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Background: Kidney transplantation represents the method of choice of end stage renal disease., Methods and Results: The program of kidney transplantation was established in 1966 in our centre. In recent years, roughly 200 patients have undergone kidney transplantation annually, and 20-30 of them have received a graft from the living donor. Triple immunosuppressive regimen based on tacrolimus, MMF and steroids is given to majority of patients, in a case of high rejection risk; patients have received the induction protocols with polyclonal or monoclonal antilymphocyte globulins. Acute rejection is not a frequent finding in recent years and has occurred in 15% of cases in the first 3 months, the use of induction immunosuppression has decreased the rejection risk. Valgancyclovir has been used as prophylactic agent to prevent and treat cytomegalovirus infection. The usage of this strategy reduced the incidence of CMV infection below 10%. Kidney transplant recipients suffer from similar comorbidities as other renal patients in the long term, as cardiovascular complications, infections and malignancies. Anemia is a frequent complication in patients with graft dysfunction and erythropoesis stimulating agents have been used in its therapy. The median kidney graft survival is 8 years., Conclusions: Kidney transplantation is associated with better long-term results when compared with dialysis therapy and thus this method should be offered to all of suitable end stage renal disease patients.

Background/aims: Protocol biopsies offer new possibilities to predict kidney allograft outcome. The aim of this study was to find clinical, laboratory, morphological and molecular predictors of short-term renal graft survival., Methods: Three-month protocol kidney graft biopsy was carried out on 257 patients. The real-time RT-PCR was used to identify intragraft mRNA expression of several cytokines and chemokines and predictive statistics was performed to find markers connected with the risk of premature graft failure., Results: Compared to patients with normal morphology at 3 months, patients with subclinical rejection including borderline changes had experienced more frequent (p < 0.001) acute rejections before 3-month biopsy, serum creatinine >or=170 micromol/l (p < 0.01), and higher intrarenal expression of RANTES, IP-10 (p < 0.001), C3, CD3, IgJ (p < 0.01) and CD20 (p < 0.05). There was a significant correlation between subclinical rejection and the occurrence of late acute rejection and graft failure at the first year after transplantation. Moreover, higher RANTES and IP-10 expressions in subclinical rejection predicted graft loss at one year after transplantation in the univariate analysis., Conclusions: Patients with subclinical rejection including borderline changes in 3-month biopsy and particularly those with higher intrarenal expression of RANTES and IP-10 mRNA were found to be at risk for premature kidney graft loss., (Copyright 2010 S. Karger AG, Basel.)

Objectives: Rage (receptor for advanced glycation end products) is involved in pathogenesis of many diseases. The aim of the study was to test whether polymorphisms of RAGE gene are associated with the outcome of kidney transplantation., Design and Methods: Four polymorphisms of the RAGE gene (-429T/C, -374T/A, Gly82Ser and 2184A/G) were assessed in 145 renal transplant recipients and their relationship to histological changes in 12 months protocol kidney graft biopsy and renal function was examined., Results: Genotype frequencies of each polymorphism corresponded to expected frequencies according to Hardy-Weinberg equilibrium. No differences between allelic and genotype frequencies among patients with normal histological findings, chronic allograft nephropathy and subclinical rejection were observed., Conclusion: This is the first study on polymorphisms of the RAGE gene in patients with the transplanted kidney. No association of RAGE selected gene polymorphisms with 12-months outcome of renal transplants was shown in study.

Aim: The primary aim of the study was detection of subclinical acute rejection and borderline changes in protocol biopsies at 3 months after transplantation, and assessment of possible clinical and laboratory associations., Methods: Biopsy was carried out in 194 patients with stabilized graft function. Patients were treated with immunosuppressive regimen based on cyclosporine A (n = 34), tacrolimus (n = 152), or sirolimus/everolimus (n = 10). Samples were processed by standard paraffine technique, and stained according to laboratory protocol. All samples were tested by immunofluorescence or immunohistochemical procedures for C4d presence as a sign of humoral rejection., Results: Of 192 representative samples, subclinical acute rejection and borderline changes were found in 24 samples (12.5%). In patients with this finding, the mean serum creatinine was significantly higher (185.2 +/- 2.2 micromol/L), than in patients with normal finding (128.2 +/- 28.3 micromol/L) p < 0.001. Using the ROC curve analysis of serum creatinine, the cut-off point 170 micromol/L was found to discriminate normal findings from subclinical rejection and borderline changes. A significant correlation between acute rejections before protocol biopsy and subclinical acute rejections together with borderline changes in protocol biopsy was found. C4d positivity was found in 6 samples. Immunosuppressive therapy (cyclosporine versus tacrolimus) did not have any impact on subclinical acute rejections and borderline changes prevalence., Conclusions: The main conclusion of this study is a finding, that acute rejection early after renal transplantation and serum creatinine > or = 170 micromol/l at three months after transplantation are risks for development of subclinical acute rejection, even of humoral type, or borderline changes.

