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Biomedical subjects

A Meguid El Nahas

Publications and source records attributed to A Meguid El Nahas.

At least 19 recordsLinked to original sources
PubMed2006

Immunosuppressive treatment of idiopathic focal segmental glomerulosclerosis: a five-year follow-up study.

BACKGROUND/AIMS: Focal segmental glomerulosclerosis (FSGS) is a common type of glomerular disease that can lead to chronic renal failure. Various therapeutic regimens have been used in nephrotic FSGS patients. The effect of treatment with prednisolone alone or its combination with azathioprine and cyclosporin and parameters related to a poor outcome are studied. METHODS: Fifty-one patients with idiopathic FSGS and a follow-up period of 5 years were included. Twenty-five were treated with prednisolone alone (1 mg/kg BW/day) or combination of prednisolone (0.5 mg/kg BW/day) with azathioprine (2 mg/kg BW/day) or cyclosporine (3 mg/kg BW/day) in gradually reduced doses whereas 26 patients received no immunosuppressive drugs. Lower prednisolone dose regimens were used as initial treatment in obese, borderline diabetics or patients with bone disease. The clinical course was estimated using the end-points of 50% or doubling of baseline serum creatinine and/or end-stage renal failure. The contribution of clinical and histological parameters in the clinical outcome was estimated by univariate and multivariate analyses. RESULTS: Increase of baseline serum creatinine by 50% during the follow-up period was observed in 2 treated and 9 untreated patients (8% vs. 35%, p = 0.03) whereas doubling of serum creatinine in 2 and 5 patients respectively (8% vs. 19%, p = NS). End-stage renal failure developed in 4 of 51 patients (8%), 2 treated and 2 untreated (p = NS). Parameters related to a poor outcome were baseline serum creatinine and severity of glomerulosclerosis (multivariate analysis OR = 1.08, p = 0.01). Most of patients (68%) who reached end-points had persistent nephrotic syndrome during the follow-up. Remission of nephrotic syndrome was observed more frequently among treated (75 vs. 30.7%, p = 0.05). Prednisolone alone was followed by remission of nephrotic syndrome in 62.5% whereas combination of lower prednisolone dose with azathioprine and cyclosporin in 80 and 85.7% of patients. No serious side-effects were observed. CONCLUSION: This and previous studies suggest that steroid and/or immunosuppressive therapy have a role in amelioration of the clinical course and remission of nephrotic syndrome in patients with FSGS A combination of low predisolone dose with cyclosporine could be used as initial treatment in patients with higher risk for side-effects from the usual prednisolone dose.

Adult↗
PubMed2005

An IGF-I antagonist does not inhibit renal fibrosis in the rat following subtotal nephrectomy.

Insulin-like growth factor I (IGF-I) has been proposed as a mediator of kidney scarring, although no interventional studies on the role of IGF-I in models of chronic kidney disease have been reported. The effect of a peptide IGF-I receptor antagonist (JB3) has been examined on kidney fibrosis and function in the rat following 5/6 subtotal nephrectomy (SNx). Male Wistar rats were anesthetized with halothane and subjected to SNx. JB3 was delivered by subcutaneous infusion using Alzet osmotic minipumps. In vitro studies showed JB3 to displace (125)I-IGF-I binding to isolated rat glomeruli and to inhibit IGF-I-induced receptor phosphorylation in renal tubular cells in culture. In the 7-day SNx rats, IGF-I immunostain was present in collecting tubules and JB3 inhibited compensatory renal growth, the maximum effect occurring at 10 microg. kg(-1).day(-1). After 90 days, the SNx rats developed proteinuria, hypertension, and a fall in glomerular filtration rate. IGF-I immunostain was present in the tubulointerstitial space of the remnant kidney together with marked tubulointerstitial fibrosis. Treatment with JB3 at a dose of 10 microg. kg(-1).day(-1) had no effect on the renal fibrosis measured by Masson's trichrome staining or immunostain for collagen III and collagen IV. The proteinuria, hypertension, and lower creatinine clearance all remained unchanged. The remnant kidney was associated with a 50% decrease in renal IGF-I mRNA, which was partially restored by treatment with JB3. Thus an interventional study with an IGF-I receptor antagonist does not support a role for IGF-I in the development of renal fibrosis in the SNx rat, although IGF-I does make an important contribution to compensatory kidney growth.

