Changes in matrix metalloproteinases and their inhibitors in kidney transplant recipients.

OBJECTIVES: Chronic allograft nephropathy remains one of the main causes of late graft loss after kidney transplant owing to multifactorial development of kidney scarring. Chronic allograft nephropathy is characterised by an excess accumulation of extracellular matrix. A key system regulating extracellular matrix homeostasis are matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases. This study sought to determine if a change in the matrix metalloproteinases/tissue inhibitors of matrix metalloproteinases system contributes to chronic allograft nephropathy-associated progressive kidney scarring. MATERIALS AND METHODS: Examination of sequential renal biopsies was done at implantation, acute rejection, and subsequent chronic allograft nephropathy. In situ localisation of matrix metalloproteinase activity was assessed with a high-resolution in situ zymography technique using gelatin and collagen 1 substrates. Matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases were localised using immunohistochemistry. RESULTS: In situ zymography showed over a 50% reduction in matrix metalloproteinase activity against both collagen 1 and gelatin substrates in chronic allograft nephropathy biopsies. A similar loss of matrix metalloproteinase activity was seen in the glomerular and tubulointerstitial compartments. Immunoreactive matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases were observed intracellularly in mesangial and tubular epithelial cells. Matrix metalloproteinases-1, -2, -3, and -9 were significantly reduced in acute rejection and later in chronic allograft nephropathy. However, glomerular matrix metalloproteinases 1 and 9 and tubulointerstitial matrix metalloproteinase-2 were reduced at implantation. Tissue inhibitors of matrix metalloproteinase-2 and -3 were elevated from implantation onwards. We were unable to stain reproducibly for tissue inhibitors of matrix metalloproteinase-1. CONCLUSIONS: Kidney scarring underlying chronic allograft nephropathy is associated with a reduction in matrix metalloproteinases activity that may be due to reduced expression of matrix metalloproteinases -1, -2, -3, and -9, and up-regulation of tissue inhibitors of matrix metalloproteinases -2 and -3. Some of these changes originate from implantation.

Do changes in transglutaminase activity alter latent transforming growth factor beta activation in experimental diabetic nephropathy?

BACKGROUND: Diabetic nephropathy is the leading cause of end-stage kidney failure worldwide. It is characterized by excessive extracellular matrix accumulation. Transforming growth factor beta 1 (TGF-ß1) is a fibrogenic cytokine playing a major role in the healing process and scarring by regulating extracellular matrix turnover, cell proliferation and epithelial mesanchymal transdifferentiation. Newly synthesized TGF-ß is released as a latent, biologically inactive complex. The cross-linking of the large latent TGF-ß to the extracellular matrix by transglutaminase 2 (TG2) is one of the key mechanisms of recruitment and activation of this cytokine. TG2 is an enzyme catalyzing an acyl transfer reaction leading to the formation of a stable ε(γ-glutamyl)-lysine cross-link between peptides. METHODS: To investigate if changes in TG activity can modulate TGF-ß1 activation, we used the mink lung cell bioassay to assess TGF-ß activity in the streptozotocin model of diabetic nephropathy treated with TG inhibitor NTU281 and in TG2 overexpressing opossum kidney (OK) proximal tubular epithelial cells. RESULTS: Application of the site-directed TG inhibitor NTU281 caused a 25% reduction in kidney levels of active TGF-ß1. Specific upregulation of TG2 in OK proximal tubular epithelial cells increased latent TGF-ß recruitment and activation by 20.7% and 19.7%, respectively, in co-cultures with latent TGF-ß binding protein producing fibroblasts. CONCLUSIONS: Regulation of TG2 directly influences the level of active TGF-ß1, and thus, TG inhibition may exert a renoprotective effect by targeting not only a direct extracellular matrix deposition but also TGF-ß1 activation and recruitment.

The impact of stopping inhibitors of the renin-angiotensin system in patients with advanced chronic kidney disease.