Transforming growth factor (TGF)-beta1 is a key profibrogenic cytokine associated with the pathogenesis of chronic allograft nephropathy (CAN). The primary aim of this study was to evaluate TGF-beta1 expression in protocol kidney graft biopsy in patients treated with different immunosuppressive regimens. Protocol kidney graft biopsies were carried out in 77 patients with stable graft function at 1 year after kidney transplantation, treated with a triple-drug regimen based on cyclosporin A (CyA; n = 49) or tacrolimus (TAC; n = 28). Morphological findings were assessed using the Banff 97 classification. TGF-beta1 expression was analysed using immunochemistry, and semiquantitatively scored in different renal structures (total score 0-18). Clinical data were analysed at the time of biopsy, and 12 months thereafter. No significant relation was found between the used immunosuppressive regimen and the histomorphological picture in the graft. TGF-beta1 expression within graft tissue was significantly higher in patients treated with CyA when compared with TAC (9.94 +/- 4.2 vs. 5.0 +/- 3.2; P < 0.001). Serum creatinine and glomerular filtration rate (GFR; Cockroft-Gault calculation) were comparable in both groups but, in the course of the next 12 months, GFR significantly decreased only in the CyA-treated group (from 1.03 +/- 0.33 to 0.96 +/- 0.37 ml/s) while not changing in the TAC-treated group. Patients treated with TAC had significantly lower diastolic blood pressure and serum cholesterol. The significantly lower TGF-beta1 expression in 1-year protocol kidney graft biopsy in TAC-treated patients with stable renal function, and the different development of graft function in both groups suggest a possible benefit of TAC for long-term graft acceptance.

Objectives: The aim of this study was to evaluate the role of genetic polymorphisms on the development of chronic allograft nephropathy (CAN)., Design and Methods: Using the polymerase chain reaction (PCR), polymorphisms of methylenetetrahydrofolate reductase (MTHFR C677T), interleukin-6 (IL-6 G-174C) and CD14 (C-260T) were evaluated in 92 kidney transplant recipients with stable renal graft function and no signs of acute rejection in a protocol that included graft biopsy at 12 months after kidney transplantation. A normal population sample (n = 365) was also included. Multivariate analysis was used to evaluate the effect of different variables on the CAN appearance., Results: There were no differences in alleles and genotypes distribution between transplant group and normal population sample. The CAN+ group (n = 69) significantly differed from CAN- (n = 23) in both MTHFR (P < 0.05) and IL-6 (P < 0.01) genotype distribution. Using logistic regression multivariate analysis, MTHFR T677 allele (OR: 3.91, CI: 1.11-13.8; P < 0.05), patient age (OR: 0.94, CI: 0.88-0.98; P < 0.01) and proteinuria (OR: 3.63, CI: 1.25-10.6; P < 0.05) were associated with CAN. Although the IL-6 G-174 allele was shown to be associated with CAN development in univariate analysis (P < 0.01), the multivariate analysis did not show an association. There was no relation between CD14 gene polymorphism and CAN., Conclusion: The MTHFR T677 allele is associated with the presence of CAN in kidney graft biopsies 12 months after transplantation.

Background: The aim of protocol biopsy after renal transplantation was to assess the prevalence of chronic allograft nephropathy (CTN) and to correlate the degree of CTN with clinical and laboratory data., Methods and Results: In 105 patients with a stabilized graft function, a protocol biopsy was carried out at 1 year after transplantation. CAN was found in 75% of patients, and in 6% an acute subclinical rejection was revealed. Statistically significant correlation was confirmed between CAN and recipient's age, development of acute rejection in the first year posttransplant, serum creatinine, clearance of creatinine, and proteinuria. There was no significant difference in CAN degree distribution between patients treated with cyclosporine-A or with tacrolimus. Twelve months after the biopsy, there was no significant change in kidney graft function. In patients treated with tacrolimus, cholesterol and triglycerides levels were significantly lower than in cyclosporine treated patients Over the next year, these values significantly decreased in both subgroups., Conclusions: The CAN was found in the majority of protocol biopsies at 1 year after kidney transplantation; subclinical acute rejection was revealed rarely.

Chronic allograft nephropathy (CAN) represents a frequent and irreversible cause of long-term renal graft loss. TGF-beta1 is a key profibrogenic cytokine associated with CAN pathogenesis. Because of clinical diagnostic inaccuracy, protocol biopsy has been suggested to be a beneficial method for early CAN detection. Protocol core biopsy was carried out in 67 consecutive cyclosporine-based immunosuppression-treated kidney transplant recipients with stable renal function 12 months after renal transplantation. Biopsy specimens were analyzed morphologically according to Banff-97' criteria and immunohistologically for TGF-beta1 staining. The data obtained were correlated with plasma TGF-beta1 levels and clinical data. CAN (grade I-III) was found in 51 patients (76 %). CAN grade I was found to be the most frequent one (44 %). A normal finding within the graft was made in only 12 patients (18 %). Clinically silent acute rejection Banff IA was present in 4 patients (6 %). In 8 patients (12 %) with CAN, borderline changes were present. We found a significant correlation between CAN grade and creatinine clearance, as measured by the Cockroft-Gault formula (p<0.01) as well as body mass index (p<0.01). There was a significant correlation between chronic vasculopathy (Banff cv) and creatinine clearance, and between the degree of TGF-beta1 staining and chronic vasculopathy (p<0.01). There were no relations between morphological findings and TGF-beta1 plasma levels, cyclosporine levels, plasma lipids, HLA-mismatches, panel reactive antibodies (PRA), proteinuria, and the donor's age. In conclusion, CAN is a frequent finding in protocol kidney graft biopsies 12 months after transplantation. TGF-beta1 tissue expression is linked with chronic vasculopathy.

