Huma Fatima

AKI Associated with Synthetic Cannabinoids: A Case Series

SPICE, or K2, encompasses preparations of synthetic cannabinoids marketed as incense products, bath additives, and air fresheners and used for recreational purposes. These preparations are usually smoked for their cannabis-like effects and do not appear on routine urine toxicology screens. We report four cases of oliguric AKI associated with SPICE use in previously healthy men. All showed improvement in renal function without need for renal replacement therapy. Renal biopsy, performed in three of the patients, revealed acute tubular necrosis. The close temporal and geographic associations between the clinical presentation and the development of AKI strongly suggest an association between these SPICE preparations and AKI. Further investigations are required to identify the potential nephrotoxic agent(s). Nephrotoxicity from designer drugs should be included in the differential diagnosis of AKI, especially in young adults with negative urine drug screens.

Parietal Epithelial Cell Activation Marker in Early Recurrence of FSGS in the Transplant

BACKGROUND AND OBJECTIVES Podocyte loss is key in glomerulosclerosis. Activated parietal epithelial cells are proposed to contribute to pathogenesis of glomerulosclerosis and may serve as stem cells that can transition to podocytes. CD44 is a marker for activated parietal epithelial cells. This study investigated whether activated parietal epithelial cells are increased in early recurrent FSGS in transplant compared with minimal change disease. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS CD44 staining in renal allograft biopsies from 12 patients with recurrent FSGS was performed and compared with native kidneys with minimal change disease or FSGS and normal control native and transplant kidneys without FSGS. CD44+ epithelial cells along Bowmans capsule in the parietal epithelial cell location and over the glomerular tuft in the visceral epithelial cell location were assessed. RESULTS Cases with early recurrent FSGS manifesting only foot process effacement showed significantly increased CD44+ visceral epithelial cells involving 29.0% versus 2.6% of glomeruli in minimal change disease and 0% in non-FSGS transplants. Parietal location CD44 positivity also was numerically increased in recurrent FSGS. In later transplant biopsies, glomeruli with segmental lesions had more CD44+ visceral epithelial cells than glomeruli without lesions. CONCLUSIONS Parietal epithelial cell activation marker is significantly increased in evolving FSGS versus minimal change disease, and this increase may distinguish early FSGS from minimal change disease. Whether parietal epithelial cell activation contributes to pathogenesis of sclerosis in idiopathic FSGS or is a regenerative/repair response to replace injured podocytes awaits additional study.

Eculizumab-induced reversal of dialysis-dependent kidney failure from C3 glomerulonephritis

C3 glomerulopathy (C3G) is characterized by C3 deposits with minimal immunoglobulin deposition caused by alternative complement pathway dysregulation. Unfortunately, no therapeutic intervention has consistently improved outcomes for patients with C3G. Eculizumab, a monoclonal antibody to C5, is currently the only approved complement-specific agent with some efficacy in the treatment of C3 glomerulonephritis (C3GN). Here, we describe a patient with acute crescentic C3GN with no identified complement mutation or family history of renal disease who required dialysis for 6 months. Five months after initiation of eculizumab, she became dialysis independent, showing improvement is possible after adequate time on eculizumab.

Dasatinib-induced nephrotic-range proteinuria.

Since the introduction of imatinib, tyrosine kinase inhibition has been a mainstay in the treatment of many malignancies. The number of these medications is growing, as are the number of targeted tyrosine kinases. Off-target effects of these medications can have beneficial or adverse effects on the kidney. The onus of knowing the implications of these medications on kidney function, and appropriate treatment when such adverse effects occur, is on the nephrologist. We present a patient with chronic myelogenous leukemia who developed nephrotic-range proteinuria after initiation on dasatinib therapy that resolved after changing therapy to imatinib. The mechanism of kidney injury caused by dasatinib has not been described previously in the literature. We provide a review of vascular endothelial growth factor and its pharmacologic inhibition as it pertains to kidney pathology and propose possible mechanisms by which dasatinib induces kidney injury.