BACKGROUND: Inhibition of the renin-angiotensin-aldosterone system (RAAS) has shown to slow chronic kidney disease (CKD) progression. This is most notable at the earlier stages of diabetic and proteinuric nephropathies. Objective. Here, we observed the impact of discontinuation of angiotensin converting enzyme inhibitors (ACEi)/angiotensin receptors blockers (ARB) in patients with advanced kidney disease. METHODS: 52 patients (21 females and 31 males) with advanced CKD (stages 4 and 5), who attended our low clearance clinic (LCC) in preparation for renal replacement therapy (RRT). Mean age was 73.3 ± 1.8 years with an estimated glomerular filtration rate (eGFR) of 16.38 ± 1 ml/min/1.73 m(2). Baseline urine protein:creatinine ratio (PCR) was 77 ± 20 mg/mmol. 46% suffered from diabetes mellitus. Patients were followed for at least 12 months before and after ACEi/ARB were stopped. RESULTS: 12 months after discontinuation of ACEi/ARB eGFR increased significantly to 26.6 ± 2.2 ml/min/ 1.73 m(2) (p = 0.0001). 61.5% of patients had more than a 25% increase in eGFR, whilst 36.5% had an increase exceeding 50%. There was a significant decline in the eGFR slope -0.39 ± 0.07 in the 12 months preceding discontinuation. The negative slope was reversed +0.48 ± 0.1 (p = 0.0001). Mean arterial blood pressure (MAP) increased from 90 ± 1.8 mmHg to 94 ± 1.3 mmHg (p = 0.02), however ≥50% of patients remained within target. Overall proteinuria was not affected (PCR before = 77 ± 20 and after = 121.6 ± 33.6 mg/mmol). CONCLUSION: Discontinuation of ACEi/ARB has undoubtedly delayed the onset of RRT in the majority of those studied. This observation may justify a rethink of our approach to the inhibition of the RAAS in patients with advanced CKD who are nearing the start of RRT.

Cardiovascular disease on hemodialysis: predictors of atherosclerosis and survival.

Cardiovascular disease (CVD) is the leading cause of mortality in hemodialysis (HD) patients. This could not be explained by the known traditional CVD risk factors. In this study, we attempted to elucidate the factors influencing atherosclerosis, as measured by carotid artery intima-media thickness (IMT), in HD patients and their impact on cardiovascular mortality. A cohort of 50 patients started on HD was selected for this study. At baseline, IMT and the presence of atheromatous plaques were assessed. Plasma homocysteine (Hcy), malondialdehyde, total antioxidant capacity, von Willebrand factor, vitamins C, E, B(6), B(12), folate, and C-reactive protein (CRP) were also measured. Patients were followed up for 2 years to determine the impact of IMT and associated markers on mortality using survival analysis as well as Cox proportional hazard. At baseline, 40% of the patients had IMT>0.8 mm. They were older, had higher CRP (P<0.001), and lower serum albumin (P=0.03). Intima-media thickness >0.8 mm was associated with high calcium (risk ratio [RR]: 6.06; confidence interval [CI]: 0.75-12.25) and CRP (RR: 10.94 [CI: 2.56-46.74]). Fifteen patients (30%) died during the 2-year follow-up; the main cause of death was CVD (42%). The relative risk mortality was high with increased IMT (RR: 120.04 [CI: 4.18-3445.9]), Index of Coexistent Disease for CVD (RR: 4.04 [CI: 1.92-8.5]), and plasma Hcy (RR: 1.08 [CI: 1.02-1.13]). Markers of inflammation and increased serum calcium were significant predictors of increased carotid artery IMT. High IMT, Index of Coexistent Disease, and Hcy were associated with a high RR of all-cause mortality among a cohort of HD patients.

Influence of obesity on progression of non-diabetic chronic kidney disease: a retrospective cohort study.

BACKGROUND: There is increasing awareness of the impact of obesity on chronic diseases including chronic kidney disease (CKD). Until recently, a limited number of epidemiologic studies have examined the association between obesity and CKD. We conducted a retrospective cohort study to evaluate whether obesity impacts on the rate of non-diabetic CKD progression. METHODS: The medical records of 125 non-diabetic CKD patients in the Sheffield Kidney Institute, Sheffield, UK, who have been followed-up for around 10 years, were reviewed. Various socio-demographic, clinical and biochemical parameters were retrospectively collected from the patients' database. Participants were categorized into normal weight, overweight and obese groups. Multivariate regression analysis was used for modelling with estimated glomerular filtration rate (eGFR) reduction per year as the dependent variable to evaluate the impact of obesity (BMI) on CKD progression. RESULTS: Patients studied were mostly CKD stage 3 with a mean GFR of 36.2 ml/min/1.73 m(2) for the control group and 44.3 ml/min/1.73 m(2) for those who were overweight or obese. Baseline diastolic and mean arterial blood pressure were significantly higher in overweight than normal weight CKD patients (p = 0.009 and p = 0.014 respectively). On follow-up, systolic, diastolic and mean arterial blood pressure were significantly higher in overweight (p = 0.03, p = 0.005 and p = 0.003, respectively) and obese (p = 0.008, p = 0.022 and p = 0.003, respectively) compared to normal weight CKD patients. Mean follow-up triglycerides level was significantly higher in obese than normal weight patients (p = 0.042). The frequency of CKD progression based on eGFR fall per year (>1 ml/min/1.73 m(2)/year) was 62.5% in overweight and 79.5% in obese compared to 44.7% in normal weight CKD patients (p = 0.007). However, no significant difference in the rate of progression (fall of eGFR ml/min/1.73 m(2)/year) was observed between the three groups. On multivariate regression analysis, adjusted for other covariates (age, BP and proteinuria), baseline BMI was an independent predictor of CKD progression (fall in eGFR, ml/min/1.73 m(2)/year) (R(2) = 0.122 and p < 0.001). Percentage changes in BMI over the observation period did not affect the rate of eGFR decline. Young age also predicted a faster CKD progression. CONCLUSIONS: Baseline BMI and young age are strongly and independently associated with faster CKD progression based on the annual rate of eGFR fall. Prospective studies to investigate the relationship between BMI and CKD and its complications are warranted.