This was a multi-center, open-label, randomized, dose-comparative study on 202 renal transplantation patients. We evaluated for the first time an alternative dosing regimen for basiliximab, consisting of a single 40-mg intravenous dose on day 1 post-transplantation plus triple therapy, in comparison with the conventional two-dose regimen (2 h before transplantation and on day 4) plus triple therapy. At 6 months, the incidence of acute rejection was low: 22.5% of patients in the basiliximab 2 x 20-mg group and 20.0% of patients in the basiliximab 1 x 40-mg group experienced an acute rejection episode ( P = 0.628) (biopsy-proven rejection: 19.6% and 17.0%, P = 0.585). There was no statistically significant difference in any of the secondary efficacy parameters. The incidence of graft loss by 12 months was 4.9% and 6.0% in the 2 x 20-mg and 1 x 40-mg group, respectively ( P = 0.73). No differences were observed between the dosage groups with regards to safety assessments (adverse events (AEs), infections, vital signs, laboratory safety evaluations, and physical examinations). The data reveal that basiliximab can be safely and effectively administered as a single 40-mg dose on day 1 after renal transplantation as a therapeutic option to the established 2 x 20-mg dosing regimen. This alternative dosing regimen may be of significant convenience under circumstances when a first dose of basiliximab was not given prior to transplantation. Both regimens can conveniently be used during the initial hospitalization of the patient.

Transformation growth factor (TGF-beta) is a cytokine, which takes part in many clinical conditions linked to different chronic disease states. Its production is regulated by genes and polymorphism of TGF-beta gene individually predetermines levels of its production. TGF-beta is produced by a number of normal, predominately haemopoietic and tissue cells. Moreover, it controls cell proliferation and differentiation, and namely it stimulates fibrogenesis. Profibrogenic efficacy plays a physiological role in wound healing and it is implicated in a spectrum of disease states, such as diabetic nephropathy, chronic glomerulonepthritis, lung fibrosis, or postirradiation fibrosis. In kidney transplant recipients. TGF-beta has been suggested to be involved in the chronic rejection pathogenesis by enhancing fibrogenesis.

Background: The role of nitric oxide (NO) after the cadaveric kidney transplantation has not been fully clarified yet. The aim of our study was to examine benefits of the administration of a NO precursor--L-arginine in the model of renal ischaemia and after the subsequent cyclosporine (CsA) treatment, which simulates the state resulting from the kidney transplantation., Methods and Results: 60 male rats of the Wistar strain were exposed to ischaemia for 45 minutes. Then they were divided into six groups: 1. Controls, 2. Rats administered by gastric sonde with 300 mg/kg of L-arginine since the first day after ischaemia, 3. Rats administered in a similar way with 10 mg/kg of cyclosporine A, 4. Group of rats receiving both drugs in the same doses, 5. Rats receiving 10 mg/kg of cyclosporine A since the first day after ischaemia and L-arginine in the dose 300 mg/kg since the seventh day, 6. Group of animals administered with L-arginine and cyclosporin A in the same doses with nonselective blocker of NO synthesis--L-NNA in the dose of 5 mg/kg. We examined renal functions (blood and urine levels of creatinine, urea, Na, K, Cl, osmolality, proteinuria), blood and urine levels of NO metabolites (NO2- and NO3-) in the fourth week after ischaemia. We found that L-arginine administration (when groups 1 and 2 were compared) decreased S-creatinine (< 0.05), it increased U-osmolality (p < 0.01), tubular resorption (p < 0.001), and blood levels of NO metabolites (p < 0.05). Changes in urine levels of NO metabolites (U-NOx/U-Cr) and in proteinuria were not found. In animals with renal ischaemia treated with cyclosporine (comparison of groups 3 and 4), L-arginine administration brought about a decrease of blood creatinine levels (p < 0.05), higher creatinine clearance (p < 0.05) and higher blood levels of NO metabolites (S-NOx; p < 0.01). However, differences in tubular functions, proteinuria and U-NOx/U-Cr were not detected. When L-arginine was added 7 days after the beginning of cyclosporine treatment, no significant difference was found between groups 5 and 3 and differences between groups 5 and 4 were similar to those between groups 4 and 3. Animals of the group 6 were not tested due to high mortality indicating high toxicity of the combination ischaemia + cyclosporine + L-arginine + L-NNA., Conclusion: Our study shows the benefits of L-arginine treatment in the renal ischaemia and during cyclosporine administration. The treatment should start immediately after the ischaemic period and at the same time as the cyclosporine administration. L-arginine added later has no positive effect.