Podocyte‐specific soluble epoxide hydrolase deficiency in mice attenuates acute kidney injury

Podocytes play an important role in maintaining glomerular function, and podocyte injury is a significant component in the pathogenesis of proteinuria. Soluble epoxide hydrolase (sEH) is a cytosolic enzyme whose genetic deficiency and pharmacological inhibition have beneficial effects on renal function, but its role in podocytes remains unexplored. The objective of this study was to investigate the contribution of sEH in podocytes to lipopolysaccharide (LPS)‐induced kidney injury. We report increased sEH transcript and protein expression in murine podocytes upon LPS challenge. To determine the function of sEH in podocytes in vivo we generated podocyte‐specific sEH‐deficient (pod‐sEHKO) mice. Following LPS challenge, podocyte sEH‐deficient mice exhibited lower kidney injury, proteinuria, and blood urea nitrogen concentrations than controls suggestive of preserved renal function. Also, renal mRNA and serum concentrations of inflammatory cytokines IL‐6, IL‐1β, and TNFα were significantly lower in LPS‐treated pod‐sEHKO than control mice. Moreover, podocyte sEH deficiency was associated with decreased LPS‐induced NF‐κB and MAPK activation and attenuated endoplasmic reticulum stress. Furthermore, the protective effects of podocyte sEH deficiency in vivo were recapitulated in E11 murine podocytes treated with a selective sEH pharmacological inhibitor. Altogether, these findings identify sEH in podocytes as a contributor to signaling events in acute renal injury and suggest that sEH inhibition may be of therapeutic value in proteinuria.

Transcription Factor Avian Erythroblastosis Virus E26 Oncogen Homolog-1 Is a Novel Mediator of Renal Injury in Salt-Sensitive Hypertension

Transcription factor E26 transformation-specific sequence-1 (ETS-1) is a transcription factor that regulates the expression of a variety of genes, including growth factors, chemokines, and adhesion molecules. We recently demonstrated that angiotensin II increases the glomerular expression of ETS-1 and that blockade of ETS-1 ameliorates the profibrotic and proinflammatory effects of angiotensin II. The Dahl salt-sensitive rat is a paradigm of salt-sensitive hypertension associated with local activation of the renin–angiotensin system. In these studies, we determined whether: (1) salt-sensitive hypertension is associated with renal expression of ETS-1 and (2) ETS-1 participates in the development of end-organ injury in salt-sensitive hypertension. Dahl salt-sensitive rats were fed a normal-salt diet (0.5% NaCl diet) or a high-salt diet (4% NaCl) for 4 weeks. Separate groups on high-salt diet received an ETS-1 dominant-negative peptide (10 mg/kg/d), an inactive ETS-1 mutant peptide (10 mg/kg/d), the angiotensin II type 1 receptor blocker candesartan (10 mg/kg/d), or the combination high-salt diet/dominant-negative peptide/angiotensin II type 1 receptor blocker for 4 weeks. High-salt diet rats had a significant increase in the glomerular expression of the phosphorylated ETS-1 that was prevented by angiotensin II type 1 receptor blocker. ETS-1 blockade reduced proteinuria, glomerular injury score, fibronectin expression, urinary transforming growth factor-&bgr; excretion, and macrophage infiltration. Angiotensin II type 1 receptor blocker reduced proteinuria, glomerular injury score, and macrophage infiltration, whereas concomitant ETS-1 blockade and angiotensin II type 1 receptor blocker had additive effects and reduced interstitial fibrosis. Our studies demonstrated that salt-sensitive hypertension results in increased glomerular expression of phosphorylated ETS-1 and suggested that ETS-1 plays an important role in the pathogenesis of end-organ injury in salt-sensitive hypertension.