Transglutaminase inhibition ameliorates experimental diabetic nephropathy.

Diabetic nephropathy is characterized by excessive extracellular matrix accumulation resulting in renal scarring and end-stage renal disease. Previous studies have suggested that transglutaminase type 2, by formation of its protein crosslink product epsilon-(gamma-glutamyl)lysine, alters extracellular matrix homeostasis, causing basement membrane thickening and expansion of the mesangium and interstitium. To determine whether transglutaminase inhibition can slow the progression of chronic experimental diabetic nephropathy over an extended treatment period, the inhibitor NTU281 was given to uninephrectomized streptozotocin-induced diabetic rats for up to 8 months. Effective transglutaminase inhibition significantly reversed the increased serum creatinine and albuminuria in the diabetic rats. These improvements were accompanied by a fivefold decrease in glomerulosclerosis and a sixfold reduction in tubulointerstitial scarring. This was associated with reductions in collagen IV accumulation by 4 months, along with reductions in collagens I and III by 8 months. This inhibition also decreased the number of myofibroblasts, suggesting that tissue transglutaminase may play a role in myofibroblast transformation. Our study suggests that transglutaminase inhibition ameliorates the progression of experimental diabetic nephropathy and can be considered for clinical application.

High prevalence of microalbuminuria in the overweight and obese population: data from a UK population screening programme.

BACKGROUND: Microalbuminuria (MA) is associated with increased risk of cardiovascular and possibly chronic kidney disease (CKD). Obesity has been linked to MA, though the prevalence of MA in overweight groups is not well documented. This population study with an overrepresentation of individuals with BMI >25 (calculated as kg/m2) investigates the prevalence of MA in different BMI categories, and the relationship between MA and BMI. METHODS: Data from two cross-sectional epidemiological studies in the City of Sheffield were combined to produce a cohort of non-diabetic, non-CKD subjects over the age of 18. The first study, Kidney Evaluation and Awareness Programme in Sheffield (KEAPS), is a general population screening programme, whilst Kidney Evaluation in Overweight Population in Sheffield (KEOPS) is a screening programme specifically for individuals with BMI >25. RESULTS: The combined database had 1,179 subjects eligible for analysis after applying exclusion criteria. The prevalence of MA in subjects with BMI <25 was 3.1% compared to 12.1% in those with BMI 25-30 and 27.2% in obese subjects with BMI >30 (p < 0.001). The prevalence of MA increased exponentially with the BMI category. BMI is a predictor of MA in logistic regression analyses in the population as a whole, males, females, younger and older age categories, and higher BMI groups (above median and upper tertile). The effect of BMI persists after adjusting for confounding variables. The relative risk for having urine albumin concentration >20 mg/l is 8.0 (95% CI 3.8-16.8, p < 0.0001) if BMI is above the 80th percentile (BMI >27.2). CONCLUSION: The prevalence of MA increases with increasing BMI in the population of Sheffield. The risk of having MA increases exponentially with BMI. The significance of the high prevalence of MA in overweight and obese individuals should be investigated longitudinally.

Lack of effect of IGF-I on the glomerular filtration rate in non-diabetic patients with advanced chronic kidney disease.

Recombinant human insulin-like growth factor I (rhIGF-I) acutely increases the glomerular filtration rate (GFR) in human volunteers and patients with advanced chronic kidney disease (CKD). However, on chronic administration, rhIGF-I induces tolerance to its renal effects attributed to a fall in serum IGF-binding protein 3 (IGFBP-3) enhancing its systemic clearance. Tolerance may be avoided by the use of an intermittent dosage regimen of rhIGF-I. A randomised, double-blind, placebo-controlled study was undertaken in non-diabetic patients with advanced CKD to establish whether intermittent subcutaneous injections of rhIGF-I (50 microg/kg, four days/week) could increase GFR over a 24 week period and thereby have the potential to delay the onset of renal replacement therapy. Twenty-seven patients were randomised into rhIGF-I/placebo groups using a 2:1 treatment ratio. GFR was determined by inulin clearance. RhIGF-I therapy produced a sustained increase serum total and free IGF-I elevating IGFBP-1 without decreasing IGFBP-3. Inulin clearance however, was not increased after either four weeks or over the 24 week observation period. Only 4/18 rhIGF-I treated patients compared to 6/9 placebo patients completed the study, the major reason being the requirement for dialysis. Compared with healthy volunteers, advanced CKD patients had elevated serum levels of IGFBP-1, IGFBP-2, tumour necrosis factor-alpha and asymmetric dimethylarginine, all factors proposed to mediate IGF-I resistance. In conclusion, although intermittent rhIGF-I therapy elevated serum total IGF-I and prevented any fall in serum IGFBP-3, it failed to increase GFR in non-diabetic patients with advanced CKD. The lack of efficacy was attributed to the presence of renal IGF-I resistance in CKD.

