Improved parathyroid hormone control by cinacalcet is associated with reduction in darbepoetin requirement in patients with end-stage renal disease.

BACKGROUND: Uncontrolled hy-per-parathyroidism causes bone marrow fibrosis, leading to erythropoietin (EPO) resistance. Medical treatment with cinacalcet is effective in reducing plasma parathyroid hormone (PTH) levels, but its effect on darbepoetin dosing is unknown. METHODS AND AIMS: We conducted a retrospective cohort study of 40 end-stage renal disease (ESRD) patients (age: 55 ± 14; mean ± SD; 21:male) who had at least 12 months of cinacalcet therapy. The distribution of renal replacement therapies were: 14 peritoneal dialysis, 18 conventional hemodialysis and 8 nocturnal hemodialysis. Standard dialysis related biochemical indices and medications used were recorded. The primary objective of the study was to ascertain the difference in darbepoetin responsiveness before and after 12 months of cinacalcet therapy. Our secondary objective was to determine if there was a relationship between the changes in PTH and darbepoetin requirement. RESULTS: Overall, PTH levels decreased from 197.5 (151.8; 249.2) to 66.1 (41.2; 136.5) (median (25th;75th percentile)) pmol/l; p < 0.001. Cinacalcet dose increased from 30.0 ± 6 to 63 ± 25 mg/day, p < 0.05. Hemoglobin remained unchanged (116 ± 13 to 116 ± 13 g/l), while darbepoetin requirement decreased from 40 (20; 60) to 24 (19; 59) µg/week, p = 0.02. The remainder of the dialysis-related biochemistry (electrolytes, calcium, phosphate, iron status) and vitamin D use remained unchanged. A reduction in PTH level of greater than 30% was experienced by 82.5% (33/40) of our cohort. Among the responders, the fall in PTH and reduction darbepoetin requirement were related (R = -0.48, p = 0.004). CONCLUSIONS: Reduction of PTH by cinacalcet is associated with a decrease in darbepoetin requirement. The interface between bone and bone marrow in uremia represents a critical step in red blood cell production which merits further investigation.

Early determinants of atherosclerosis in paediatric systemic lupus erythematosus.

OBJECTIVES: To assess traditional and non-traditional cardiovascular risk factors and to determine the prevalence and correlates of early vascular markers of atherosclerosis in paediatric systemic lupus erythematosus (pSLE). METHODS: Fifty-four adolescents with pSLE had cardiovascular risk factor assessment, disease activity and vascular testing including carotid intima-media thickness (CIMT), flow-mediated dilatation (FMD), arterial stiffness measures, and myocardial perfusion studies. RESULTS: The traditional risk factors of hypertension, elevated triglycerides, apolipoprotein B, haemoglobin A1c and insulin levels and non-traditional risk factors of elevated homocysteine and fibrinogen were present (all p<0.001). Some arterial stiffness measures, central pulse wave velocity and characteristic impedance were elevated (p<0.001), but CIMT, FMD and myocardial perfusion were normal. Cumulative prednisone dose correlated with total cholesterol (r=0.5790, p<0.001) and elevated LDL-C (r=0.4488, p=0.0012). Hydroxychloroquine treatment correlated negatively with total cholesterol (r=-0.4867, p=0.0002), LDL-C (r=-0.4805, p=0.0002) and apolipoprotein B (r=-0.4443, p=0.0011). In multivariate analysis LDL-C correlated with cumulative prednisone dose and negatively with hydroxychloroquine treatment (R2=0.40, p<0.001). CONCLUSIONS: An increased burden of traditional and non-traditional risk factors and early evidence of insulin resistance and increased central arterial stiffness were present in paediatric SLE. Disease-specific and therapy-related factors are likely modifying these cardiovascular risk profiles warranting prospective longitudinal studies.

The higher risk of death on peritoneal dialysis in the United States is not explained by background general population mortality: the CANUSA study revisited.

