Physicochemical characterization of inorganic deposits associated with granulomas in cutaneous sarcoidosis.

BACKGROUND: Sarcoidosis, characterized by epithelioid granulomas, is considered to be caused by a complex interplay between genetics and environmental agents. It has been hypothesized that exogenous inorganic particles as crystalline silica could be a causal or adjuvant agent in sarcoidosis onset. OBJECTIVES: To investigate the location, frequency and physicochemical characteristics of foreign materials and mineral tissue deposits in the granulomatous area of cutaneous sarcoidosis. METHODS: Skin biopsies (n = 14) from patients diagnosed with cutaneous sarcoidosis (mean age 43 years; 11 patients with extracutaneous involvement) were investigated using polarized light examination (PLE), µFourier Transform Infra-Red (µFT-IR) spectroscopy and Field Emission Scanning Electron Microscopy coupled with Energy Dispersive X-ray Spectroscopy (FE-SEM/EDX). RESULTS: Combined PLE, µFT-IR, FE-SEM/EDX analysis allowed to characterize mineral deposits in 7/14 biopsies (50%). It identified crystalline silica (SiO2 ) inside granulomas in three biopsies and calcite (CaCO3 ) at their periphery in 4. CONCLUSION: This study emphasizes the need of using combined methods for assessment of mineral deposits in granulomatous diseases. According to the location and characteristics of deposits, we can hypothesize that SiO2 particles contribute to the granuloma formation, whereas CaCO3 deposits are related to the granuloma biology. However, the significance of the association between SiO2 deposits and sarcoidosis is still disputed.

Autoantibodies specific for the phospholipase A2 receptor in recurrent and De Novo membranous nephropathy.

Recent findings in idiopathic membranous nephropathy (MN) suggest that in most patients, the disease is because of anti-phospholipase A(2) receptor (PLA(2) R1) autoantibodies. Our aim was to analyze the prevalence and significance of anti-PLA(2) R1 antibodies in recurrent and de novo MN after transplantation. We assessed circulating PLA(2) R1 autoantibodies by a direct immunofluorescence assay based on human embryonic kidney cells transfected with a PLA(2) R1 cDNA, and the presence of PLA(2) R1 antigen in immune deposits. We showed that PLA(2) R1 was involved in 5 of 10 patients with recurrent MN, but in none of the 9 patients with de novo MN. We also showed a marked heterogeneity in the kinetics and titers of anti-PLA(2) R1, which may relate to different pathogenic potential. We provide evidence that some patients with PLA(2) R1-related idiopathic MN and anti-PLA(2) R1 antibodies at the time of transplantation will not develop recurrence. Because PLA(2) R1 autoantibody was not always associated with recurrence, its predictive value should be carefully analyzed in prospective studies.

Risk factors for early epithelial to mesenchymal transition in renal grafts.

Epithelial-to-mesenchymal transition (EMT) of tubular epithelial cells (TECs) may participate in the pathogenesis of renal fibrosis. We performed a prospective study of EMT markers in protocol biopsies obtained 3 months after engraftment from 56 patients who received deceased donor kidneys and who had stable renal function. The presence of EMT was examined, and quantified by immunohistochemical staining for vimentin and translocation of beta-catenin to the cytoplasm. EMT status was defined as the presence of EMT markers in > or = 10% of TECs. EMT features were virtually absent in implantation biopsies, whereas 41% of the grafts were EMT-positive in the absence of advanced chronic allograft nephropathy. Thirteen patients (23%) had borderline changes or acute rejection. EMT features were more frequent in these patients than in those with normal kidney grafts (vimentin expression, p = 0.003; beta-catenin translocation, p = 0.002). EMT in grafts corresponded with elevated serum creatinine of the donor before the recovery of kidney (p = 0.02) and longer cold ischemia time (p = 0.02). In contrast, the donor age had no influence on the expression of EMT markers. These results suggest that EMT is an early and frequent phenomenon in kidney transplants that could be triggered by immunological and/or ischemic tubular injury.

Erythropoietin enhances recovery after cisplatin-induced acute renal failure in the rat.

