Stanley S. A. Fenton

Hemodialysis versus peritoneal dialysis: A comparison of adjusted mortality rates

Although kidney transplantation is the preferred treatment method for patients with ESRD, most patients are placed on dialysis either while awaiting transplantation or as their only therapy. The question of which dialytic method provides the best patient survival remains unresolved. Survival analyses comparing hemodialysis and continuous ambulatory peritoneal dialysis/continuous cyclic peritoneal dialysis (CAPD/CCPD), a newer and less costly dialytic modality, have yielded conflicting results. Using data obtained from the Canadian Organ Replacement Register, we compared mortality rates between hemodialysis and CAPD/CCPD among 11,970 ESRD patients who initiated treatment between 1990 and 1994 and were followed-up for a maximum of 5 years. Factors controlled for include age, primary renal diagnosis, center size, and predialysis comorbid conditions. The mortality rate ratio (RR) for CAPD/CCPD relative to hemodialysis, as estimated by Poisson regression, was 0.73 (95% confidence interval: 0.68 to 0.78). No such relationship was found when an intent-to-treat Cox regression model was fit. Decreased covariable-adjusted mortality for CAPD/CCPD held within all subgroups defined by age and diabetes status, although the RRs increased with age and diabetes prevalence. The increased mortality on hemodialysis compared with CAPD/CCPD was concentrated in the first 2 years of follow-up. Although continuous peritoneal dialysis was associated with significantly lower mortality rates relative to hemodialysis after adjusting for known prognostic factors, the potential impact of unmeasured patient characteristics must be considered. Notwithstanding, we present evidence that CAPD/CCPD, a newer and less costly method of renal replacement therapy, is not associated with increased mortality rates relative to hemodialysis.

Outcome of kidney transplantation from high-risk donors is determined by both structure and function.

METHOD Despite the need to expand the donor pool, it is unclear what parameters should be used. The value of donor renal pathology and calculated creatinine clearance (CrCl) in determining recipient outcome was assessed in 57 kidney transplants from 34 donors in whom pretransplant renal biopsies were performed because of age > or =60, hypertension, and/or vascular disease. We retrospectively compared clinical outcomes in these recipients and 57 control recipients selected to have the same baseline demographics but receiving transplants from low risk donors who were significantly younger (32+/-13.9 vs. 61+/-7.3 years) and lighter weight (71+/-18.1 vs. 84+/-20.2 kg) than the high-risk donors (P<.001 for both). RESULTS Recipients of high-risk kidneys had a higher incidence of delayed graft function, defined by a <10% fall in serum creatinine (Cr) in the first 24 hr, (56% vs. 30%, P<.01), a higher incidence of rejection (60% vs. 37%, P = .02) and a higher Cr level (197+/-64 vs. 144+/-54 micromol/L at 18 months, P<.005). Graft and patient survival were similar; 12% and 5% vs. 91% and 9% in high-risk vs. control groups, respectively (P = NS). Donor renal pathology was scored 0-3 (none to severe disease) in four areas: glomerulosclerosis, interstitial fibrosis, tubular atrophy, and vascular disease. A donor vessel score of 3/3 was associated with a 100% incidence of delayed graft function and a mean 1-year Cr level of 275+106 micromol/L (compared with 43% and 192+54 micromol/L in those with lower vessel scores, P<.05). Calculated donor CrCl <100 ml/min was associated with higher recipient Cr levels at 1 year, 240+/-95 micromol/L vs. 180+/-54 micromol/L in recipients of kidneys from donors with CrCl levels >100 ml/min (P<.05). The mean 1-year Cr level was 320+/-102 micromol/L in recipients with both a vascular score of 3/3 and a donor CrCl <100 ml/min and 184+/-63 micromol/L in those with neither factor (P = .001). CONCLUSION Calculated donor CrCl and donor vascular pathology predict recipient graft function and may be helpful in selecting high-risk donors for single kidney transplantation.

Clinical benefits of neoral C2 monitoring in the long-term management of renal transplant recipients.