The CANUSA investigators reported a near doubling of the risk of death in peritoneal dialysis patients treated at U.S. sites compared to Canadian centers. Recently, evidence has suggested that background mortality rates in the general population might be responsible for differences in death rates on dialysis. The objective of this study was to determine if differences in background mortality in the general population were responsible for the increased risk of death observed in American patients in the CANUSA study. The CANUSA study was a prospective cohort study of 680 consecutive peritoneal dialysis patients at 14 centers in the U.S. and Canada. Extensive baseline data were available for all patients. The expected mortality rate of an individual of the same age, sex, and country of residence was determined at the time of enrollment in the CANUSA study. Cox proportional hazards models were used to determine if background mortality rates were responsible for the observed differences in survival between the two countries. Background mortality rate in the general population was associated with an increased risk of death on peritoneal dialysis, but after adjustment for other baseline factors, it was no longer significant. The adjusted, relative hazard of dying in the U.S. compared to Canada was unchanged after further adjusting for background mortality rate in statistical models (HR = 1.93; 95% confidence interval: 1.13 - 3.28). In conclusion, the increased risk of mortality in U.S. patients enrolled in the CANUSA study was not explained by differences in the background mortality rate in the general population.

Acute renal failure in paediatric systemic lupus erythematosus: treatment and outcome.

OBJECTIVE: To determine the outcome of paediatric SLE (pSLE) patients with nephritis who developed acute renal failure (ARF). Efficacy and safety of treatment regimens were compared. METHODS: A total of 249 pSLE patients were diagnosed and prospectively followed at a single centre between July 1973 and July 2003; 127 children (51%) had lupus nephritis. ARF was defined as serum creatinine of > 250 micromol/l or > 75% above baseline. Standardized assessments included clinical data and medications, laboratory testing, disease activity and damage scores were obtained. Subsequent renal flares were documented. PRIMARY OUTCOME: renal function at last follow-up. SECONDARY OUTCOMES: treatment efficacy and safety. AZA- and cyclophosphamide (CYCLO)-treated patients were compared. Propensity score methods were applied to balance covariates. An intention to treat approach was chosen. RESULTS: The ARF study cohort included 50 patients; 13 boys and 37 girls with a median age of 13.2 yrs at diagnosis and a mean follow-up of 45 months. Renal histology: Class III nephritis in 16; Class IV in 34. Dialysis requirement and disease activity were similar in both groups. TREATMENT: AZA in 33 patients, CYCLO in 9 and corticosteroids only in 8. OUTCOME: no statistically significant or clinically relevant differences were found for any of the outcome measures including last serum creatinine, time to renal flare, overall renal survival, disease activity over time, disease damage, mean annual corticosteroid dose and rate of infection. CONCLUSION: The treatment of renal failure in this pSLE cohort was associated with an excellent outcome. AZA and CYCLO were equally efficacious.

Vascular complications of the lower extremities in diabetic patients on peritoneal dialysis.

BACKGROUND: Diabetic patients with end-stage renal disease (ESRD) are at high risk for developing foot complications and few have studied this complication in the diabetic patients treated with peritoneal dialysis (PD). The purpose of this study was to examine peripheral vascular disease (PVD) in diabetic patients with ESRD, who are being treated with PD, and to identify those factors that may contribute to its development. PATIENTS: We reviewed retrospectively the charts of 71 diabetic patients who started PD between January 1999 and January 2006, inclusive, and recorded their demographic data, their treatment regimens, their complications and the results of biochemical investigation(s) at the beginning and throughout their follow-up period. All patients were under the care of a chiropodist who examined them at regular intervals and more often when needed. We divided the patients into two groups with respect to the presence of complications in the lower extremities, such as ulcers, open wounds, osteomyelitis, necrotizing or gangrenous lesions, and amputations, intermittent claudication and/or the presence on an imaging examination of changes in the leg vessels consistent with vascular disease. RESULTS: 33 of the 71 patients had some type of a foot lesion. There were 8 amputations in the course of 176 patient-years (2 double amputations), or 1 amputation per 30 PD patient-years. Those patients with foot complications were treated more frequently with CCPD (p<0.05), more often had peripheral neuropathy (p<0.002), as well as coronary artery disease (p<0.044). They had lower serum albumin (p<0.005), significantly higher serum phosphorus (p<0.047) and they received higher doses of erythropoietin (p<0.042). There was no statistically significant difference between the groups regarding sex, age at initiation of PD, type of diabetes, use of insulin, levels of HbA(1c), body mass index (BMI), presence of retinopathy, cerebral vascular disease, hyperlipidemia, smoking, rate of transplantation, rate of drop-out from PD, time-averaged Kt/V, creatinine clearance, serum calcium, Ca x P and intact PTH. In a multiple logistics regression model, only peripheral neuropathy and hypoalbuminemia were independently associated with the development of lower-extremity complications (p<0.0066 and p <0.026, respectively). One-, two- and three-year cumulative survival of the whole group was 91.5%, 78.8% and 69%, respectively. Patients with foot lesions had a lower survival than those without. Interestingly though, those patients, who had had an amputation, survived as long as those patients, who did not have foot complications at all. CONCLUSION: In conclusion, compared to reports in the literature, our diabetic patients on PD had a lower rate of foot complications and amputation probably because of early intervention by our chiropodist. This fact stresses the need for constant and expert monitoring of the condition of the diabetic patient's feet, especially in those with low serum albumin and peripheral neuropathy.

