[Papillary microcarcinoma of the thyroid and secondary hyperparathyroidism in a patient on hemodialysis]. / Papilarni mikrokarcinom stitaste zlezde i sekundarni hiperparatireoidizam kod bolesnika na hemodijalizi.

Association between non-medullary thyroid carcinoma and secondary hyperparathyroidism have been rarely reported in patients with renal failure. A few cases of micropapillary thyroid carcinoma have been reported in patients before and after renal transplantation. We present a case of incidental detection of thyroid carcinoma at the time of parathyroidectomy in patient on dialysis after cadaver renal transplantation.

[Peritoneal dialysis and kidney transplantation]. / Peritoneumska dijaliza i transplantacija bubrega.

The results of pretransplantation preparation of patients undergoing peritoneal dialysis program before the kidney transplantation at our clinic have been presented. Residual kidney function, and bladder function, respectively, as well as the incidence of the hepatotropic viruses B and C infections and cytotoxic antibodies percentage following blood transfusion have been particularly analyzed. Obtained results have been correlated with those found in 40 patients on hemodialysis and to whom kidneys were transplanted at our clinic. Satisfactory bladder function, the absence of urologic posttransplantation complications, non-existence of hepatotropic viral infections and cytotoxic antibodies resulted in an introduction of a new strategy based on the peritoneal dialysis as the first method of the dialysis treatment prior to kidney transplantation.

[Use of mycophenolate mofetil in kidney transplantation]. / Primena mikofenolat mofetila kod transplantacije bubrega.

Mycophenolate mofetil (MMF) is a new immunosuppressive agent for the prevention of renal allograft rejection. MMF is a prodrug of mycophenolic acid (MPA), a fermentation product of several Penicillium species of fungus. MPA acts at a late stage in T and B lymphocyte proliferation by selective, uncompetitive and reversible inhibition of inosine monophosphate dehydrogenase, a key enzyme in the de novo pathway of purine nucleotide synthesis. The three large studies individually and the combined (pooled) 1-year patient efficacy data have shown that MMF, given in combination with cyclosporine and corticosteroids, significantly reduces the incidence of acute rejection episodes (by 50%), without detectable difference in patient mortality. Analysis of secondary efficacy endpoints revealed that patients treated with MMF required less additional immunosuppressive therapy for treatment of acute rejection episodes and showed better renal function. In another studies, the efficacy of MMF in the treatment of first acute rejection episodes and in the treatment of refractory, acute, cellular renal transplant rejections has been shown. The principal adverse events associated with MMF administration included diarrhea, vomiting, leukopenia and a higher frequency of certain types of infections. The efficacy of MMF for the treatment of chronic allograft nephropathy is controversial. The ability of MMF to reduce the occurrence of acute rejection episodes and improve allograft function may have significant implications for promoting the long-term survival of renal allografts, but we need long-term observations to prove this benefit.

[Replacement of mycophenolate mofetil with azathioprine in patients with renal transplants]. / Zamena mikofenolat mofetila azatioprinom kod bolesnika sa presadjenim bubregom.

Numerous clinical studies demonstrated that mycophenolate mofetil (MMF) was significantly more effective in prevention of acute rejection episodes than azathioprine. Since the data supporting the long-term benefits of MMF therapy are not available, and considering the high cost of this therapy, we examined the safety of conversion from MMF to azathioprine in renal transplant patients. In 12 renal transplant patients (4 cadaveric and 8 living related donors) on triple immunosuppressive therapy (prednisone/MMF/cyclosporine) conversion from MMF to azathioprine was done after the first six to twelve post-transplant months. The majority of patients were in the low immunological risk of transplantation, and 7 (58.3%) received antithymocite globulin due to the delayed graft function. The mean follow-up period after the conversion to azathioprine was 6.4 months (range 3-12 months). Acute rejection episode was noticed only in one patient 8 months after the conversion following acute graft pyelonephritis. In all other patients graft function remained unchanged. We have concluded that the conversion from MMF to azathioprine in renal transplant patients on triple immunosuppressive therapy is safe and without detrimental effects on short-term allograft function. Long-term follow-up studies on larger number of patients are needed to confirm these observations.

