Peter T. McNamee

The changing pattern of adult primary glomerular disease

BACKGROUND Published biopsy series have shown geographical and temporal variations in the patterns of primary glomerulonephritis (GN). IgA nephropathy is the most common type of GN in most European studies, but there is evidence suggesting that focal segmental glomerulosclerosis (FSGS) is increasingly common in the USA in all ethnic groups. We report the analysis of 30 years of native renal biopsies and the temporal pattern of primary glomerular disease in a single United Kingdom (UK) region. METHODS All 1844 adult native kidney biopsies for 30 years (1976-2005 inclusive) were analysed. The data were divided into three 10-year time frames, and trends in the biopsy rate and diagnosis of primary glomerular disease were considered. RESULTS Biopsy rates increased significantly from 2.02 to 7.08 per hundred thousand population per year (php/year) (chi(2) = 55.9, P < 0.001), and the mean patient age at biopsy rose from 33 to 49 years over the study period (F = 58, P < 0.001). Primary GN was documented in 49% of biopsies; the most common diagnoses within this group were IgA nephropathy (38.8%), membranous nephropathy (29.4%), minimal change disease (9.8%), membranoproliferative GN type 1 (9.6%) and FSGS (5.7%). There was a significant increase in the proportion of IgA nephropathy (chi(2) = 9.6, P = 0.008) and a decrease in membranous nephropathy (chi(2) = 7.2, P = 0.03) over time. The population incidence of FSGS was low and unchanged at 0.18 php/ year from 1986 to 2005. CONCLUSIONS Consistent with several other European studies, IgA nephropathy was the most common primary glomerular disease in this UK region. The diagnosis of FSGS was uncommon with no evidence of a rise in incidence.

Elevated serum phosphate predicts mortality in renal transplant recipients.

Background. High serum phosphate has been identified as an important contributor to the vascular calcification seen in patients with chronic kidney disease (Block et al., Am J Kidney Dis 1998; 31: 607). In patients on hemodialysis, elevated serum phosphate levels are an independent predictor of mortality (Block et al., Am J Kidney Dis 1998; 31: 607; Block, Curr Opin Nephrol Hypertens 2001; 10: 741). The aim of this study was to investigate whether an elevated serum phosphate level was an independent predictor of mortality in patients with a renal transplant. Methods. Three hundred seventy-nine asymptomatic renal transplant recipients were recruited between June 2000 and December 2002. Serum phosphate was measured at baseline and prospective follow-up data were collected at a median of 2441 days after enrolment. Results. Serum phosphate was significantly higher in those renal transplant recipients who died at follow-up when compared with those who were still alive at follow-up (P<0.001). In Kaplan-Meier analysis, serum phosphate concentration was a significant predictor of mortality (P=0.0001). In multivariate Cox regression analysis, serum phosphate concentration remained a statistically significant predictor of all-cause mortality after adjustment for traditional cardiovascular risk factors, estimated glomerular filtration rate, and high sensitivity C reactive protein (P=0.036) and after adjustment for renal graft failure (P=0.001). Conclusions. The results of this prospective study are the first to show that a higher serum phosphate is a predictor of mortality in patients with a renal transplant and suggest that serum phosphate provides additional, independent, prognostic information to that provided by traditional risk factors in the risk assessment of patients with a renal transplant.

Association of Functional Heme Oxygenase‐1 Gene Promoter Polymorphism with Renal Transplantation Outcomes

Heme oxygenase‐1 (HO‐1) is a cytoprotective molecule and increased expression in experimental transplant models correlates with reduced graft injury. A functional dinucleotide repeat (GT)n polymorphism, within the HO‐1 promoter, regulates gene expression; a short number of repeats (S‐allele <25) increases transcription. The role of this HO‐1 gene promoter polymorphism on renal transplant outcomes was assessed. DNA from 707 donor/recipient pairs (n = 1414) of first deceased donor renal transplants (99% Caucasian) was genotyped. Graft survival was not significantly impacted by carriage of an S‐allele by the donor (hazard ratio 0.89, 95% CI 0.71–1.11; p = 0.28) or recipient (hazard ratio 1.19, 95% CI 0.95–1.48; p = 0.13). Similarly neither donor nor recipient genotype influenced recipient survival (hazard ratio 0.89, 95% CI 0.67–1.18; p = 0.41, and hazard ratio 1.22, 95% CI 0.93–1.62; p = 0.16). The hazard ratios changed only minimally in multivariate analysis including significant survival factors. Genotype did not alter the incidence of acute rejection or chronic allograft nephropathy. There is no evidence of a protective effect for the S‐allele of the HO‐1 gene promoter polymorphism on graft or recipient survival in clinical renal transplantation.

