Visnja Lezaic

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.

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.

Does tuberculosis after kidney transplantation follow the trend of tuberculosis in general population

Despite improvement in graft survival, infection continues to be an important cause of morbidity and mortality after kidney transplantation. We analyzed the clinical courses and outcomes of 16 transplanted patients with positive cultures for mycobacterium tuberculosis. In the course of a 20 year period, there were 13 cases of tuberculosis registered that developed in 456 patients who underwent kidney transplantation in our department, and in three refugees transplanted in other centers (a prevalence of 3.13%). Five of them developed tuberculous infections during 1997. Five patients had residual tuberculosis in preoperative chest X-ray, and specific pyelonephritis as an underlying kidney disease in two of them. All patients with treated with triple immunosuppressives. Before tuberculosis onset, 14 patients experienced one or more episodes of acute rejection and were treated with steroid pulses, ALG or OKT3. Tuberculosis was diagnosed after a period of 1.5 months to 10 years after transplantation. At the time of an infection, the graft function was normal in eight patients and chronic graft failure was evident in eight patients (sCr 210–700 μmol/L). The infection was pulmonary in 12 patients; urinary in two; disseminated in two; pulmonary and urinary, pulmonary and intestinal, and pancytopenia in one patient. All patients were treated with rifampicin and isoniazid in addition to ethambutol for the first two-month period. Treatment lasted from 1–22 months. With 14 patients favorable microbiological responses were registered. Two patients died within the first six months (both with disseminated disease), and the mortality rate was 14.3%. Throughout the followup period, the graft function remained stable and normal in eight patients who had normal graft function at the time of infection onset. Although six patients recovered, progressive graft failure developed and hemodialysis was restarted in one patient two months after antituberculous therapy introduction, and in two patients three years later. Four patients died 2–14 months after AT therapy withdrawal. The causes of death were severe liver failure, cerebrovascular insult and CMV.

Recombinant Human Erythropoietin Treatment of Anemia in Renal Transplant Patients

The rHuEpo effect on anemia in eight renal transplant patients (group A) with severe anemia (Hb 6.0-7.5 g/dL) and chronic graft failure (CGF) (sCr 281-794 mumol/L) was compared to the rHuEpo effect on anemia in predialysis (20 patients-group B) and hemodialysis patients (17 patients-group C) in order to examine the rHuEpo effect on anemia and graft failure progression, and to find out whether the response to therapy in these three patient groups differed. Although renal function impairment was similar in patients from group A and B, anemia was more severe in patients from group A. Serum immunoreactive erythropoietin levels were within normal limits for nonanemic persons, that is, inadequate for the level of anemia in all patients before therapy. Maintenance immunosuppression given after renal transplantation consisted of cyclosporine, azathioprine, and prednisone in standard doses. The startig rHuEpo dose of 150 U/kg/wk increased by 25 U/kg if the target Hb of 10.0 g/dL was not achieved at the end of a 4-week period. When target Hb was achieved, the rHuEpo dose was regularly adjusted to maintain Hb of 10.0 g/dL. Most patients from group A and group C were polytransfused before rHuEpo therapy and consequently with iron overload so that only some patients from these groups and all predialysis patients needed iron supplementation given orally. Anemia improved in all patients with 2 to 10 weeks of treatment. Mean rHuEpo doses for the first 2 months were similar in three studied groups, but the patients with the lowest initial hemoglobin values responded better to rHuEpo therapy. The rate of Hb increase during the initial phase of therapy was significantly higher in patients from group A and B comparing to patients from group C, indicating the importance of residual renal function for rHuEpo effect on anemia. Progression of CGF expressed by the slope of l/sCr vs. time did not change in either patients from group A or in predialysis patients. It could be concluded that rHuEpo therapy improved anemia in transplant patients as in predialysis and hemodialysis patients. Anemia improvement by rHuEpo did not accelerate the progression of graft function.

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.

