James G. Heaf

Cardiovascular and noncardiovascular mortality among patients starting dialysis

CONTEXT Cardiovascular mortality is considered the main cause of death in patients receiving dialysis and is 10 to 20 times higher in such patients than in the general population. OBJECTIVE To evaluate if high overall mortality in patients starting dialysis is a consequence of increased cardiovascular mortality risk only or whether noncardiovascular mortality is equally increased. DESIGN, SETTING, AND PATIENTS Using data from between January 1, 1994, and January 1, 2007, age-stratified mortality in a European cohort of adults starting dialysis and receiving follow-up for a mean of 1.8 (SD, 1.1) years (European Renal Association-European Dialysis and Transplant Association [ERA-EDTA] Registry [N = 123,407]) was compared with the European general population (Eurostat). MAIN OUTCOME MEASURES Cause of death was recorded by ERA-EDTA codes in patients and matching International Statistical Classification of Diseases, 10th Revision codes in the general population. Standardized cardiovascular and noncardiovascular mortality rates, their ratio, difference, and relative excess of cardiovascular over noncardiovascular mortality were calculated. RESULTS Overall all-cause mortality rates in patients and the general population were 192 per 1000 person-years (95% confidence interval [CI], 190-193) and 12.055 per 1000 person-years (95% CI, 12.05-12.06), respectively. Cause of death was known for 90% of the patients and 99% of the general population. In patients, 16,654 deaths (39%) were cardiovascular and 21,654 (51%) were noncardiovascular. In the general population, 7,041,747 deaths (40%) were cardiovascular and 10,183,322 (58%) were noncardiovascular. Cardiovascular and noncardiovascular mortality rates in patients were respectively 38.1 per 1000 person-years (95% CI, 37.2-39.0) and 50.1 per 1000 person-years (95% CI, 48.9-51.2) higher than in the general population. On a relative scale, standardized cardiovascular and noncardiovascular mortality were respectively 8.8 (95% CI, 8.6-9.0) and 8.1 (95% CI, 7.9-8.3) times higher than in the general population. The ratio of these rates, ie, relative excess of cardiovascular over noncardiovascular mortality in patients starting dialysis compared with the general population, was 1.09 (95% CI, 1.06-1.12). Relative excess in a sensitivity analysis in which unknown/missing causes of death were regarded either as noncardiovascular or cardiovascular varied between 0.90 (95% CI, 0.88-0.93) and 1.39 (95% CI, 1.35-1.43). CONCLUSION Patients starting dialysis have a generally increased risk of death that is not specifically caused by excess cardiovascular mortality.

An update on renal replacement therapy in Europe: ERA–EDTA Registry data from 1997 to 2006

BACKGROUND Recent studies have indicated a stabilization in the incidence rates of renal replacement therapy (RRT) for end-stage renal disease (ESRD) in a number of European countries. The aim of this study was to provide an update on the incidence, prevalence and outcomes of RRT in Europe over the past decade. METHODS Nineteen European national or regional renal registries with registry data from 1997 to 2006 participated in the study. Incidence and prevalence trends were analysed with Poisson and Joinpoint regression. Cox regression methods were used to examine patient survival. RESULTS The total adjusted incidence rate of RRT for ESRD increased from 109.9 per million population (pmp) in 1997 to 119.7 pmp in 2000, i.e. an average annual percentage change (AAPC) of 2.9% (95% CI 2.1-3.8%). Thereafter, the incidence increased at a much lower rate to 125.4 pmp in 2006 [AAPC 0.6% (95% CI 0.3-0.8%)]. This change in the trend of the incidence of RRT was largely due to a stabilization in the incidence rates of RRT for females aged 65-74 years, males aged 75-84 years and patients receiving RRT for ESRD due to hypertension/renal vascular disease. The overall adjusted prevalence in Europe continued to increase linearly at 2.7% per year. Between the periods 1997-2001 and 2002-2006, the risk of death decreased for all treatment modalities, with the most substantial improvement in patients starting peritoneal dialysis [19% (95% CI 15-22%)] and in patients receiving a kidney transplant [17% (95% CI 11-23%)]. CONCLUSION This European study shows that the annual rise of the overall incidence rate of RRT for ESRD has diminished and that in several age groups the incidence rates have now stabilized. The survival of dialysis patients and kidney transplant recipients has continued to improve.

