Acute kidney injury associated with smoking synthetic cannabinoid.

CONTEXT AND OBJECTIVES: Synthetic cannabinoids are illegal drugs of abuse known to cause adverse neurologic and sympathomimetic effects. They are an emerging health risk: 11% of high school seniors reported smoking them during the previous 12 months. We describe the epidemiology of a toxicologic syndrome of acute kidney injury associated with synthetic cannabinoids, review the toxicologic and public health investigation of the cluster, and describe clinical implications of the cluster investigation. MATERIALS AND METHODS: Case series of nine patients affected by the toxicologic syndrome in Oregon and southwestern Washington during May-October 2012. Cases were defined as acute kidney injury (creatinine > 1.3 mg/dL) among persons aged 13-40 years without known renal disease who reported smoking synthetic cannabinoids. Toxicology laboratories used liquid chromatography and time-of-flight mass spectrometry to test clinical and product specimens for synthetic cannabinoids, their metabolites, and known nephrotoxins. Public health alerts informed clinicians, law enforcement, and the community about the cluster and the need to be alert for toxidromes associated with emerging drugs of abuse. RESULTS: Patients were males aged 15-27 years (median, 18 years), with intense nausea and flank or abdominal pain, and included two sets of siblings. Peak creatinine levels were 2.6-17.7 mg/dL (median, 6.6 mg/dL). All patients were hospitalized; one required dialysis; none died. No alternate causes of acute kidney injury or nephrotoxins were identified. Patients reported easily purchasing synthetic cannabinoids at convenience, tobacco, and adult bookstores. One clinical and 2 product samples contained evidence of a novel synthetic cannabinoid, XLR-11 ([1-(5-fluoropentyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone). DISCUSSION AND CONCLUSION: Whether caused by direct toxicity, genetic predisposition, or an as-yet unidentified nephrotoxin, this association between synthetic cannabinoid exposure and acute kidney injury reinforces the need for vigilance to detect new toxicologic syndromes associated with emerging drugs of abuse. Liquid chromatography and time-of-flight mass spectrometry are useful tools in determining the active ingredients in these evolving products and evaluating them for toxic contaminants.

Enteric oxalate nephropathy in the renal allograft: an underrecognized complication of bariatric surgery.

Enteric hyperoxalosis is a recognized complication of bariatric surgery, with consequent oxalate nephropathy leading to chronic kidney disease and occasionally end-stage renal failure. In patients with prior gastrointestinal bypass surgery, renal allografts are also at risk of oxalate nephropathy. Further, transplant recipients may be exposed to additional causes of hyperoxalosis. We report two cases of renal allograft oxalate nephropathy in patients with remote histories of bariatric surgery. Conservative management led to improvement of graft function in one patient, while the other patient returned to dialysis. Interpretation of serologic, urine and biopsy studies is complicated by oxalate accumulation in chronic renal failure, and heightened excretion in the early posttransplant period. A high index of suspicion and careful clinicopathologic correlation on the part of transplant nephrologists and renal pathologists are required to recognize and treat allograft oxalate nephropathy. As the incidence of obesity and pretransplant bariatric surgery increases in the transplant population, allograft oxalate nephropathy is likely to be an increasing cause of allograft dysfunction.

Guidelines for the diagnosis of antibody-mediated rejection in pancreas allografts-updated Banff grading schema.

The first Banff proposal for the diagnosis of pancreas rejection (Am J Transplant 2008; 8: 237) dealt primarily with the diagnosis of acute T-cell-mediated rejection (ACMR), while only tentatively addressing issues pertaining to antibody-mediated rejection (AMR). This document presents comprehensive guidelines for the diagnosis of AMR, first proposed at the 10th Banff Conference on Allograft Pathology and refined by a broad-based multidisciplinary panel. Pancreatic AMR is best identified by a combination of serological and immunohistopathological findings consisting of (i) identification of circulating donor-specific antibodies, and histopathological data including (ii) morphological evidence of microvascular tissue injury and (iii) C4d staining in interacinar capillaries. Acute AMR is diagnosed conclusively if these three elements are present, whereas a diagnosis of suspicious for AMR is rendered if only two elements are identified. The identification of only one diagnostic element is not sufficient for the diagnosis of AMR but should prompt heightened clinical vigilance. AMR and ACMR may coexist, and should be recognized and graded independently. This proposal is based on our current knowledge of the pathogenesis of pancreas rejection and currently available tools for diagnosis. A systematized clinicopathological approach to AMR is essential for the development and assessment of much needed therapeutic interventions.