(-)-Epigallocatechin 3-O-gallate (EGCG)-induced apoptosis in normal rat kidney interstitial fibroblast (NRK-49F) cells.

(-)-Epigallocatechin 3-O-gallate (EGCG), a major catechin in green tea, suppresses renal failure in animals, and inhibits the growth of mesangial cells and opossum kidney proximal tubular cells. In addition, gallic acid, a structural constituent of this catechin, induces apoptosis in tumor cell lines. However, the effects of catechins on renal fibroblastic cells have not been investigated. In this experiment, the growth of normal rat kidney interstitial fibroblast (NRK-49F) cells was significantly inhibited by EGCG at concentrations higher than 6.25 microM, and almost completely inhibited at concentrations over 200 microM. The numbers of in situ end-labeled (ISEL) cells in cultures treated with EGCG at 6.25 to 200 microM increased dose-dependently. Furthermore, exposure to 6.25 to 50 microM EGCG for 24 hr led to a significant increase in caspase-3 activity compared to the control. These results suggest that EGCG induces apoptosis in NRK-49F cells.

Reduction of ischemia-reperfusion injury in the rat kidney by FTY720, a synthetic derivative of sphingosine.

BACKGROUND: The current shortage of organ donors has led many centers to use marginal and nonheart-beating donors (NHBDs). Recent research has implicated the infiltration of lymphocytes as an important mediator of ischemia-reperfusion injury (IRI). FTY720 is an immunosuppressant that promotes lymphocyte sequestration into lymph nodes. The purpose of this study was to examine the potential for FTY720 to abrogate IRI when subjected to increasing ischemic times. METHODS: Male Sprague-Dawley rats underwent bilateral flank incision with removal of the right kidney and clamping of the left hilum. Groups were divided into ischemia times of 45, 55, and 65min; each group was further divided into a control group (IRI only), IRI+FTY720 (1 mg/kg/d), and IRI+cyclosporine (15 mg/kg/d), n=4 per group. RESULTS: Thre days after 45 min of ischemia, serum creatinine in the ischemia only (477+/-37 micromol/L) and cyclosporine groups (698+/-32 micromol/L) was significantly increased compared with the FTY720-treated animals (194+/-66 micromol/L). The beneficial effect of FTY720 was also observed at 55 and 65 min; indeed, FTY720-treated animals demonstrated signs of recovery from 65 min of ischemia whereas control and cyclosporine-treated animals required sacrifice between days 3 and 5. Treatment with FTY720 reduced renal damage assessed histologically and also reduced apoptosis and increased cell proliferation. CONCLUSION: Treatment with FTY720 reduced IRI and prevented unrecoverable acute renal failure after significant ischemic injury. This study suggests that FTY720 may help improve the quality of grafts from NHBD and marginal donors by abrogating the IRI insult.

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.

Vascular calcifications in uremia: old concepts and new insights.

The annual mortality rate in uremic patients, corrected for age, sex, and race, is significantly higher than in the general population. This is primarily due to cardiovascular events. Vascular calcifications play a vital role in the development of cardiovascular morbidity and subsequent increased mortality. Vascular calcification affects both vascular intima and media layers and its mechanism remains poorly understood. Over the last few years it has been shown that, in addition to traditional cardiovascular risk factors, disturbances in mineral metabolism in the uremic milieu, calcium-containing phosphate binders, and vitamin D treatment of secondary hyperparathyroidism may contribute to the pathogenesis of vascular calcifications. Other uremia-related risk factors (e.g.increased oxidized low-density lipoprotein cholesterol, uremic toxins, increased oxidative stress, dialysis and dialysate-related factors, hemodynamic overload, hyperhomocysteinemia) may also play a role. In uremic patients, apart from these facilitating factors, decreased levels of endogenous calcification inhibitors such as fetuin-Amatrix Gla protein, osteoprotegerin, and osteopontin have also been associated with increased calcium-phosphate precipitation in extraskeletal tissues. Finally, vascular calcification is the outcome of the active and dynamic balance of procalcifying and anticalcifying influences. For the prevention and treatment of vascular calcifications, it is essential to avoid treatment modalities that lead to calcium overload, achieve good metabolic control, and optimize dialysis.

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.

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.

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.

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.

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.