BACKGROUND: Erythropoietin (Epo) is a growth factor whose synthesis mainly takes place in the kidney. Epo has been shown to support the growth not only of erythroid progenitor cells but also of certain other cell types. We attempted to establish whether Epo enhances the recovery from acute renal failure induced by cisplatin. METHODS: Sprague-Dawley rats were randomized into three groups. In the cisplatin group, animals received one intraperitoneal injection of cisplatin (6 mg/kg) and a daily injection of placebo for 9 days. In the cisplatin+Epo group, animals received intrapertoneal cisplatin and a daily injection of Epo (100 IU/kg) for 9 days. In the control group, animals received both placebo preparations alone. Para-aminohippuric acid and inulin clearances were determined after 4 and 9 days to evaluate renal blood flow and glomerular filtration rate. In addition, light microscopy and immunohistochemistry examinations were performed, and in situ proliferating cell nuclear antigen (PCNA) staining was done to estimate the degree of renal tubular cell regenerative activity. The potential role of epithelial growth factor (EGF) was evaluated by semi-quantitative assessment of EGF immunostaining. RESULTS: Renal blood flow and glomerular filtration rate decreased significantly in cisplatin and cisplatin+Epo groups versus control group at day 4. However, at day 9, they both were significantly greater in cisplatin+Epo-treated animals than in rats that had received cisplatin alone. Tubular cell regeneration was significantly enhanced at day 4 in cisplatin+Epo group, compared with cisplatin and control groups respectively. EGF immunostaining was not significantly different between the three groups. CONCLUSION: Epo significantly enhanced the rate of recovery from acute renal failure induced by cisplatin. PCNA staining indicated that Epo might act directly via stimulation of tubular cell regeneration.

Transjugular versus percutaneous renal biopsy for the diagnosis of parenchymal disease: comparison of sampling effectiveness and complications.

PURPOSE: To compare the effectiveness and safety of transjugular renal biopsy with those of percutaneous renal biopsy for diagnosis of renal parenchymal disease. MATERIALS AND METHODS: Results and complications of 400 consecutive transjugular renal biopsies performed between 1993 and 1998 with a modified Colapinto transjugular hepatic biopsy system were compared retrospectively with those of 400 percutaneous renal biopsies performed during the same period. Transjugular renal biopsy was associated with 14 cardiac and 35 hepatic biopsies. Number of glomeruli per tissue core, adequacy of tissue core for histopathologic diagnosis, and rate and severity of complications were analyzed. RESULTS: Renal tissue was obtained with percutaneous renal biopsy in 382 (95.5%) of 400 patients and with transjugular renal biopsy in 383 (95.8%) of 400 patients. The mean numbers of intact glomeruli per tissue core with optical microscopy were 11.2 +/- 7.7 (SD) and 9.8 +/- 7.6 for percutaneous renal biopsy and transjugular renal biopsy, respectively. With immunofluorescent microscopy, the mean numbers were 6.4 +/- 5.3 and 4.6 +/- 4.6 for percutaneous renal biopsy and transjugular renal biopsy, respectively. Tissue cores were adequate for histopathologic diagnosis in 98.2% with both techniques. Major complications occurred with transjugular renal biopsy in four patients and with percutaneous renal biopsy in three patients. CONCLUSION: Use of transjugular renal biopsy provides diagnostic yield and safety similar to those of percutaneous renal biopsy and allows multiorgan biopsy during the same procedure. It can be recommended in patients with percutaneous renal biopsy contraindication or failure.

Sodium restriction decreases AP-1 activation after nephron reduction in the rat: role in the progression of renal lesions.

Renal hyperplasia and hypertrophy are early events after nephron reduction which precede progressive destruction of the remnant kidney. Restriction of dietary sodium content was shown to reduce renal lesions following nephron reduction. AP-1 is a transcription factor, resulting from heterodimerization of fos and jun proteins, which mediates the effects of mitogenic growth factors. To elucidate the role of AP-1 in growth processes involved in renal deterioration, we evaluated whether restriction of dietary sodium content (0.25 vs. 0.50% sodium w/w) affected AP-1-DNA binding and hyperplasia in the remnant kidney after nephron reduction (70% nephrectomy). Cell proliferation, evaluated by PCNA immunostaining, increased progressively from day 7 to day 60 in glomeruli, proximal and distal tubules and loops of Henle of nephrectomized (Nx) rats compared to control sham-operated (C) animals. AP-1-DNA binding activity increased 7 and 14 days after surgery, but it was reduced below C values at day 60. c-fos and c-jun expression were also reduced in Nx rats at day 60. Sodium restriction significantly reduced the number of PCNA-stained cells in glomeruli and tubules at days 14 and 60, but not at day 7, whereas it decreased AP-1 activation at all times of the study. This effect was associated to a marked reduction of renal lesions in Nx rats. In conclusion, we showed that, after nephron reduction, the beneficial effect of sodium restriction was associated with a reduction of hyperplasia and AP-1 activation, but that the latter did not parallel delayed cell proliferation rate in remaining nephrons. Thus, we propose that different transduction pathways are involved in cell proliferation after nephron reduction, according to the time of evolution of renal lesions.