Background. Cyclosporine monitoring using the 2-hr postdose sample, C2, has been shown to have advantages in monitoring de novo renal transplant recipients. The purpose of this study was to assess cyclosporine exposure, using C2, in stable renal transplant patients previously monitored by C0 to determine the effect of dose reduction on patients with C2 more than 10% above target and the course of those with C2 at and more than 10% below target, whose dose was not modified. Methods. One hundred and seventy-five patients, three or more months after transplantation, had C2 assessed. The relationship of C2 to C0 and of both to renal function was analyzed by linear regression. Blood pressure, serum creatinine level, and lipids were followed for a mean of 15±2.6 months. Results. Eighty-five patients had values more than 10% above target, 42 were within 10% of target, and 48 were more than 10% below target. Cyclosporine dose was reduced in all patients above target. In this group, serum creatinine level was stable overall, but fell significantly in 46 (54%) of 85 from 153±55 to 132±49 &mgr;M. Blood pressure also fell in that group from 135/82 to 131/77. Serum creatinine level was stable in the remaining two groups of patients. Conclusions. These data suggest that dose reduction in many overexposed patients leads to improvements in renal function and blood pressure. Further study is required to confirm the long-term benefits of this strategy.

Survival experience among elderly end-stage renal disease patients. A controlled comparison of transplantation and dialysis.

Renal transplantation is a relatively recent treatment option among the elderly with end-stage renal disease (ESRD). Since little is known regarding the clinical benefits of transplantation relative to dialysis in this age group, this study compares transplantation and dialysis among the elderly with respect to patient survival. Data utilized in this investigation were obtained from the Canadian Organ Replacement Register (CORR). The study population consisted of the 6400 patients aged 60 and over at registration, diagnosed between 1987 and 1993, for whom data on comorbid conditions were available. Survival probability, death rates, age-standardized mortality ratios (SMRs) and Cox regression analysis were employed to evaluate the survival experience among the transplant and dialysis groups. Transplant recipients were matched (by age, underlying diagnosis leading to ESRD, and number of comorbid conditions) to 2 randomly selected patients who did not undergo transplantation. Using Cox regression, the time-dependent hazard ratio for transplantation versus dialysis patients was estimated at 0.47 (P < 0.0001), indicating that even after adjusting for other known prognostic factors, elderly patients who received a transplant experienced significantly greater survival probability than those who remained on dialysis. When transplant patients were matched to randomly selected dialysis patients with the constraint that the corresponding dialysis patient have at least as much follow-up time as the transplant patient had waiting time, five-year survival rates were 81% and 51% for the transplant and dialysis groups, respectively (P < 0.0001). These results support the potential advantage of transplantation among the elderly, and may have important implications for renal care in this age group.

Changes in survival among elderly patients initiating dialysis from 1990 to 1999

Background: Over the past decade, there has been a steep rise in the number of people with complex medical problems who require dialysis. We sought to determine the life expectancy of elderly patients after starting dialysis and to identify changes in survival rates over time. Methods: All patients aged 65 years or older who began dialysis in Canada between 1990 and 1999 were identified from the Canadian Organ Replacement Register. We used Cox proportional hazards models to examine the effect that the period during which dialysis was initiated (era 1, 1990–1994; era 2, 1995–1999) had on patient survival, after adjusting for diabetes, sex and comorbidity. Patients were followed from initiation of dialysis until death, transplantation, loss to follow-up or study end (Dec. 31, 2004). Results: A total of 14 512 patients aged 65 years or older started dialysis between 1990 and 1999. The proportion of these patients who were 75 years or older at the start of dialysis increased from 32.7% in era 1 (1990–1994) to 40.0% in era 2 (1995–1999). Despite increased comorbidity over the 2 study periods, the unadjusted 1-, 3- and 5-year survival rates among patients aged 65–74 years at dialysis initiation rose from 74.4%, 44.9% and 25.8% in era 1 to 78.1%, 51.5% and 33.5% in era 2. The respective survival rates among those aged 75 or more at dialysis initiation increased from 67.2%, 32.3% and 14.2% in era 1 to 69.0%, 36.7% and 20.3% in era 2. This survival advantage persisted after adjustment for diabetes, sex and comorbidity in both age groups (65–74 years: hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.72– 0.81; 75 years or more: HR 0.86, 95% CI 0.80–0.92). Interpretation: Survival after dialysis initiation among elderly patients has improved from 1990 to 1999, despite an increasing burden of comorbidity. Physicians may find these data useful when discussing prognosis with elderly patients who are initiating dialysis.

Evaluating the survival benefit of kidney retransplantation.