Renal replacement therapy in Europe: a summary of the 2012 ERA-EDTA Registry Annual Report

Background This article summarizes the 2012 European Renal Association—European Dialysis and Transplant Association Registry Annual Report (available at www.era-edta-reg.org) with a specific focus on older patients (defined as ≥65 years). Methods Data provided by 45 national or regional renal registries in 30 countries in Europe and bordering the Mediterranean Sea were used. Individual patient level data were received from 31 renal registries, whereas 14 renal registries contributed data in an aggregated form. The incidence, prevalence and survival probabilities of patients with end-stage renal disease (ESRD) receiving renal replacement therapy (RRT) and renal transplantation rates for 2012 are presented. Results In 2012, the overall unadjusted incidence rate of patients with ESRD receiving RRT was 109.6 per million population (pmp) (n = 69 035), ranging from 219.9 pmp in Portugal to 24.2 pmp in Montenegro. The proportion of incident patients ≥75 years varied from 15 to 44% between countries. The overall unadjusted prevalence on 31 December 2012 was 716.7 pmp (n = 451 270), ranging from 1670.2 pmp in Portugal to 146.7 pmp in the Ukraine. The proportion of prevalent patients ≥75 years varied from 11 to 32% between countries. The overall renal transplantation rate in 2012 was 28.3 pmp (n = 15 673), with the highest rate seen in the Spanish region of Catalonia. The proportion of patients ≥65 years receiving a transplant ranged from 0 to 35%. Five-year adjusted survival for all RRT patients was 59.7% (95% confidence interval, CI: 59.3–60.0) which fell to 39.3% (95% CI: 38.7–39.9) in patients 65–74 years and 21.3% (95% CI: 20.8–21.9) in patients ≥75 years.

Bone disease after renal transplantation

Bone disease is common after renal transplantation. The main syndromes are bone loss with a consequent fracture rate of 3% per year, osteonecrosis of the hip, and bone pain. The causes of disease include preexisting uremic osteodystrophy (hyperparathyroidism, aluminum osteomalacia, beta2-associated amyloidosis, and diabetic osteopathy), postoperative glucocorticoid therapy, poor renal function, and ongoing hyperparathyroidism, as the result of either autonomous transformation of the parathyroid gland or ongoing physiologic stimuli. Cyclosporine A treatment, hyperphosphaturia, and a pathogenic vitamin D allele have also been implicated. Bone loss is particularly pronounced during the first year after operation, amounting to up to 9% of bone mass. The clinical and biochemical picture is consistent with a high turnover bone disease, but histomorphometric studies do not completely support this. Principal prophylactic options include preoperative osteodystrophy prophylaxis; postoperative calcium, vitamin D, or calcitriol therapy; estrogen therapy for postmenopausal women; and parathyroidectomy for medically intractable hyperparathyroidism. Recently, prophylactic biphosphonate treatment has shown promise, but the exact indications for treatment remain to be determined.

Timing and Outcome of Renal Replacement Therapy in Patients with Congenital Malformations of the Kidney and Urinary Tract

BACKGROUND AND OBJECTIVES Congenital anomalies of the kidney and urinary tract (CAKUT) are the leading cause of ESRD in children, but the proportion of patients with individual CAKUT entities progressing to ESRD during adulthood and their long-term clinical outcomes are unknown. This study assessed the age at onset of renal replacement therapy (RRT) and patient and renal graft survival in patients with CAKUT across the entire age range. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Patients with CAKUT were compared with age-matched patients who were undergoing RRT for other renal disorders on the basis of data from the European Renal Association-European Dialysis and Transplant Association Registry. Competing risk and Cox regression analyses were conducted. RESULTS Of 212,930 patients commencing RRT from 1990 to 2009, 4765 (2.2%) had renal diagnoses consistent with CAKUT. The proportion of incident RRT patients with CAKUT decreased from infancy to childhood and then increased until age 15-19 years, followed by a gradual decline throughout adulthood. Median age at RRT start was 31 years in the CAKUT cohort and 61 years in the non-CAKUT cohort (P<0.001). RRT was started earlier (median, 16 years) in patients with isolated renal dysplasia than in those with renal hypoplasia and associated urinary tract disorders (median, 29.5-39.5 years). Patients with CAKUT survived longer than age- and sex-matched non-CAKUT controls because of lower cardiovascular mortality (10-year survival rate, 76.4% versus 70.7%; P<0.001). CONCLUSIONS CAKUT leads to ESRD more often at adult than pediatric age. Treatment outcomes differ from those of acquired kidney diseases and vary within CAKUT subcategories.