Donor Kidney Glomerular Filtration Rate and Post-Transplant Graft Function

This study aimed to estimate the relationship between the single kidney glomerular filtration rate (SKGFR) of a planned kidney transplant and the subsequent graft function and survival of living related kidney recipients (LKRs). Of 180 LKRs with the graft functioning for more than a year, 70 patients without delayed graft function (DGF) or acute rejection (AR) were selected for the study. According to SKGFR, assessed by 99mTcDTPA, the patients were allocated into Group 1, receiving kidney with SKGFR < 50 mL/min (32 patients), and Group 2, with SKGFR > 50 mL/min (38 patients). The database included donor, recipient and transplant variables. No significant difference was found between the patient and graft survival rate, creatinine clearance (CCr) and the rate of CCr change between the groups. Additional evaluation revealed no significant influence of the ratio of SKGFR and the recipients body weight/size on patient and graft outcome. The analysis of factors of influence on patient and graft survival and function revealed the major influence of nonimmunological factors but not of SKGFR of the transplanted kidney. Our study did not confirm the influence of SKGFR on graft function and survival in the LKRs without DGF and AR but the limited number of patients must not be disregarded.

Factors affecting graft function in pediatric and adult recipients of adult live donor kidney transplants.

Abstract:  The aims of this investigation were to compare changes of function of adult living kidney grafts transplanted into adult and child recipients and to analyze factors associated with graft function during the first post‐transplant year. The study involved 53 adult and 23 pediatric recipients with immediate graft function and without complications that could influence graft function. In comparison to children, adult recipients and their donors were older, and having been longer on hemodialysis they had received more transfusions. Although similar baseline graft function – GFR0 was transplanted in both groups, absolute and relative GFR in adults rose and maintained stable, while in children absolute GFR decreased and remained similar to the GFR0 until the end of the study. Significant predictors of kidney function in both adult and child recipients were donor age, ratio between GFR0 and recipient BSA, induction immunosuppression, and systolic hypertension. In conclusion, the function of adult live kidney grafts changed differently in children and adults because of different functional requirements of recipients but donor age, induction immunosuppression and hypertension are significant predictor of graft function in both adults and children.

Parathyroidectomy and improving anemia.

W e have read with great interest the article written by Chow and coworkers showing that anemia improved after total parathyroidectomy (PTX), especially in the patients who received therapy with human recombinant erythropoietin. As the mechanisms for the improvement were not considered in the article, we would like to share our results concerning increased erythropoiesis after PTX, even though they were obtained from an investigation of a small patient group. Nine patients (5 men; mean [SD] age, 45.0 [15.4] years) who had been receiving regular hemodialysis for 76.8 [43.8] months were included in the study after subtotal PTX. All of them gave informed consent to participate in the study. Indication for PTX was based on clinical, biochemical, and radiological criteria. Three patients (patients 6, 7, and 8 in the Table) were positive for hepatitis virus B or C. None of the patients had iron deficiency anemia or blood loss, and none of them were treated with human recombinant erythropoietin before or after PTX. Histological examination found hyperplasia in all extirpated glands. The following laboratory analyses were done before and 6 months after PTX in all patients: hemoglobin, serum calcium, phosphorus, alkaline phosphatase, intact parathormone (iPTH) (radioimmunoassay; Nichols InstituteDiagnostics,SanJuanCapistrano,California) (normal values, 10-55 pg/mL), erythropoietin (Epo) (enzymelinked immunosorbent assay 500; Medac, Wedel, Germany) (normal values for healthy nonanemic adults, 4-25 mU/mL), bone marrow burst-forming units erythroid (BFU-E) (assayed by methyl cellulose culture technique in vitro), and bone marrow cellularity. Six months after PTX, serum iPTH levels were 10 to 69 times lower than the initial value in all but 1 patient (Table). In the first 8 patients presented in the Table, mean (SD) iPTH levels decreased significantly (1453.7 [634.2] vs 71.0 [75.8] pg/mL, P=.02) after successful PTX. This was accompanied by increases of mean (SD) hemoglobin level (88.5 [19.4] vs 99.2 [10.7] g/L, P=.31) and mean (SD) serum Epo level (23.54 [21.1] vs 31.1 [22.5] IU/mL, P=.04) and a decline in mean (SD) BFU-E number (40.1 [12.5] vs 26.2 [10.6], P=.14). Individual data showed that serum Epo concentration increased after successful PTX in 6 of 8 patients. In 2 patients who were positive for hepatitis virus, serum Epo levels were higher than the normal range even before PTX. The increase of serum Epo levels was accompanied by greater hemoglobin values and increased bone marrow cellularity from proliferation of erythroblasts, which lowered the myeloid to erythroid ratio in the bone marrow (4.4:1 before and 1.8:1 after PTX). Numbers of BFU-E were decreased in all the patients with successful PTX (including the patient with high initial Epo). The results presented show erythropoiesis stimulation after successful PTX by an increase in serum Epo, which suggests a direct inhibitory effect of PTH on Epo synthesis. These data are in concert with those obtained by others and confirm that even in patients with endstage renal disease and without excretory kidney function, increase of erythropoietin synthesis could occur. Increased serum Epo before PTX found in 2 of our patients who were positive for hepatitis is in agreement with our previous results. However, in all patients with successful PTX, including these 2, bone marrow cellularity improved and BFU-E numbers decreased. That indicated that more efficacious erythroid maturation after successful PTX resulted not only from the increase of Epo synthesis but also from a decrease of bone marrow suppression. The role of PTH as a uremic toxin and inhibitor of erythropoiesis was described 2 decades ago.