Locally produced specific cytomegalovirus immunoglobulin for intramuscular use as a therapy in renal allograft recipients.

Immunomodulator, i.e. specific hyperimmune anticytomegalovirus immunoglobulin for intramuscular administration, produced in 1999 with the aim of prevention of CMVI, and the development of the disease, was for the first time applied in kidney transplant recipients in January 2000, in the Center for kidney transplantation at the Military Medical Academy. Therapy was administered in four cytomegalovirus (CMV)--seronegative kidney recipients from CMV-seropositive donors--the combination that in the majority of cases lead to the development of CMVI/disease resulting in transplant rejection. Patients received 0.2-0.3 ml/kg of cytomegalovirus immunoglobulin (CMVIG) 6 hours before the transplantation, and subsequently the same dose during the following 5 weeks. Simultaneously, they received ganciclovir in therapeutic doses adjusted according to creatine clearance during the first three post-transplantation months (2 weeks parenterally, the rest orally). Kidney transplant recipients tolerated well i.m. applied CMVIG without any adverse effects. Test result obtained from the Paul-Erlich Institute, Germany in 1999 spoke in favor of the quality of the first national CMVIG preparation.

[Use of mycophenolate mofetil in patients with a transplanted kidney and cyclosporin nephrotoxicity]. / Primena mikofenolat mofetila kod bolesnika sa presadjenim bubregom i ciklosporinskom nefrotoksicnoscu.

Cyclosporine (CsA) nephrotoxicity is an important problem in renal transplant recipients, which can influence long-term graft survival. The safety of conversion from CsA to azathioprine (AZA) remains controversial and can result in higher incidence of acute rejection. Mycophenolate mofetil (MMF) is a new immunosuppressive agent superior to AZA in the prevention of acute rejection. Five patients with cyclosporine nephrotoxicity were converted from CsA/AZA/prednisolon to MMF/prednisolon protocol. All patients had low immunological risk and 4 out of 5 patients received antithymocyte globulin before conversion as the induction therapy or as the treatment for acute rejection. Mean follow-up after conversion was 16.8 months (range 4-32 months). No patient experienced acute rejection during follow-up period. The mean serum creatinine concentration decreased from 219 +/- 44.18 (range 168-280) to 122.6 +/- 48.02 mumol/l (range 72-187 mumol/l) (p = 0.002). Arterial hypertension improved after CsA withdrawal in 20% of patients. We have concluded that, in selected patients with cyclosporine nephrotoxicity, CsA withdrawal with concomitant use of MMF is safe and effective in the improvement of graft function and arterial hypertension.

[Interleukin-1 beta in patients with primary immunocomplex glomerulonephritis]. / Interleukin-1 beta kod bolesnika sa primarnim imunokompleksnim glomerulonefritisom.

Interleukin-1 is one of the most important pro-inflammatory cytokines whose role in the pathogenesis of glomerulonephritic process was proved in numerous studies. The aim of this study was to determine the urinary level of this cytokine in patients with primary immunocomplex glomerulonephritis and its significance in diagnosis of this disease. This prospective study comprised a total of 96 patients (84 males and 12 females) with primary immunocomplex glomerulonephritis. The elevated urinary IL-1 beta level was noticed in 43 (49.4%) patients with different histological forms of glomerulonephritis. The mean concentration was significantly higher in patient's group (57.7 +/- 120.7 pg/mg creatinine) (range 1.1-731) compared to control group (10.2 +/- 5.96 pg/mg creatinine) (range 1.6-25.4) (p < 0.05). There was no significant difference in the frequency of elevated urinary IL-1 beta concentration in different patients group based on histological type of glomerulonephritis (chi 2 = 6.377, p > 0.05). On the basis of our results we concluded that the elevated concentration of IL-1 beta in majority of patients with primary immunocomplex glomerulonephritis had suggested its role in the pathogenesis of glomerulonephritic process. The urinary level of IL-1 beta represents a novel, non-invasive parameter in the diagnosis of this disease, but its measurement is not useful in predicting the histological type of primary immunocomplex glomerulonephritis. The results of our study suggest the possibility that urinary IL-1 beta level reflects the activity of glomerulonephritic process and it could be useful in non-invasive monitoring of the disease progression.