Background. The magnitude of the survival benefit associated with kidney retransplantation has not been well studied. Methods. Using data from the Canadian Organ Replacement Register (CORR), we studied patients (n=3,067) initiating renal replacement therapy during 1981–1998 who had received a transplant and experienced graft failure (GF). Such patients were followed until death, loss to follow-up or the end of the observation period (December 31, 1998). Using Cox regression, we estimated the post-GF covariate-adjusted hazard ratio (HR) for retransplant versus dialysis, and determined whether the contrast differed across patient subgroups. Through nonproportional hazards models, we also examine patterns in the retransplant/dialysis HR with time following retransplant. Results. Overall, retransplantation is associated with a covariate-adjusted 50% reduction in mortality, relative to remaining on dialysis (HR=0.50; P<0.0001). This benefit is most pronounced in the 18- to 59-year age group. Retransplanted patients were at significantly higher risk of death relative to patients on dialysis only during the first month posttransplant (HR=1.66; P=0.047), and experienced significantly reduced mortality thereafter. Conclusions. Following primary graft failure, retransplantation is associated with significantly reduced mortality rates among Canadian end-stage renal disease patients. Further study should be undertaken to assess the applicability of our findings to other patient populations.

Impact of nocturnal home hemodialysis on anemia management in patients with end-stage renal disease.

AIM Anemia is adversely associated with poor uremia control and is an established cardiovascular risk factor in patients with end-stage renal disease (ESRD). Nocturnal home hemodialysis (NHD) is a novel form of renal replacement therapy that offers superior clearance of uremic solutes and improvements in several cardiovascular outcome parameters. We conducted a retrospective cohort study to test the hypotheses that augmenting the dose and frequency of dialysis by NHD would improve hemoglobin (Hb) concentrations and decrease requirement of erythropoietin (EPO) in ESRD patients. METHODS In 63 patients (mean age: 46 +/- 2 years) receiving NHD (mean duration: 2.1 +/- 0.2 years), Hb, EPO dose, iron saturation, ferritin were determined before and at six monthly repeated intervals after conversion to NHD. For comparison, 32 ESRD patients (mean age: 57 +/- 3 years) who remained on self-care conventional hemodialysis (CHD) were also studied. RESULTS There were no differences in baseline Hb concentrations, iron saturation, ferritin, or EPO dose between the two cohorts. After transfer from CHD to NHD, there were significant improvements in Hb concentrations (from 115 +/- 2 to 122 +/- 3 (6 months) and 124 +/- 2 (12 months) g/l, p = 0.03) despite a fall in EPO requirement (from 10,400 +/- 1400 to 8500 +/- 1300 (6 months) and 7600 +/- 1100 (12 months) U/week, p = 0.03). In contrast, CHD cohort had no change in EPO requirement (from 8300 +/- 1100 to 8100 +/- 1300 (6 months) and 8600 +/- 1000 (12 months) U/week, p > 0.05) or Hb concentrations (from 110 +/- 2 to 115 +/- 3 (6 months) and 115 +/- 2 (12 months), p > 0.05). There was a higher percentage of ESRD patients who did not require EPO in the NHD cohort (24% vs. 9.4%, p = 0.01). Lower Hb concentrations were noted in the CHD cohort despite higher iron saturation (0.25 +/- 0.01 (NHD) vs. 0.33 +/- 0.02 (CHD), p = 0.02) at the end of follow-up. CONCLUSIONS Enhancing uremic clearance by NHD resulted in a rise in Hb and a fall in EPO requirement.

Reduced Incidence of New-Onset Diabetes Mellitus after Renal Transplantation with 3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase Inhibitors (Statins)

Statins have anti‐inflammatory effects, modify endothelial function and improve peripheral insulin resistance. We hypothesized that statins influence the development of new‐onset diabetes mellitus in renal transplant recipients. The records of all previously non‐diabetic adults who received an allograft in Toronto between January 1, 1999 and December 31, 2001 were reviewed with follow‐up through December 31, 2002. All patients receiving cyclosporine or tacrolimus, mycophenolate mofetil and prednisone were included. New‐onset diabetes was diagnosed by the Canadian Diabetic Association criteria: fasting plasma glucose ≥7.0 mmol/L or 2‐h postprandial glucose ≥11.1 mmol/L on more than two occasions. Statin use prior to diabetes development was recorded along with other variables. Cox proportional hazards models analyzing statin use as a time‐dependent covariate were performed. Three hundred fourteen recipients met study criteria, of whom 129 received statins. New‐onset diabetes incidence was 16% (n = 49). Statins (p = 0.0004, HR 0.238[0.109–0.524]) and ACE inhibitors/ARB (p = 0.01, HR 0.309[0.127–0.750]) were associated with decreased risk. Prednisone dose (p = 0.0001, HR 1.007[1.003–1.010] per 1 mg/d at 3 months), weight at transplant (p = 0.02, HR 1.022[1.003–1.042] per 1 kg), black ethnicity (p = 0.02, HR 1.230[1.023–1.480]) and age ≥45 years (p = 0.01, HR 2.226[1.162–4.261]) were associated with increased diabetes. Statin use is associated with reduced new‐onset diabetes development after renal transplantation.