Amino Acid Sequence↗
PubMed2005

GFR prediction using the MDRD and Cockcroft and Gault equations in patients with end-stage renal disease.

BACKGROUND: Although prediction equations are recommended to determine GFR and creatinine clearance (CrCl), neither the MDRD equations nor the Cockcroft and Gault formula have been validated for the low levels of GFR present in end-stage renal disease (ESRD). The accuracy of the MDRD equations and the Cockcroft and Gault formula in predicting GFR and CrCl, respectively, was examined in patients with ESRD and its relationship to the basal GFR and two markers of malnutrition, urinary creatinine and body fat determined. METHODS: Inulin clearance (C(in)) was measured in 26 non-diabetic patients with ESRD and the 24 h CrCl determined. GFR was predicted using three equations derived from the MDRD study population containing four to six variables. Both CrCl and GFR were predicted from the Cockcroft and Gault formula. Estimates of bias and precision were obtained and Bland and Altman analysis performed. Body fat was measured by DEXA scan. RESULTS: The predicted GFR (MDRD) was 10% lower than C(in) (8.83+/-0.71 ml/min/1.73 m2) with all three MDRD equations, showing a similar degree of precision and bias. C(in) gave a negative correlation with the difference between the predicted GFR (MDRD) and the measured GFR. The predicted GFR (MDRD) underestimated GFR when C(in) >8 ml/min/1.73 m2 but overestimated GFR when C(in) <8 ml/min/1.73 m2. The Cockcroft and Gault formula overestimated CrCl by 14% and overestimated C(in) by 35%. C(in) gave a negative correlation with the difference between the predicted GFR (Cockcroft and Gault) and measured GFR, overestimating GFR when C(in) <13 ml/min/1.73 m2. The overestimation of GFR by the MDRD equation was not associated with urinary creatinine excretion. However, both Cockcroft and Gault and the MDRD predictions showed a positive, but weak, correlation with body fat. CONCLUSION: The MDRD equations were more accurate in predicting the group mean GFR in patients with ESRD than the Cockcroft and Gault formula. However, the predicted GFR using either formula was related to the basal GFR and percentage body fat.

Adolescent↗
PubMed2005

The outcome of acute renal failure in the intensive care unit according to RIFLE: model application, sensitivity, and predictability.

BACKGROUND: The definition, classification, and choice of management of acute renal failure (ARF) in the setting of the intensive care unit (ICU) remain subjects of debate. To improve our approach to ARF in the ICU setting, we retrospectively applied the new classification of ARF put forward by the Acute Dialysis Quality Initiative group, RIFLE (acronym indicating Risk of renal failure, Injury to the kidney, Failure of kidney function, Loss of kidney function, and End-stage renal failure), to evaluate its sensitivity and specificity to predict renal and patient outcomes. METHODS: RIFLE classification was applied to 183 patients with ARF admitted to the ICU (2002 to 2003) at the Northern General Hospital, Sheffield, UK. Patients were divided into 4 groups according to percentage of decrease in glomerular filtration rate from baseline. The risk group included 60 patients; injury group, 56 patients; failure group, 43 patients; and control group, 24 patients. Demographic, biochemical, hematologic, clinical, and long-term health status were studied and compared in the 4 groups. An attempt was made to evaluate, by means of logistic regression analysis and receiver operator characteristic curve analysis, the predictive value of RIFLE classification for mortality in the ICU. RESULTS: The failure group showed the worst parameters with regard to Acute Physiology and Chronic Health Evaluation (APACHE) II score, pH, lowest and highest mean arterial pressures, and Glasgow Coma Scale (P < 0.001). Mortality rate in the ICU (1 month) was significantly greater in the failure group compared with all groups (32 of 43 patients [74.4%]; P < 0.001) and, again, 6-month mortality rate (37 of 43 patients [86%]; P < 0.001). Receiver operator characteristic curve analysis showed that Simplified Acute Physiology Score (SAPS) II was more sensitive than APACHE II score for prediction of patient death in the risk and injury groups compared with the failure and control groups (risk group: SAPS II, 0.8 +/- 0.06; P < 0.001; APACHE II, 0.63 +/- 0.07; P = 0.14; injury group: SAPS II, 0.76 +/- 0.08; P < 0.001; APACHE II, 0.72 +/- 0.07; P = 0.006). CONCLUSION: RIFLE classification can improve the ability of such older and established ICU scoring systems as APACHE II and SAPS II in predicting outcome of ICU patients with ARF.

