Kimberley Oliver

Atypical HUS associated with severe, unexpected antibody‐mediated rejection post kidney transplant

We present a case of an unsensitized patient with end‐stage kidney disease secondary to atypical haemolytic uremic syndrome (aHUS) with mutations in CD46/MCP and CFH who developed severe, intractable antibody‐mediated rejection (ABMR) unresponsive to therapy post kidney transplantation. There were no haematological features of thrombotic microangiopathy. The patient received standard induction therapy and after an initial fall in serum creatinine, severe ABMR developed in the setting of urosepsis. Despite maximal therapy with thymoglobulin, plasma exchange and methylprednisolone, rapid graft loss resulted and transplant nephrectomy was performed. Luminex at 4 weeks showed a new DSA and when repeated after nephrectomy showed antibodies to each of the 5 mismatched antigens with high MFI. The rate of recurrence of disease in patients with aHUS referred for transplantation is 50% and is associated with a high rate of graft loss. It is dependent in part on the nature of the mutation with circulating factors CFH and CFI more likely to cause recurrent disease than MCP which is highly expressed in the kidney. There is increasing interest in the role of complement in the development and propagation of ABMR via terminal complement activation. This case suggesting that dysregulation of the alternative complement pathway within the transplant kidney may have contributed to the severe AMR. Very little is known about the impact of complement dysregulation and the development of anti HLA antibodies however the strength of HLA antibody formation was prominent in this case.

Life-threatening adenovirus infection in a kidney transplant recipient

Adenovirus causes 5–10% of all childhood febrile illnesses [1]. In the immunocompetent host, infection is usually associated with mild, self-limiting upper respiratory tract syndromes. Most individuals have serologic evidence of prior adenoviral infection by age 10 [1]. Following initial infection, adenovirus establishes lifelong latent infection in lympho-epithelial tissues [2]. In immunocompromised hosts, the spectrum of adenovirus infection can range from asymptomatic shedding to fatal disseminated disease [2]. It may represent primary infection, usually the case in paediatric transplant recipients, or reactivation of latent disease. Latent viruses may be of donor or recipient origin [2]. Adenovirus infection has been documented in solid organ transplantation, but is relatively rare and therefore a paucity of epidemiologic data exists. This case of adenovirus infection in a kidney transplant recipient is unusual for the severity of allograft dysfunction and the life-threatening nature of disease. It highlights the need for consideration of adenovirus as a cause of fever of unknown origin in the post-transplant setting. Potential therapeutic options are discussed, including use of cidofovir in a dialysis-dependent patient.

Decreased apoptosis repressor with caspase recruitment domain confers resistance to sunitinib in renal cell carcinoma through alternate angiogenesis pathways.

Apoptosis repressor with caspase recruitment domain (ARC), an endogenous inhibitor of apoptosis, is upregulated in a number of human cancers, thereby conferring drug resistance and giving a rationale for the inhibition of ARC to overcome drug resistance. Our hypothesis was that ARC would be similarly upregulated and targetable for therapy in renal cell carcinoma (RCC). Expression of ARC was assessed in 85 human RCC samples and paired non-neoplastic kidney by qPCR and immunohistochemistry, as well as in four RCC cell lines by qPCR, Western immunoblot and confocal microscopy. Contrary to expectations, ARC was significantly decreased in the majority of clear cell RCC and in three (ACHN, Caki-1 and 786-0) of the four RCC cell lines compared with the HK-2 non-cancerous human proximal tubular epithelial cell line. Inhibition of ARC with shRNA in the RCC cell line (SN12K1) that had shown increased ARC expression conferred resistance to Sunitinib, and upregulated interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF). We therefore propose that decreased ARC, particularly in clear cell RCC, confers resistance to targeted therapy through restoration of tyrosine kinase-independent alternate angiogenesis pathways. Although the results are contrary to expectations from other cancer studies, they were confirmed here with multiple analytical methods. We believe the highly heterogeneous nature of cancers like RCC predicate that expression patterns of molecules must be interpreted in relation to respective matched non-neoplastic regions. In the current study, this procedure indicated that ARC is decreased in RCC.

Hydralazine-induced anti-neutrophil cytoplasmic antibody-positive renal vasculitis presenting with a vasculitic syndrome, acute nephritis and a puzzling skin rash: a case report