Predictive factors of low HCO3- levels in peritoneal dialysis patients.

BACKGROUND: Metabolic acidosis is a major metabolic abnormality in end-stage renal disease (ESRD) and alkali is provided with dialysis treatment to patients on chronic peritoneal dialysis (CPD) to keep their acid-base balance within normal serum HCO3- levels. METHODS AND RESULTS: We examined the levels of venous serum HCO3- in 163 patients on CPD and the predictive factors for HCO3- levels low enough to indicate metabolic acidosis. The mean value for HCO3- was 26+/-2.4 mmol/l and for anion gap was 13.1+/-3.1 mEq/l. A serum bicarbonate concentration of less than 24 mmol/l, compatible with metabolic acidosis, was observed in 13.5% of the patients. In a multivariate analysis HCO3- levels were directly correlated with older age and use of CaCO3- as phosphate binders, and inversely associated with serum potassium, the use of sevelamer and low lactate dialysis solutions. Higher serum urea levels, the use of low lactate solutions and sevelamer instead of CaCO3 were significantly predictive factors for HCO3- levels < 24 mmol/l. CONCLUSIONS: Venous HCO3- and anion gap values were within the normal ranges in stable CPD patients. In 13.5% of them, however, chronic metabolic acidosis was observed based on venous HCO3- levels < 24 mmol/l. Dietary protein intake, the use of sevelamer and low (35 mmol/l) concentration of lactate in dialysis solutions are important predictive factors for chronic metabolic acidosis in these patients.

Renal cell carcinoma in peritoneal dialysis patients.

Renal cell carcinoma is a rare but serious complication in ESRD patients. In these patients the incidence of renal cell carcinoma (RCC) is 20-40 times higher than in the general population. We performed a retrospective study to measure the incidence rate, prevalence, characteristics and survival among our peritoneal dialysis (PD) patients diagnosed with renal cell carcinoma. The study was carried out among 607 patients who were on the PD program from January 1997 to June 2002. RCC was detected in eight patients (four males and four females) with mean age of 52.1 +/- 10.6 years. Among these eight patients four were new cases that were diagnosed before the patients were started on dialysis (three in native kidneys and one in a transplanted kidney). In the other four patients the RCC was diagnosed after they had been on dialysis for 33-204 months (mean 60.75 +/- 50.48). We found an incidence rate of 1.3 per 1000 patients per year and a prevalence of 1.3%. Six of the eight patients had renal cysts. Tumor size was less than 7 cm in seven patients and in the other patient it was 8.5 cm. Seven of eight patients were alive at the time of study with a survival time ranging from 3-138 months (mean 122.25 +/- 88.2) months. In one patient, the RCC metastasised to the scalp, and, in two other patients, the tumors subsequently involved the second kidney. A cardiovascular complication was the cause of one death. Two patients received a renal transplant 36 and 66 months after diagnosis. We conclude that despite the low rate of metastases and mortality in our study, regular ultrasonography should be added to the follow-up of PD patients. Renal transplantation can be considered in these ESRD patients with RCC; however, close follow-up for metastases is recommended.