Susceptibility of VLDL to oxidation in patients on regular haemodialysis

Oxidation of VLDL in vitro increases macrophage uptake and promotes foam cell formation, and the dyslipidaemia of chronic renal failure is characterised by an increase in VLDL. However, little information is available with regard to the susceptibility of VLDL to oxidation in patients at increased risk of atherosclerosis. We have therefore assessed the composition and susceptibility to oxidation of VLDL from haemodialysis patients and control subjects. VLDL from haemodialysis patients contained increased lipid hydroperoxides (81.6 +/- 12.6 versus 16.1 +/- 3.4 nmol/mg protein, P < 0.001) and malondialdehyde (35.9 +/- 7.3 versus 16.0 +/- 4.1 nmol/mg protein, P < 0.05). Susceptibility to oxidation was increased as shown by an increased rate of propagation of the copper induced lipid peroxidation chain-reaction (11.6 +/- 1.5 x 10(-5) versus 7.6 +/- 1.1 x 10(-5)abs. U/min, P < 0.05) and a greater increase in conjugated diene formation during peroxidation (0.47 +/- 0.04 versus 0.25 +/- 0.03 abs. U, P < 0.001). Increased VLDL peroxidation in dialysis patients may contribute to the increased risk of cardiovascular disease observed in this group of patients.

The uptake of cervical cancer screening by renal transplant recipients

BACKGROUND Renal transplant recipients are at an increased risk of developing cervical cancer compared to women in the general population. At least annual cervical smear screening is currently recommended, but little information is available regarding the actual uptake of such screening. METHODS All female renal transplant recipients in one United Kingdom region who were alive with a functioning graft were identified. The uptake and results of cervical smear testing over a 10-year period in this cohort were determined. RESULTS Of the 173 women eligible for cervical cancer screening, 18 (10%) undertook the recommended number of screening procedures; 56 (32%) had never had a cervical smear performed. The year of transplantation, age at engraftment and the social deprivation status did not significantly influence the uptake of screening (P > 0.05). In those women who were screened, the incidence of smear test abnormalities was 20% in renal transplant recipients compared with 7% in the general population. The cytological findings in the positive smear tests ranged from borderline changes to grade III cervical intraepithelial neoplasia. CONCLUSIONS The renal transplant population is at higher risk of abnormal cervical cytology, but the uptake of cervical cancer screening is low. The reasons for this low screening rate are unclear, and changes in practice are necessary to improve the uptake of cervical smear testing in women with renal transplants.

The evolution of renal transplantation in clinical practice: for better, for worse?

BACKGROUND Kidney transplantation is the optimal form of renal replacement therapy for most patients with end-stage renal disease. Attempting to improve graft and recipient survival remains challenging in clinical practice. AIM To identify the factors that have significantly changed over the past four decades and assess their impact on renal transplant outcomes. DESIGN Retrospective review of all renal transplant procedures in a single UK region. METHODS All 1346 renal transplant procedures performed between 1 January 1967 and 31 December 2006 were reviewed. Clinical data, histological reports and outcomes were available from a prospectively recorded database. The study period was divided into four decades to assess the changes in renal transplantation over time. RESULTS Significant changes that have occurred include an increase in donor and recipient ages, a greater proportion of recipients with diabetic nephropathy, a longer wait before the first transplant procedure, a fall in the incidence and impact of acute rejection, a smaller proportion of deaths due to cardiovascular disease, (P < 0.001 for all) and a trend to increased deaths from malignancy (P = 0.06) over time. In multivariate analysis, death censored graft survival was significantly influenced by the era of transplantation, donor and recipient ages, living vs. deceased donor status, and histological evidence of acute rejection, chronic allograft nephropathy, or disease recurrence. Significant factors in recipient survival were the era of transplantation, recipient age, a primary renal diagnosis of diabetic nephropathy or unspecified chronic renal failure, and biopsy proven acute rejection. CONCLUSION There have been major changes in the clinical practice related to renal transplantation over the past four decades; some have been beneficial and others detrimental to survival. Regular review of outcomes is essential to guide renal services development and maximize graft and recipient survival.

Is screening for Factor V Leiden and Prothrombin G20210A Mutations in Renal Transplantation worthwhile? Results of a large single-center U.K. study

This single center study is the largest series of renal transplant recipients and donors screened for the commonest prothrombotic genotypes. A total of 562 transplant recipients and 457 kidney donors were genotyped for the factor V Leiden and prothrombin G20210A mutations. The prevalence of heterozygous factor V Leiden was 3.4% and 2.6% and prothrombin G20210A was 2.0% and 1.1% in recipients and donors, respectively, similar frequencies to that of the general U.K. population. The 30-day and 1-year graft survival rates in recipients with thrombophilic mutations were 93% and 93%, compared with 88% and 82% in patients without these mutations (log-rank P=0.34). Thrombophilia in recipients (odds ratio 0.55; confidence interval 0.06-2.29; P=0.56) or in donors (odds ratio 1.53; confidence interval 0.27-5.74; P=0.46) did not correlate with graft loss at 30 days after transplantation. In contrast to recent reports, this study did not demonstrate an association between thrombophilia and renal allograft loss, and routine screening is not recommended.

