Biopsy-proven BK virus nephropathy in renal transplant recipients: A multi-central study from Turkey (BK-TURK STUDY).

AIM: BK polyomavirus infection is a challenging complication of renal transplantation. The management is not standardized and is based on reports from transplantation centers' experiences, usually with small sample sizes. Therefore, we aimed to present our countrywide experience with BK virus nephropathy (BKVN) in renal transplant recipients. MATERIALS AND METHODS: Our study was carried out with the participation of 30 transplantation centers from all regions of Turkey. Only cases with allograft biopsy-proven BKVN were included in the study. RESULTS: 13,857 patients from 30 transplantation centers were screened, and 207 BK nephropathy cases were included. The mean age was 46.4 ±  13.1 years, and 146 (70.5%) patients were male. The mean time to diagnosis of BK nephropathy was 15.8 ± 22.2 months after transplantation. At diagnosis, the mean creatinine level was 1.8 ±  0.7 mg/dL, and the mean estimated glomerular filtration rate was 45.8 ± 19.6 mL/min/1.73m2. In addition to dose reduction or discontinuation of immunosuppressive drugs, 18 patients were treated with cidofovir, 11 patients with leflunomide, 17 patients with quinolones, 15 patients with intravenous immunoglobulin (IVIG), 5 patients with cidofovir plus IVIG, and 12 patients with leflunomide plus IVIG. None of the patients receiving leflunomide or leflunomide plus IVIG had allograft loss. During follow-up, allograft loss occurred in 32 (15%) out of 207 patients with BK nephropathy. CONCLUSION: BKVN is still a frequent cause of allograft loss in kidney transplantation and is not fully elucidated. The results of our study suggest that leflunomide treatment is associated with more favorable allograft outcomes.

Reduction of Dialysate Calcium Level Reduces Progression of Coronary Artery Calcification and Improves Low Bone Turnover in Patients on Hemodialysis.

Exposure to high Ca concentrations may influence the development of low-turnover bone disease and coronary artery calcification (CAC) in patients on hemodialysis (HD). In this randomized, controlled study, we investigated the effects of lowering dialysate Ca level on progression of CAC and histologic bone abnormalities in patients on HD. Patients on HD with intact parathyroid hormone levels ≤300 pg/ml receiving dialysate containing 1.75 or 1.50 mmol/L Ca (n=425) were randomized to the 1.25-mmol/L Ca (1.25 Ca; n=212) or the 1.75-mmol/L Ca (1.75 Ca; n=213) dialysate arm. Primary outcome was a change in CAC score measured by multislice computerized tomography; main secondary outcome was a change in bone histomorphometric parameters determined by analysis of bone biopsy specimens. CAC scores increased from 452±869 (mean±SD) in the 1.25 Ca group and 500±909 in the 1.75 Ca group (P=0.68) at baseline to 616±1086 and 803±1412, respectively, at 24 months (P=0.25). Progression rate was significantly lower in the 1.25 Ca group than in the 1.75 Ca group (P=0.03). The prevalence of histologically diagnosed low bone turnover decreased from 85.0% to 41.8% in the 1.25 Ca group (P=0.001) and did not change in the 1.75 Ca group. At 24 months, bone formation rate, trabecular thickness, and bone volume were higher in the 1.25 Ca group than in the 1.75 Ca group. Thus, lowering dialysate Ca levels slowed the progression of CAC and improved bone turnover in patients on HD with baseline intact parathyroid hormone levels ≤300 pg/ml.

Glycated hemoglobin predicts overall and cardiovascular mortality in non-diabetic hemodialysis patients.

