Perioperative administration of high-dose recombinant human erythropoietin for delayed graft function prevention in kidney transplantation: a meta-analysis.

Delayed graft function (DGF) due to ischemia-reperfusion injury is a major early complication of kidney transplantation (KT). Recombinant human erythropoietin (rHuEPO) has been shown to exert nephroprotective action in animal models. We conducted a meta-analysis to explore the impact of rHuEPO on DGF in KT. Eligible studies comparing perioperative high-dose rHuEPO with placebo or no therapy for prevention of DGF were identified through MEDLINE, CENTRAL, and Transplant Library. Their design and data were assessed by two independent reviewers. Among 737 examined studies, four randomized controlled trials, involving 356 recipients of kidney allografts from deceased donors, fulfilled inclusion criteria. Statistical heterogeneity across studies was not significant (P = 0.98, I(2) = 0%). In a random effects model, no significant difference was found in the occurrence of DGF (odds ratio: 0,74, 95% CI: 0.47-1.18, P = 0.21). At 4 weeks after KT, the rHuEPO group exhibited higher systolic blood pressure (mean difference: 6.47 mmHg, 95% CI: 1.25-11.68, P = 0.02). Perioperative, high-dose rHuEPO administration does not prevent DGF in deceased donor KT. Furthermore, it is associated with higher systolic blood pressure leading to safety concerns. Nonerythropoietic rHuEPO derivatives, designed for nephroprotective action without increasing cardiovascular risk, might prove an alternative but still are at early stages of development.

Effect of Smad pathway activation on podocyte cell cycle regulation: an immunohistochemical evaluation.

BACKGROUND: Mature podocytes are in cell cycle arrest and their inability to proliferate successfully is a consequence of negative cell-cycle regulators' expression, such as p57. Phosphorylated smad2/smad3 (pSmad2/3) is an intracellular heteromeric mediator of transforming growth factor beta (TGF-ß) signals and, together with co-activators such as P300, regulates gene transcription, including cell cycle regulator proteins. METHODS: In order to investigate Smad pathway activation and podocyte cell cycle regulation in glomerular injury, we studied the glomerular immunohistochemical expression of p57, pSmad2/3 and P300 in samples from 67 patients with various types of glomerulonephritis (GN) and 10 normal kidney tissue specimens. RESULTS: pSmad2/3 and p300 expression were found significantly increased in all glomerular cell types in both proliferative and nonproliferative GN, while a significant reduction in p57-positive podocytes was observed when compared to controls. Staining for p57 was found to inversely correlate to pSmad2/3 suggesting that glomerular Smad pathway activation is related to down-regulation of p57 expression in proliferative glomerulonephritis. To our knowledge, this is the first study that indicates a relation between the TGF-beta/Smad signalling pathway and the cell cycle regulatory protein p57 in human GN. CONCLUSION: The increased pSmad2/3 staining together with the reduced p57 expression found in biopsy specimens with intense interstitial inflammation, indicate a possible relation between interstitial inflammation, glomerular Smad pathway activation and podocyte cell-cycle deregulation.

Statins in chronic kidney disease and kidney transplantation.

HMG-CoA reductase inhibitors (statins) have been shown to improve cardiovascular (CV) outcomes in the general population as well as in patients with cardiovascular disease (CVD). Statins' beneficial effects have been attributed to both cholesterol-lowering and cholesterol-independent "pleiotropic" properties. By their pleiotropic effects statins have been shown to reduce inflammation, alleviate oxidative stress, modify the immunologic responses, improve endothelial function and suppress platelet aggregation. Patients with chronic kidney disease (CKD) exhibit an enormous increase in CVD rates even from early CKD stages. As considerable differences exist in dyslipidemia characteristics and the pathogenesis of CVD in CKD, statins' CV benefits in CKD patients (including those with a kidney graft) should not be considered unequivocal. Indeed, accumulating clinical evidence suggests that statins exert diverse effects on dialysis and non-dialysis CKD patients. Therefore, it seems that statins improve CV outcomes in non-dialysis patients whereas exert little (if any) benefit in the dialysis population. It has also been proposed that dyslipidemia might play a causative role or even accelerate renal injury. Moreover, ample experimental evidence suggests that statins ameliorate renal damage. However, a high quality randomized controlled trial (RCT) and metaanalyses do not support a beneficial role of statins in renal outcomes in terms of proteinuria reduction or retardation of glomerular filtration rate (GFR) decline.

