Edward P. Nord

Epstein-Barr virus infection of renal proximal tubule cells: possible role in chronic interstitial nephritis

Chronic interstitial nephritis frequently accompanies renal diseases of different etiologies. Far less common is the entity of primary interstitial nephritis wherein the glomerular and vascular structures of the kidney are not the primary focus of the disease process. Using in situ hybridization and the polymerase chain reaction, we detected DNA from the Epstein-Barr Virus (EBV) exclusively in renal tissue of patients with the idiopathic variety of chronic interstitial nephritis. The EBV genome, but not that of cytomegalovirus or adenovirus, was detected primarily in renal proximal tubule cells. Furthermore, the CD21 antigen, which serves as the receptor for EBV in B lymphocytes, was detected by immunocytochemistry primarily on proximal tubule cells and was markedly upregulated in the EBV-infected tissue. Western blot analysis of primary cultures of normal proximal tubule cells identified a 140-kDa protein, confirming the expression of the CD21 antigen. Colocalization experiments using proximal and distal tubule markers confirmed that EBV DNA and the CD21 antigen are found primarily in proximal tubule cells. EBV infection of renal proximal tubular cells may participate in evoking a cellular immune response that results in a damaged renal interstitium.

IL-8 amplifies CD40/CD154-mediated ICAM-1 production via the CXCR-1 receptor and p38-MAPK pathway in human renal proximal tubule cells

Activation of the CD40 receptor by its cognate ligand, CD154, results in interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) production and increased intercellular adhesion molecule-1 (ICAM-1) expression in proximal tubule cells (PTCs). The independent role of these two proinflammatory chemokines, IL-8 and MCP-1, in inciting an inflammatory response in PTCs was explored. Exposure of primary cultures of human renal PTCs to recombinant IL-8 and MCP-1 resulted in increased ICAM-1 expression measured by quantitative real-time PCR, but confirmed only for IL-8 by immunoblot. The mechanism of action of IL-8 was explored in further detail. Immunohistochemistry identified both the CXCR-1 and CXCR-2 receptors, confirmed by RT-PCR, immunoprecipitation, immunoblot, and FACS analysis. IL-8 increased ICAM-1 expression only via the CXCR-1 receptor, which in turn resulted in activation of the p38 mitogen-activated protein kinase (MAPK) pathway; neither the extracellular signal-related kinase (ERK) 1/2 MAPK pathway nor the stress-activated protein kinase (SAPK)/c-Jun NH(2) terminal kinase (JNK) pathway was involved. CD154/CD40-mediated ICAM-1 upregulation was not affected by preincubation of monolayers with the CXCR-1 blocking antibody, indicating that ICAM-1 expression occurs independent of CD154-mediated IL-8 production. Coincubation of monolayers with both CD154 and IL-8 resulted in a greater ICAM-1 response than either compound alone. We conclude that in human renal PTCs, IL-8 upregulates ICAM-1 production by engaging the CXCR-1 receptor and p38 MAPK signaling pathway. This cascade of events is independent of CD40/CD154-mediated IL-8 stimulation and ICAM-1 production and serves to amplify the inflammatory response.

Delayed renal allograft dysfunction and cystitis associated with human polyomavirus (BK) infection in a renal transplant recipient: a case report and review of literature

Human polyomavirus type BK (BKV) associated nephritis (BKVAN) has recently emerged as an important cause of renal allograft dysfunction and failure. Early recognition of this entity as a cause of allograft dysfunction is extremely important since misdiagnosis can accelerate graft loss. We report a case of BKVAN that presented with symptoms related to cystitis, and review the risk factors, the diagnostic tools and the approach to treatment of BK virus associated allograft nephropathy.

SYMPOSIUM Experimental Biology 1995 Endothelin Receptors: Role in Renal Function and Dysfunction SIGNALLING PATHWAYS ACTIVATED BY ENDOTHELIN STIMULATION OF RENAL CELLS

1. Endothelin mediates its effects in a variety of renal cells via a multiplicity of intracellular signalling pathways.

Osmolar regulation of endothelin signaling in rat renal medullary interstitial cells.

We tested the hypothesis that endothelin (ET) responsiveness in the renal medulla is modulated by ambient osmolarity. Cultured renal medullary interstitial cells (RMICs) were incubated from 3 to 24 h in isosmolar culture medium (300 mOsm/kg H2O) or media rendered hyperosmolar (600 mOsm/kg H2O) by the addition of urea. Under hyperosmolar conditions, the peak of ET-evoked Ca2+ transient was blunted by 45-58% (P < 0.02) and PGE2 accumulation decreased from 16- to 2-fold above basal values (P < 0.001). To explore whether hyperosmolar conditions blunt intracellular signaling via modulation of receptor number or expression, kinetics of ET binding and Northern blot analysis of ETA receptor mRNA was performed. Under hyperosmolar conditions, ETA receptor density was reduced by 84% versus isosmolar conditions (238 +/- 12 vs. 1450 +/- 184 fmol/mg) (P < 0.01). In contrast to the ligand binding studies, ETA receptor mRNA was increased by 58% (P < 0.05) in cells grown under hyperosmolar versus isosmolar media. These observations indicate that in the hyperosmolar setting, ET-evoked intracellular signaling is blunted in RMICs due to ET receptor downregulation. Since ETA receptor mRNA is increased under hyperosmolar conditions, we conclude that ET receptor downregulation is the consequence of either decreased translation of message, increased degradation of receptor peptide, or increased internalization of specific receptor sites.