APACHE↗
PubMed2005

Prevention of chronic kidney disease: a global challenge.

In view of the increasing number of patients requiring renal replacement therapy (RRT) every year worldwide, attention has focused over the last two decades on meeting the health care need of patients with end-stage renal failure (ESRF). More recently, increasing awareness of the growing burden of chronic kidney disease (CKD), with a large percentage of the population affected by early stages of CKD, has shifted attention and health care priority to the prevention and early detection of CKD. This article addresses issues related to general population as well as targeted screening, favoring the latter. It also examines some of the screening initiatives undertaken in both the developing and developed worlds. It also highlights the links between albuminuria, CKD, and cardiovascular disease (CVD) as an increasing number of studies identify albuminuria/proteinuria, as well as CKD as major markers of CVD. Finally, a brief review is included of primary and secondary intervention strategies for CKD and issues related to their implementation: manpower and funding.

Albuminuria↗
PubMed2004

Inhibition of transglutaminase activity reduces extracellular matrix accumulation induced by high glucose levels in proximal tubular epithelial cells.

Diabetic nephropathy affects 30-40% of diabetics leading to end-stage kidney failure through progressive scarring and fibrosis. Previous evidence suggests that tissue transglutaminase (tTg) and its protein cross-link product epsilon(gamma-glutamyl)lysine contribute to the expanding renal tubulointerstitial and glomerular basement membranes in this disease. Using an in vitro cell culture model of renal proximal tubular epithelial cells we determined the link between elevated glucose levels with changes in expression and activity of tTg and then, by using a highly specific site directed inhibitor of tTg (1,3-dimethyl-2[(oxopropyl)thio]imidazolium), determined the contribution of tTg to glucose-induced matrix accumulation. Exposure of cells to 36 mm glucose over 96 h caused an mRNA-dependent increase in tTg activity with a 25% increase in extracellular matrix (ECM)-associated tTg and a 150% increase in ECM epsilon(gamma-glutamyl)lysine cross-linking. This was paralleled by an elevation in total deposited ECM resulting from higher levels of deposited collagen and fibronectin. These were associated with raised mRNA for collagens III, IV, and fibronectin. The specific site-directed inhibitor of tTg normalized both tTg activity and ECM-associated epsilon(gamma-glutamyl)lysine. Levels of ECM per cell returned to near control levels with non-transcriptional reductions in deposited collagen and fibronectin. No changes in transforming growth factor beta1 (expression or biological activity) occurred that could account for our observations, whereas incubation of tTg with collagen III indicated that cross-linking could directly increase the rate of collagen fibril/gel formation. We conclude that Tg inhibition reduces glucose-induced deposition of ECM proteins independently of changes in ECM and transforming growth factor beta1 synthesis thus opening up its possible application in the treatment other fibrotic and scarring diseases where tTg has been implicated.

Animals↗
PubMed2004

Tissue transglutaminase: a mediator and predictor of chronic allograft nephropathy?

