Ljubica Djukanovic

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.

Uremic Pruritus and Skin Mast Cells

The number of mast cells in the skin was evaluated in 25 patients with end-stage renal failure on different treatment modality (conservative, hemodialysis and peritoneal dialysis). According to the presence of pruritus, uremic patients were divided into two groups: group A, 13 patients with diffuse pruritus, and group B, 12 patients without pruritus. Controls were 6 age- and sex-matched healthy subjects. In comparison with patients without pruritus, patients with pruritus had mainly degranulated, diffusely spread and more numerous mast cells in the skin; significantly higher levels of plasma middle molecular weight substances, serum histamine and PTH and significantly lower serum iron levels. However, no differences were noted in observed parameters between groups on different treatment modalities. Favorable therapeutic effects in patients with pruritus were achieved either with iron supplementation in those with hypoferremia or with antihistamines, mast cell membrane stabilizers and high-permeability membranes.

Effect of donor age on the outcome of living‐related kidney transplantation

The study compared the results of kidney transplantation from living‐related donors older and younger than 60 years. The 273 kidney graft recipients were divided into group 1 (115 recipients of older grafts) and group 2 (158 recipients of younger grafts). The frequency of acute rejection (AR) episodes was similar in both groups but slow graft function occurred more frequently in group 1. The frequency of chronic renal allograft dysfunction in the first post‐transplant year was significantly higher in group 1 than in group 2. Patient and graft survival was significantly worse in group 1. Risk factors for graft loss were the difference between donor and recipient age and AR. Donor age and graft function were risk factors for patient death. Although kidneys from older donors provide a statistically poorer transplant outcome, they are clinically acceptable, especially when waiting time is prolonged and access to dialysis limited.

Prevalence of Balkan Endemic Nephropathy Has Not Changed Since 1971 in the Kolubara Region in Serbia

Background/Aims: Thirty-one years after the first cross-sectional study, the population of Vreoci, a Balkan endemic nephropathy (BEN) village, was reinvestigated in order to determine the current prevalence of BEN and the clinical and laboratory characteristics of BEN family members with detected signs of kidney disease. Methods: A total of 2,009 inhabitants (82% of the adult population) of the village were examined. Danilovic’s criteria were used for diagnosis and classification of BEN. Results: The prevalence of BEN (1.70%) was similar to that in 1971 (1.67%). Diagnosis of BEN was established in 19 BEN family members, suspected BEN in 23, proteinuria in 29, while 16 healthy members were examined as controls. Urine protein, alpha1-microglobulin levels and frequency of glucosuria were significantly higher and kidney length significantly smaller in the three patient groups than in healthy persons. Serum urea and creatinine levels were significantly higher, but creatinine clearance was lower in BEN and BEN suspected patients than in the other two groups. Conclusion: The prevalence of BEN remains stable over time in Vreoci village. Manifested disease was found in both BEN and BEN suspected patients. In persons with proteinuria but not enough criteria for BEN, tubular disorders and hypertension were frequently found.

Detection of Renal Dysfunctions in Family Members of Patients with Balkan Endemic Nephropathy

Background/Aim: Recent studies have questioned whether new cases of Balkan endemic nephropathy (BEN) are occurring. The aim of the present study was to find out whether new members with renal dysfunctions can be identified among family members of BEN patients from the Kolubara region. Methods: The study included 47 family members of 5 BEN patients on hemodialysis (HD) and 17 members of 3 non-BEN patients on HD. Their medical and epidemiological histories were taken, an objective survey made, and all persons were examined for global and tubular kidney function. Results: Seven BEN family members (2 with previously known BEN) had creatinine clearance (Ccr) below the 75th percentile rank according to sex and age. All non-BEN family members had normal Ccr and no evidence of previous renal disorders. Hypertension was found in 20 (43%) BEN and 6 (35%) non-BEN family members. No significant differences in the frequency of renal function disorders (proteinuria, α1-microglobulinuria, urine specific gravity, osmolality, functional excretion of sodium, tubular phosphate resorption) or anemia were found between the groups. Renal disorders were detected in 18 BEN family members without previously detected disease, 3 of whom fulfilled criteria for a diagnosis of BEN and another 2 for BEN-suspected persons. Conclusion: New cases of BEN are still arising among the affected families in the Kolubara region.