Acute kidney injury with cryoglobulinemic peritubular neutrophilic capillaritis.

BACKGROUND: Neutrophil predominant capillaritis and interstitial inflammation is an uncommon renal biopsy finding, with a broad differential diagnosis. CASE: A 77-year-old woman presented with a complicated history including vasculitis, cryoglobulinemia, malaise, and systemic symptoms, which progressed to acute kidney injury. Renal biopsy demonstrated prominent neutrophilic capillaritis with interstitial inflammation, and fibrinoid deposits in medullary capillaries and interstitium. Glomeruli showed membranoproliferative glomerulonephritis, but no crescents or necrosis. DISCUSSION: We interpret the capillary and interstitial changes as evidence of cryoglobulin-associated vasculitis, and discuss the differential diagnosis of this uncommon histologic pattern of renal pathology, including other vasculitides, infection, ischemia-infarction, collagen vascular disease, and antibody-mediated allograft rejection, among others.

Concurrent anti-glomerular basement membrane disease and membranous glomerulonephritis: a case report and literature review.

BACKGROUND: Anti-glomerular basement membrane disease (anti-GBM) is a relatively rare entity characterized by antibodies to collagen type IV of glomerular and alveolar basement membranes. The sequential or simultaneous presentation of anti-glomerular basement membrane disease with membranous glomerulonephritis has been infrequently described. CASE: We present the case of a 49-year-old man who had fatigue, flank pain, hematuria and renal failure. Serology was positive for anti-GBM antibodies; crescentic glomerulonephritis was seen on renal biopsy. Immunofluorescence and electron microscopy demonstrated evidence of both anti-GBM glomerulonephritis and membranous deposits. DISCUSSION: Simultaneous anti-GBM disease and membranous glomerulonephritis is the most common temporal presentation of this rare entity. However, cases of membranous glomerulonephritis preceding or following recovery from anti-GBM disease have been described. Study of such cases provides insight into pathophysiologic mechanisms, including the possibility of increased antigen synthesis, exposure of cryptic epitopes, and/or capping and shedding of antigen-antibody complexes, in analogy to Heymann nephritis.

Mutant cadherin affects epithelial morphogenesis and invasion, but not transformation.

MDCK cells were engineered to reversibly express mutant E-cadherin protein with a large extracellular deletion. Mutant cadherin overexpression reduced the expression of endogenous E- and K-cadherins in MDCK cells to negligible levels, resulting in decreased cell adhesion. Despite severe impairment of the cadherin adhesion system, cells overexpressing mutant E-cadherin formed fluid-filled cysts in collagen gel cultures and responded to hepatocyte growth factor/scatter factor (HGF/SF) that induced cellular extension formation with a frequency similar to that of control cysts. However, cells were shed from cyst walls into the lumen and into the collagen matrix prior to and during HGF/SF induced tubule extension. Despite the propensity for cell dissociation, MDCK cells lacking cadherin adhesion molecules were not capable of anchorage-independent growth in soft agar and cell proliferation rate was not affected. Thus, cadherin loss does not induce transformation, despite inducing an invasive phenotype, a later stage of tumor progression. These experiments are especially relevant to tumor progression in cells with altered E-cadherin expression, particularly tumor samples with identified E-cadherin extracellular domain genomic mutations.

Inhibiting cadherin function by dominant mutant E-cadherin expression increases the extent of tight junction assembly.