BACKGROUND: The precise mechanisms underlying the development of chronic allograft nephropathy (CAN) and the associated renal fibrosis remain uncertain. The protein-crosslinking enzyme, tissue transglutaminase (tTg), has recently been implicated in renal fibrosis. METHODS.: We investigated the involvement of tTg and its crosslink product, epsilon-(gamma-glutamyl) lysine, in 23 human kidney allografts during the early posttransplantation period and related these to changes of CAN that developed in 8 of them. Sequential biopsies were investigated using immunohistochemical, immunofluorescence, and in situ enzyme activity techniques. RESULTS: From implantation, tTg (+266%) and epsilon-(gamma-glutamyl) lysine crosslink (+256.3%) staining increased significantly (P <0.001) in a first renal biopsy performed within 3 months from transplantation. This was paralleled by elevated tTg in situ activity. The eight patients who developed CAN had further increases in immunostainable tTg (+197.2%, P <0.001) and epsilon-(gamma-glutamyl) lysine bonds (+465%, P <0.01) that correlated with interstitial fibrosis (r=0.843, P =0.009 and r=0.622, P =0.05, respectively). The staining for both was predominantly located within the mesangium and the renal interstitium. Both implantation and first biopsies showed tTg and epsilon-(gamma-glutamyl) lysine crosslinking levels in patients who developed CAN to be twice the levels of those with stable renal function. Cox regression analysis suggested the intensity of the early tTg staining was a better predictor of inferior allograft survival that other histologic markers (hazard ratio=4.48, P =0.04). CONCLUSIONS: tTg and epsilon-(gamma-glutamyl) lysine crosslink correlated with the initiation and progression of scarring on sequential biopsies from renal-allograft recipients who experienced CAN. Elevated tTg may offer an early predictor of the development of CAN, whereas tTg manipulation may be an attractive therapeutic target.

Adult↗
PubMed2004

Cyclosporine A sensitizes the kidney to tubulointerstitial fibrosis induced by renal warm ischemia.

BACKGROUND: Renal warm ischemic injury and immunosuppression with cyclosporin A (CsA) may contribute to chronic allograft nephropathy after cadaveric transplantation. This study establishes whether CsA can sensitize the kidney to injury and fibrosis induced by renal warm ischemia (RWI). METHODS: The left kidney of Sprague-Dawley rats was subjected to 30 min of warm ischemia and/or intraperitoneal CsA (15 mg/kg/d) for 30 days (n=6 per group). Renal injury and fibrosis were assessed histologically together with immunohistochemistry for collagen III, transforming growth factor (TGF)-beta1, ED1 (macrophage marker), and alpha-smooth muscle actin. Renal mRNAs for collagen III, TGF-beta 1, matrix metalloproteinase (MMP)-2, and tissue inhibitor of metalloproteinase-1 together with MMP enzyme activity were also determined. RESULTS: RWI or CsA alone produced only minor effects on renal injury and fibrosis. However, in CsA-treated rats, RWI produced a marked increase in tubulointerstitial fibrosis, as shown by the potentiation of collagen III and TGF-beta1 determined by immunochemistry and mRNA analysis. The up-regulation of tissue inhibitor of metalloproteinase-1 mRNA was associated with a decrease in MMP enzyme activity. In CsA-treated rats, RWI was also associated with an increase in inflammatory infiltrates, elevated immunostain for ED1 (indicating extensive macrophage influx), and elevated immunostain for alpha-smooth muscle actin (indicating myofibroblast activation). CONCLUSIONS: In the rat, CsA can sensitize the kidney to fibrosis induced by renal warm ischemia. In renal transplantation, when cadaveric donor kidneys have been subjected to a period of warm ischemia, CsA may be an inappropriate choice for immunosuppressive therapy.

Animals↗
PubMed2004

Inhibitors directed towards caspase-1 and -3 are less effective than pan caspase inhibition in preventing renal proximal tubular cell apoptosis.

