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Idiopathic nodular glomerulosclerosis is an enigmatic condition closely resembling diabetic nodular glomerulosclerosis without evidence of diabetic mellitus or other specific disease. Idiopathic nodular glomerulosclerosis remains a rare disease entity with an unclear pathogenesis. Clinicopathologic features of 15 patients with idiopathic nodular glomerulosclerosis were evaluated in a retrospective review of renal biopsies between 1998 and 2007. Our study cohort consisted predominantly of older (mean age, 64.2 years) white (73%) women (67%). Fourteen patients (93%) had a history of hypertension, and 10 (67%) were active smokers at the time of biopsy. Nine patients (60%) were obese (body mass index, >30 kg/m(2)) and 4 (27%) were overweight (body mass index, 25-29.9 kg/m(2)). Fourteen patients (93%) presented with renal insufficiency with mean serum creatinine level of 2.8 mg/dL. All 15 patients presented with proteinuria (mean urinary protein excretion, 5.6 g/24 h). Eleven patients (73%) presented with nephrotic-range proteinuria and 8 (53%) with nephrotic syndrome. Histopathologic findings showed nodular glomerulosclerosis (100%), moderate to severe arterio-arteriolosclerosis (100%), and glomerular basement membrane thickening (100%). Immunofluorescence and electron microscopy studies had no other specific findings. Our results confirm previous studies of a close association of hypertension and smoking with idiopathic nodular glomerulosclerosis. A significantly higher incidence of obesity and overweight in patients with idiopathic nodular glomerulosclerosis suggests that increased body mass index may also contribute to the development and progression of idiopathic nodular glomerulosclerosis.

Objective: To report a case of interstitial nephritis associated with the administration of bevacizumab. Case Summary: A 26-year-old man diagnosed with metastatic rectal leiomyosarcoma was treated with intravenous bevacizumab 5 mg/kg and received a total of 3 doses at 2 week intervals. His creatinine had increased from 1.0 mg/dL at baseline to 1.6 mg/dL after 2 doses of bevacizumab and to 4.7 mg/dL after the third dose, prompting admission. Acute renal failure was diagnosed, and hemodialysis was initiated. A renal biopsy revealed interstitial nephritis. Renal failure resolved with cessation of the drug, and the patient did not require further hemodialysis. Discussion: Bevacizumab is a recombinant humanized monoclonal immunoglobulin G antibody to vascular endothelial growth factor. Bevacizumab has shown efficacy in treatment of patients with renal cell carcinoma and colorectal cancer and has been approved by the Food and Drug Administration as a first-line treatment for metastatic colorectal cancer. Our patient had no other confounding factors that might have caused renal failure. The presence of primary glomerular disease was excluded by biopsy. According to the Naranjo probability scale, bevacizumab was the probable cause of acute renal failure in this patient. Conclusions: Bevacizumab can cause acute renal failure by inducing interstitial nephritis. Renal function should be monitored during bevacizumab therapy.

Background The addition of phosphorothioate (PS) groups to natural phosphodiester (PD) antisense oligodeoxynucleotides (oligo) prevents their in vivo hydrolysis by nucleases allowing an RNase-dependent elimination of targeted mRNA. To further improve oligo function 2'-methoxyethyl (ME) groups were attached to selected nucleotides at the 3'-end because ME groups block RNase activity. Methods/results ME modification of PS- or PD/PS-oligo targeting human intracellular adhesion molecule (ICAM)-1 mRNA significantly increased the degree and duration of the in vitro inhibitory effects without compromising selectivity and specificity. A 7-day intravenous or oral therapy with rat ME/PS-modified ICAM-1 antisense oligo extended the survivals of kidney allografts. In addition, ME/PS-modified ICAM-1 antisense oligo reduced ischemic-reperfusion injury in kidneys, as measured by glomerular filtration rate, creatinine levels, and infiltration with leukocytes. Finally, a 14-day treatment with cyclosporine (CsA)-induced nephrotoxicity in syngeneic kidney transplants correlated with both increased ICAM-1 protein expression and infiltration with leukocytes. Graft perfusion and treatment of recipients with ICAM-1 antisense ME/PS-oligo alleviated the nephrotoxic effect and decreased ICAM-1 expression and leukocyte infiltration. Conclusions ME/PS-modified ICAM-1 antisense oligo is very effective in inhibiting the ICAM-1-dependent mechanism of graft infiltration and tissue damage involved in allograft rejection, ischemic-reperfusion injury, and CsA-induced nephrotoxicity.