Background: The role of nitric oxide (NO) after cadaveric renal graft transplantation has not been yet fully clarified. The aim of our study was to examine NO production into the urine of patients following cadaveric renal graft transplantation with a normal course and complications (acute rejection and cyclosporin toxicity)., Methods and Results: Production of stabile NO metabolites (NO2 and NO3) into urine (U-NOx) was examined in recipients of cadaveric renal transplantation. Only patients with standard triple immunosuppressive therapy (cyclosporin, azathioprine, prednisone) were include into the study. Patients receiving other immunosuppressive agents or drugs affecting NO formation (nitrates, ACE inhibitors) were excluded from the study, as were those with infectious or other serious post-transplant complications. Overall, we examined 33 patients (21 men and 12 women), with acute rejection and cyclosporin-induced toxicity in ten each, and a normal course with no complications in 13. The mean age of the patients was 50.96&#95;11.13 years. U-NOx was examined by biochemistry using Griesse reaction every day after transplantation both in a morning urine sample and in a sample from 24-hour collection over the preceding day and calculated to 1 mmol/l of urinary creatinine (U-Cr). The levels of U-NOx/U-Cr in patients with acute rejection over the past 2 days before its development were lower compared with those in patients with a normal course (p&#95;0.05). No difference was found between the groups of patients with cyclosporin-induced toxicity and a normal course. The levels of U-NOx were inversely correlated (p&#95;0.01) to the levels of serum creatinine (S-Cr), but did not correlate with the blood levels of cyclosporin A., Conclusions: The study demonstrated a decrease in urinary U-NOx production within the past 2 days before renal transplant rejection. The levels of U-NOx in patients with cyclosporin-induced toxicity remain unaltered. U-NOx/U-Cr could possibly become a non-invasive marker of rejection.

Chronic rejection represents the most common cause of transplanted graft loss in the long term. Rapamycin (sirolimus), and it's derivate RAD, are new and potent, immunosuppressive drugs. They inhibit cell proliferation driven by various growth factors. These drugs were successfully tested in some experimental models of the chronic rejection. Results of the first clinical trials have defined rapamycin pharmacokinetics and proved immunosuppressive efficacy. Rapamycin acts synergistically with cyclosporin A. The side effects are a dose-dependent thrombocytopenia and leukopenia but the most frequent is hyperlipidemia. The question, if rapamycin and RAD inhibit development of chronic rejection in man, will be solved by the prospective clinical trials over years.

Chronic rejection represents an important cause of renal allograft loss in the long term follow up. New insights into etiopathogenesis of the chronic rejection offer possibilities for experimental therapy. Novel immunosuppressants, such as mycophenolic acid, tacrolimus or rapamycin as well as lipid lowering drugs, angiotensin-converting enzyme inhibitors or AT-1 receptor blockers, may reduce of effects the risk factors on the progression of chronic rejection. In the future, gene therapy may offer additional possibilities to prevent chronic rejection. This review deals with possibilities of prevention of the chronic renal allograft rejection based on experimental evidences and current therapeutic concepts and puts these options into a rational perspective.

The last decade has witnessed an expansion of the arsenal of new immunosuppressive agents to include several novel drugs and antibodies. The main indication of all these immunosuppressive agents is organ transplantation. In terms of its action, tacrolimus resembles cyclosporin A and is employed as the mainstay immunosuppressant or for what is referred to as rescue therapy in refractory rejection. Mycophenolate mofetil is an anti-metabolite replacing azathioprine in immunosuppressive protocols. Sirolimus is an agent for prophylactic use, either as part of a cyclosporin-based regimen to enhance the effect of cyclosporin or as an alternative of non-nephrotoxic immunosuppression to cyclosporin-based regimens; its indications are still being specified. Gusperimus could be used for anti-rejection therapy; however, it is not being used in this country as yet. Recently, two monoclonal antibodies against the IL-2 receptor, chimeric basiliximab and humanized daclizumab, have been employed. Both agents are of non-depletion type and are indicated for induction therapy in the early post-transplant period.

Background: Triple-drug immunosuppression may not be necessary in a majority of stabilized patients over 1 year after kidney transplantation. In contrary steroid withdrawal may be beneficial for the patient by elimination of side-effects. The primary aim of this study was assessment of the risk of rejection after the prednisone withdrawal., Methods and Results: 88 patients 1 year after the first renal transplantation with stable graft function and serum creatinine < 160 mumol/l treated with cyclosporine-A, azathioprine and prednisone were randomized into group A (n = 46) with a prednisone withdrawal and group B (n = 42) on triple-drug therapy without change. At the time of randomization, fine-needle biopsy was carried out in all of the patients. In group A, the dose of prednisone was gradually reduced to zero in the course of six months and the patients were followed up for the next 12 months. In the group B, patients on triple-drug therapy were followed for the corresponding period of time. 3 patients (6.6%) in group A, and 2 (4.8%) in group B experienced rejection (NS). Mean values of serum creatinine were in the course of follow-up in both groups without any statistical difference. Suspect immunological activity or proved immunological activity in aspiration biopsy was present in 4 patients in each group, but one of them rejected the graft. In comparison with group B, a significant decrease of cholesterol and leukocytes was observed in group A. Prednisone withdrawal had no influence on hypertension and triglyceride., Conclusions: Gradual withdrawal of steroids is not associated with higher risks of rejection and has a beneficial effect on cholesterol levels. Aspiration biopsy was of no use for the prediction of rejection.