BACKGROUND: Uncontrolled apoptosis contributes to tubular cell deletion in renal scarring. Caspase-3 has a central role in the execution of apoptosis and may provide a target for regulating cell death. Here we evaluate three caspase inhibitors: B-D-FMK (pan caspase inhibitor), Z-DEVDFMK (predominantly Caspase-3 inhibitor) and Z-VAD-FMK (predominantly Caspase-1 and -3 inhibitor) to ameliorate apoptosis induced by cisplatin in rat proximal tubular (RPT) cells. METHODS: Caspase-3 activity (substrate cleavage assay) and protein (immunocytochemistry and Western blotting), apoptosis (Annexin V flow cytometry, in situend labelling of fragmented DNA, light/electron microscopy and DNA laddering) and cell survival (trypan blue exclusion and propidium iodide flow cytometry) were determined in RPT cells exposed to cisplatin with and without caspase inhibitors. RESULTS: Cisplatin induced a dose-dependent increase in Caspase-3 activity and 8-fold of increase in apoptosis (p < 0.01) when applied for 24 h at 100 microM. B-D-FMK (40 microM), Z-DEVD-FMK (15 microM) and Z-VAD-FMK (22 microM) almost completely inhibited the 25-fold increase in Caspase-3 activity and decreased apoptosis from 15.9 +/- 4.4 to 2.0 +/- 0.6% (p < 0.01), 15.0 +/- 2.2 and 15.0 +/- 2.2% respectively. DNA ladders were visible in cisplatin-treated cells, which disappeared following addition of B-D-FMK and decreased with Z-VAD-FMK and Z-DEVD-FMK. Cisplatin reduced cell survival to 61% by trypan blue exclusion. B-D-FMK and Z-VAD-FMK increased this to 87 and 75%, but Z-DEVD-FMK had no significant effect. CONCLUSIONS: Cisplatin causes an increase in RPT apoptosis that is associated with increased Caspase-3 activity. All caspase inhibitors were equally effective at reducing Caspase-3 activity, however the pan caspase inhibitor B-D-FMK was more effective at preventing apoptosis and increasing cell survival. Therefore, pan caspase inhibition offers the greatest potential for the prevention of renal tubular cell deletion by uncontrolled apoptosis.

Amino Acid Chloromethyl Ketones↗
PubMed2004

Cellular toxicity of catechin analogues containing gallate in opossum kidney proximal tubular (OK) cells.

A variety of catechins exist in green tea and Chinese rhubarb. It is also known that the green tea tannin mixture and its individual tannin components such as (-)-epicatechin 3-O-gallate (ECG) and (-)-epigallocatechin 3-O-gallate (EGCG) suppress renal failure in animals and inhibit the growth of mesangial cells. In addition, gallic acid (GA), a structural constituent of these catechins, induces apoptosis in tumor cell lines. However, the effects of catechins on renal tubular cells have not been investigated. In this experiment, the growth of opossum kidney proximal tubular (OK) cells was inhibited by GA (36.9 +/- 9.5%, p < 0.01) and EGCG (48.6 +/- 16.7%, p < 0.01) at 50 microM, and was almost completely inhibited by these compounds at concentrations over 100 microM. Furthermore, ECG inhibited the growth of OK cells at concentrations over 200 microM (52.6 +/- 16.5%, p < 0.01). The numbers of in situ end-labeled (ISEL) cells in cultures treated with GA at 25 and 50 microM, ECG at 100 and 200 microM, or EGCG at 25 microM were significantly less than those in the cultures treated with high-concentration EGCG (50 microM). In addition, exposure to 50 microM EGCG or 400 microM GA for 24 hr led to a significant increase in fragmented DNA, but ECG did not significantly induce DNA fragmentation compared to the control. These results suggest that EGCG induces mostly apoptosis in OK cells, but the cellular toxicity of GA involves both apoptosis and other mechanisms. Finally, ECG inhibits the growth largely via some mechanism other than apoptosis. This chemical-specific difference of cytotoxic pattern may be dependent on the combination of GA and basal catechin structures, or NADH oxidase (NOX) activity on the OK cell surface.

Animals↗
PubMed2003

Relationship of leptin and insulin-like growth factor I to nutritional status in hemodialyzed children.