AIMS: Besides diabetic patients, glycated hemoglobin (HbA1c) levels have been reported to predict mortality in non-diabetics patients. However, the importance of HbA1c levels in non-diabetic hemodialysis patients still remains unknown. Thus, we aimed to prospectively investigate the impact of HbA1c on all-cause and cardiovascular mortality in a large group of prevalent non-diabetic hemodialysis patients. METHODS: HbA1c was measured quarterly in 489 non-diabetic prevalent hemodialysis patients. Overall and cardiovascular mortality were evaluated over a 3 year follow-up. RESULTS: Mean HbA1c level was 4.88 ± 0.46% (3.5 - 6.9%). During the 28.3 ± 10.6 months follow-up period, 67 patients (13.7%) died; 31 from cardiovascular causes. In Kaplan-Meier analysis, patients in the lowest (< 4.69%) and highest HbA1c (> 5.04%) tertiles had poorer overall survival compared to the middle HbA1c tertile (p < 0.001). Adjusted Cox-regression analysis revealed that the highest HbA1c tertile was associated with both overall (HR = 3.60, 95% CI 1.57 - 8.27, p = 0.002) and cardiovascular (HR = 6.66, 95% CI 1.51 - 29.4; p = 0.01) mortality. Also, low HbA1c levels tended to be associated with overall mortality (HR = 2.26, 95% CI 0.96 - 5.29, p = 0.06). CONCLUSION: Upper normal HbA1c levels are independently associated with cardiovascular and overall mortality in non-diabetic hemodialysis patients, whereas lower HbA1c levels are not.

Hypothyroidism induced severe rhabdomyolysis in a hemodialysis patient.

Hypothyroidism occurs relatively common and is a significant cause of morbidity and mortality during the course of chronic kidney disease. Rhabdomyolysis is a potentially life-threatening condition characterised by necrosis of muscular tissue and rarely associates with hypothyroidism. Here we describe a case of rhabdomyolysis due to severe hypothyroidism in a 56-year-old female hemodialysis patient.

Massive bone marrow involvement in an end stage renal failure case with erythropoietin-resistant anemia and primary hyperoxaluria.

Primary hyperoxaluria is a rare autosomal recessive disorder. Type 1 PH is the most common form and develops due to a defect in a liver specific enzyme the alanine aminotransferase enzyme. As a result of the enzyme deficiency, there is an overproduction of oxalate and excessive urinary excretion. Recurrent urolithiasis and nephrocalcinosis are the most important findings of the disorder and often at the beginning end-stage renal disease develops. This report presents a case backed up by literature of a patient with end stage renal failure and erythropoietin-resistant anaemia whose bone marrow biopsy showed crystal deposition which received delayed diagnosis of oxalosis.

The impact of membrane permeability and dialysate purity on cardiovascular outcomes.

The effects of high-flux dialysis and ultrapure dialysate on survival of hemodialysis patients are incompletely understood. We conducted a randomized controlled trial to investigate the effects of both membrane permeability and dialysate purity on cardiovascular outcomes. We randomly assigned 704 patients on three times per week hemodialysis to either high- or low-flux dialyzers and either ultrapure or standard dialysate using a two-by-two factorial design. The primary outcome was a composite of fatal and nonfatal cardiovascular events during a minimum 3 years follow-up. We did not detect statistically significant differences in the primary outcome between high- and low-flux (HR=0.73, 95% CI=0.49 to 1.08, P=0.12) and between ultrapure and standard dialysate (HR=0.90, 95% CI=0.61 to 1.32, P=0.60). Posthoc analyses suggested that cardiovascular event-free survival was significantly better in the high-flux group compared with the low-flux group for the subgroup with arteriovenous fistulas, which constituted 82% of the study population (adjusted HR=0.61, 95% CI=0.38 to 0.97, P=0.03). Furthermore, high-flux dialysis associated with a lower risk for cardiovascular events among diabetic subjects (adjusted HR=0.49, 95% CI=0.25 to 0.94, P=0.03), and ultrapure dialysate associated with a lower risk for cardiovascular events among subjects with more than 3 years of dialysis (adjusted HR=0.55, 95% CI=0.31 to 0.97, P=0.04). In conclusion, this trial did not detect a difference in cardiovascular event-free survival between flux and dialysate groups. Posthoc analyses suggest that high-flux hemodialysis may benefit patients with an arteriovenous fistula and patients with diabetes and that ultrapure dialysate may benefit patients with longer dialysis vintage.

Relation between serum estradiol levels and mortality in postmenopausal female hemodialysis patients.

