David Kipgen

MicroRNA-214 Antagonism Protects against Renal Fibrosis

Renal tubulointerstitial fibrosis is the common end point of progressive renal disease. MicroRNA (miR)-214 and miR-21 are upregulated in models of renal injury, but the function of miR-214 in this setting and the effect of its manipulation remain unknown. We assessed the effect of inhibiting miR-214 in an animal model of renal fibrosis. In mice, genetic deletion of miR-214 significantly attenuated interstitial fibrosis induced by unilateral ureteral obstruction (UUO). Treatment of wild-type mice with an anti-miR directed against miR-214 (anti-miR-214) before UUO resulted in similar antifibrotic effects, and in vivo biodistribution studies demonstrated that anti-miR-214 accumulated at the highest levels in the kidney. Notably, in vivo inhibition of canonical TGF-β signaling did not alter the regulation of endogenous miR-214 or miR-21. Whereas miR-21 antagonism blocked Smad 2/3 activation, miR-214 antagonism did not, suggesting that miR-214 induces antifibrotic effects independent of Smad 2/3. Furthermore, TGF-β blockade combined with miR-214 deletion afforded additional renal protection. These phenotypic effects of miR-214 depletion were mediated through broad regulation of the transcriptional response to injury, as evidenced by microarray analysis. In human kidney tissue, miR-214 was detected in cells of the glomerulus and tubules as well as in infiltrating immune cells in diseased tissue. These studies demonstrate that miR-214 functions to promote fibrosis in renal injury independent of TGF-β signaling in vivo and that antagonism of miR-214 may represent a novel antifibrotic treatment in the kidney.

ANCA-Associated Renal Vasculitis Following Anti–Tumor Necrosis Factor α Therapy

We report the case of a 62-year-old woman with rheumatoid arthritis treated with adalimumab, an anti-tumor necrosis factor alpha drug, who presented with 4 weeks of lethargy, upper respiratory tract symptoms, a vasculitic skin rash, and rapidly deteriorating renal function. She had cytoplasmic antineutrophil cytoplasmic antibodies and skin and renal biopsy specimens diagnostic of small vessel vasculitis and necrotizing crescentic glomerulonephritis, respectively. After immunosuppressive therapy and discontinuation of adalimumab therapy, vasculitis resolved and renal function recovered. This is the first report of antineutrophil cytoplasmic antibody associated necrotizing glomerulonephritis with adalimumab.

Kidney biopsy findings in primary Sjögren syndrome

BACKGROUND Renal involvement is rare in primary Sjögren syndrome (PSS). In this study, we examined renal biopsy findings in patients with PSS and correlated them with their clinical and renal findings. METHODS Twenty-five patients with PSS who underwent renal biopsies from two renal units in Scotland between 1978 and 2013 were identified from renal biopsy database. We examined the renal morphologic, clinical and renal findings at the time of renal biopsy, renal and patient outcomes. RESULTS The diagnosis of PSS preceded renal biopsy in 18/25 patients. In this group, the median duration of the disease was 5.5 years. Significant proteinuria, combined microscopic haematuria and proteinuria and reduced renal excretory function were found in 76, 56 and 84% of patients, respectively. The 3-year actuarial patient survival was significantly lower in patients with glomerulonephritis as compared with tubulointerstitial nephritis (66 versus 100%, P = 0.02). There was no difference in 3-year actuarial renal survival between these two groups (92 versus 92%, P = 1.0). CONCLUSIONS Renal biopsy is rare in PSS and often reveals diverse pathological findings. Glomerulonephritis, as compared with tubulointerstitial nephritis, is associated with higher early mortality. Further studies are needed to evaluate the utility of renal biopsy and its impact on disease management.

A rare cause of nephrotic syndrome in autosomal dominant polycystic kidney disease

We report the case of a 49-year-old lady who presented with hypertension, breathlessness and malaise. She was thrombocytopenic, with polycystic kidneys on imaging, and was found to have nephrotic syndrome. Serological results were consistent with systemic lupus erythematosus (SLE) and a renal biopsy confirmed WHO class V lupus nephritis. This is the first reported case of nephrotic syndrome due to lupus nephritis in a patient with autosomal dominant polycystic kidney disease (ADPKD) and underlines the importance of renal biopsy in patients with ADPKD and nephrotic range proteinuria.

Early Focal Segmental Glomerulosclerosis as a Cause of Renal Allograft Primary Nonfunction

Background. Primary focal segmental glomerulosclerosis (FSGS) is one of the commonest causes of glomerular disease and if left untreated will often progress to established renal failure. In many cases the best treatment option is renal transplantation; however primary FSGS may rapidly recur in renal allografts and may contribute to delayed graft function. We present a case of primary nonfunction in a renal allograft due to biopsy-proven FSGS. Case Report. A 32-year-old man presented with serum albumin of 22 g/L, proteinuria quantified at 12 g/L, and marked peripheral oedema. Renal biopsy demonstrated tip-variant FSGS. Despite treatment, the patient developed progressive renal dysfunction and was commenced on haemodialysis. Cadaveric renal transplantation was undertaken; however this was complicated by primary nonfunction. Renal biopsies failed to demonstrate evidence of acute rejection but did demonstrate clear evidence of FSGS. The patient was treated to no avail. Discussion. Primary renal allograft nonfunction following transplantation is often due to acute kidney injury or acute rejection. Recurrent FSGS is recognised as a phenomenon that drives allograft dysfunction but is not traditionally associated with primary nonfunction. This case highlights FSGS as a potentially aggressive process that, once active in the allograft, may prove refractory to targeted treatment. Preemptive therapies in patients deemed to be at high risk of recurrent disease may be appropriate and should be considered.