Potential Influence of Tubular Dysfunction on the Difference Between Estimated and Measured Glomerular Filtration Rate After Kidney Transplantation

PURPOSE Because no consensus exists regarding the most accurate calculation to estimate glomerular filtration rate (GFR) based on serum creatinine concentrations (sCr) after kidney transplantation, this study sought to assess the potential role of tubular dysfunction on GFR estimates using various equations as well as the effect of pharmacologic blockades on tubular secretion of creatinine on creatinine clearance (ClCr). METHODS Iohexol GFR (mGFR) was performed in 17 stable kidney transplant recipients(R) at >24 months post-transplantation. Their mean age was 48.3 ± 11.3 years. All R were treated with a calcineurin inhibitor (CNI). At the time of study we measured sCr, 24 hour-ClCr, cystatin C, 24-hour proteinuria, microalbuminuria, FE Na, alfa1-microglobulinuria (alfa1-MG), and CNI concentrations. To block tubular secretion of Cr, recipients were prescribed cimetidine (2400 mg) 2 days before the sCr measurement. Additionally, to exclude dietary influences on sCr, R did not eat meat for 2 days before testing. GFR was estimated using the Modification of Diet in Renal Disease (MDRD), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), Cockroft-Gault (C&G), and Cystatin C (Cyst C) GFR equations. Mean kidney graft function over the previous 6 months was used as the control. Pearson correlation was determined between the differences between mGFR and estimatedGFR: Iohexol minus MDRD, EPI, Cyst C or C&G GFR for paired estimates. The diagnostic accuracy of the eGFRs to detect an mGFR of 60 mL/min/1.73 m(2) was examined by receiver operating characteristic curves. RESULTS Mean mGFR was 75.2 ± 35.8 mL/min/1.73 m(2). The sCr increased but the 24-hour ClCr, MDRD, EPI, and C&G decreased after vs before cimetidine. The difference was significant for sCr (F = 12.933; P = .002) and MDRD GFR (F = 15.750; P = .001). mGFR was not significantly higher than all pair values of eGFRs, and not significantly lower than 24-hour ClCr before and after cimetidine. However, in comparison to all eGFRs, ClCr after cimetidine most approached mGFR. A significant positive correlation was observed between alfa1-MG and the difference between mGFR and MDRD (before, r = .543 [P = .045]; after cimetidine, 0.568 [P = .034]), EPI (before, r = 0.516 [P = .050]; after cimetidine, r = 0.562 [P = .036]), and ClCr (r = 0.633; P = .016), C&G (P = .581; P = .029) before cimetidine. Accuracy of eGFRs to detect mGFR of 60 mL/min/1.73 m(2) showed EPI GFR before cimetidine to show diagnostic accuracy for patients with GFR >60 mL/min/1.73 m(2) with a sensitivity of 81.8% and a specificity of 71.4%. CONCLUSIONS Because mGFR is unavailable in many transplant centers, determination of ClCr after cimetidine may help to achieve a more accurate diagnosis of CKD among transplant patients.