BACKGROUND: Recently, low serum estradiol levels have been associated with increased cardiovascular risk and mortality in non-uremic patient populations. We investigated the predictive value of serum estradiol levels for mortality in female hemodialysis patients. METHODS: One hundred and forty-seven prevalent female hemodialysis patients were included in March 2005 and followed up for 32 ± 16 months. Serum estradiol levels were determined by ELISA at baseline and studied in relation to cardiovascular and overall mortality. RESULTS: Mean serum estradiol level was 28.6 ± 15.4 pg/ml (5.7-81.3). Patients in the higher estradiol tertile were likely to be more often diabetic and to have more cardiovascular diseases and higher body mass index (BMI). Serum estradiol was inversely correlated with age and urea reduction rate and positively correlated with postdialysis body weight, BMI and hs-CRP levels. During the follow-up period, 52 (35.6 %) patients died. Patients who died were older, had shorter dialysis vintage, were more likely to have a history of diabetes and cardiovascular disease, and lower serum creatinine, albumin, hemoglobin, and higher hs-CRP levels than those who survived. In Cox regression analysis, estradiol levels, in a bimodal (U-shaped) distribution, along with diabetes, low serum albumin and high hs-CRP levels, were predictors for overall mortality. CONCLUSIONS: A U-shaped association between serum estradiol levels and cardiovascular and overall mortality was found in postmenopausal hemodialysis patients.

Mortality and cardiovascular events in online haemodiafiltration (OL-HDF) compared with high-flux dialysis: results from the Turkish OL-HDF Study.

BACKGROUND: Online haemodiafiltration (OL-HDF) is considered to confer clinical benefits over haemodialysis (HD) in terms of solute removal in patients undergoing maintenance HD. The aim of this study was to compare postdilution OL-HDF and high-flux HD in terms of morbidity and mortality. METHODS: In this prospective, randomized, controlled trial, we enrolled 782 patients undergoing thrice-weekly HD and randomly assigned them in a 1:1 ratio to either postdilution OL-HDF or high-flux HD. The mean age of patients was 56.5 ± 13.9 years, time on HD 57.9 ± 44.6 months with a diabetes incidence of 34.7%. The follow-up period was 2 years, with the mean follow-up of 22.7 ± 10.9 months. The primary outcome was a composite of death from any cause and nonfatal cardiovascular events. The major secondary outcomes were cardiovascular and overall mortality, intradialytic complications, hospitalization rate, changes in several laboratory parameters and medications used. RESULTS: The filtration volume in OL-HDF was 17.2 ± 1.3 L. Primary outcome was not different between the groups (event-free survival of 77.6% in OL-HDF versus 74.8% in the high-flux group, P = 0.28), as well as cardiovascular and overall survival, hospitalization rate and number of hypotensive episodes. In a post hoc analysis, the subgroup of OL-HDF patients treated with a median substitution volume >17.4 L per session (high-efficiency OL-HDF, n = 195) had better cardiovascular (P = 0.002) and overall survival (P = 0.03) compared with the high-flux HD group. In adjusted Cox-regression analysis, treatment with high-efficiency OL-HDF was associated with a 46% risk reduction for overall mortality {RR = 0.54 [95% confidence interval (95% CI) 0.31-0.93], P = 0.02} and a 71% risk reduction for cardiovascular mortality [RR = 0.29 (95% CI 0.12-0.65), P = 0.003] compared with high-flux HD. CONCLUSIONS: The composite of all-cause mortality and nonfatal cardiovascular event rate was not different in the OL-HDF and in the high-flux HD groups. In a post hoc analysis, OL-HDF treatment with substitution volumes over 17.4 L was associated with better cardiovascular and overall survival.

Neither oxidized nor anti-oxidized low-density lipoprotein level is associated with atherosclerosis or mortality in hemodialysis patients.