[Outcome of kidney transplantation in patients on peritoneal dialysis]. / Ishod transplantacije bubrega kod bolesnika na peritoneumskoj dijalizi.

The initial experience suggested that kidney transplantation could be hazardous for patients on peritoneal dialysis due to the high risk of peritonitis and a possible high incidence of acute rejection. In this paper we have presented our experience with kidney transplantation in these patients. During the last four years kidney transplantation was performed in 9 patients on peritoneal dialysis. The average time spent on peritoneal dialysis was 20.6 +/- 7.6 months. In all patients peritoneal catheter was removed during the surgery. During the posttransplantation period a triple immunosuppressive therapy including steroids, cyclosporin and azathioprineor mycophenolate mofetil was administered in all patients. In comparison to patients on hemodialysis no significant difference in the incidence of acute rejection episodes, delayed graft function, graft arterial thrombosis and graft function recovery was observed. Patients on peritoneal dialysis had significantly greater and longer wound drainage in comparison to patients on hemodialysis. It was concluded that peritoneal dialysis had no negative influence on short-term outcome of kidney transplantation.

[Importance of determining the absolute CD3+ lymphocyte count during induction therapy with antithymocyte globulin in kidney transplantation patients]. / Znacaj odredjivanja apsolutnog broja CD3+ limfocita tokom indukcione terapije antitimocitnim globulinom kod bolesnika sa transplantovanim bubregom.

Antithymocyte globulin (ATG) is successfully applied in prophylaxis and treatment of renal allograft rejection. However, it is an expensive mode of therapy, associated with increased risk of opportunistic infections and lymphoproliferative diseases. For this reason, monitoring of ATG immunosuppressive effects as well as individual dose adjustment represent an important therapeutic approach. Here we report our results of ATG dose titration according to total lymphocyte count (< 300/microliter) and absolute CD3+ count (< 50/microliter) in seven renal transplant patients. Monitoring of absolute CD3+ count enabled reduction of the mean daily dose from the recommended dosage in all patients. Our results have also shown that the absolute CD3+ count is a more reliable parameter than the total lymphocyte count for monitoring of ATG biological effects on T cells. When rapid, significant and stable decrease of absolute CD3+ count is reached, ATG dose can be further adjusted according to the total lymphocyte count. With this approach, ATG treatment becomes rational and safe, with well established immunosuppressive effect, reduced risk of overimmunosuppression and considerable cost benefit.

[Significance of blood transfusion in the development of cytotoxic antibodies in patients on hemodialysis]. / Znacaj transfuzija krvi za razvoj citotoksicnih antitela kod bolesnika na hemodijalizi.

The aim was to evaluate the influence of red blood cells (RBC) transfusion on the development of cytotoxic antibodies (C-Ab) in patients subjected to hemodialyses (HD) and planned for the kidney transplantation. The group of 71 HD patients, of mean age 42 years (19-65), 48 males and 23 females, planned for the kidney information was examined. Out of 71 HD patients, only 42 (59.19%) HD patients (group I) received subcutaneously recombinant human erythropoietin--rhuEPO (Eprex--epoetin-alpha or Recormon SE--epoetin-beta in dosage of 4,000 IU during every HD; i.e. one to three times a week) and they were not treated by RBC transfusion. The other 29 (40.85%) HD patients (group II) received RBC transfusion: 18 (62.07%) HD patients received < 10 units 18 of RBC, 8 (27.59%) HD patients received 10-20 units of RBC; 3 (10.35%) HD patients received > 20 units of RBC. Testing of C-Ab was done in all patients every three months by standard lymphocytotoxicity test on the panel from 20 different lymphocyte donors with definite class I phenotype of antigen HLA. C-Ab was not found in HD patients who were not treated by RBC transfusion. Out of 18 HD patients who received < 10 units of RBC only 3 (16.67%) HD patients developed C-Ab; out of 8 HD patients who received 10-20 units of RBC, in 4 (50%) patients was proved C-Ab; and C-Ab was proved in all 3 HD patients who received > 20 units of RBC. RhuEPO administration is very important for the transfusiologic treatment of HD patients; especially those who are planned for the kidney transplantation. Development of C-Ab is in direct correlation with the number of transfunded units of RBC. HD patients who received 10 or more units of RBC were at great risk to develop C-Ab.