A unique renal lesion in common variable immunodeficiency.

This article reports the case of a 33-year-old woman with common variable immunodeficiency (CVI) who developed renal failure 17 years after diagnosis and initiation of treatment with monthly IVIG. A renal biopsy revealed mesangial and paramesangial immune complex deposition and interstitial granulomatous infiltration. Renal function improved with oral corticosteroids, but did not return to normal. Decreasing the dose of IVIG had no effect on renal function. Immune dysfunction can be associated with both granulomatous disease and immune complex glomerulonephritis, or the latter may be related to chronic infection or immunoglobulin use. This is the first report of concomitant glomerular-tubulointerstitial lesions in this immunodeficiency syndrome. Renal function should be closely followed in patients with CVI.

Long-term blood pressure control in a cohort of peritoneal dialysis patients and its association with residual renal function.

BACKGROUND: Hypertension is the prime contributor for cardiovascular mortality in the dialysis population. Peritoneal dialysis (PD) has been thought to improve blood pressure (BP) control in the short term, but the long-term benefits are not conclusively proven. We aimed to evaluate the degree of BP control in PD patients in the long term and analyse the factors associated with poor control. METHODS: Data of all patients who were initiated on PD at one centre between July 1994 and July 1998 and completed at least 1 year of PD were analysed retrospectively at initiation of PD, at 6 months, and annually thereafter until 5 years or until discontinuation of therapy. Hypertension was defined as per WHO/ISH criteria. A 'Blood Pressure Control Index' was empirically defined to account for the effect of antihypertensives on measured BP. Factors associated with poor BP control were analysed. RESULTS: Out of 207 patients (age 57.0+/-16.0 years, 103 male, 104 female) 91.3% were hypertensive at the start of PD. About 33.8% had diabetic nephropathy. Systolic and mean arterial pressure index improved in early phase reaching a nadir between 6 months and 1 year followed by steady progressive worsening through out the rest of follow up. On multiple linear regression analysis age (P<0.001), duration of hypertension prior to dialysis (P<0.001), and declining residual renal function, expressed as both average of urea and creatinine clearance (P=0.002) and residual urine output (P<0.001) were independently associated with poor BP control. Diabetes (P=0.836), peritoneal transport (D/P 4 of creatinine at start) (P=0.218), peripheral oedema (P=0.479) and dose of erythropoetin (P=0.488) were not associated. CONCLUSIONS: Initiation of PD results in early improvement of hypertension in end-stage renal disease (ESRD). BP control thereafter deteriorates steadily with time and this is associated with age, duration of hypertension, and declining residual renal function. This suggests that hypertension in ESRD patients is a progressive disease primarily related to falling glomerular filtration rate, the preservation of which might improve BP control and possibly modify cardiovascular risk.

Late renal transplant failure: an adverse prognostic factor at initiation of peritoneal dialysis.

BACKGROUND: Early renal transplant failure necessitating a return to dialysis has been shown to be a poor prognostic factor for survival. Little is known about the outcome of patients with late transplant failure returning to dialysis. It was our clinical impression that late transplant failure (>2 months) carries an increased morbidity and mortality risk in patients returning to dialysis. OBJECTIVE: To determine whether patients with a failed renal transplant have an outcome different to those on dialysis who have never received a kidney transplant. SETTING: Peritoneal dialysis (PD) unit in a teaching hospital. PATIENTS AND DESIGN: All failed renal transplant patients (fTx) in the Toronto Hospital Peritoneal Dialysis program between 1989 and 1996 were identified. This cohort of 42 fTx patients was compared with a cohort of randomly selected never-transplanted PD patients (non-Tx). The PD program was selected because of the availability of well-documented patient archival material. The non-Tx group was matched for age and presence of diabetes. Data were collected until retransplantation, change of dialysis modality or center, death, or until June 1998. RESULTS: There was no difference at initiation of PD between groups in serum albumin, residual renal function, or mean serum parathyroid hormone level. The mean low-density lipoprotein level was significantly higher in the fTx cohort. The duration of dialysis before Tx in fTx patients accounted for the increased total length of dialysis in fTx (mean 15 months). However, post-Tx the duration of PD was similar for both groups (30.7 months for fTx vs 31.6 months for non-Tx). The fTx group had a considerably worse outcome than the non-Tx group. The time to first peritonitis, subsequent episodes of peritonitis, catheter change, or transfer to hemodialysis occurred at a much faster rate in fTx patients. The most dramatic difference was in survival. There were 3 deaths in the non-Tx group and 12 in the fTx group (p < 0.01). The mean age at time of death in the fTx group was 47.5 years. Deaths were due mainly to gram-negative peritonitis and cardiovascular disease. CONCLUSIONS: We conclude that late failed renal transplant patients starting dialysis are at increased risk of complications and have strikingly higher mortality rates than non-Tx patients. A previously failed kidney transplant can be considered an adverse prognostic factor for patients commencing PD; these patients need to be closely monitored. Although this study was limited to PD patients, the same principles likely apply to fTx patients returning to any form of renal replacement therapy.