It is anticipated that oxidized low-density lipoprotein (oxLDL) and anti-oxLDL are associated with atherosclerosis and mortality. However, data on this issue are controversial and limited. We aimed to investigate the effect of these two markers on the extent and progression of atherosclerosis and mortality in a group of hemodialysis patients. In this prospective observational study with a follow-up of 36 months, 124 hemodialysis patients were studied. Ninety-five patients underwent carotid intima media thickness (CA-IMT) measurement by B-Mode ultrasonography both at baseline and at the end of the study. oxLDL and anti-oxLDL were measured by enzyme-linked immunosorbent assay. The extent and progression of CA-IMT, along with overall and cardiovascular mortality, were assessed. The mean age at baseline was 54.0 ± 14.8 years, 57.3% male and 20% diabetic. The mean oxLDL and anti-oxLDL levels were 8.11 ± 3.16 mU/L and 1.30 ± 0.31, respectively. Baseline mean CA-IMT was 0.82 ± 0.20 mm. Fifteen patients died during a follow-up period of 28.5 ± 6.6 months, 11 from cardiovascular causes. Only oxLDL, not anti-oxLDL, was correlated with the extent of atherosclerosis at baseline. However, both had no role in the progression of atherosclerosis. Also, in unadjusted and adjusted models, both parameters were not associated with overall or cardiovascular mortality. Neither oxLDL nor anti-oxLDL level is associated with the progression of atherosclerosis or mortality in hemodialysis patients.

Relationship between glucose exposure via peritoneal dialysis solutions and coronary artery calcification in non-diabetic peritoneal dialysis patients.

INTRODUCTION: Vascular calcification is frequent in dialysis patients and is associated with increased mortality. Impaired glucose metabolism is proposed as a contributing factor for vascular calcification. We investigated whether glucose exposure via dialysate may have a role in vascular calcification in non-diabetic peritoneal dialysis patients. METHOD: We measured coronary artery calcification by multi-slice computerized tomography in 50 prevalent non-diabetic peritoneal dialysis patients and assessed its relations with fasting blood glucose, homeostasis model assessment of insulin resistance (HOMA-IR), and glucose exposure from peritoneal dialysis fluid. RESULTS: Twenty-four patients (48%) had no coronary calcification. When patients were grouped according to the presence or absence of calcification, patients with calcification were mostly men and had higher burden of cardiovascular disease history, vitamin D dose intake, serum calcium, total glucose exposure from dialysis solution, and lower total weekly Kt/Vurea. In multivariate analysis, dialysate glucose exposure was an independent predictor of coronary artery calcification score, besides serum calcium and Kt/Vurea. CONCLUSION: These data suggest that high glucose exposure from dialysis solution, which is potentially correctable, is a risk factor for vascular calcification in non-diabetic PD patients.

Magnesium reduces calcification in bovine vascular smooth muscle cells in a dose-dependent manner.

BACKGROUND: Vascular calcification (VC), mainly due to elevated phosphate levels, is one major problem in patients suffering from chronic kidney disease. In clinical studies, an inverse relationship between serum magnesium and VC has been reported. However, there is only few information about the influence of magnesium on calcification on a cellular level available. Therefore, we investigated the effect of magnesium on calcification induced by ß-glycerophosphate (BGP) in bovine vascular smooth muscle cells (BVSMCs). METHODS: BVSMCs were incubated with calcification media for 14 days while simultaneously increasing the magnesium concentration. Calcium deposition, transdifferentiation of cells and apoptosis were measured applying quantification of calcium, von Kossa and Alizarin red staining, real-time reverse transcription-polymerase chain reaction and annexin V staining, respectively. RESULTS: Calcium deposition in the cells dramatically increased with addition of BGP and could be mostly prevented by co-incubation with magnesium. Higher magnesium levels led to inhibition of BGP-induced alkaline phosphatase activity as well as to a decreased expression of genes associated with the process of transdifferentiation of BVSMCs into osteoblast-like cells. Furthermore, estimated calcium entry into the cells decreased with increasing magnesium concentrations in the media. In addition, higher magnesium concentrations prevented cell damage (apoptosis) induced by BGP as well as progression of already established calcification. CONCLUSIONS: Higher magnesium levels prevented BVSMC calcification, inhibited expression of osteogenic proteins, apoptosis and further progression of already established calcification. Thus, magnesium is influencing molecular processes associated with VC and may have the potential to play a role for VC also in clinical situations.

