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.

Application of artificial neural networks in estimating predictive factors and therapeutic efficacy in idiopathic membranous nephropathy.

Idiopathic membranous nephropathy (IMN) is one of the most frequent causes of the nephrotic syndrome in adults and one of the most common cause of chronic renal failure among primary glomerular diseases. The aim of this study was to develop artificial neural networks (ANN) to investigate factors of poor outcome for IMN and to evaluate the efficacy of different therapeutic protocols. Data were collected retrospectively for 124 patients with IMN (82 males, mean based on the received therapy patients were divided into three groups: corticosteroids only (group 1), cyclophsophamide with corticosteroids (group 2), and so called Ponticelli protocol (group 3). After achieving satisfactory truthfulness of the transcription function of ANN through clustering, we have applied the efficacy analysis to all patients and then compared them to each group separately, and evaluated the influence of initial characteristics on disease outcome as well as the therapy efficacy. The greatest therapy inefficiency was recorded for isolated corticosteroid therapy (29.41%) and the smallest inefficiency for Ponticelli protocol, for which the greatest accuracy of prognosis was recorded (82.09%). The greatest negative prognostic influence had kidney insufficiency (22%), quantitative proteinuria (15%) and index of interstitial infiltration (14%). Based on our results, we can recommend that patients diagnosed with IMN with renal insufficiency, nephrotic syndrome or a high degree of interstitial infiltration at the time of diagnosis should be treated concomitantly with cytotoxic drugs and corticosteroids, particularly with the Ponticelli protocol.

Efficacy of hyperphosphatemia control in the progression of chronic renal failure and the prevalence of cardiovascular calcification.

BACKGROUND AND AIMS: Chronic kidney disease mineral- and bone disorder (CKD-MBD) has been studied more often in dialysis than in predialysis CKD patients. The association between efficacy of hyperphosphatemia control and chronic renal failure (CRF) progression, prevalence of bone disease and cardiovascular calcification was the objective of the present investigation. MATERIAL AND METHODS: 42 patients with CKD in Stage 5, regularly monitored for 5 years, were divided into Group 1 of 20 patients with normal serum phosphate (sPO4) levels and Group 2 of 22 patients with hyperphosphatemia registered at the majority of checks. Serum urea, creatinine, calcium (sCa) and sPO4 levels were regularly determined in the retrospective 5-year period. At the end of this period iPTH, bone alkaline phosphatase-BAP and inflammation markers (CRP, fetuin-A) were measured, valvular and arterial calcifications were detected by B mode echocardiogram and soft-tissue native radiograms of the pelvis and the wrist. RESULTS: Progression of CRF (1/sCr over time) was faster in Group 2 than in Group 1 (b = -0.0577 vs. -0.0288, p = 0.003) during the study period. Average BAP and iPTH values were similar in both groups and 23/42 patients had PTH > 300 pg/ml. Arterial and valvular calcifications were found in 5/23 patients from Group 1 and 14/22 patients from Group 2 (p = 0.011). Linear regression analysis revealed sPO4 as a predictor for total calcification number, inflammatory diseases as a predictor for valvular calcifications, while sPO4 and iPTH were predictors for arterial calcifications. CONCLUSIONS: More than half the patients with Stage 5 CKD not yet on dialysis exhibited elevated PTH. Faster CRF progression and frequent arterial and valvular calcifications were seen in patients with poor phosphate control and sPO4 was selected as an independent predictor of total calcification score.

Hemodialysis modality, percentage of body fat, and patient survival.

BACKGROUND: A number of studies have reported lower mortality of overweight hemodialysis patients. This post hoc analysis of an observational prospective single-center study was aimed at elucidating whether both being overweight and surviving longer could result from changes in the hemodialysis modality. METHODS: The study included a cohort of 242 patients who were gradually switched from cuprophane membrane and acetate dialysis to polysulfone (including high-flux) membranes and bicarbonate dialysis. The analysis involved 12 months of baseline data obtained during the first calendar year after the patients entered the study (1994-2001) and repeated measurements for up to 132 months of follow-up (until 2004). Anthropometric measurements were made during the winter season and the percentage of body fat (%fat) was calculated from triceps, biceps, subscapular, and suprailiac skinfolds (K/DOQI guidelines).Kt/V, normalized protein catabolic rate, and cardiovascular comorbidity were also determined and laboratory analyses undertaken. RESULTS: Significant correlations were found between %fat and bicarbonate dialysate as well as polysulfone membrane and high-flux membrane. The linear mixed model showed dependence of %fat on polysulfone and high-flux membrane (p<0.01) Multivariate Cox regression (time-dependent covariates) found %fat to be an independent factor for longer survival, in addition to polysulfone and high-flux membranes. CONCLUSION: Changes in hemodialysis modality were followed by both higher body fat percentage and patient survival. The reverse epidemiology of overweight patients might be at least partially the result of the influence of nonnutritional factors, such as a change in hemodialysis modality (introducing biocompatible high-flux and low-flux membranes and bicarbonate dialysis).