Chronic rejection is the most common cause of the long term renal graft loss. It is characterized by luminal thickening and obliteration, interstitial sclerosis, glomerulosclerosis and tubular atrophy development. The pathology is still unclear. Alloantigen-dependent factors (acute rejection, HLA mismatch) and allograft-independent factors (ischaemia-reperfusion, hyperlipidaemia, hypertension, infection, nephrotoxicity, reduced nephron dose) have been implicated in the etiology of chronic rejection. As a result of these factors, endothelial cells are activated and express a variety of adhesion molecules, cytokines and growth factors. Lymphocytes and macrophages infiltrate the areas of local damage and express other cytokines and growth factors (TGF, bFGF, PDGF). In the next step, vascular smooth muscle cells proliferate and migrate from the media into the vascular intima and produce local extracellular matrix. Which factors are the most important and which mechanisms are the key for the development of chronic rejection are in the focus of ongoing research.

In a group of patients after transplantation of the kidney with stabilized graft function treated by Consupren sol. combined with prednisone and azathioprin in 20 patients (group A) Consupren sol. was replaced by Consupren S capsules, in 17 patients (group B) Consupren sol. therapy proceeded without any change. To maintain the cyclosporin blood concentration within the therapeutic range it was necessary after the change of drug form in group A to adjust the dosage of the drug in 12 patients of group A while in group B only in one patient (p<0.01). The mean doses and levels of Cy-A however did not change significantly during the three-month investigation period in the two groups and and the bioequivalence of the two preparations was evident. Conversion from Consupren sol. to Consupren S capsules is not associated with the risk of rejection or undesirable effects. It can be implemented at a ratio of 1:1 or 1: the closest dose divisible by 25 (the smallest capsules are 25 mg) and after conversion a check-up or possible modification of the dose is necessary.

The objective of the paper is to draw attention to a rare cause of rapidly progressing renal failure which developed in the course of four months as a result of light chain deposition disease. The authors submit two case-histories of the disease assessed by renal biopsy after previous clinical and laboratory suspicion of monoclonal gammapathy. In one patient in the sternal punctate plasmacytoma was diagnosed and in the second case it was not possible to detect any type of monoclonal gammapathy or another possible cause of disease. Renal failure was in both cases irreversible and both patients were enlisted in regular haemodialyzation treatment.

Background: The objective of the study was an analysis of results of repeated kidney transplantations (Tx2, Tx3) implemented during the first 29 years of activities of the Transplantation Centre of the Institute of the Clinical and Experimental Medicine in subjects with a different maintenance immunosuppression., Methods and Results: The retrospective study pertains to 134 Tx2 and 17 Tx3 in 134 non-diabetic subjects: 43 of them had during Tx1 and Tx2 (1966-1981 and 1966-1985 resp.) immunosuppression on the basis of azathioprin (Aza, sub-group AA), 42 during Tx1 (1972-85), Aza, while during Tx2 (1984-85) immunosuppression on the basis of cyclosporin (CyA, subgroup AC) and 49 both during Tx1 and Tx2 (1985-93 and 1986-95 resp.) CyA (subgroup CC). Compared was survival of grafts by the actuarial method (with regard to all losses regardless of cause) by the end of the 4th year inside the subgroups (Tx2, vs. Tx1 and Tx3 vs. Tx2 in the same subjects) and between subgroups (Tx1 vs. Tx1 and Tx2 vs. Tx2 in different subjects). Moreover in paired investigations the survival of recipients and grafts after Tx2 was compared after immunosuppression on the basis of CyA with the same parameters after Tx1 in different subjects with the same immunosuppression, operated at approximately the same time (n = 81) and survival of subjects with Tx1 + Tx2 on the CC regime regardless whether the second grafts functioned at the time of the last examination, with survival of subjects after Tx1 where after graft failure Tx2 was not performed (n = 34). Prophylaxis with antilymphocyte globulins was not used. Survival of second and first grafts did not differ in any of the subgroups, third grafts survived at the end of the third year more frequently than second grafts (66 vs. 18%, p < 0.01). Second grafts in CC survived more than in AA (55 vs. 28%, p < 0.01). In the paired study Tx2 vs. Tx1 the survival of grafts and recipients was the same (88 vs. 89%, N.S. and 47 vs. 62% resp.), in the paired study Tx1 + Tx2 vs. Tx1 more subjects with Tx1 + Tx2 survived 10 years after Tx1 than subjects who did not have Tx2 (82 vs. 49%, p < 0.05)., Conclusions: A further transplantation of the kidney after functional loss of the first graft is the method of choice: the mortality is low, the probability of several years' function is considerable and the prognosis as regards quality and length of life better than with regular dialysis treatment.