Malnutrition is prevalent in patients with end-stage renal disease (ESRD). Elevated serum leptin levels were thought to contribute to the anorexia and poor nutrition in renal failure. However, studies of the relationship between nutritional status and leptin concentration in chronic renal failure have yielded conflicting results. Plasma insulin-like growth factor I (IGF-I) level has been used as an indicator of nutritional status in patients with renal failure. The relationship between leptin and IGF-I is controversial. The present study was conducted with the aim of assessing the relationship between nutritional status, hyperleptinemia, and serum IGF-I. Seventeen ESRD patients (8 male, 9 female), aged 8-18 years (mean 15.3+/-3.3 years) and undergoing standard hemodialysis for 58.8+/-23.1 months were enrolled. Nine age-matched healthy children served as controls. In all patients, energy and protein intakes were 40-70 kcal/kg per day and 1-1.54 g/kg per day, respectively. Predialysis serum leptin and IGF-I levels were measured by radioimmunoassay. Body mass index was decreased in 13 (76%) patients. Triceps skinfold thickness (TST) was reduced (below the 5th percentile) in 7 (41%), whereas mid arm circumference and mid arm muscle circumference were reduced in 14 (82.5%) and 13 (76.5%), respectively. The median serum leptin level was significantly higher in patients than in controls [13.7 interquartile range (IQR) 30.50 pg/ml vs. 6.50 IQR 8.65 pg/ml, P=0.01]. The median serum IGF-I level was lower in the patients (205.1 ng/ml IQR 194.4 ng/l) than controls (418.0 ng/l IQR 310.5 ng/ml) ( P=0.01). IGF-I levels were more decreased in patients with severe malnutrition, defined according to TST (145.0 ng/ml IQR 125.5 ng/l) than patients without malnutrition (301.2 ng/l IQR 218.8 ng/ml) ( P=0.03) and healthy children ( P=0.002). Although statistically not significant, IGF-I levels tended to be decreased, while leptin levels were increased. The median plasma insulin concentration was 15 microU/ml (1.63-45.80) and did not correlate with leptin and IGF-I levels. In conclusion, the results of this study confirm the presence of high circulating plasma leptin levels, which may be one of the many factors involved in the pathogenesis of the malnutrition in children on hemodialysis.

Adolescent↗
PubMed2003

Stem cell factor and crescentic glomerulonephritis.

BACKGROUND: Numerous cells and cytokines have been implicated in the pathogenesis of crescentic glomerulonephritis (CGN). Recently, there has been growing awareness of the role of mast cells and their growth factor, stem cell factor (SCF), in the process of tissue inflammation and fibrosis. METHODS: In this study, renal biopsy specimens from 28 patients with a histopathologic diagnosis of CGN were evaluated immunohistochemically for the presence of mast cells, SCF, and its receptor (c-kit). In addition, CD34+ hematopoietic cells, monocytes (CD68+ cells), and myofibroblasts (alpha-smooth muscle actin-positive [alpha-SMA+] cells) were counted. Renal biopsy specimens from cadaveric kidney donors and kidneys removed for hypernephroma (n = 6) served as controls. Point counting of positive immunostaining for SCF, alpha-SMA, and collagens III and IV was undertaken. Glomerular and interstitial fibrosis (IF) scores were determined. RESULTS: Patients who developed progressive chronic kidney failure showed a significant increase in percentage of crescents, number of interstitial c-kit+ cells, and glomerular CD68+ cells compared with those with a favorable outcome. Analysis showed a significant elevation of tryptase+ mast cells in the interstitium of renal biopsy specimens of patients with CGN compared with controls. SCF and c-kit+ cells were found in glomeruli and interstitium, with occasional immunostaining of the crescent with SCF. Both glomerular and interstitial SCF immunostaining was significantly higher in biopsy specimens of patients compared with controls. Glomerular and interstitial SCF showed a significant positive correlation with 24-hour urinary protein level. There were a few CD34+ cells in both glomeruli and interstitium, but their numbers did not differ between patients and controls. Colocalization of CD34+ and c-kit+ was seen in some rounded interstitial and spindle-shaped cells. Number of interstitial mast cells proved to be a strong predictor of IF. Glomerular SCF correlated negatively with creatinine clearance and positively with glomerular CD68+ cells. Interstitial immunostainable SCF correlated positively with interstitial CD68+ cells and interstitial collagen III. On double antigen labeling, SCF was shown in the vicinity of alpha-SMA+ cells. CONCLUSION: These results show the potential involvement of mast cells and their growth factor SCF/c-kit in CGN.