IntroductionAnti-neutrophil cytoplasmic antibody-associated vasculitis has been associated with many drugs and it is a relatively rare side effect of the antihypertensive drug hydralazine. The diagnosis and management of patients who have anti-neutrophil cytoplasmic antibody-associated vasculitis may be challenging because of its relative infrequency, variability of clinical expression and changing nomenclature. The spectrum of anti-neutrophil cytoplasmic antibody-associated vasculitis is wide and can be fatal. This case documents a 62-year-old woman who presented with hydralazine-induced anti-neutrophil cytoplasmic antibody-positive renal vasculitis with a puzzling cutaneous rash.Case presentationWe report a rare case of hydralazine-induced anti-neutrophil cytoplasmic antibody-associated vasculitis in a 62-year-old Caucasian woman who presented with a vasculitic syndrome with a sore throat, mouth ulcers and otalgia after several months of constitutional symptoms. She then proceeded to develop a rash over her right lower limb. Clinically, the rash had features to suggest Sweet’s syndrome, but also had some appearances consistent with embolic phenomena and did not have the appearance of palpable purpure usually associated with cutaneous vasculitis. Differential diagnoses were hydralazine-associated Sweet’s syndrome, streptococcal-induced cutaneous eruption or an unrelated contact dermatitis. A midstream urine sample detected glomerular blood cells in the setting of anti-neutrophil cytoplasmic antibody-positive renal vasculitis and Streptococcus pyogenes bacteremia. A renal biopsy revealed a pauci-immune, focally necrotizing glomerulonephritis with small crescents. Her skin biopsy revealed a heavy neutrophil infiltrate involving the full thickness of the dermis with no evidence of a leucocytoclastic vasculitis, but was non-specific. She was initially commenced on intravenous lincomycin for her bloodstream infection and subsequently commenced on immunosuppression after cessation of hydralazine. The patient was subsequently discharged from hospital after a rapid clinical improvement.ConclusionHydralazine-induced anti-neutrophil cytoplasmic antibody-positive renal vasculitis is a rare adverse effect and can present with a severe vasculitic syndrome with multiple organ involvement. Features of this association include the presence of high titres of anti-myeloperoxidase-anti-neutrophil cytoplasmic antibody with multi-antigenicity, positive anti-histone antibodies and the lack of immunoglobulin and complement deposition histopathogically. A rash that is characteristic of Sweet’s syndrome has also been described as an association. Prompt cessation of hydralazine may be sufficient to reverse disease activity but immunosuppression may be needed for definite treatment.

Mini review: A unique case of crescentic C3 glomerulonephritis

Kidney involvement is an under‐recognized complication of non‐Hodgkin lymphomas. They occur in a variety of mechanisms and differ widely in their clinical presentation. We take this opportunity to report a case of a 65 year‐old man who developed a rapidly progressive glomerulonephritis within days after completing his first cycle of R‐CHOP (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, Prednisolone) chemotherapy for newly diagnosed mantle cell lymphoma. He was odematous, hypertensive, oliguric with nephrotic range proteinuria and an active urine sediment. A renal biopsy showed a crescentic C3 glomerulonephritis (C3GN) with no evidence endocapillary or mesangial hypercellularity. He was promptly treated with immunosuppression and dialysis, with resumption of his chemotherapy. Genetic testing on complement proteins revealed a homozygous deletion spanning the CFHR1 and CFHR3 genes. Crescentic C3GN is a rare form of kidney injury, and this is the first known case of lymphoma‐associated kidney involvement manifesting as C3GN. This article explores the possible mechanism of disease and reviews the literature of lymphoma‐related kidney disease.

Expression of Bcl-xL and Mcl-1 in the Nonmelanoma Skin Cancers of Renal Transplant Recipients

OBJECTIVES This study aims to investigate how immunosuppression influences the protein expression of antiapoptotic members of the Bcl-2 family-namely, Bcl-xL and Mcl-1-in nonmelanoma skin cancer (NMSC) and the peritumoral epidermis of renal transplant recipients. METHODS NMSC and peritumoral epidermis protein expression of Bcl-xL and Mcl-1 were assessed by immunohistochemistry in renal transplant recipients receiving tacrolimus or sirolimus and the general population not receiving immunosuppression. RESULTS NMSC from renal transplant recipients compared with patients not receiving immunosuppressant medications had a reduced Bcl-xL expression intensity (P = .042). Mcl-1 expression intensity in NMSC was decreased in tacrolimus-treated patients compared with sirolimus-treated patients and the nonimmunosuppressed population (P = .024). Bcl-xL expression intensity was increased in peritumoral epidermis compared with NMSC (P = .002). CONCLUSIONS It was shown for the first time that Bcl-xL and Mcl-1 expression are widespread in the peritumoral epidermis and NMSC of renal transplant recipients. Importantly in NMSC, Bcl-xL expression was reduced with immunosuppression exposure, and Mcl-1 expression was reduced in tacrolimus-treated compared with sirolimus-treated patients.

An unusual case of severe acute tubular necrosis

guidewires but to our knowledge this is the first case of a fractured guidewire that ultimately lodged in the right ventricle with no clinical signs or complications for the patient. The lesson to be learned from this case is that fracture of the wire is possible, due to, for example, the manufacturing process. Therefore, during the procedure, the operator should avoid excessive folding of the wire, making sure to inspect the catheter guidewire after removal and carefully examining the X-ray results. However, this may not be enough to entirely avoid the problem as a guidewire that was easily inserted and normally shaped after removal can still be associated with fracture and embolism and X-rays may have a delay in demonstrating a retained foreign body.

Advances in Antibody Mediated Rejection

Kidney transplantation is considered the treatment of choice for patients with end-stage renal disease, and is associated with improved survival, better quality of life and reduced costs when compared with dialysis.[1, 2] However, the renal transplantation waiting list is forever growing, out of proportion to the number of donors.[2, 3] Therefore it is all the more crucial to develop strategies to extend the life and functionality of every allograft.