Dyslipidemia, statins, and CKD patients' outcomes - review of the evidence in the post-sharp era.

Hyperlipidemia in the general population is strongly associated with an increased incidence of major adverse cardiovascular (CV) events (MACE). It is well established that HMG-CoA reductase inhibitors (statins) reduce CV and all-cause mortality in the general population, as well as in patients with CV disease (CVD). However, such a finding has not been definitively confirmed in patients with chronic kidney disease (CKD). Given that CV risk gradually increases with increasing stages of CKD (and is even higher in dialysis patients), it is of major relevance and importance to identify whether CKD patients might also benefit from alteration of lipid fractions, and how this might best be achieved. Bearing in mind that animal model and preclinical evidence suggests dyslipidemia might also be a factor promoting worsening renal function, it could legitimately be asked whether treating it may also therefore have a nephroprotective effect.

The role of statins in chronic kidney disease (CKD): friend or foe?

The effects of statins in chronic kidney disease (CKD) are incompletely understood. To date, no clinical trial has provided definitive evidence that cholesterol lowering treatments reduce cardiovascular morbidity and mortality in CKD patients. Moreover, existing preclinical data suggest both a renoprotective effect of statins (highlighted by reduction in the rate of the decline of GFR and reduction of proteinuria) and a harmful effect (mainly by accelerating renal fibrosis) in the long-term management of patients with CKD. Although several post-hoc analyses and meta-analyses of large randomized clinical trials of statins in cardiovascular disease have provided important insights into their role in affecting the rate of renal function deterioration in CKD, no randomized clinical study has directly addressed this issue in CKD patients. In this review, we discuss the preclinical and clinical evidence supporting the beneficial or harmful effects of statins in CKD patients and propose specific recommendations regarding their use in this patient population.

Immunohistochemical evaluation of phosphorylated SMAD2/SMAD3 and the co-activator P300 in human glomerulonephritis: correlation with renal injury.

BACKGROUND: Smad2 and Smad3 are transcription factors that mediate transforming growth factor beta (TGF-beta) signals. Upon their activation, phosphorylated Smad2/Smad3 (pSmad2/Smad3), translocate to the nucleus and associate with co-activators such as p300, regulating the transcription of genes that contribute to the fibrotic processes. METHODS: We investigated the immunohistochemical expression of pSmad2/Smad3 and the co-activator p300 in 152 renal biopsy specimens from patients with various types of glomerulonephritides (GNs) and in 15 normal kidney specimens. Patients' clinical data (serum creatinine levels and proteinuria) had been collected. RESULTS: There was a dramatic increase in the expression of pSmad2/3 and p300 in all glomerular cell types in all GNs. pSmad2/3 expression was increased in all tubular segments (except for the proximal tubules in nonproliferative GNs), while p300 expression was significantly increased only in the proximal tubular cells in all GNs. Glomerular and tubular pSmad2/Smad3 and p300 were significantly increased in proliferative GNs (compared to the nonproliferative), particularly in the secondary group. The expression profile of p300 correlated positively with the expression of pSmad2/Smad3 in the diseased glomeruli and proximal tubules. pSmad2/3 and p300 were very often detected in segmental hyperplastic lesions, cellular crescents, microadhesions and segmental or global sclerotic areas. Glomerular and proximal tubular pSmad2/Smad3 was positively correlated with serum creatinine levels, while distal and collecting tubular pSmad2/3 and p300 correlated positively with tubular atrophy. Glomerular and proximal tubular pSmad2/3 expression and glomerular p300 expression correlated positively with lupus nephritis activity. CONCLUSION: Our results suggest that pSmad2/3-p300 pathway may play a pivotal role in the pathogenesis and progression of human glomerulonephritis.