletion of miR-92a in mice de-repressed the expression of p57Kip2 and prevented glomerular injury in RPGN. Administration of an anti-miR-92a after disease initiation prevented albuminuria and kidney failure, indicating miR-92a inhibition as a potential therapeutic strategy for RPGN. We demonstrate that miRNA induction in epithelial cells can break glomerular tolerance to immune injury.Crescentic rapidly progressive glomerulonephritis is a severe form of glomerula disease characterized by podocyte proliferation and migration. Here Henique et al. demonstrate that inhibition of miRNA-92a prevents kidney failure by promoting the expression of CDK inhibitor p57Kip2 that regulates podocyte cell cycle.

Sarcoidosis presenting as severe renin-dependent hypertension due to kidney vascular injury

Renal sarcoidosis embraces a wide variety of clinical patterns. Renal vascular involvement has seldom been reported and usually in the setting of systemic vasculitis. We report the case of a 22-year-old patient in whom inaugural manifestation of renal sarcoidosis consisted of severe hypertension associated with bilateral perfusion defects and tumour-like nodules. In the setting of renal sarcoidosis, our case suggests that renin-dependant hypertension may arise from renal ischaemia as a result of extrinsic compression of kidney blood vessels due to severe granulomatous inflammation.