Association of insulin resistance with arterial stiffness in nondiabetic peritoneal dialysis patients.

BACKGROUND: Insulin resistance is a risk factor for cardiovascular morbidity and mortality in the general and end-stage renal disease populations. In this study, we investigated the association between insulin resistance and arterial stiffness in nondiabetic peritoneal dialysis (PD) patients. METHODS: Fifty-three patients were enrolled. Patients were divided into 2 groups as homeostasis model assessment of insulin resistance (HOMA-IR) ≤ 2.97 (low) and >2.97 (high). Carotid-femoral pulse wave velocity (c-f PWV) analysis and intima-media thickness of the carotid artery were measured. RESULTS: Mean age was 46 ± 12 years and HOMA-IR was 2.97 ± 1.77 (0.77-8.88). Mean c-f PWV was 7.6 ± 1.7 m/s. HOMA-IR was positively correlated with age, body mass index, and c-f PWV and negatively with serum HDL cholesterol and parathormone. In linear regression analysis, age and mean arterial pressure were predictors for c-f PWV. When patients were divided into 2 groups according to median age as ≤ 49 and >50, mean arterial pressure, male gender, and age were predictors for c-f PWV in patients aged ≤ 49, whereas HOMA-IR was the only predictor for c-f PWV in patients aged >50 years. CONCLUSION: Insulin resistance is an independent risk factor for arterial stiffness in PD patients older than 50 years. IR is not associated with carotid intima-media thickness.

Nutritional state alters the association between free triiodothyronine levels and mortality in hemodialysis patients.

BACKGROUND: Serum free triiodothyronine (fT3) level is suggested to be a risk factor for mortality in unselected dialysis patients. We investigated the prognostic value of serum fT3 levels and also low-T3 syndrome on overall survival in a large cohort of hemodialysis (HD) patients with normal thyroid-stimulating hormone levels. METHODS: A total of 669 prevalent HD patients were enrolled in the study. Serum fT3 level was measured by enzyme immune assay in frozen sera samples at the time of enrollment. Overall mortality was assessed during 48 months of follow-up. RESULTS: Baseline fT3 was 1.47 ± 0.43 (0.01-2.98) pg/ml, and low-T3 syndrome was present in 71.7% of the cases. During a mean follow-up of 34 ± 16 months, 165 (24.7%) patients died. fT3 level was a strong predictor for mortality in crude and adjusted Cox models including albumin or high-sensitivity C-reactive protein (hs-CRP). Further adjustment for both albumin and hs-CRP made the impact of fT3 on mortality disappear. The presence of low-T3 syndrome was associated with mortality in only the unadjusted model. CONCLUSIONS: Low-T3 syndrome is a frequent finding among HD patients, but it does not predict outcome. However, serum fT3 level is a strong and inverse mortality predictor, in part explained by its underlying association with nutritional state and inflammation.

The impact of strict volume control strategy on patient survival and technique failure in peritoneal dialysis patients.

Strict volume control strategy provides better cardiac functions and control of hypertension in dialysis patients. We investigated the effect of this strategy on mortality and technique failure in peritoneal dialysis patients over a 10-year period. 243 patients were enrolled. Strict volume control by dietary salt restriction and ultrafiltration was applied. Mean systolic and diastolic blood pressures decreased from 138.4 ± 29.9 and 86.3 ± 16.8 to 114.9 ± 32.3 and 74.7 ± 18.3 mm Hg, respectively. Overall and cardiovascular mortality rates were 48.4 and 29.6 per 1,000 patient-years, respectively. In multivariate analysis, age, diabetes and baseline serum albumin level were independent predictors of overall mortality, and age, diabetes and baseline serum calcium of cardiovascular mortality. Residual diuresis and peritoneal equilibration test values were not related to mortality. Strict volume control leads to lower mortality than comparable series in the literature. Technique survival is better during the first 3 years, but not after 5 years.