OBJECTIVE To report a case of acute renal failure associated with the administration of imatinib mesylate. CASE SUMMARY A 64-year-old man diagnosed with prostate cancer was enrolled in a Phase I trial of imatinib mesylate plus taxotere on a protocol that required a run-in period of imatinib mesylate alone. During therapy with imatinib mesylate, the patient developed acute renal failure, requiring hemodialysis. A renal biopsy revealed tubular vacuolization. Renal failure resolved with cessation of imatinib mesylate. DISCUSSION Imatinib mesylate is a protein tyrosine kinase inhibitor that inhibits the BCR-ABL tyrosine kinase, the receptor tyrosine kinases for platelet-derived growth factor, and stem cell factor c-kit. Prostate cancer has been identified as a target for therapy with imatinib mesylate. This patient had no other confounding factors for the cause of the renal failure. An objective causality assessment determined that imatinib mesylate was the probable cause of the acute renal failure. The presence of a primary glomerular disease was excluded by biopsy. CONCLUSIONS Imatinib mesylate–induced acute renal failure has now been linked to toxic effects on renal tubular cells in 3 cases. Renal function should be closely monitored during imatinib mesylate therapy.

Dose-limiting nephrotoxicity has hampered the clinical usefulness of amphotericin-B (AmpB). Recently, vascular decongestants, such as pentoxifylline, have shown benefit in reducing drug-associated renal damage of AmpB in rats. The present study investigated a dose-dependent protection of a structurally similar methylxanthine, HWA-448, in the candidiasis rat model given a single dose of AmpB. Forty-eight hours after inoculation with Candida albicans, each rat was treated with 0.8 mg/kg of AmpB or sterile water; animals were further randomized to receive 0.5, 1, 5, or 10 mg/kg i.v. of HWA-448 or saline given every 12 h for 3 doses. Kidney fungal counts, morphology, and renal function were compared between treatment groups upon completion of the study. Rats administered AmpB with HWA-448 had markedly improved renal function compared with those given AmpB alone; these effects were independent of the administered dose of HWA-448. The antifungal effect of AmpB was not impaired with concomitant HWA-448. Marked accumulation of granulomas and organisms was found in all rat groups. In summary, coadministration of low doses of HWA-448 attenuated the dose-limiting nephrotoxicity without impairing the antifungal effect of AmpB.

Changing patterns in the histopathology of idiopathic nephrotic The International Study of Kidney Disease in Children syndrome in children. (ISKDC) reported in the 1970s that minimal change ne- Background. It is widely accepted that minimal change ne- phrotic syndrome (MCNS) was the most common histo- phrotic syndrome (MCNS) is the most common cause of ne- logical lesion in renal biopsies from children with idio- phrosis in children. Recent studies have demonstrated an in- pathic nephrotic syndrome (1, 2). This observation was creasing incidence of focal segmental glomerulosclerosis (FSGS) confirmed by single centers that reported MCNS in al- in adults. Methods. To determine possible changes in the etiology of most 90% of cases (3). The same studies showed that childhood nephrosis, the clinical charts of 152 pediatric patients focal segmental glomerulosclerosis (FSGS) was a rare diagnosed with idiopathic nephrotic syndrome between 1978 cause of nephrosis in children, observed in only 5 to 7% and 1997 were reviewed. Histopathological diagnosis was avail- of the biopsies (1-3). More recent studies in adults have able in 105 patients. reported an increasing incidence of FSGS during the last Results. MCNS was present in 35% of all biopsies, whereas FSGS was observed in 31%. Even if we assume that all patients 20 years, accompanied by a significant decline in the without a histological diagnosis had MCNS (presumptive incidence of MCNS (4). D'Agati has suggested that FSGS MCNS), the total incidence of MCNS (biopsy proven 1 pre- constitutes the most common glomerulopathy observed sumptive) in our population was only 55%. We observed a among biopsies performed in adult native kidneys (5). dramatic increase in the incidence of FSGS during recent years. Unfortunately, in the pediatric population, the only stud- Before 1990, FSGS was diagnosed in 23% of all renal biopsies ies performed during the last 20 years have focused on but increased to 47% afterward (P 5 0.02). This pattern was observed in all ethnic groups. In African Americans, there was selected patient populations that were either steroid de- a trend for an increase in the incidence of FSGS from 38% pendent or frequent relapsers. In 1981, Siegel et al re- before 1990 to 69% after 1990. A similar trend was observed ported that FSGS was present in 29% of renal biopsies in Caucasians (from 20 to 45%) and Hispanics (from 8 to 33%). performed in children with steroid-dependent nephrotic Hispanics had the highest incidence of MCNS (biopsy proven 1 syndrome (6). Trachtman and colleagues later observed presumptive: 73%), followed by Caucasians (53%) and African Americans (37%). The mean age for presentation of nephrotic that MCNS was present in 25% of the biopsies per- syndrome in African Americans (8.0 6 0.9 years) was higher formed in pediatric patients with frequently relapsing, than in Caucasians (4.1 6 0.05) and Hispanics (3.3 6 0.5). steroid-sensitive nephrotic syndrome (7). Conclusions. Our study showed that the incidence of FSGS It has been our impression that the incidence of FSGS in children with idiopathic nephrotic syndrome has increased has increased in our practice during recent years. In recently. Furthermore, in African American children, FSGS is addition, in agreement with observations from other cen- the most common cause of nephrotic syndrome. These findings may have significant implications in the management of child- ters, we have observed a marked predominance of FSGS hood nephrotic syndrome.