Increased mortality of elderly female peritoneal dialysis patients with diabetes--a descriptive analysis.

Three recent studies using registry data from the United States, in comparing the mortality risks between peritoneal dialysis (PD) and hemodialysis (HD), have consistently found that elderly diabetic women on PD have a higher mortality risk as compared with their counterparts on HD. Though the cause for this observation is not clear, the phenomenon may be unique to the United States. Alternatively, a selection bias impossible to decipher may be at work in these studies, as none of them have data on comorbidity, nutrition, or adequacy of dialysis. Finally, the possibility that elderly diabetic women are, for some reason, more vulnerable to the ill effects of peritoneal dialysis should be considered. We report here a retrospective analysis of 47 diabetic women, above 55 years of age, with end-stage renal disease, who were started on PD and who later died on dialysis. The primary outcome of interest was cause of death. Demographic details about the patients, comorbid conditions, dialysis adequacy, and biochemical parameters at the start of PD were noted. Death in these patients was attributed mainly to vascular causes, and there appeared to be a high prevalence of peripheral vascular disease. Infection was the next major cause of death, being the primary cause in 14 patients. Of these, only 5 patients had peritonitis. On a Cox regression analysis, only patient age and duration of diabetes at onset of dialysis were found to be predictive of vascular death. No factor was found to be predictive of death from infection. It appears that elderly diabetic women on PD die mainly of the long-term complications of diabetes.

Deterioration in renal function associated with fibrate therapy.

BACKGROUND: Fibric acid derivatives (fibrates) are commonly used for the treatment of hyperlipidemia. A side-effect of these medications that is not well recognized is deterioration in renal function during therapy. This study reviewed a series of patients who showed such a deterioration. METHODS: The design was a retrospective chart review. Data extracted included creatinine, urea, cyclosporine levels, medical history, and medications. Charts were examined for other potential reasons for a change in creatinine. RESULTS: There were a total of 10 patients. All were males between the ages of 37 and 71. All had a history of renal insufficiency. Six had received a renal transplant and, of these, 5 were on cyclosporine. Reasons for underlying renal impairment included diabetes, hypertension, nephrosclerosis, and renal disease of unknown etiology. Most patients had risk factors for or the presence of vascular disease. The mean pre-treatment creatinine was 182 +/- 14 micromol/l (2.1 +/- 0.2 mg/dl) (mean +/- SE), compared to a peak creatinine on the medication of 247 +/- 16 micromol/l (2.8 +/- 0.2 mg/dl) (p < 0.001). The post-medication mean was 183 +/- 13 (2.1 +/- 0.1 mg/dl) (p < 0.001 vs maximum creatinine). Urea values also increased with therapy and decreased following discontinuation of the fibrate. Cyclosporine levels did not change with treatment. All recorded creatine kinase values were within the normal range. CONCLUSIONS: A group of 10 men showed a reversible deterioration in renal function while being treated with a fibrate for hyperlipidemia. The mechanism involved in the deterioration in renal function is not clear. The most plausible mechanism is one based on renal hemodynamics, given the rapid and complete reversibility that was noted and the finding that most patients had risk factors for vascular disease. If patients with pre-existing renal dysfunction are to receive a trial of fibrate therapy, this should be done with caution and