Previous studies have shown that induction of cadherin-mediated cell-cell adhesion leads to tight junction formation, and that blocking cadherin-mediated cell-cell adhesion inhibits tight junction assembly. Here we report analysis of tight junction assembly in MDCK cells overexpressing a mutant E-cadherin protein that lacks an adhesive extracellular domain (T151 cells). Mutant E-cadherin overexpression caused a dramatic reduction in endogenous cadherin levels. Despite this, tight junction assembly was extensive. The number of tight junction strands observed by freeze-fracture electron microscopy significantly increased in T151 cells compared to that in control cells. Our data indicate that the hierarchical regulation of junctional complex assembly is not absolute, and that inhibition of cadherin function has both positive and negative effects on tight junction assembly.

Cadherin function in junctional complex rearrangement and posttranslational control of cadherin expression.

The role of E-cadherin, a calcium-dependent adhesion protein, in organizing and maintaining epithelial junctions was examined in detail by expressing a fusion protein (GP2-Cad1) composed of the extracellular domain of a nonadherent glycoprotein (GP2) and the transmembrane and cytoplasmic domains of E-cadherin. All studies shown were also replicated using an analogous cell line that expresses a mutant cadherin construct (T151) under the control of tet repressor. Mutant cadherin was expressed at approximately 10% of the endogenous E-cadherin level and had no apparent effect on tight junction function or on distributions of adherens junction, tight junction, or desmosomal marker proteins in established Madin-Darby canine kidney cell monolayers. However, GP2-Cad1 accelerated the disassembly of epithelial junctional complexes and delayed their reassembly in calcium switch experiments. Inducing expression of GP2-Cad1 to levels approximately threefold greater than endogenous E-cadherin expression levels in control cells resulted in a decrease in endogenous E-cadherin levels. This was due in part to increased protein turnover, indicating a cellular mechanism for sensing and controlling E-cadherin levels. Cadherin association with catenins is necessary for strong cadherin-mediated cell-cell adhesion. In cells expressing low levels of GP2-Cad1, protein levels and stoichiometry of the endogenous cadherin-catenin complex were unaffected. Thus effects of GP2-Cad1 on epithelial junctional complex assembly and stability were not due to competition with endogenous E-cadherin for catenin binding. Rather, we suggest that GP2-Cad1 interferes with the packing of endogenous cadherin-catenin complexes into higher-order structures in junctional complexes that results in junction destabilization.

Effect of initial resection of small-cell carcinoma of the lung: a review of Southwest Oncology Group Study 7628.

The role of surgery in small-cell carcinoma of the lung (SCCL) has been recently re-evaluated. We reviewed the records of 262 patients with limited SCCL on Southwest Oncology Group (SWOG) protocol 7628. Fifteen patients were identified who presented after surgical resection (12 lobectomy, three pneumonectomy). All patients were subsequently treated with chemotherapy, radiotherapy +/- immunotherapy (BCG). Median survival time was 10.5 months. Median survival time of patients with initial surgical resection was 25 months (P = .004). Forty-five percent of the surgical patients were alive at two years v 13.7% of the nonsurgical patients (P less than .05). A second subgroup of 33 patients was identified with small primary tumors who did not undergo surgical resection. Median survival time in this group was ten months (P = .03). Site of initial relapse was clearly documented in 142 patients. Fifty-six percent of patients not receiving surgery had initial relapse within the chest compared to 13% of patients undergoing surgery (P = .002). Whether the survival benefit identified was caused by or was incidental to surgical resection of the primary lesion remains to be determined in randomized prospective trials of operable candidates.

The hypereosinophilic syndrome in acute lymphocytic leukemia.

A 21-year-old white man presented with marked peripheral blood eosinophilia that later evolved into acute lymphocytic leukemia (FAB2 ALL). He died precipitously from refractory congestive heart failure immediately after antileukemic therapy was started. Autopsy revealed multiorgan infiltration with eosinophils and the typical cardiac findings of Löfflers endocarditis. Clinical and pathologic features of this and the 14 other cases of ALL and the hypereosinophilic syndrome (HES) reported in the English-language literature are described. The eosinophilia in these cases is reactive and resolves with successful leukemia remission induction. Hydroxyurea is effective in rapidly lowering eosinophil counts. Early use of hydroxyurea in this disease may improve patient survival and decrease the risk of sudden cardiac death.