Tenascin, a large oligomeric glycoprotein, is a recent addition to a list of increasing extracellular matrix proteins. Previous studies have documented the strong expression of tenascin in embryonic kidney and in both normal and abnormal mature glomeruli implicating an important role of this extracellular matrix protein in nephrogenesis and glomerular scarring. Whether tenascin plays any role in interstitial fibrosis, a common final pathway of tubulointerstitial nephritis, is not known; on the other hand, a detailed knowledge of the structural components of interstitial fibrosis is essential for further studies on other fundamental aspects of this biologically and clinically important process. In this study, the expression of tenascin in the renal interstitium was immunohistochemically evaluated in 208 renal specimens including normal kidney (23 cases), acute tubular necrosis (8), acute tubulointerstitial nephritis (8), chronic primary tubulointerstitial nephritis (30), tubulointerstitial nephritis secondary to glomerular diseases of mild (46) and severe (55) degree, ischemic damage (24), and rejection (14). It was found that in normal kidney tenascin expression was limited to the medullary interstitium. In kidney with tubulointerstitial nephritis, tenascin was ubiquitously and constantly expressed in any areas with tubulointerstitial damage regardless of diagnosis, etiology, the cortical vs. medullary location of the lesions, stage of the fibrogenetic process, density of fibroblasts, or severity of interstitial inflammation in the affected areas. Indeed, strong tenascin expression was seen in areas where there was only interstitial edema or inflammation as judged by routine light microscopic preparations. In summary, this study systematically documents tenascin as a novel extracellular matrix protein selectively expressed in the medullary interstitium in normal kidney, and ubiquitously present in areas with interstitial fibrosis.

We report a 16-year-old male who developed nephrotic syndrome related to membranous glomerulopathy with clinical and serological evidence of systemic lupus erythematosus after treatment with griseofulvin. To our knowledge, this is the first case of griseofulvin-exacerbated lupus in which nephrotic syndrome has been observed.

The effect of exogenous atrial natriuretic peptide (ANP) on urine excretion and glomerular filtration rate (GFR) during acute renal allograft rejection was evaluated in a canine model. Eight animals underwent simultaneous allotransplantation and unilateral native nephrectomy. No preoperative or postoperative immunosuppressive therapy was given. Acute renal function studies were performed on the allografts and companion, native kidneys following surgical exposure and mobilization on the third postoperative day. At reexploration, the allografts were found to be grossly enlarged (138 +/- 10 gm.) and contained moderate-to-marked perivascular interstitial infiltration. Glomerular filtration rate, determined by measurement of urinary inulin clearance, was significantly reduced from prenephrectomy baseline values (19 +/- 4 ml. per minute versus 32 +/- 5 ml. per minute, p.05). During a 30 minute, intravenous ANP infusion, allograft urine flow rates increased from 1.4 +/- 0.5 ml. per minute to 3.3 +/- 0.4 ml. per minute (p.01), and GFR increased from 19 +/- 4 ml. per minute to 24 +/- 4 ml. per minute (p.05). During ANP infusion, mean arterial pressure declined from 136 +/- 7 mm. Hg to 116 +/- 7 mm. Hg (p.05), and the hematocrit remained unchanged. These observations are consistent with previously described, ameliorative effects of ANP in other models of acute ischemic renal injury and provide an experimental basis for more extended studies examining the potential usefulness of ANP as adjunctive therapy in the treatment of acute renal allograft rejection.

