Fish oil for kidney transplant recipients.

BACKGROUND: Calcineurin inhibitors used in kidney transplantation for immunosuppression have adverse effects that may contribute to nephrotoxicity and increased cardiovascular risk profile. Fish oils are rich in very long chain omega-3 fatty acids, which may reduce nephrotoxicity by improving endothelial function and reduce rejection rates through their immuno-modulatory effects. They may also modify the cardiovascular risk profile. Hence, fish oils may potentially prolong graft survival and reduce cardiovascular mortality. OBJECTIVES: To assess the benefits and harms of fish oil supplementation on kidney transplant recipients on a calcineurin inhibitor-based immunosuppressive regimen. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL in The Cochrane Library, issue 2 2005), MEDLINE (1966-April 2005) and EMBASE (1980-April 2005). SELECTION CRITERIA: All randomised controlled trials (RCTs) and quasi-RCTs of fish oils in kidney transplant recipients on a calcineurin inhibitor-based immunosuppressive regimen. RCTs of fish oil versus statins were included. DATA COLLECTION AND ANALYSIS: Data was extracted and the quality of studies assessed by two authors, with differences resolved by discussion with a third independent author. Dichotomous outcomes were reported as relative risk (RR) and continuous outcome measures were reported as the mean difference (MD) with 95% confidence intervals using the random effects model. Heterogeneity was assessed using a Chi(2) test on n-1 degrees of freedom and the I(2) statistic. Data not suitable for pooling were tabulated and described. MAIN RESULTS: Sixteen studies (733 patients) were suitable for analysis. Fish oil did not significantly affect patient or graft survival, acute rejection rates, calcineurin inhibitor toxicity or renal function, when compared to placebo. Fish oil treatment was associated with a lower diastolic blood pressure (MD 4.5 mmHg; P = 0.004) compared to placebo. Patients receiving fish oil for more than six months had a modest increase in HDL (MD 0.12 mmol/L; P = 0.01) compared to placebo. Fish oil effects on lipids were not significantly different from low-dose statins. There was insufficient data to analyse cardiovascular outcomes. Fishy aftertaste and gastrointestinal upset were common but did not result in significant patient drop-out. AUTHORS' CONCLUSIONS: There is insufficient evidence from currently available RCTs to recommend fish oil therapy to improve renal function, rejection rates, patient survival or graft survival. The improvements in HDL cholesterol and diastolic blood pressure were too modest to recommend routine use. To determine a benefit in clinical outcomes, future RCTs will need to be adequately powered with these outcomes in mind.

Vascular expression of clusterin in experimental cyclosporine nephrotoxicity.

Clusterin is a widely expressed glycoprotein, which appears to be induced during tissue damage. We have examined the expression of the clusterin gene in the kidney during the development of cyclosporine (CyA)-induced nephrotoxicity in the rat using in situ hybridization histochemistry. Female Sprague-Dawley rats (170 g) were divided into experimental or control groups and were given intraperitoneal injections of CyA (25 mg/kg) or vehicle respectively for 2, 4 and 6 weeks. Kidneys from animals sacrificed at these times were fixed in 4% paraformaldehyde and embedded in paraffin. Tissue sections were hybridized using either a sense or antisense riboprobe complementary to clusterin mRNA which was labelled with 32P-UTP. Clusterin gene expression was detected in scattered tubules in kidneys from control animals. Expression of clusterin in cortical collecting ducts of CyA-treated animals was evident at 2 weeks and increased substantially at 4 and 6 weeks. Clusterin expression was also seen in afferent arterioles, the glomerular capsule and transitional epithelium of the renal pelvis of kidney sections from rats treated with CyA for 6 weeks. No labelling above background was seen at any time with the sense probe. Renin immunostaining in afferent arterioles of kidney sections from animals treated with CyA showed a marked increase after 4 and 6 weeks of CyA treatment.

Atrial natriuretic peptide receptors are present and functional by midgestation in fetal sheep.

This study examined the ontogeny of the mRNA for three atrial natriuretic peptide (ANP) receptors in the ovine fetal kidney and the effect of systemic ANP infusion in the very immature ovine fetus. mRNA was isolated from the kidneys of 60-, 100-, and 140-day fetuses (n = 4 at each age). Northern blots [5 micrograms poly(A)+ RNA per track] were probed for the guanylate cyclase (GC)-A, GC-B, and clearance receptors, using beta-actin as a control for variations in loading. The results were quantitated using laser densitometry. Levels of clearance receptor mRNA were significantly higher in 140-day than 60-day fetal kidneys (P < 0.05), whereas levels of mRNA for the GC-A and GC-B receptors remained steady. We propose that binding of ANP to an increased number of C receptors in the late-gestation fetal kidney could explain the previously documented increase in total ANP receptor number in late-gestation ovine kidneys without increased ANP biological activity. Systemic ANP infusion into four fetuses of approximately 74 days gestation resulted in a natriuresis and diuresis, indicating the presence of functional ANP receptors in the ovine kidney early in gestation.

Sodium status affects GC-B natriuretic peptide receptor mRNA levels, but not GC-A or C receptor mRNA levels, in the sheep kidney.

1. In humans and experimental animals the natriuresis and diuresis resulting from infusion of atrial natriuretic peptide varies with the sodium status of the subject. Tissue binding studies have suggested that this may be related to changes in the renal receptors for the hormone. 2. In order to establish whether these changes are under transcriptional control, we examined the levels of mRNA for the three natriuretic peptide receptors [GC-A, GC-B and clearance (C) receptors] in renal cortex and medulla from six sodium-loaded, six sodium-depleted and four control sheep. cDNA probes specific to each receptor were generated using the polymerase chain reaction. 3. GC-B receptor mRNA levels were increased approximately two-fold in the renal cortex of sodium-depleted animals, whereas there was no influence on GC-B receptor mRNA levels in the renal medulla. There was no significant difference in mRNA levels for the GC-A and C receptors. 4. At present the role of the GC-B receptor and its natural ligand C-type natriuretic peptide in the control of renal function is unknown. The present experiments imply some intrarenal function for the GC-B receptor and its natural ligand, although the site of any such function, e.g. renal vasculature or tubules, remains unclear. In addition, we have shown that if GC-A and C receptor levels in the sheep are modulated by sodium, the regulation occurs beyond the level of gene transcription.