Background: Long-term follow-up of the glomerular filtration rate (GFR) in subjects with a transplanted kidney revealed that changes of this function in the course of time are frequently irregular and cannot be expressed by a simple mathematical function. This fact causes problems when evaluating the rate of progression of chronic transplant nephropathy. Characterization of changes of the GFR of the graft by values of this function at the beginning and at the end of the follow-up period does not take into account transient changes and the predominating level of GFR during the entire follow-up period. The authors tried to elaborate a method which would render it possible to evaluate in a simple manner the level of the GFR during the entire investigation period. The method is based on assessment of the area under the curve (AUC) of GFR., Methods and Results: This method was used to investigate the time course of GFR in 22 subjects after transplantation of the kidney from a cadaverous donor. The investigated group included nine women and 13 men aged 30-65 years (mean 50 years). The time interval after transplantation was 1-84 months (mean 22 months). The GFR was assessed after 3-months intervals for a period of 9-21 months (mean 13.5 months). GFR was assessed on the basis of renal clearance of polyfructosan. The time course and level of GFR was evaluated in the common way based on GFR values at the beginning and end of the investigation period and according to the new method based on calculation of AUC. It was found that the two methods of evaluation of graft function do not provide the same results. In one third of the examined subjects the differences were higher than 20%., Conclusions: The results of this study provide evidence that evaluation of changes and the level of the GFR of the graft throughout the follow-up period based on AUC provides more detailed information then evaluation of the GFR only at the beginning and end of the follow-up period. The authors assume that this method of evaluation of the GFR of the graft could be helpful in a more accurate assessment of the effect of different therapeutic procedures.

From previous work it is known that in subjects with a transplanted kidney treated with cyclosporin A hyperkalaemia may develop even if the glomerular filtration rate is within the normal range or only slightly reduced. The mechanism of this defect was not elucidated so far. In the present work the authors try to study the question whether and how renal potassium excretion by the transplanted kidney is influenced by the intensity of sodium excretion. Focused on renal excretion of potassium, sodium, chlorides, all osmotically active substances, glomerular filtration rate (polyfructosan clearance) and renal plasma flow (paraaminohippuric acid clearance) the authors examined 12 patients after transplantation of the kidney from a cadaverous donor (group A), 11 subjects after unilateral nephrectomy for the purpose of donorship for transplantation (group B) and 27 subjects after nephrectomy on account of a pathological process in one kidney (group C). The glomerular filtration rate in the investigated groups was greater than 1.0 ml/s/1.73 m2. The mean value of the fractional potassium excretion (FEK) in group A was 15.2 (+/- 6.3)%, in group B 18.4 (+/- 6.6)% and in group C 20.1 (+/- 8.6)%. The value of FEK in group A was significantly lower than in group C (p < 0.01). Groups B and C did not differ significantly in the mean value of FEK. Between values of FEK and FENA a significant direct correlation was found (r = 0.621, p < 0.001) in the group of subjects with a single kidney of their own (B + C). On the other hand, this correlation was not found in subjects with a transplanted kidney (A). The achieved results support the idea that in subjects with a transplanted kidney treated with cyclosporin A there are deviations in tubular potassium transport even when its serum level is not elevated. This deviation is manifested by lower FEK values and also by and inadequate response of the distal tubule to an increased sodium supply by increased tubular potassium secretion. The authors assume that when drugs with a potential potassium retaining effect are administered to subjects with a transplanted kidney it is important to check carefully the serum potassium level even when the glomerular filtration rate is within normal limits or only slightly reduced.

The authors describe the case of a 66-year-old female patient after transplantation of the kidney where a rare complication of immunosuppressive treatment was diagnosed--progressive multifocal leukoencephalopathy. The disease was manifested by gradually developing hemiparesis of the lower extremity five months after transplantation. Examination of the brain by computed tomography and examination of cerebrospinal fluid were normal. Subsequently the neurological finding developed into quadruparesis. Imaging of the brain by magnetic resonance revealed multiple demyelinization foci. In brain biopsy there were typical structures of progressive multifocal leukoencephalopathy and positive hybridization in situ for JC-virus in cell nuclei. Immunosuppressive treatment was restricted and ganciclovirus administration was started. Further progression of the clinical symptomatology ceased, the function of the transplanted kidney remained satisfactory. The patient died 14 months after the transplantation from sepsis. Examination of the post-mortem material revealed positivity of the JC-virus only in the cytoplasm of the affected cells. As effective treatment of infection with JC-virus is not known so far, the possible action of ganciclovirus is only speculative.

Secondary hyperlipidaemia (HLP) is one of the most serious metabolic complications in patients after transplantations of the kidney. In its development a number of factors may participate, the most important ones being immunosuppressive drugs (cyclosporin A and prednisone) and the patients dietary habits. In a prospective metabolic trial a group of 248 patients after transplantation of the kidney with a long-term stable function of the graft were followed up for 12 months. Group I (128 patients) was systematically followed up in the Institute of Clinical and Experimental Medicine and the patients were treated by individualized dietetic and pharmacological intervention. Group II (120 patients) were out-patients who were treated according to current procedures in other departments than the Institute of Clinical and Experimental Medicine. The cholesterol and LDL-cholesterol increased significantly in both groups starting with the 3rd month of the follow-up. A subsequent decline was observed in group I from the 9th month onward, while in group II both values rose steadily. The triacylglycerol level rose in both groups during the 6th month, there were however great interindividual differences. There was a significant rise of the HDL-cholesterol. The Lp(a) level changed also significantly--its values--after an initial drop during the 3rd month--rose significantly in group II.