Invasive Aspergillosis in a Renal Transplant Recipient Successfully Treated with Interferon-Gamma

Invasive aspergillosis is a serious complication of solid organ transplantation. An early diagnosis is hampered by the lack of reliable serum markers and, even if appropriately diagnosed and treated with current antifungal agents, has a high mortality rate. We report a case of invasive pulmonary and cerebral aspergillosis in a renal transplant patient treated with IFN-γ in conjunction with combination anti-fungal therapy for six weeks in whom complete resolution of the fungal infection was achieved. Renal function remained intact throughout the treatment period. Surveillance CT scans of the chest and head showed resolution of prior disease but revealed a new left upper lobe mass four months after completion of treatment with IFN-γ. Biopsy of the lesion was positive for primary lung adenocarcinoma, for which she underwent left upper lobe resection. The pathology report confirmed clear surgical margins and lymph nodes and no evidence of fungal hyphae. IFN-γ should be considered early in the management of invasive aspergillosis in renal transplant patients. To date, allograft rejection has not been encountered.

Arteriojejunal Fistula Presenting with Recurrent Obscure GI Hemorrhage in a Patient with a Failed Pancreas Allograft.

We present a case of a patient with a failed pancreaticoduodenal allograft with exocrine enteric-drainage who developed catastrophic gastrointestinal (GI) hemorrhage. Over the course of a week, she presented with recurrent GI bleeds of obscure etiology. Multiple esophago-gastro-duodenoscopic (EGD) and colonoscopic evaluations failed to reveal the source of the hemorrhage. A capsule endoscopy and a technetium-labeled red blood cells (RBC) imaging study were similarly unrevealing for source of bleeding. She subsequently developed hemorrhagic shock requiring emergent superior mesenteric arteriography. Run off images revealed an external iliac artery aneurysm with fistulization into the jejunum. Coiled embolization was attempted but abandoned because of hemodynamic instability. Deployment of a covered endovascular stent into the right external iliac artery over the fistula site resulted in immediate hemodynamic stabilization. A high index of suspicion for arterioenteric fistulae is needed for diagnosis of this uncommon but eminently treatable form of GI hemorrhage in this patient population.

Reversible left ventricular dysfunction and acute kidney injury in a patient with nonamyloid light chain deposition disease.

Non-amyloid light chain deposition disease (LCDD) is a rare entity that most commonly presents as proteinuria and/or renal dysfunction. We report on a patient who initially presented with acutely decompensated heart failure and subsequently developed nephrotic range proteinuria with attendant advanced renal dysfunction. The diagnosis of LCCD was made on renal biopsy.She was treated with five cycles of bortezomib and dexamethasone followed by cyclophosphamide priming for peripheral blood stem cell (PBSC) mobilization and auto logousstem cell transplant (ASCT). Four years later, she remains in very good partial response (VGPR) with a left ventricular ejection fraction (LVEF) of 58% and serum creatinine of 1.1 mg/dl. This observation supports the approach of aggressive management of patients with LCDD who have multiple organ failure.

5 Years Experience With Drug Eluting and Bare Metal Stents as Primary Intervention in Transplant Renal Artery Stenosis

Background Transplant renal artery stenosis (TRAS) is a common vascular complication after kidney transplantation and is associated with refractory hypertension, volume overload, and graft injury or loss. This article describes 5-year outcomes of endovascular intervention for TRAS with bare metal and drug eluting stents (DES). Methods We investigated, as a prospective cohort study, patient and graft outcomes after the targeted use of DES for vessel diameter less than 5 mm and bare metal stents (BMS) for vessel diameter greater than 5 mm as the primary management for TRAS. Results From March 2008 to November 2014, 57 patients were stented for hemodynamically significant TRAS; 29 received DES, 26 received BMS, and 2 patients received both stent types. They were followed up for a mean of 35.1 ± 22.8 months; a subset of these patients who all received DES were followed up for 61.7 ± 17.5 months. Mean serum creatinine declined from 2.87 ± 1.5 mg/dL at the time of intervention to 1.98 ± 0.76 mg/dL (P < 0.001) at one month follow-up and was 1.96 ±0.92 mg/dL (P < 0.001) at 35.1 ± 22.8 months. Mean systolic blood pressure declined from 159.05 ± 19.68 mm Hg at time of intervention to 135.65 ± 15.10 mm Hg (P < 0.001) at most recent visit. Clinically driven restenosis requiring repeat revascularization occurred in 15.7% of patients. Conclusions Primary stenting with DES and BMS is both successful in the initial treatment of TRAS and also produced an immediate and long-term reduction in serum creatinine and systolic blood pressure.

Intestinal Infarction and Portal Vein Thrombosis in a Patient with Henoch Schonlein Purpura

Henoch Schonlein purpura is a systemic vasculitis that commonly affects children and teenagers but also affects adults of all ages. In most instances it has a benign course. Organ involvement, particularly in adults, and notably the kidneys and gastrointestinal tract may require therapeutic intervention and may have a less favorable outcome. We report a case of a 58-year-old man who presented with purpura and who rapidly developed catastrophic intestinal vasculitis, leading to his demise.