Bone loss after renal transplantation: role of hyperparathyroidism, acidosis, cyclosporine and systemic disease

In order to determine risk factors for bone loss after renal transplantation, dual energy X‐ray absorptiometry was performed in 125 renal transplant patients. The bone mineral density (BMD) was expressed as a percentage of the normal population (BMD%) and Z‐score (SD from normal). The whole body, lumbar spine and femoral neck BMD% (Z‐score) values were 93.9±8.9 (−0.90 SD), 91.6±14.9 (−0.98 SD) and 87±15.3 (−1.0 SD)%, respectively. Low BMD% was associated with low creatinine clearance (<40 mL/min: 91.6±7.9, >40 mL/min: 95.6±8.0, p<0.01), repeated graft loss (0: 94.4±9.1, >1: 87.4±9.3, p<0.05), long dialysis duration (<1 yr: 95.2±7.9, >5: 90.1±10.6, p<0.05), acidosis (bicarbonate <21 mmol/L: 89.6±8.0, >27: 96.7±7.2, p<0.01), secondary and tertiary hyperparathyroidism (<50 ng/L: 95.9±7.1, >200: 87.7±5.0, p<0.01), raised alkaline phosphatase (<200 units/L: 95.7±7.2, >300: 85.6±13.2, p<0.001), osteocalcin (<50 μg/L: 95.2±6.7, >100: 89.3±7.6, p<0.01) and urinary deoxypyridinoline (<5 nM/mM creatinine: femoral neck 89.6±10.7, >10: 82.1±20.1, p<0.05), low 25‐OH‐vitamin D (<10 μg/L: 91.3±9.8, >20: 96.9±7.4, p<0.001) and high cyclosporine concentration (0 ng/L: 98.3±7.0, >150: 92.1±9.3, p<0.05). Patients with clinical atherosclerosis (91.7±8.6 vs. 95.4±8.8, p<0.01), hypoalbuminemia (<550 μmol/L: 87.6±13.2, >550: 94.2±7.8, p<0.01), renovascular disease (89.7±5.7 vs. 95.0±5.7, p<0.05) and diabetic nephropathy (femoral neck 76.6±8.8 vs. 89.3±15.1, p<0.01) had lower bone masses. High bone mass was associated with previous dialysis alphacalcidol therapy (0: 92.2±7.5, >3 μg/wk: 97.3±6.9, p<0.05). No relationships with transplantation duration, 1,25‐OH‐vitamin D, aluminium, calcium or steroid dose were found. No involutional changes in tertiary hyperparathyroidism could be discerned. 
Conclusion. The major threats to bone mass after renal transplantation appear to be ongoing hyperparathyroid bone disease, low renal function, acidosis, systemic disease and hypo‐vitaminosis D.

Plasma exchange for induction and cyclosporine A for maintenance of remission in Wegener’s granulomatosis—a clinical randomized controlled trial

BACKGROUND The use of plasma exchange (PE) for induction treatment of anti-neutrophil cytoplasm autoantibody (ANCA)-associated vasculitis (AAV), including Wegeners granulomatosis (WG), is still controversial. The use of PE in AAV is not commonly accepted in patients with a plasma creatinine <500 μmol/L (5.7 mg/dL) despite experimental support for involvement of ANCA in the pathogenesis of vasculitis. METHODS In a single-centre study from a tertiary referral centre, 32 patients with ANCA-positive WG were treated with standard immunosuppressive therapy, prednisolone and cyclophosphamide (CYC). In addition, they were randomized to treatment with or without initial PE. After 3 months, they were further randomized in a Latin square design to continue CYC or to change to cyclosporine A (CyA) for 9 months. The renal follow-up was at least 5 years. RESULTS Renal survival after 1, 3 and 12 months, and 5 years was significantly better in the PE groups. For all groups, the kidney/patient survival was 87.5%/93.7% at 1 year and 72%/56% at 5 years. All patients who were on dialysis when recruited were dialysis dependent 5 years later. There was no difference in morbidity or mortality between PE and control groups. Multivariate analysis demonstrated that PE improved renal survival (P < 0.01) at initial plasma creatinine levels >250 µmol/L (2.85 mg/dL). Change from CYC to CyA did not influence rate of relapses or time to relapse. CONCLUSIONS PE is recommended for induction therapy in WG patients at creatinine levels >250 µmol/L (2.85 mg/dL), whereas previous randomized studies have limited PE to patients with creatinine >500 µmol/L (5.65 mg/dL).