Retroperitoneal fibrosis and membranous nephropathy.

We report on a patient with a past history of Pott's abscess who suffered both from a retroperitoneal fibrosis and a membranous glomerulonephritis. Five cases of retroperitoneal fibrosis and immune complex glomerulonephritis are already reported in the literature. These associations might result from a particular systemic immune response to an unknown antigen. Consequently, we consider the role of tuberculosis in our case.

Identification of crystals in kidneys of AIDS patients treated with foscarnet.

Three acquired immune deficiency syndrome patients given foscarnet to treat cytomegalovirus retinitis developed renal failure with crystal deposits within the renal glomeruli. We identified these crystals as a mixture of sodium salt, calcium salt, and a mixed salt containing both sodium and calcium ions. This composition has not been previously reported. Foscarnet can complex available ionized calcium and secondarily precipitate in glomeruli. The percentage of complexing depends on calcium concentration in serum and the poor calcium salt solubility.

HIV-associated IgA nephropathy--a post-mortem study.

Between November 1983 and December 1991, we undertook a systematic study of kidney in deceased AIDS patients using light and immunofluorescence microscopy. Among the 116 examined kidneys (from 106 men and 10 women), nine (7.75%) showed diffuse mesangial IgA deposits. By light microscopy, glomerular lesions were absent or moderate (mesangial hypertrophy or some mesangial deposits). Urinary abnormalities were mild in all cases. Our study shows that the association between IgA nephropathy and HIV infection is not rare, and a review of the literature disclosed 18 reported cases. Some reported immunopathogenic data support the possibility of a link between HIV infection and IgA nephropathy.

Comparative effects of low- and high-osmolar contrast media on the renal function during early degenerative gentamicin-induced nephropathy in rats.

The nephrotoxic potentials of a high-osmolar contrast medium, diatrizoate, and of a low-osmolar contrast medium, ioxaglate, were compared during early degenerative gentamicin-induced nephropathy in the rat. Male rats (13-22/group) were uninephrectomized. Six days later, the aorta was clamped above the renal artery, and either diatrizoate or ioxaglate was administered (1 ml/min for 3 min) via an aortic puncture into the remaining kidney. Some of the rats received chronic treatment with gentamicin (50 mg/kg/day i.m., 4 days), starting 2 days before and ending 1 day after contrast medium administration. Two control groups, only one of which received gentamicin, were subjected to a 3-min renal ischemia. The creatinine clearance (CrCl) per 100 g body weight was determined before and 24 and 48 h after contrast medium injection. A second study (6 rats/group) evaluated urinary N-acetyl-beta-D-glucosaminidase (NAG) excretion and the histologic appearance of the kidneys (blinded analysis) in the same experimental groups. Gentamicin induced a significant decrease in CrCl at baseline (0.35 +/- 0.19 vs. 0.41 +/- 0.19 ml/min; p < 0.01) and an increase in urinary NAG (128 +/- 92 vs. 39 +/- 57 mumol/h/mmol creatinine; p < 0.01). Taking into account these differences at baseline, univariate repeated-measures analysis showed that on day 1 diatrizoate caused a more marked decrease in CrCl than ioxaglate (p < 0.05), whether or not gentamicin was also administered. On day 2, the depressant effect of diatrizoate associated with gentamicin persisted (CrCl vs. day 0 = -0.19 +/- 0.10 ml/min), while that of diatrizoate alone returned to baseline (-0.05 +/- 0.24 ml/min).(ABSTRACT TRUNCATED AT 250 WORDS)

Iobitridol, a new nonionic low-osmolality contrast agent, and iohexol. Impact on renal histology in the rat.