Actins↗
PubMed2003

Effects of caspase inhibition on the progression of experimental glomerulonephritis.

BACKGROUND: Caspase-3 has a central role in the execution of apoptosis. In a nephrotoxic nephritis (NTN) model, we previously demonstrated an up-regulation of caspase-3 that was associated with inappropriate renal apoptosis, inflammation, tubular atrophy, and renal scarring. METHODS: We applied a pan caspase inhibitor, Boc-Asp (OMe)-fluoro-methyl-ketone (B-D-FMK), directly to rat NTN kidney using an intrarenal cannula fed from an osmotic pump. Animals were treated either for the first 7 days (acutely) to determine the effects on renal inflammation (ED-1 staining) and apoptosis (in situ end labeling of fragmented DNA), or for 28 days commencing 15 days after NTN (chronically) to observe the effects on cell death and renal fibrosis. Changes of caspase-3 and caspase-1 activity were detected by fluorometric substrate cleavage assay. Changes in caspase-3 and caspase-1, interleukin-1 beta (IL-1 beta), and collagen I, III, and IV proteins and mRNA were detected by Western blotting and Northern blotting, respectively. RESULTS: In both treated groups, caspase-3 activity was inhibited, and 17 and 24 kD active caspase-3 proteins were reduced significantly. A compensatory increase of caspase-3 mRNA occurred in the acutely treated group, but decreased in the chronically treated group (P < 0.05). Although there were no significant changes in caspase-1 activity and its active protein, the observed decrease in its precursor in the chronic group was increased by treatment (P < 0.05). Further, IL-1 beta precursor and its mRNA were significantly reduced by treatment only in the chronically treated group. Apoptosis was decreased in the glomeruli of acutely treated rats, and in the tubules and interstitium of chronically treated animals (P < 0.05). Glomerular inflammation was decreased only in the acutely treated group, whereas tubulointerstitial inflammation was lowered in both treated groups (P < 0.05). Glomerulosclerosis was reduced in both inhibitor groups, with a reduction in tubulointerstitial fibrosis and collagen I, III, and IV mRNA restricted to chronically treated animals (P < 0.05). Proteinuria was significantly decreased with caspase inhibition in both treated groups, but not serum creatinine level. CONCLUSION: This study clearly indicates that caspase inhibition reduces renal apoptosis, ameliorates inflammation and fibrosis, and improves proteinuria in experimental glomerulonephritis, which may mainly be related to changes in the caspase enzymatic system.

Amino Acid Chloromethyl Ketones↗
PubMed2003

Tissue transglutaminase and the progression of human renal scarring.

Experimental renal scarring indicates that tissue transglutaminase (tTg) may be associated with the accumulation of extracellular matrix (ECM), both indirectly via TGF-beta1 activation and directly by the formation of epsilon(gamma-glutamyl) lysine dipeptide bonds within the ECM. The latter potentially accelerates deposition and confers the ECM with resistance to proteolytic digestion. Studied were 136 human renal biopsy samples from a range of chronic renal diseases (CRD) to determine changes in tTg and epsilon(gamma-glutamyl) lysine crosslinking. Immunofluorescence for insoluble tTg showed a 14-fold increase in the kidneys of CRD patients (5.3 +/- 0.5 versus 76 +/- 54 mV/cm(2)), which was shown to be active by a similar 11-fold increase in the epsilon(gamma-glutamyl) lysine crosslink (1.8 +/- 0.2 versus 19.3 +/- 14.2 mV/cm(2)). Correlations were obtained with renal function for tTg and crosslink. In situ hybridization for tTg mRNA showed that tubular epithelial cells were the major source of tTg; however, both mesangial and interstitial cells also contributed to elevated levels in CRD. This mRNA pattern was consistent with immunohistochemistry for soluble tTg. Changes in renal tTg and its product, the epsilon(gamma-glutamyl) lysine crosslink, occur in progressive renal scarring in humans independently of the original etiology and in a similar manner to experimental models. tTg may therefore play a role in the pathogenesis of renal scarring and fibrosis in patients with CRD and can therefore be considered a potential therapeutic target.