Renal replacement therapy for autosomal dominant polycystic kidney disease (ADPKD) in Europe: prevalence and survival-an analysis of data from the ERA-EDTA Registry.

BACKGROUND Autosomal dominant polycystic kidney disease (ADPKD) is the fourth most common renal disease requiring renal replacement therapy (RRT). Still, there are few epidemiological data on the prevalence of, and survival on RRT for ADPKD. METHODS This study used data from the ERA-EDTA Registry on RRT prevalence and survival on RRT in 12 European countries with 208 million inhabitants. We studied four 5-year periods (1991-2010). Survival analysis was performed by the Kaplan-Meier method and by Cox proportional hazards regression. RESULTS From the first to the last study period, the prevalence of RRT for ADPKD increased from 56.8 to 91.1 per million population (pmp). The percentage of prevalent RRT patients with ADPKD remained fairly stable at 9.8%. Two-year survival of ADPKD patients on RRT (adjusted for age, sex and country) increased significantly from 89.0 to 92.8%, and was higher than for non-ADPKD subjects. Improved survival was noted for all RRT modalities: haemodialysis [adjusted hazard ratio for mortality during the last versus first time period 0.75 (95% confidence interval 0.61-0.91), peritoneal dialysis 0.55 (0.38-0.80) and transplantation 0.52 (0.32-0.74)]. Cardiovascular mortality as a proportion of total mortality on RRT decreased more in ADPKD patients (from 53 to 29%), than in non-ADPKD patients (from 44 to 35%). Of note, the incidence rate of RRT for ADPKD remained relatively stable at 7.6 versus 8.3 pmp from the first to the last study period, which will be discussed in detail in a separate study. CONCLUSIONS In ADPKD patients on RRT, survival has improved markedly, especially due to a decrease in cardiovascular mortality. This has led to a considerable increase in the number of ADPKD patients being treated with RRT.

Consistent absorption of cyclosporine from a microemulsion formulation assessed in stable renal transplant recipients over a one-year study period.

To evaluate the pharmacokinetic properties of the new microemulsion formulation of cyclosporine (Sandimmun Neoral), a double-blind, prospective study in stable renal transplant recipients was performed. The patients were randomized on a 4:1 basis either to receive Sandimmun Neoral (n = 45) or continue on regular Sandimmun (n = 12). Before randomization, a steady-state pharmacokinetic profile study was performed in all patients while they were still on regular Sandimmun. Pharmacokinetic assessments were then performed after 8 and 12 weeks and after 1 year. A milligram-to-milligram dose conversion was shown to be adequate to maintain the patients within a predefined target therapeutic window. Changes in pharmacokinetic parameters after conversion to Sandimmun Neoral were consistent with an increased rate and extent of cyclosporine absorption from the Neoral formulation. This was reflected by a shorter time to reach peak concentration and also by a mean increase in peak concentration by 67%, and an overall mean increase in drug exposure (area under the curve) by 34%. These findings were also confirmed 1 year after conversion. Furthermore, significantly reduced intraindividual variability in pharmacokinetic parameters was found, as well as improvements in the correlation between trough concentrations and area under the curve after conversion to Sandimmun Neoral. In conclusion, our results indicate an improved and consistent absorption of cyclosporine from the Neoral formulation, which should make clinical management easier and safer.

Hyperparathyroidism and long-term bone loss after renal transplantation

Abstract: Background:  While early bone loss after renal transplantation (RT) is well described, factors affecting the long‐term fate of bone have received less attention.