RATIONALE AND OBJECTIVES: To compare the histologic effects on rat tubular cells of two nonionic contrast media with equivalent osmolalities and viscosities. METHODS: Histologic, functional (creatinine clearance), and biochemical (proteinuria and enzymuria) profiles of iohexol and iobitridol (both at 350 mg I/mL) were compared in the uninephrectomized rat. A control group (n = 14) received compared isotonic saline solution. Test substances (3 mL) were injected into the kidney at a rate of 1 mL/minute while transitory ischemia was induced by clamping the aorta above the renal artery. RESULTS: In terms of their (moderate) effects on creatinine clearance, proteinuria, and urinary N-acetyl-beta-D-glucosaminidase activity, no statistically significant difference was detected between the two low-osmolar contrast agents either 24 or 48 hours after injection. However, blinded histologic analysis of the kidneys showed significantly greater epithelial cell vacuolization in the proximal convoluted tubules of the outer cortex with iohexol (14 of 14 rats versus 3 of 14 rats for iobitridol; P < .001). The same degree of vacuolization in the inner cortex was observed for all three substances. Iobitridol also induced fewer congestive lesions in the glomerular capillaries than iohexol (4 of 14 versus 10 of 14, respectively; P < .05) and saline (5 of 6; P < .05). It is difficult to explain the lesser degree of cytoplasmic vacuolization using standard physicochemical parameters. CONCLUSION: Although iobitridol and iohexol showed similar functional and biochemical profiles when selectively injected into the single remaining kidney of rats, iobitridol induced significantly less tubular vacuolization and capillary congestion than iohexol.

Modulation of the renal effects of contrast media by endothelium-derived nitric oxide in the rat.

RATIONALE AND OBJECTIVES: A possible involvement of endothelium derived relaxing nitric oxide (NO) in the pathogenesis of iodinated contrast media (CM)-induced nephrotoxicity was investigated in the rat. METHODS: Male rats (6 to 12 per group) were uninephrectomized. Six days later, the aorta was clamped above the renal artery and a low-osmolar contrast medium (CM), ioxaglate, was injected (1 mL/min; 3 minutes) via an aortic puncture in the single remaining kidney. Contrast medium was injected with or without the NO-synthase inhibitor L-NAME (100 mg/kg intravenously [i.v.] 5 minutes before CM). One group received L-Arginine, the physiological precursor of NO (100 mg/kg i.v.), 5 minutes before L-NAME. Phenylephrine (300 micrograms/kg; 30 min) was used as a vasoconstrictive NO-independent control. The effects of iohexol, another low-osmolar CM, on creatinine clearance (CrCl) were also studied with and without pretreatment with L-NAME. A control group was subjected to a 3-minute renal ischemia only. Creatinine clearance and urinary N-acetyl-beta-D-glucosaminidase (NAG) excretion were determined before, and 24 and 48 hours after CM administration. Blinded histologic analysis was carried out after completion of the study. RESULTS: When administered alone, neither L-NAME nor L-arginine modified CrCl. Ioxaglate mildly but significantly decreased CrCl at 24 hours (-26.5% of preinjection value). This was similar to the effect observed in the control group subjected to ischemia only. When associated with L-NAME, ioxaglate markedly decreased CrCl (-58 + 11% at 24 hours, P < .05 vs. ioxaglate alone). A similar interaction was noted in the case of iohexol. L-NAME also markedly increased ioxaglate-induced urinary NAG excretion. Phenylephrine had a similar impact on renal function. L-arginine pretreatment reduced the increase in serum creatinine induced by L-NAME+ioxaglate (68 + 17 mumol/L vs. 175 + 59 mumol/L for L-NAME+ioxaglate; P < .05) and urinary NAG excretion. Ioxaglate alone induced only tubular epithelial vacuolization. When associated with L-NAME, this CM induced tubular and vascular lesions, as well as necrosis in the outer medulla. Such histologic effects were clearly inhibited by L-arginine. CONCLUSION: These data indicate that L-NAME, a specific inhibitor of NO-synthase, and phenylephrine, accentuate the nephrotoxicity of CM in the rat. This is consistent with results from the literature showing that CM-toxicity is enhanced by renal ischemia.

Chronic cisplatin nephropathy in rats.