The differences in glomerular filtration rate (GFR) based on creatinine clearance (Ccr) or obtained by the more exact methods are caused mainly by tubular creatinine secretion. In this study, we monitored creatinine clearance (Ccr), GFR on the basis of polyfructosan renal clearance (C(PF)) and parameters characterizing tubular creatinine secretion (Ccr/C(PF), Ccr - C(PF), Tcr/C(PF) x 100) in 12 individuals with renal grafts (Group A), 12 kidney graft donors for related transplantation (Group B), and in 27 individuals undergoing nephrectomy for a pathological process in one kidney (Group C). In the monitored groups, C(PF) and Ccr values were within the limits consistent with the normal function of a single kidney in a healthy individual. The values characterizing tubular creatinine secretion in Group A did not differ significantly from those obtained in Groups B and C. However, the parameters showed a wide range in all groups. In seven individuals with a renal graft, all the above functional parameters were monitored at three-month intervals for a period of 24 months. Significant differences in the time courses of Ccr and C(PF) due to marked intra-individual fluctuations were found in tubular creatinine secretion. The findings suggest that the rate of tubular creatinine secretion in the renal graft does not differ significantly from that in individuals with a single native (normally functioning) kidney. However, there are large inter-individual differences. The large intra-individual fluctuations in tubular creatinine secretion in the kidney graft result in significant differences in the time courses of Ccr and C(PF) and a possibility of erroneous evaluation of graft function if based exclusively on Ccr.

The authors compared in a controlled clinical study two groups of patients after a first renal transplantation treated by triple drug immunosuppressive therapy. In a group of 31 patients the triple combination comprised Sandimmune Neoral. In the control group there were 30 patients who received Sandimmune. No differences were found between the two groups as regards the effectiveness of this treatment and the authors did not confirm a lower incidence of rejections described in patients treated with Sandimmune Neoral. They confirmed, however, a lower interindividual variability of Cy-A levels assessed specifically in patients treated with Sandimmune Neoral.

In subjects with a transplanted kidney frequently tubular functions are impaired even when the glomerular filtration is within the normal range. In the present work the authors are dealing in more detail with the problem of tubular sodium reabsorption in the transplanted kidney. The purpose of the investigation was to assess to what extent these changes can be explained as the consequence of adaptational changes due to reduction of the number of nephrons and whether these changes have to be taken into consideration in the differential diagnosis of acute changes of graft function. The glomerular filtration rate (GF) was assessed on the basis of polyfructosan clearance, fractional sodium and potassium excretion (FENa and FEK) in a group of 12 subjects with a stabilized function of a transplanted kidney (group A), in 11 subjects after nephrectomy in healthy donors for transplantation (group B) and in 27 subjects after nephrectomy indicated for a pathological process in one kidney (group C). The mean values of GFR were as follows: Group A: 1.21 (+/- 0.19)ml/s/1.73 sq.m Group B: 1.19 (+/- 0.17)ml/s/1.73 sq.m Group C: 1.24 (+/- 0.21)ml/s/1.73 sq.m The mean values of GFR in different groups did not differ significantly. The mean values of FENa in different groups were as follows: Group A: 3.02 (+/- 1.59)% Group B: 2.05 (+/- 0.77)% Group C: 2.01 (+/- 1.17)% The mean value of FENa in group A was significantly higher than the mean value in group B (p < 0.01) and in group C (p < 0.01). The assembled findings support the idea that reduced tubular sodium reabsorption in the transplanted kidney (with a stabilized value of GFR) cannot be explained only as a manifestation of adaptation of tubular function as a result of the reduced number of functioning nephrons. The persisting osmotic sodium diuresis in the transplanted kidney must be viewed from the aspect of possibly impaired water preservation and the development of dehydration associated with a drop of GFR and must be differentiated from rejection.

Background: The second part of the study was designed to assess Consupren side effects., Methods and Results: The groups of patients studied were described in Part I. Side affects typical of Cy-A were evaluated only in the CS group. Gastrointestinal intolerance, only mild and temporary, was observed in 31%, neurotoxicity in 44%, hypertrichosis in 37%, nephrotoxicity in 25%, and gingival hypertrophy in 19%. Mean values of systolic and diastolic blood pressure did not change significantly in the course of treatment. When changes in blood pressure were individually investigated in particular patients, they were found in 31% in the CS group and in none in the K group. Mean values of uric acid non-significantly increased in the CS group and, on individual investigation, hyperuricaemia was observed in 31%. Mean values of serum potassium did not alter significantly. Signs of possible hepatotoxicity were found in 37% patients of the CS group. In this group, there was a significant decrease in haemoglobin mean values and a decrease in haemoglobin of more than 25 g/l was observed in 44% of CS group patients. In the K group significant decrease in mean leukocyte count was noted, but no patient developed real leukopenia., Conclusions: The occurrence of side effects was comparable to data known from the literature.