Effects of Lowering Dialysate Calcium Concentration on Mineral Metabolism and Parathyroid Hormone Secretion: A Multicentric Study

Abstract:  This prospective study was conducted with the aim of examining the efficacy of lowering dialysate calcium (dCa) in order to: (i) stimulate bone turnover in hemodialysis patients with biochemical signs of adynamic bone disease (ABD) (hypercalcemia, normal alkaline phosphatase and intact parathyroid hormone (iPTH) <150 pg/mL); and (ii) diminish hypercalcemia in patients with secondary hyperparathyroidism (sHPT) (hypercalcemia, high alkaline phosphatase and iPTH > 400 pg/mL), thus permitting the use of calcium‐containing phosphorus binders and vitamin D metabolites. Patients were divided into: an ABD–treated group (24 patients), a sHPT–treated group (18 patients), an ABD–control group (12 patients) and a sHPT–control group (11 patients). For the ABD‐ and sHPT–treated patients, hemodialysis was conducted with dCa 1.5 mmol/L for three months and then with dCa 1.25 mmol/L for an additional three months, while in the control groups hemodialysis was conducted with dCa 1.75 mmol/L during the entire study. Reduction of dCa in patients with ABD caused a slight but insignificant decrease of Ca, but a significant and permanent increase of bone‐specific alkaline phosphatase and intact parathyroid hormone level serum levels. Reduction of dCa in patients with sHPT slightly but insignificantly decreased Ca and intact parathyroid hormone level values. Nevertheless, this enabled the calcium‐based phosphate binder dose to be raised and vitamin D3 metabolites to be introduced. Logistic regression analysis indicated that milder bone disease (both ABD and sHPT) was associated with more the favorable effect of dCa reduction. Thus, low dCa stimulated parathyroid glands and increased bone turnover in ABD patients, and enabled better control of mineral metabolism in sHPT patients.

Epoetin treatment improves red blood cell and plasma antioxidant capacity in hemodialysis patients.

The efficiency of human recombinant epoetin in alleviating anemia in hemodialyzed patients has been well documented. However, the effects of rhEPO therapy in correction of antioxidant capacity are not completely explained. In this study we examined both extracellular (plasma) and intracellular (red blood cells) antioxidant potential in hemodialyzed patients before and after three and six months of epoetin treatment by evaluating markers of oxidative stress (malondialdehyde) and antioxidant capacity (thiol groups, superoxide dismutase, and glutathione peroxidase). Six months of treatment with epoetin was followed by significant increases in thiol groups, superoxide dismutase and glutathione peroxidase activities in both plasma and red blood cells of hemodialyzed patients. Hence, during accelerated erythropoiesis, an increase in the number of young hematopoietic cells may replenish erythrocyte superoxide dismutase and glutathione peroxidase activity. However, the consequences of an imbalance between enzymatic antioxidant system (higher superoxide dismutase and lower glutathione peroxidase activity) that exists in these patients are the very high red blood cell and plasma malondialdehyde levels. These results suggest that, in spite of epoetin treatment and improvement in red blood cells and plasma antioxidant capacity, the production of reactive oxygen species overwhelms the intracellular and extracellular antioxidant capacity.

Beta2-Microglobulin and Alpha1-Microglobulin as Markers of Balkan Endemic Nephropathy, a Worldwide Disease

Background: Urine beta2-microglobulin (beta2-MG) was mainly used as a tubular marker of Balkan endemic nephropathy (BEN) but recently alpha1-microglobulin (alpha1-MG) was proposed for the diagnosis of BEN. In this study, the potential of urine beta2-MG, alpha1-MG, albumin, and total protein in the differentiation of BEN from healthy persons and patients with glomerulonephritis (GN) and nephrosclerosis (NS) was examined. Methods: This study involved 47 patients with BEN, 36 with GN, 11 with NS, 30 healthy subjects from BEN families, and 46 healthy subjects from non-BEN families. Results: In BEN patients area under the curve (AUC) for urine beta2-MG (0.828) and alpha1-MG (0.782) was higher than for urine albumin (0.740), but in GN patients AUC for urine protein (0.854) and albumin (0.872) was significantly higher than for the two low molecular weight proteins. AUC for all four urinary markers in NS patients was significantly lower than in BEN patients, ranging between 500 and 595. Median urine beta2-MG excretion in BEN patients was 17.5 times higher than in GN patients and 18.3 times higher than in controls; median alpha1-MG excretion was higher only 3.0 and 2.25 times, respectively. In the differentiation of BEN from healthy controls, beta2-MG had higher sensitivity and specificity at the cutoff levels (p < 0.001) than alpha1-MG (p < 0.05). In the differentiation of BEN from GN, beta2-MG was the best marker. Conclusion: All four urinary markers can be used for the differential diagnosis of BEN, beta2-MG being the best. Like in aristolochic acid nephropathy, beta2-MG seems to be an early marker of tubular damage in BEN.