The long-term renal effects of cisplatin have been very poorly studied. Therefore we investigated the chronic renal effects of various doses of cisplatin in three groups of male Sprague-Dawley rats. Group I received two injections of 5 mg/kg body weight (bw) at 4-week intervals, group II four injections of 2.5 mg/kg bw at 4-weeks intervals, and group III one injection of 5 mg/kg bw and four injections of 2.5 mg/kg bw at 4-weeks intervals. Controls received an equivalent amount of isotonic saline. Each group was evaluated 1, 3, or 6 months after the last injection of cisplatin. One, 3 and 6 months after the last injection, cisplatin induced a marked decrease in glomerular filtration rate (GFR) evaluated as clearance of [99mTc]DTPA and creatinine clearance in all treated rats. Urinary NAG excretion remained unaltered. At 3 months post-cisplatin treatment GFR was significantly less (P < 0.05) in group III (0.18 +/- 0.02 ml/min/100 g bw) when compared with group I (0.23 +/- 0.02 ml/min/100 g bw) or II (0.23 +/- 0.04 ml/min/100 g bw). In group I GFR was similar 1 month (0.24 +/- 0.02), 3 months (0.23 +/- 0.02) and 6 months (0.23 +/- 0.03 ml/min/100 g bw) after cisplatin treatment. Cisplatin induced atrophy and dilatation of tubules with mononuclear cell infiltration associated with cyst formation. The glomerular and tubulointerstitial lesions were significantly enhanced in group III when compared with groups I and II. This study indicates that repeated administration of cisplatin may induce a chronic tubulointerstitial nephropathy associated with a marked decrease in GFR, which is stable over time. The incidence and severity of chronic cisplatin toxicity is dose-related and is not modified by dividing the dose.

Idiopathic acute interstitial nephritis associated with anterior uveitis in adults.

Concomitant renal and ocular lesions have been described in a few systemic diseases. The association of acute interstitial nephritis (AIN) and anterior uveitis without determined cause was first described in children. Recently, the same clinical association has been reported in adults. We report 3 cases of this association and present a review of the literature. Including our 3 patients, 7 cases of this association have been reported in adults. All patients were females aged 27-74 years. Initial symptoms were either ocular, or pseudoviral (fever, myalgia and fatigue). Histological renal studies revealed acute interstitial nephritis with tubular lesions. Immunofluorescence and electron microscopy were not contributive. Ocular prognosis was always good. In 5 patients, the evolution of renal function was excellent with complete resolution of acute renal failure within a few weeks. Chronic renal failure developed in two of the four patients who did not receive systemic steroid therapy (with evolution towards terminal renal failure in one patient). Three of the patients received 60 mg per day of prednisone and none of them developed chronic renal failure. Despite the small number of patients reported and the possibility of spontaneous regression, these data suggest a beneficial effect of systemic steroid therapy to prevent or reduce interstitial inflammation and subsequent fibrosis.

Effects of nifedipine on cisplatinum-induced nephrotoxicity in rats.

The effects of calcium channel blockade with nifedipine (N) on cis-diammine dichloroplatinum II (CDDP)-induced nephrotoxicity were tested in male Sprague-Dawley rats. Renal function was evaluated before and five days after CDDP administration (5 mg/kg). The rats were treated with various doses of N (0.1; 0.3; 0.6 mg/kg/day) 2 days before CDDP administration and throughout the study. The severity of CDDP-induced acute renal failure was markedly modified in N-treated animals according to the daily dosage of N. At 0.3 and 0.6 mg/kg BW/day, N enhanced CDDP nephrotoxicity. Serum creatinine was 637 +/- 45 and 611 +/- 71 mumoles/liter, respectively, 5 days after CDDP administration (vs. 313 +/- 24 mumoles in animals treated with CDDP alone; p less than 0.05). In these animals the plasma potassium level was significantly elevated at day 7 when compared with CDDP-treated and control rats. In contrast, at the dose of 0.1 mg/kg BW/day N attenuated CDDP nephrotoxicity with a serum creatinine of 214 +/- 35 mumoles at the end of the study. The pathologic changes were also more severe in the groups receiving 0.3 and 0.6 mg/kg of nifedipine. We postulate that at the higher doses (0.3 and 0.6 mg/kg) the systemic hemodynamic effects of nifedipine may override the potentially beneficial intrarenal effect which may account for the favorable results recorded with a dosage of 0.1 mg/kg.

Kidney and cancer: results of immunofluorescence microscopy.

Kidneys obtained at autopsy were studied by immunofluorescence in order to detect the presence of glomerular deposits in 129 patients who had presented with solid tumors, and in 55 patients without carcinoma utilized as controls. Deposits were observed in 22 of the neoplastic patients (17%), but only in 3 of the others (5.4%) (p less than 0.05). Among all solid tumors, glomerular deposits were most often observed in digestive carcinoma (p less than 0.02). These deposits were usually mesangial and they were never subepithelial. IgG and/or IgM and/or C3 deposits were demonstrated in 14 of 22 patients, IgA deposits were present in the 8 others (36%). Thus malignant neoplastic diseases should be taken into account as a possible etiologic factor in IgA nephropathy and they should be looked for in older patients with Berger's disease.