Renal artery aneurysm in a cadaveric donor kidney

overdose, where continuous venovenous haemodiafiltration (CVVHDF) led to a significant decrease in blood levels. A 54-year-old woman was admitted to our intensive care unit after a VA overdose. She was unconscious and required mechanical ventilation. Blood VA level on admission was 1664 μg/mL. The patient’s condition progressively worsened. The day after admission, she demonstrated most of the VA poisoning symptoms. Despite supportive care, her status deteriorated, leading to multiple organ failure. CVVHDF was initiated for acute renal failure and anuria with an AN69 hollow-fibre dialyzer of 0.9 m2 (Hospal, Lyon, France), using the predilutional method, with blood flow set at 120 mL/min. The dialysate and substitution fluid rates were 1000 mL/min and 2000 mL/min, respectively (Hemosol, Hospal, Lyon, France). Arterial blood samples were collected from the sampling point of the dialyzer, which is at a point before the blood passes through the haemofilter. Paired ultradiafiltrate samples were collected. VA concentration was measured by a fluorescence polarization immunoassay. VA clearance was determined as Cl = [CUF ∗ VUF]/[CA ∗ t] where CUF and CA are ultradiafitrate and arterial serum VA concentrations at the midpoint of the time of collection, respectively; VUF is ultradiafiltrate volume and t is the time of collection. The sieving coefficient (Sc) was calculated as Sc = CUF/CA (Table 1). VA is a small (144 Da), water-soluble molecule with a volume of distribution ranging from 0.1 to 0.5 L/kg. At therapeutic levels, VA is almost completely bound to plasma proteins; thus drug removal by extrarenal epuration is negligible. In the case of overdose, a much larger percentage of VA is unbound and so accessible to extrarenal epuration techniques [3]. Johnson [4] reported that the use of HD with a high dialysate flow rate (800 mL/min) is effective in obtaining excellent clearance of the drug (>80 mL/min). Hicks [5] found a marked decrease in serum VA occurring after 7.7 h of HD, and an improvement of VA half-life from 31.3 to 2.25 h. HD can be difficult to perform (particularly with high blood or dialysate flow rates) in patients with haemodynamic instability. In such a case, continuous renal replacement therapies may be an alternative, but very few data are available on their efficacy. Our results suggest that CVVHDF, although less effective than HD, significantly lowers VA blood concentration in the case of overdose. Indeed, no definitive conclusion about the clinical usefulness of this technique can be drawn from these data. Conflict of interest statement. None declared.

Erratum to: Risk factors for progression in children and young adults with IgA nephropathy: an analysis of 261 cases from the VALIGA European cohort

Rosanna Coppo & Danilo Lofaro & Roberta R. Camilla & Shubha Bellur & Daniel Cattran & H. Terence Cook & Ian S. D. Roberts & Licia Peruzzi & Alessandro Amore & Francesco Emma & Laura Fuiano & Ulla Berg & Rezan Topaloglu & Yelda Bilginer & Loreto Gesualdo & Rosaria Polci & Malgorzata Mizerska-Wasiak & Yasar Caliskan & Sigrid Lundberg & Giovanni Cancarini & Colin Geddes & Jack Wetzels & Andrzej Wiecek & Magdalena Durlik & Stefano Cusinato & Cristiana Rollino & Milena Maggio & Manuel Praga & Hilde K. Smerud & Vladimir Tesar & Dita Maixnerova & Jonathan Barratt & Teresa Papalia & Renzo Bonofiglio & Gianna Mazzucco & Costantinos Giannakakis & Magnus Soderberg & Diclehan Orhan & Anna Maria Di Palma & JadwigaMaldyk &YaseminOzluk &Birgitta Sudelin &Regina Tardanico &DavidKipgen & Eric Steenbergen & Henryk Karkoszka & Agnieszka Perkowska-Ptasinska & Franco Ferrario & Eduardo Gutierrez & Eva Honsova

AA amyloidosis in a patient with Langerhans cell histiocytosis

We report the case of a 37-year-old woman who presented with progressive renal dysfunction and proteinuria, in whom renal biopsy confirmed a diagnosis of AA amyloidosis. No evidence of chronic suppurative infection, connective tissue disease or malignancy was found. A past history of Langerhans cell histiocytosis (LCH) diagnosed in childhood was noted for which the patient had been successfully treated with surgical excision, corticosteroids, radiotherapy and chemotherapy. Renal disease in LCH is not widely recognized and thus we describe a patient with LCH in whom AA amyloidosis developed in the absence of any other established cause.