A comparison of rabbit antithymocyte serum and OKT3 as prophylaxis against renal allograft rejection

A total 166 first cadaveric renal allograft recipients were randomly assigned to receive either rabbit antithymocyte serum (RATS) (n = 83) or OKT3 (n = 83) for 10 to 14 days after transplant as prophylaxis against rejection. Both groups were similar with respect to age, sex, donor age, diabetes, time on dialysis, panel-reactive antibody, HLA matching, and transfusion before transplantation. All patients were followed for 1 year after transplantation. A comparison of the rejection rates between the 2 groups of patients showed that patients receiving OKT3 had a rate of first rejection 1.87 times higher than those receiving RATS (95% confidence interval 1.18-2.8, P = 0.007). Twenty-five steroid-resistant rejections occurred in OKT3-treated patients as compared with 12 in the RATS-treated group (P < 0.05). There was no significant difference in early or late renal function between the 2 groups of patients. Actuarial 1-year graft survival for the RATS group was 78% and for the OKT3 group, 80.7% (P = NS). Actuarial 1-year patient survival was similar: 89.5% in the RATS group and 94.6% in the OKT3 group (P = NS). Total hospitalization time was 29.8 +/- 19.9 days for RATS vs. 39.5 +/- 22.1 days for those treated with OKT3 (P < 0.006). A number of infections were observed but there were no significant differences between the groups. We conclude that RATS provides better prophylaxis than OKT3 in first cadaveric renal transplants because it is associated with fewer rejection episodes, less hospitalization, and no additional morbidity or mortality.

Quotidian Nocturnal Hemodialysis Improves Cytokine Profile and Enhances Erythropoietin Responsiveness

Inflammation is implicated in the pathogenesis of erythropoietin (EPO) resistance in patients with end-stage renal disease. Interleukin (IL)-6 and tumor necrosis factor (TNF)-&agr; are suggested to suppress erythropoiesis in uremia. Insulin like growth factor (IGF)-1 has been proposed to stimulate erythropoiesis. Nocturnal hemodialysis (NHD) has been demonstrated to improve anemia management with enhanced EPO responsiveness without altering survival of red blood cells. We tested the hypothesis that augmentation of uremia clearance by NHD results in a reduction of proinflammatory cytokine levels, thereby enhancing EPO responsiveness. Using a cross-sectional study design, 14 prevalent patients on NHD and 14 patients on conventional hemodialysis (CHD) matched for age and comorbidities and controlled for hemoglobin concentrations and iron status were studied. Outcome variables included EPO requirement and plasma levels of EPO, parathyroid hormone, C reactive protein, IL-6, TNF-&agr;, and IGF-1. The primary outcome was to determine the between group differences in (1) cytokine profile and (2) EPO requirement. The secondary outcome was to examine the potential correlation between cytokine levels and EPO requirement. There were no significant differences in patient characteristics, comorbidities, hemoglobin, iron indices, and parathyroid hormone levels between the two cohorts. EPO requirement was significantly lower in the NHD cohort [90.5 ± 22.1 U/kg/week (NHD) vs. 167.2 ± 25.4 U/kg/week (CHD), p = 0.04]. Plasma IL-6 levels were lower in the NHD cohort [3.9 ± 0.7 pg/ml (NHD) vs. 6.5 ± 0.8 pg/ml (CHD), p = 0.04]. C reactive protein tended to decrease [4.59 ± 1.34 (NHD) vs. 8.43 ± 1.83 mg/L (CHD), p = 0.14]. TNF-&agr;, and IGF-1 levels did not differ between the two groups. Direct associations were found between EPO requirement and C reactive protein levels (R = 0.62, p = 0.001), and IL-6 levels (R = 0.57, p = 0.002). Augmentation of uremic clearance by NHD improves EPO responsiveness in end-stage renal disease. A possible mechanism for this improvement is through better control of inflammation, as manifested by lowering of plasma IL-6 levels. Further studies are required to clarify the mechanisms by which NHD decreases inflammation.