Although a significant interaction between cyclosporine and amphotericin-B (AmpB) has been observed clinically, these findings have not been duplicated in animal studies. A total of 64 male albino rats were used in single- and multiple-dose experiments with AmpB and CsA in the absence or presence of systemic Candida infection. No significant differences in glomerular filtration rate were found in rats given single i.v. doses of AmpB 1 mg/kg compared with AmpB and CsA. Furthermore, rats given i.p. AmpB 1 mg/kg and CsA 10 mg/kg daily for 10 days showed no significant differences in GFR compared with animals given CsA alone. Morphology and CsA whole-blood pharmacokinetics were not different between groups administered single-dose CsA, AmpB, or the combination; similarities also existed with multiple-dose studies. In an attempt to mimic the clinical setting, 2 groups of rats were administered i.p. CsA 10 mg/kg/day for 10 days followed by inoculation of Candida albicans. After 48 hr, a single i.v. dose of AmpB 1.0 mg/kg was associated with a 33% decline in GFR compared with those given sterile water (P less than 0.05). Systemic clearance of CsA was markedly reduced in candidiasis rats administered AmpB compared with controls given sterile water. A significant reduction in renal Candida colony-forming units was found in rats given CsA and AmpB compared with those administered CsA alone. These data suggest that the presence of systemic Candida highlights the interaction of CsA and AmpB in the rat model.

The mechanism of acute nephrotoxicity following the administration of amphotericin B (AmpB) remains unclear despite a number of studies describing hypermagnesuria, hyperkaluria, and hemodynamic changes. The present experiments attempted to elucidate the mechanism by using a novel hemorheologic probe, pentoxifylline (PTX). Acute studies were performed with rats given single intravenous doses of AmpB (1 mg/kg of body weight) with or without intraperitoneal PTX (45 mg/kg). Renal function, assessed by inulin clearance (CLIN) and electrolyte handling, and morphology were compared with those of controls given sterile water and PTX. A significant decrease in CLIN not observed in rats given AmpB and PTX or in the controls was found in rats given AmpB. Electrolyte handling was not different among groups. Whereas pronounced (3 and 4+ on a scale of mild to significant [1+ to 4+]) vascular congestion was found in rats given AmpB, rats coadministered PTX had mild (1 and 2+) medullary and glomerular vascular congestion. In chronic studies, intravenous AmpB (1 mg/kg per day) or sterile water was coadministered with intraperitoneal PTX (45 mg/kg every 12 h) or saline for 10 days. Mean CLIN of rats coadministered AmpB and PTX was not significantly different from that of PTX control rats (1.61 +/- 0.19 versus 1.31 +/- 0.29 ml/min per g of kidney weight). A 46% decline in CLIN was found in rats treated with AmpB and saline (P less than 0.05). Renal sodium and potassium excretions were increased in both AmpB-treated groups compared with controls. Coupled with histologic evidence of the acute studies, these data suggest that the benefit of PTX in the prevention of AmpB-induced nephrotoxicity is, in part, due to vascular decongestion.

We report a case in a 38-year-old white woman of a benign primary intratracheal neurilemoma that recurred 12 years after an initial endoscopic excision. Of the 12 intratracheal neurilemomas that have previously been reported, all occurred in white persons in an age range of 6 to 71 years and most were located in the lower trachea and produced symptoms of cough and wheezing.

International standardization of criteria for the histologic diagnosis of renal allograft rejection: The Banff working classification of kidney transplant pathology. A group of renal pathologists, nephrologists, and transplant surgeons met in Banff, Canada on August 2–4, 1991 to develop a schema for international standardization of nomenclature and criteria for the histologic diagnosis of renal allograft rejection. Development continued after the meeting and the schema was validated by the circulation of sets of slides for scoring by participant pathologists. In this schema intimal arteritis and tubulitis are the principal lesions indicative of acute rejection. Glomerular, interstitial, tubular, and vascular lesions of acute rejection and “chronic rejection” are defined and scored 0 to 3+, to produce an acute and/or chronic numerical coding for each biopsy. Arteriolar hyalinosis (an indication of cyclosporine toxicity) is also scored. Principal diagnostic categories, which can be used with or without the quantitative coding, are: (1) normal, (2) hyperacute rejection, (3) borderline changes, (4) acute rejection (grade I to III), (5) chronic allograft nephropathy (“chronic rejection”) (grade I to III), and (6) other. The goal is to devise a schema in which a given biopsy grading would imply a prognosis for a therapeutic response or long-term function. While the clinical implications must be proven through further studies, the development of a standardized schema is a critical first step. This standardized classification should promote international uniformity in reporting of renal allograft pathology, facilitate the performance of multicenter trials of new therapies in renal transplantation, and ultimately lead to improvement in the management and care of renal transplant recipients.

Two cases of adenoid cystic carcinoma of the breast are reported. One case is an example occurring in a man, a rare circumstance. In the other patient, a woman, metastases appeared in axillary lymph nodes. In addition to the usual histologic appearance of this tumor, one of these cases also exhibited the unusual features of collagenous nodules, psammoma bodies, and necrosis.