Conversion of azathioprine to mycophenolate mofetil and chronic graft failure progression.

The purpose of the study was to evaluate the impact of conversion from azathioprine (AZA) to mycophenolate mofetil (MMF) on graft function in 35 renal transplant recipients with chronic allograft nephropathy (CAN). The immunosuppressive regimen originally consisted of AZA, cyclosporine (CsA), and prednisone (Pr). At the onset of the study (mean period = 39 posttransplant months), a graft biopsy was performed on all patients who were randomly divided into group 1 (n = 17) in whom MMF was introduced instead of AZA. The remaining 18 subjects (group 2) were maintained on the previous regimen. Two periods were analyzed: period I: 12 months before, and period II: 12 months after biopsy and therapy conversion. Graft function was assessed monthly by measurements of the 24-hour creatinine clearance (CCr). Analysis of variance (ANOVA) was used to compare the differences in CCr and proteinuria between the two groups. No difference was observed in the baseline characteristics, in the incidence of delayed graft function and acute rejection, or in the mean CsA dose. Pathohistological analysis revealed advanced CAN in the majority of patients in both groups. The morphological changes negatively correlated with graft function. The graft function showed parallel deterioration in the two groups; no significant difference was observed in the mean CCr values in the periods studied. Proteinuria was similar for both groups throughout the study. Conversion of AZA to MMF in recipients with CAN, albeit safe, was without significant benefit on the progression of chronic graft failure over the period of a year.

Erythropoiesis after kidney transplantation: the role of erythropoietin, burst promoting activity and early erythroid progenitor cells.

Successful kidney transplantation is followed by the anemia correction due to re-establishment of normal erythropoietin secretion. The possible role of growth factors and cytokines regulating hematopoiesis in this anemia correction are not completely understood. The aim of this study was to investigate the role of erythropoietin and other stimulators in the regulation of erythropoiesis after kidney transplantation. Thirty-six kidney graft recipients with stable graft function for more than 12 months were studied. According to the hemoglobin levels they were divided into: group 1 (12 patients) with normal graft function (sCr = 145.2 +/- 15.8 micromol/l) and normal hemoglobin (12.7+/-0.3 g/dl), group 2 (11 patients) with normal graft function (sCr = 135 +/- 6.5 miromol/l) and posttransplant erythrocytosis (Hb = 18.1 +/- 0.2 g/dl) and group 3 (13 patients) with chronic graft failure (sCr = 223.7 +/- 28.9 micromol/l, range 181-294) and anemia (Hb = 9.0 +/- 0.8 g/dl). Early erythroid progenitors (BFU-E) from peripheral blood, serum immunoreactive Epo and burst promoting activity (BPA) in PHA-LCM prepared from patients' peripheral blood mononuclear cells were measured in all studied patients. The expected Epo for Hb was found normal in patients with normal graft function, 10 times higher in patients with PTE and low in patients with anemia. BPA in PHA-LCM prepared from PTE was increased in 4/6 patients, normal in 4/6 anemic patients, but it was decreased in 5 patients with normal Hb. The mean values were 20.8 +/- 6.3 in PTE group and 16.2 +/- 6.8 in anemic group, and 4.1 +/- 1.8 (at the level of normal controls) in group 1. The number of BFU-E derived colonies was low in most patients with normal hemoglobin and anemia, and increased in most patients with PTE. Spontaneous BFU-E colonies i.e. without Epo added to the cultures were found in 7 of 12 patients with PTE. The mean values of BFU-E showed significant differences between patients with PTE (17.43 +/- 7.3), and patients with normal hemoglobin and anemia (4.39 +/- 1.2 vs. 6.5 +/- 1.1). The results presented suggest that inappropriate Epo secretion depends on the graft function and is the primarily important regulator that caused PTE or anemia after kidney transplantation. Synergistic action of BPA with Epo as well as increased sensitivity of early erythroid precursors to these stimulators could explained sustained erythropoiesis in PTE patients. The high BPA levels in anemic transplant patients with moderate chronic graft failure could be beneficial if rHuEpo treatment is applied in this patient group.