Effect of immunosuppressive drug regime on cardiovascular risk profile following kidney transplantation

We have previously studied cardiovascular risk markers apolipoprotein (a) (apo(a)) and plasma fibrinogen in 146 control, 60 haemodialysis (HD), 53 continuous ambulatory peritoneal dialysis (CAPD) and 66 renal transplant subjects. Fibrinogen concentration was higher in all 3 renal replacement groups compared to controls. Apo(a) was higher in the CAPD group only. We have now restudied those dialysis patients (24 HD, 16 CAPD) who have since undergone transplantation. Fibrinogen concentration remained elevated in CAPD patients (mean (SE) 3.9 (0.17) vs. 3.77 (0.20) grams/l) and increased in HD patients (2.88 (0.16) vs. 3.72 (0.13) grams/l, P < 0.0001). Apo(a) fell in both groups (CAPD, geometric mean 287 vs. 151 U/l, P = 0.008; HD, 230 vs. 179 U/l, P = 0.013). Fibrinogen concentration was higher in the recent group compared to the original group (3.74 (0.11) vs. 3.19 (0.12) grams/l, P = 0.001). None of the 66 original patients received cyclosporin (cyA) compared to 35 of the 40 in the present study. In this recent group, patients maintained on prednisolone and azathioprine alone had significantly lower fibrinogen levels than those receiving cyA. Furthermore, the fall in apo(a) was smaller (31% vs. 74%) and the increase in apolipoprotein B (apo B) greater (0.55 (0.15) vs. 0.18 (0.05) grams/l, P = 0.014) in cyA-treated patients. CyA may have an adverse effect on cardiovascular risk profile in renal transplant recipients.

Elevated Homocysteine Is a Predictor of All-Cause Mortality in a Prospective Cohort of Renal Transplant Recipients.

Background: In patients with chronic kidney disease, an elevated homocysteine concentration is associated with an increased incidence of cardiovascular events. Aim: The aim of this study was to investigate the relationship between homocysteine concentration and all-cause mortality during prospective follow-up of a renal transplant cohort. Methods: A total of 378 renal transplant recipients were recruited between June 2000 and December 2002. Homocysteine was measured at baseline and mortality data was collected at a median of 2,441 days after enrolment. Results: In univariate analysis, homocysteine was a significant predictor of mortality (p < 0.001). In multivariate analysis, homocysteine remained a significant independent predictor of mortality following adjustment for traditional cardiovascular risk factors (p = 0.01), vitamin B12 and folate (p < 0.001) and estimated glomerular filtration rate (p = 0.03). Conclusions: In the renal transplant recipients enrolled in this study, homocysteine concentration was a significant predictor of mortality in univariate survival analysis and in multivariate survival analysis following adjustment for traditional cardiovascular risk factors and following adjustment for renal function. Assessing the effect of lowering homocysteine concentration on the survival of patients with a renal transplant is therefore worthy of further study.

Cost Should Be the Principal Determinant of Choice of Erythropoiesis-Stimulating Agent in Chronic Haemodialysis Patients

Background/Aims: Erythropoiesis-stimulating agents (ESAs) are effective in the management of the anaemia of chronic kidney disease but add substantially to the treatment costs. We performed a comparison cross-sectional analysis of ESA prescribing in 4 dialysis centres in Northern Ireland. Methods: The ESA prescription and current haemoglobin (Hb) concentration for all patients on haemodialysis (HD) treatment for at least 3 months was extracted from the renal data system. Results: A total of 403 patients were analysed, 184 (46%) were prescribed epoetin β and 219 (54%) darbepoetin α. The mean Hb concentrations for both agents were comparable overall (Hb = 11.4 and 11.7 g/dl, p = 0.13), and for subcutaneous (SC) and intravenous (IV) administration: epoetin β 11.5 g/dl (n = 119) and 11.4 g/dl (n = 65) (p = 0.70), and darbepoetin α 11.8 g/dl (n = 39) and 11.6 g/dl (n = 180) (p = 0.49). The mean weekly dose was 7,941 units of epoetin β with SC and 9,200 units with IV administration (p = 0.10), and 45 µg SC and 46 µg IV of darbepoetin α (p = 0.94). The weekly cost of achieving equivalent Hb levels was GBP 61.86 (EUR 90.57/USD 115.68) with SC and GBP 71.67 (EUR 104.93/USD 134.02) with IV epoetin β, and GBP 70.78 (EUR 103.63/USD 132.36) with SC and GBP 72.18 (EUR 105.68/USD 134.98) with IV darbepoetin α. Conclusions: Epoetin β and darbepoetin α are equally effective ESAs and the choice of ESA prescribed in stable HD patients should be determined by cost.