Haploinsufficiency of the Transcription Factor Ets-1 Is Renoprotective in Dahl Salt-Sensitive Rats

Studies using Dahl salt-sensitive (SS) rats identified specific quantitative trait loci that predispose animals to hypertension-associated albuminuria and kidney injury. We explored the hypothesis that kidney-specific expression of the transcription factor Ets-1, located within one of these loci on chromosome 8, mediates glomerular injury in SS hypertension. During the first week on a high-salt diet, SS rats and SS rats with only one functioning Ets-1 gene (ES rats) demonstrated similar increases in BP. However, serum creatinine concentration, albuminuria, and glomerular expression of ETS-1 and two ETS-1 targets, MCP-1 and MMP2, did not increase as substantially in ES rats as in SS rats. Mean BP subsequently increased further in SS rats and remained higher than that of ES rats for the rest of the study. After 4 weeks of high-salt intake, ES rats still showed a lower mean serum creatinine concentration and less albuminuria, as well as less histologic evidence of glomerular injury and kidney fibrosis, than SS rats did. To investigate the specific contribution of renal Ets-1, we transplanted kidneys from ES or SS rats into salt-resistant SS-Chr 13BN/McwiCrl (SS-13BN) rats. Within 10 days on a high-salt diet, BP increased similarly in ES and SS allograft recipients, becoming significantly higher than the BP of control isograft recipients. However, mean serum creatinine concentration and albuminuria remained lower in ES allograft recipients than in SS allograft recipients at 2 weeks, and ES allografts showed less glomerular injury and interstitial fibrosis. In conclusion, reduced renal expression of ETS-1 prevented hypertension-associated kidney injury in SS rats.

Membranous glomerulopathy with superimposed pauci-immune necrotizing crescentic glomerulonephritis

We describe a 61-year-old woman with acute kidney injury, nephrotic range proteinuria and hematuria. Kidney biopsy showed membranous glomerulopathy (MG) with superimposed pauci-immune necrotizing crescentic glomerulonephritis (PNCGN). Coexistent MG and PNCGN is a rare occurrence. The diagnosis of such an exceptionally rare combination relies on the combination of renal biopsy findings and serologic testing. We also review previous reported cases and discuss possible pathogenesis of this rare dual glomerulopathy.

Appendiceal tissue confirmation of Fabry’s disease

A 15-year-old female with Fabry’s disease (FD) (P409S mutation) presented with abdominal pain. Physical findings included a temperature of 102.6 °F, blood pressure of 86/62 mm Hg, diffuse abdominal tenderness, and no angiokeratomas. Laboratory evaluation revealed a white blood cell count of 25.2 × 103/mm3. Computed tomography showed acute appendicitis, and appendectomy was performed. The patient had recently undergone a routine baseline assessment for her FD. Corneal whorls were present on ophthalmologic exam. Serum creatinine was 0.4 mg/dl and urine albumin excretion was 7 mg/day. Echocardiogram showed a ‘bright’ myocardium without left ventricular hypertrophy, whereas contrasted cardiac magnetic resonance imaging (MRI) showed posterobasal left ventricular wall late-enhancement consistent with Fabry’s cardiomyopathy. Brain MRI was normal. Confirmation of tissue involvement, preferably with electron microscopy, is necessary before initiation of enzyme replacement therapy (ERT) for FD. Coincidently, the appendiceal pathology specimen became available. Both endothelial (Figure 1a) and smooth muscle cells (Figure 1b) contained lysosomal inclusions typical of FD. With tissue confirmation of significant globotriacylceramide (Gb3) deposits, ERT was instituted.

Immune profile of IgA-dominant diffuse proliferative glomerulonephritis

The diagnosis of IgA-dominant post-infectious glomerulonephritis (PIGN) may be challenging, as it must be differentiated from that of active IgA nephropathy. Predominant clinicopathologic features of IgA-dominant PIGN substantially overlap with those of active IgA nephropathy. Here, we present a case of a 67-year-old woman with rapidly rising serum creatinine, proteinuria and severe hypertension. The kidney biopsy findings included some features of IgA-dominant PIGN while others were more consistent with classical IgA nephropathy. We describe this patients immune profile at the time of acute kidney injury and review the literature regarding differentiation of the two entities.