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 micromol/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.

Markers of oxidative stress after renal transplantation.

An increased degree of oxidative stress (OS) in chronic renal failure (CRF) and a possible role of free radicals in CRF have already been described. However, data on OS after renal transplantation are scarce. The aim of the present study was to estimate the degree of OS in renal transplant patients. The study included four groups: 1) 15 haemodialysis patients (HD group), 2) 11 renal transplant patients with stable function (SF group), 3) 12 renal transplant patients with chronic biopsy-proven rejection (CR group), and 4) 10 healthy controls (C group). Markers of OS (malondialdehyde and thiol group levels) and antioxidant activity (glutathione peroxidase and Cu,Zn-superoxide dismutase) were determined in plasma and in red blood cells of all examined individuals. After successful renal transplantation a significant improvement, but not normalization, of antioxidant enzyme activities accompanied by significantly reduced lipid peroxidation were found. In the CR group the degree of OS was increased, and our results suggest that OS may be a relevant pathophysiological factor for CR development.

In vivo effects of recombinant human erythropoietin on bone marrow hematopoiesis in patients with chronic renal failure.

Studies of hemopoietic progenitors and precursors in bone marrow before and after two months of recombinant human erythropoietin (rhEpo) therapy in 12 patients with uremic anemia are the subject of this investigation caried out in order to have a better insight into the effect of Epo in vivo. Eight patients were on hemodialysis and four others were predialysis patients with chronic renal failure. The starting dose of rhEpo was 30-50 U/kg bw and was increased by 50 percent every four weeks. The mean hemoglobin values rose from 6.08 +/- 1.03 to 9.8 +/- 1.98 g/dl at the time of study. The number of bone marrow derived erythroid colonies, both early (BFU-E) and late (CFU-E) were found to be higher than subnormal values, found before the therapy. The percentage of erythroid progenitors in cell cycle increased to higher than normal values for BFU-E and to normal values for CFU-E. At the same time granulocytic progenitors (CFU-GM) decreased to the range of normal values (67.3 per 10 superset5 cells). Slightly increased Epo levels (approx. 30mU/ml) during the replacement therapy were optimal for correction of anemia. The rhEpo therapy induced an increase of percentage of erythroblasts and the decrease of myeloid to erythroid ratio (M/E) in the bone marrow. Only in predialysis patients in whom the target hemoglobin values were achieved by rhEpo therapy at the time of the study the percentage of erythroblasts in the bone marrow increased to normal values. Increase of erythroblasts in bone marrow in patients under two months of substitutive therapy with rhEpo with the increase of both, early and late erythroid progenitors we have observed, is significant indicating the stimulative effect of rhEpo on all subsets of erythropoiesis leading to normalization of erythropoiesis at all levels. No stimulative effect of rhEpo replacement therapy on granulopoiesis was observed.

Factors inducing posttransplant erythrocytosis.

In this study factors possibly contributing to the development of erythrocytosis after renal transplantation (PTE) were analyzed. Out of 131 transplanted patients nine developed PTE (mean hemoglobin 17. 9 +/- 0.3 g/dl) 2 to 27 months after transplantation (group 1) and were compared to the nine with normal hemoglobin concentration (mean hemoglobin 12.4 +/- 0.2 g/dl, control group 2). The study was performed about two years after transplantation (25 +/- 3.9 months group 1 and 23.7 +/- 2.6 months group 2). Immunosuppressive therapy given in standard doses consisted of cyclosporine, azathioprine and prednisone. At the onset of the study no difference in renal graft function was noted between the groups (for group 1 sCr = 111.7 +/- 10.4 micromol/l and for group 2 sCr = 154.6 +/- 27.6 micromol/l). The mean serum immunoreactive erythropoietin (Epo) levels were significantly higher in PTE patients compared to control group of patients (33.9 +/- 4.6 mU/ml vs 21.6 +/- 2.5 mU/ml, p = 0.03). In addition, the ratio between observed to expected (O/E) Epo, a useful index in assessing Epo secretion in renal transplant patients, was ten times higher for group 1 than for group 2 (Median value 10.0 vs. 1.05). Spontaneous growth of Burst-forming unit- erythroid (BFU-E) in peripheral blood was detected in 5 out of 9 patients from group 1 and none in patients from group 2 (p = 0.04). Burst Promoting Activity (BPA) in Phytohemagglutinine Stimulated Leukocytes Condition Medium (PHA-LCM) from patients blood were higher in the PTE patients than in controls. Whole blood cyclosporine levels were higher in group 1 than in group 2 throughout the first 30 weeks after transplantation. It was concluded that sustained erythropoiesis after correction of renal anemia by kidney transplantation, leading to PTE could be explained as a consequence of increased levels of Epo and BPA and increased sensitivity of early erythroid progenitors to these stimulators induced by high cyclosporine levels.