Hepatitis B and Hepatitis C Virus Infection and Outcome of Hemodialysis and Kidney Transplant Patients

Aim. A comparison of the outcome of hepatitis virus-positive and -negative kidney transplant and hemodialysis patients was the aim of this investigation. Materials and Methods. The study involved 384 kidney transplant patients (67 HBsAg positive, 39 anti-HCV positive, 278 hepatitis negative), transplanted between 1987 and 2001, and 403 hemodialysis patients (128 HBsAg positive, 83 anti-HCV positive, 192 hepatitis negative) who had started hemodialysis and were referred to the kidney transplant waiting list during the same period. Results. Hemodialysis patients were older than transplant patients. Comparison of the groups’ survival rates, adjusted for patient age, showed that all kidney transplant patients survived longer than hemodialysis patients (p < 0.001). HBV infection had a negative impact on patient survival, especially in hemodialysis patients. HCV infection did not have a significant influence on patient survival. Cardiovascular disease was the main cause of death of all hemodialysis- and hepatitis-negative transplant patients. Liver failure was one of the leading causes of death in HBV-positive transplant patients. Mortality risk was higher for older patients, HBV-positive and -negative hemodialysis patients. Conclusions. Kidney transplantation offers longer survival for hepatitis-positive and -negative hemodialysis patients. HBV but not HCV infection had a negative impact on ESRD patient survival.

Ten Years' Experience in Subtotal Parathyroidectomy of Hemodialysis Patients

Secondary hyperparathyroidism (SHP) is a frequent complication of long-term dialysis patients, and surgical parathyroidectomy remains necessary in patients resistant to medical therapy. The present paper reports single center results in subtotal parathyroidectomy, presenting diagnostic procedure, indications for parathyroidectomy, and postoperative course of metabolic and endocrine disorders. Forty-seven patients (25 males and 22 females), aged 25–60 years, regularly hemodialyzed between 3–23 years, have undergone parathyroidectomy at our Clinical Center during the last 10 years. The patients had plasma iPTH levels 8–45 times higher than the top normal limit, high values of alkaline phosphatase, calcemia on the upper normal level, and hyperphosphatemia. Radiographic changes characteristic for SHP were seen in all patients before parathyroidectomy, and the most common were subperiosteal resorptions (100%), bone cysts and periosteal neostosis (66%), and extraskeletal calcifications (98%). Enlarged parathyroid glands were seen by ultrasound in 62% of patients. All patients manifested pruritus and bone pain, 89% of them had myopathy, while other symptoms and signs were present in lower proportions. After parathyroidectomy, pruritus and myopathy reduced significantly, while pain in bones and joints remained. One patient had brown tumor at the maxillary bone that regressed gradually after parathyroidectomy. Significant decreases of phosphate and calcium levels were recorded in all but two patients on the very first postoperative day. Regular peroral and parenteral supplementations of calcium and vitamin D metabolites were used, but calcemia was not normalized until the end of the third week of the postoperative period. Serum alkaline phosphatase showed an increase after the surgery, thereupon a sudden and then slower decrease up to 1 year from the surgery. Plasma iPTH levels, checked on the 21st postoperative day, were close to the lower normal limit in all but two (4.3%) patients with persistent SHP, who required reoperation. In conclusion, subtotal parathyroidectomy was proved as a successful and safe treatment for patients with SHP resistant to medical therapy, and treatment was followed by improvement of clinical symptoms and metabolic disorders.