Biomedical subjects

Sabrina Sandhu

Publications and source records attributed to Sabrina Sandhu.

4 recordsLinked to original sources

PubMed2006

Statins for improving renal outcomes: a meta-analysis.

Statins frequently are used to prevent cardiovascular events. Several recent studies suggest that statins also may have renal benefits, although this is controversial. This systematic review and meta-analysis were performed to assess the effect of statins on change in kidney function and urinary protein excretion. Medline, EMBASE, the Cochrane Central Register of Controlled Trials, conference proceedings, and the authors' personal files were searched. Published or unpublished randomized, controlled trials or crossover trials of statins that reported assessment of kidney function or proteinuria were included, and studies of individuals with ESRD were excluded. Data were extracted for study design, subject characteristics, type of statin and dose, baseline/change in cholesterol levels, and outcomes (change in measured or estimated GFR [eGFR] and/or urinary protein excretion). Weighted mean differences were calculated for the change in GFR between statin and control groups using a random-effects model. A random-effects model also was used to calculate the standardized mean difference for the change in urinary protein excretion between groups. Twenty-seven eligible studies with 39,704 participants (21 with data for eGFR and 20 for proteinuria or albuminuria) were identified. Overall, the change in the weighted mean differences for eGFR was statistically significant (1.22 ml/min per yr slower in statin recipients; 95% confidence interval [CI] 0.44 to 2.00). In subgroup analysis, the benefit of statin therapy was statistically significant in studies of participants with cardiovascular disease (0.93 ml/min per yr slower than control subjects; 95% CI 0.10 to 1.76) but was NS for studies of participants with diabetic or hypertensive kidney disease or glomerulonephritis. The standardized mean difference for the reduction in albuminuria or proteinuria as a result of statin therapy was statistically significant (0.58 units of SD greater in statin recipients; 95% CI 0.17 to 0.98). Statin therapy seems to reduce proteinuria modestly and results in a small reduction in the rate of kidney function loss, especially in populations with cardiovascular disease.

Albuminuria↗

PubMed2004

Transplanting kidneys from CMV-seropositive donors to CMV-seronegative recipients is not associated with poorer renal allograft function or survival.

BACKGROUND: Cytomegalovirus (CMV)-seronegative recipients of renal allografts from CMV-seropositive donors (D+/R-) have a higher rate of acute rejection than other renal transplant recipients. A relationship between CMV infection/disease and chronic allograft nephropathy (CAN) has been proposed from animal studies, although human studies have been inconclusive. The objective of this study was to determine if CMV seromatching has an effect on renal allograft function and allograft survival. METHODS: A retrospective single centre study was carried out in 333 first cadaveric transplant recipients from January 1, 1991 to December 31, 1997. The primary end-point was creatinine clearance at 3 years post-transplant in groups based on CMV seromatching. The secondary end-point was renal allograft survival. RESULTS: Mean creatinine clearance 3 years post-transplant was 53.4 ml/min/1.73 m2 of body surface area. There was no significant difference in the mean creatinine clearance for groups formed on the basis of CMV seromatching. Delayed graft function and acute rejection were associated with a lower creatinine clearance at 3 years and reduced overall graft survival [hazard ratios 2.35 (1.56-3.54) (P<0.001) and 1.57 (1.0-2.46) (P = 0.046), respectively]. Considering the end-point of graft loss due to acute rejection (censoring for death with a functioning graft) identified the D+/R- group as having an increased hazard of graft loss due to acute rejection [hazard ratio 3.12 (1.16-8.57) (P = 0.024)]. CONCLUSIONS: The D+/R- group does not appear to have poorer renal allograft function 3 years post-transplant. This group does, however, have an increased risk of early allograft loss due to acute rejection.

Adult↗

PubMed2004

Proteinase-activated receptor-4: evaluation of tethered ligand-derived peptides as probes for receptor function and as inflammatory agonists in vivo.