Animals↗
PubMed2003

Prednisolone and azathioprine in IgA nephropathy - a ten-year follow-up study.

BACKGROUND: Immunoglobulin A nephropathy (IgAN) is one of the most common primary glomerular diseases. Although its clinical course is usually benign, some patients develop end-stage renal failure (ESRF). The role of immunosuppressive drugs in the treatment of IgAN remains controversial. The effect of treatment with prednisolone and azathioprine and the clinical and histological parameters related to a poor outcome are examined retrospectively in this analysis. METHODS: Seventy-four patients with IgAN and a follow-up period of 10 years were included in this study. Forty-one were treated with prednisolone (initially 60 mg/day) and azathioprine (initially 2 mg/kg BW/day) in gradually reduced doses for 24 +/- 9 months, whereas 33 patients received no immunosuppressive drugs. The clinical course was estimated using the end-points of doubling of baseline serum creatinine and/or ESRF. The contribution of clinical and histological parameters in the clinical outcome was estimated by univariate and multivariate analyses. RESULTS: The overall clinical courses of both groups of patients showed a rather similar pattern. Doubling of serum baseline creatinine was observed in 9 of 41 treated (22%) and in 10 of 33 untreated (30%), whereas ESRF developed in 6 treated (15%) and 6 untreated patients (18%) (p = NS). However, treated patients with heavy proteinuria (>3 g/24 h) had a significantly better outcome compared to untreated (doubling of serum creatinine in 29 vs. 78% and ESRF in 17 vs. 55%, p < 0.05). Proteinuria (p < 0.01), mean blood pressure (p < 0.02), baseline serum creatinine (p = 0.02) and severity of interstitial myofibroblast expression (p = 0.02) were identified as independent risk factors related to a poor outcome by multivariate analysis. Side effects of treatment were not uncommon and observed in 10 (24%) patients. CONCLUSION: Treatment with prednisolone and azathioprine is beneficial in ameliorating the clinical course of a subset of IgAN patients with heavy proteinuria or impaired renal function. Patients with advanced renal failure and severe chronic histological lesions should not be treated by this regimen as no benefit is expected and there is a risk of side effects.

Adult↗
PubMed2002

A comprehensive study of the association between hepatitis C virus and glomerulopathy.

BACKGROUND: Hepatitis C virus (HCV)-related infection is commonly associated with a wide range of glomerulonephritides (GN) including membranoproliferative glomerulonephritis (MPGN). The causal link between HCV infection and renal disease has been postulated through the induction of cryoglobulinaemia and secondary GN. However, the detection of viral particles or genomes within the kidneys of HCV-infected patients has proved to be difficult. With that in mind, we have studied a population of Egyptian HCV-positive patients with associated GN in an attempt to detect viral particles, antigens or RNA within their kidneys. METHODS: Fifty patients were found to be HCV positive out of 303 who presented with a glomerulopathy between 1998 and 1999 at the Mansoura Urology and Nephrology Center, Egypt. Comprehensive investigations of these 50 patients were undertaken including an evaluation of their clinical, biochemical, histological, virological and immunological parameters. In addition, their kidney biopsy material was analysed by electron microscopy (EM) to detect viral particles, by immunohistochemistry to detect a viral core antigen and by RT-PCR to detect RNA. This was compared with 50 HCV-negative controls. RESULTS: Positivity for HCV antibodies was higher among patients with GN (38%) compared with healthy blood donors (16%). Genotype 4 was sequenced in 70% of the HCV-positive samples examined. MPGN was the most common type of GN accounting for 54% of patients. Extrarenal manifestations were absent in the majority (80%) of patients even though 54% had cryoglobulinaemia. EM revealed virus-like particles in 50% of biopsies. Immunohistochemistry failed to reveal HCV-related antigens in kidney sections. HCV RNA was detected in the cryoprecipitates in 66% of patients and 22% of frozen renal sections. Control sections were negative. CONCLUSION: Our findings suggest a causal link between HCV and GN based on the observation of virus-like particles as well as viral RNA within the kidney sections of patients with HCV-associated glomerulopathies.

Antibodies, Viral↗