Background: Withdrawal of cyclosporin-A from maintenance immunosuppressive therapy involves risk of rejection. The aim of the study was to reduce the risk of rejection and to evaluate the fine-needle aspiration biopsy in predicting rejection., Methods and Results: In 41 patients 14.4 +/- 2.6 months after the first transplantation of a cadaveric graft with good and stabilized function, cyclosporine was withdrawn from triple-drug therapy while the doses of azathioprine and prednisone were increased. Prior to the change fine-needle aspiration biopsy (FNAB) was performed and methylprednisolone 500-250-250 mg administered in 3 days. FNAB was repeated after 2 weeks. 39 patients fulfilling inclusion criteria but ineligible for the switch for different reasons served as a control group. Both groups were comparable in demographic and immunological parameters. Within 3 months after conversion, rejection was observed in 3 patients (7%) vs 2 patients (5%) of the control group over a comparable period of time: and within 6 months in 6 patients (15%) and 3 patients (8%) respectively (NS). No relationship between rejections before and after conversion was found. FNAB appeared to have some predictive value for rejection. In all of the 3 patients experiencing rejection, a rejection pattern was present in the 2nd biopsy., Conclusions: Incorporation of methylprednisolone into conversion therapeutic regime decreased the risk of rejection to 7%. The rejection pattern in the second FNAB after methylprednisolone administration may be predictive for further rejection development.

Background: Experience gained from recent studies shows, that Cyclosporine-A (Cy-A) may decrease proteinuria (PU) in some forms of chronic glomerulonephritis (GN) with the nephrotic syndrome. The aim of this study was to test the efficacy of Czech-made Cy-A, Consupren., Methods and Results: 30 patients with chronic GN, confirmed by biopsy and PU higher than 3 g/d, corticodependent or corticoresistant, were randomized according to the month of birth to either therapy with Consupren at an initial dose of 5 mg/kg/d (CS group, after dropout of 3 patients who did not finish the treatment, n = 16) or Cyclophosphamide at a dose of 1.5 mg/kg/d (K group, n = 11), and prednisone maintained at the original dose in both groups. The treatment was stopped after six months or after achieving remission. The main criterion of efficacy was PU. The decrease in mean values, statistically evaluated by Holm's procedure was highly significant in the CS group and non-significant in the K group. A similar evaluation of PU corrected by glomerular filtration rate was significant in both groups. Partial or complete remission was reached in 50% of CS group patients and in 34% of K group patients (NS). In the CS group a significant increase in the mean values of albumin and gama-globulin, and a decrease in cholesterol levels were observed. In the K group, these changes were non-significant., Conclusions: In patients with chronic GN and the nephrotic syndrome, the efficacy of Consupren treatment gives comparable, or even better results versus treatment with Cyclophosphamide.

Background: For patients having regular haemodialysis there are no suitable complete preparations for general use in case intensive treatment is needed. Nutrilac renal is a new preparation of a nutritionally defined liquid diet corresponding as to its composition to the needs of haemodialyzed patients. The purpose of the present work was to assess whether this preparation when administered as a supplement will have a favourable effect on the nutritional parameters of haemodialyzed patients., Methods and Results: Nutrilac renal was administered to haemodialyzed patients for a period of three weeks as a supplement meeting 20% of the energy requirements. The protein intake rose from 0.87 to 0.95 g/kg body weight (p < 0.05), the energy intake from 109 to 126 kJ/kg body weight (p < 0.05). As to nutritional parameters, the serum albumin values improved (from 25.0 to 29.4 g/l, p < 0.05) and Whitehead's quotient from 1.8 to 1.5, p < 0.05). The favourable effect on the amino acid spectrum was manifested by a significant rise of essential amino acids and those with branched side chains (p < 0.01). The preparation did not lead to a rise of potassium, ura and vitamin A levels., Conclusions: The newly developed preparation Nutrilac renal exerts a favourable effect on nutritional parameters. Changes in the aminogram characterized by an increase of essential amino acids, in particular threonine, valine, leucine and isoleucine indicate the high biological value of the protein component of the preparation for patients with chronic renal failure.

Background: With maintenance azathioprine+prednisone and in biopsies performed exceptionally earlier than in the 4th week (1966-1984, 476 cadaveric kidney transplantations), prevalence of obliterative arteriopathy (OA, transmural arteritis, 4/III/v3 Banff classif.) was 22.1%, with graft loss by rejection within 6 mos. in 89.4%. The aim of this analysis was to study prevalence and prognostic importance of the former and of further early vascular lesions in subjects with maintenance cyclosporin A using biopsies performed as early as in the 1st week., Methods and Results: In a retrospective study on 449 transplantation (1987-92, cyclosporin A+prednisone+azathioprine, 64.7% grafts histologically--mostly repeatedly--examined), prevalence and prognostic classification (A-good, B-uncertain, C-poor prognosis) in recipients with OA, with cellular arteriopathy (CA, intimal arteritis, 4/II-III/v2-v3 Banff classif.) and with minimal arterial lesions (MZ) were assessed. Prevalence of OA was found to be 7.1% transplantations, with graft loss by rejection within 6 mos. in 71.9%, and with A:C proportion 25.0%: 62.5%. CA was found in 5.1% and showed A:C proportion 34.7%: 34.7%; in 6/13 cases with repeated histology, OA was later encountered, which is a strong point against its humoral pathogenesis. Prevalence of MZ was 10.9%, with A:C proportion 40.8: 4.1%., Conclusions: Both OA and CA are related to rejection, while the etiology of MZ remains to be clarified. With cyclosporine, prevalence of OA markedly decreased and its prognosis somewhat improved; secondary prevention is possible when an early diagnosis (early and repeated biopsies) is done and immediate treatment (antilymphocyte globulins) started.