1. We evaluated the ability of a number of peptides based on the tethered ligand sequences of human, rat and murine proteinase-activated receptor-4 (PAR(4)), to serve as receptor-activating probes or antagonists for bioassays carried out in vitro and for in vivo models of inflammation. 2. In a rat PAR(4)-dependent platelet aggregation assay, the relative potencies of the active sequences (AYPGKF-NH(2)>GYPGKF-NH(2)>GYPGFK-NH(2)>GFPGKP-NH(2)) were consistent with an activation of PAR(4). 3. In the aggregation assay, the reverse or partial reverse-sequence peptides (VQGPYG-NH(2), YAPGKF-NH(2) and FKGPYA-NH(2)) were inactive, while trans-cinnamoyl (Tc)-YPGKF-NH(2), Tc-APGKF-NH(2) and N-palmitoyl-SGRRYGHALR-NH(2) (pepducin P4pal-10) were antagonists. 4. However, in an endothelium-dependent NO-mediated rat aorta (RA) relaxation assay and in a gastric longitudinal muscle (LM) contraction assay, these antagonist peptides were agonists as were most other peptides, with distinct orders of potencies that differed for both the RA and LM assays and from the platelet assay. 5. We conclude that PAR(4)-derived tethered ligand peptide agonists can act at receptors other than PAR(4) and that a judicious choice of ligands is required to probe for PAR(4) function in bioassay systems and in particular for in vivo models. 6. By selecting from these peptides the ones most reliably reflecting PAR(4) activation (AYPGKF-NH(2) as a standard agonist; YAPGKF-NH(2) as a PAR(4)-inactive standard), we were able to establish an inflammatory role for the PAR(4)-activating peptides acting via a non-neurogenic mechanism in a rat paw oedema model.

Amino Acid Sequence↗

PubMed2002

Glycosylation of human proteinase-activated receptor-2 (hPAR2): role in cell surface expression and signalling.

We have analysed the role of N-linked glycosylation in regulating human proteinase-activated receptor-2 (hPAR(2)) expression and function. Epitope-tagged wild-type hPAR(2) (wt-hPAR(2)) or hPAR(2) that lacked glycosylation sequons (following site-directed mutagenesis) in either the N-terminus [hPAR(2)N30A (Asn(30)-->Ala)], extracellular loop 2 [ECL2; hPAR(2)N222Q (Asn(222)-->Gln) or hPAR(2)N222A (Asn(222)-->Ala)] or both (hPAR(2)N30A,N222A or hPAR(2)N30A,N222Q) were expressed in the Chinese-hamster ovary (CHO) fibroblast cell line, Pro5. Western blot analysis of wt-hPAR(2) showed mature wt-hPAR(2) to have a molecular mass of 55-100 kDa, and 33-48 kDa following N -glycosidase F deglycosylation. FACS analysis and immunocytochemistry of the wt-hPAR(2) and PAR(2) mutant cell lines revealed that removal of both glycosylation sequons decreases (50% of wt-hPAR(2)) cell surface expression. Western blot analysis indicated that both N-linked sites are glycosylated. In functional studies, hPAR(2)N30A displayed a selective and significant increase in sensitivity towards tryptase. Interestingly, hPAR(2)N222A displayed a loss in sensitivity towards all PAR(2) agonists tested. However, further analysis revealed receptor sensitivity to alanine mutations in this domain, as the more conservative substitution hPAR(2)N222Q displayed no change in response to PAR(2) agonists. hPAR(2)N30A,N222Q displayed increased sensitivity towards tryptase, but a loss in sensitivity towards trypsin and the synthetic peptide SLIGRL-NH(2), although this loss in sensitivity towards trypsin and SLIGRL-NH(2) was secondary to changes in cell-surface expression. Finally, expression of sialic-acid-deficient wt-hPAR(2) in the CHO Lec2 glycosylation-deficient mutant cell line, showed a 40 kDa loss in molecular mass, in addition to a marked and selective increase in sensitivity towards tryptase. We conclude that hPAR(2) N-linked glycosylation and sialylation regulates receptor expression and/or signalling.

Alanine↗