[Treatment of anemia in patients with chronic renal insufficiency with recombinant human erythropoietin]. / Lecenje anemije kod bolesnika s hronicnom insuficijencijom bubrega rekombinovanim ljudskim eritropoetinom.

The discovery of recombinant human erythropoietin has enabled treatment of anaemia in patients whose anaemia was primarily caused by the lack of erythropoietin. This agent was most widely used in the treatment of anaemia in chronic renal failure patients. Non-regulated hypertension is considered to be the only absolute contraindication for recombinant human erythropoietin application, but thrombocytosis, predisposition to thromboses of arterio-venous fistulae, and convulsions are regarded as relative contraindications. Recombinant human erythropoietin may be administered intravenously, but the subcutaneous route is considered more rational. The treatment is initiated by low doses with gradual dose increase, what enables gradual anaemia correction and prevents the appearance of adverse effects. Haemoglobin level of around 100 g/l is considered the target haemoglobin level. The majority of patients respond well to treatment by human recombinant erythropoietin and the absence of anaemia improvement may be the result of iron deficiency, occult haemorrhages, chronic infection, inadequate dialysis, secondary hyperparathyroidism, aluminium intoxication. Anaemia improvement during the treatment with recombinant erythropoietin leads to the improvement of function of most organs and the quality of life in general as well as avoidance of blood transfusions and their adverse effects. The most frequent adverse effect of recombinant erythropoietin is the development of iron deficiency or hypertension aggravation.

Living related kidney donors over 60 years old.

The lack of available cadaveric organs for transplantation has resulted in an increased number of kidney transplants from living donors. During a period of 6 years, 149 kidney transplantations were performed from living related donors in our institute, 33.5% of whom were older than 60 years of age. In this study we examined the survival of patients and grafts as well as the graft function in 50 patients with transplants from donors over 60 years (mean age 65 years) as compared with those of 99 patients with transplants from donors younger than 60 years (mean age 47 years). There were no significant differences in the course of donor nephrectomy, postoperative complications, or remnant kidney function. However, delayed graft function occurred more frequently in recipients of transplants from older donors. Improvement in graft function was also slower in recipients of kidneys from older donors, with significant differences in serum creatinine levels observed during the first 12 months after transplantation. More frequent acute complications and more progressive chronic graft failure, irrespective of the causes, occurred during the 1st post-transplant year in recipients with grafts from older donors. Five-year patient survival (77% vs 92%) and kidney graft survival differed significantly for the same period with worse results for patients receiving grafts from older donors. It may be concluded that kidney grafts from donors older than 60 years -- and especially those older than 70 years -- may be used for living related kidney transplantation, but with precautions.

[Kidney transplantation in Bombay]. / Transplantacije bubrega u Bombaju.

The paper presents results of renal transplantation from a living unrelated donor in Bombay. Within the past three years 15 patients reported themselves at our Clinic immediately upon renal transplantation from a living unrelated donor, 7 of whom were women and 8 men, 17 to 52 years of age. There were no data on previous pretransplantation processing for the majority of patients, and treatment by repeated hemodialyses in 46.7% of patients lasted less than a year, which increased the risk of transplantation. On admission at our clinic, nine patients had satisfactory renal function, four patients moderate insufficiency and two advanced insufficiency. The most frequent complications occurring in these patients were various forms of infections. A three-year follow-up of these patients showed at the results of renal transplantation in Bombay were unsatisfactory, and the survival rate of the patients and the graft was far too worse that the one in Europe, that is at our Centre.