[Tuberous sclerosis]. / Tuberozna skleroza.

Tuberous sclerosis is a rare hereditary disease which appears immediately after birth of during the second and third year of life. It is a multiorgan disorder characterized by convulsions, mental retardation and focal angiofibromyoma. The main findings are brain lesions including tuberous and astrocytes hamarthomas by which this disease was named. Renal alterations are angiofibromyolipoma and cysts, which are present in 40-80% of patients. The diagnosis is based on clinical, radiological and histological findings. This disease has a progressive course and fatal outcome. The therapy is symptomatic and surgical. The aim of this paper was to present this rare disease, which occurred in this patient during fourth year of life. Besides brain changes the patient also has extensive morphological renal alterations and renal failure. She died in 40th year of life due to multiorgan dysfunction.

[Serum levels of beta 2-microglobulin in various types of hemodialysis]. / Serumska koncentracija beta 2-mikroglobulina u razlicitim vrstama hemodijalize.

beta 2-microglobulin (beta 2 m) is the major constituent of amyloid fibrils in dialysis-related amyloidosis (DRA), which is considered to be one of the most severe adverse effect of long-term dialysis. In this study we evaluated the efficiency of beta 2 m removal during different dialysis procedures. A total of 45 patients undergoing hemodialysis were divided in five groups: cuprophane dialysis (n = 10), high-flux polysulphone dialysis (n = 10), postdilutional hemodiafiltration (n = 10), conventional postdilutional hemofiltration (n = 10) and predilutional on-line hemofiltration (n = 5). Serum level of beta 2 m was determined before and after different procedures using ELISA. In the group of patients on cuprophane dialysis was registered an elevation of beta 2 m and of 16.8 +/- 11.4% on the average. Serum level of beta 2 m was decreased following all other procedures on the average of 40.7 +/- 16.4% after high-flux polysulphone dialysis, 42.0 +/- 13.7% after conventional hemofiltration, 64.7 +/- 9% after hemodiafiltration and 67.9 +/- 10.1% after predilutional hemofiltration. The best removal of serum beta 2 m was realized by predilutional hemofiltration. Also, we have noticed that patients treated with high-flux synthetic membranes in the longer time-period have lower predyalisis value of beta 2 m compared to patients treated with cuprophane membrane. Further long-term studies will be necessary to conclude whether these procedures could be successful prophylactic and/or therapeutic regimen for dialysis-related amyloidosis.

[Significance of inflammatory cytokines in the pathogenesis of IgA nephropathy]. / Znacaj inflamacijskih citokina u patogenezi IgA nefropatije.

Prospective study was performed on the concentrations of inflammatory cytokines IL-1, TNF and IL-6 in serum and urine (ELISA tests) were determined in the scope of total clinical-laboratory and histologic treatment in 59 patients with primary IgA nephropathy. Control group consisted of 20 healthy subjects. IL-6 was not detected either in serum of patients with IgAN, or in control examinees. TNF alpha and IL-1 beta were detected in control patients' sera and in patients with IgAN, but detected concentrations were not significantly different. IL-1 beta in urine was detected in 82.8%, TNF alpha in 90.0%, and IL-6 in 40% of our patients with IgAN. The concentrations of IL-1 beta were significantly higher compared to IL-1 beta concentrations in urine of healthy subjects and significantly correlated with the severity of glomerular and tubulointerstitial changes, as well as with the degree of proteinuria. Direct and indirect toxicity of TNF alpha on renal structures was confirmed in significantly higher concentrations of that cytokine in urine of patients with mesangial sclerosis of different percentage compared to the patients with isolated mesangial hypercellularity. Also in the patients with index of chronic lesion over 7 significantly higher TNF alpha concentrations in urine were found compared to the patients with lesion index 0-3 and 4-7. Creatinine clearance was in negative correlation with TNF alpha concentrations in urine of our patients with IgAN. Concentrations of IL-6 in urine were in correlation neither with laboratory parameters of renal function, nor with the degree of histologic changes.

Treatment of IgA nephropathy with nephrotic syndrome using pulse doses of IgG.

This paper presents the preliminary results of the treatment of nephrotic syndrome in IgA nephropathy (IgAN) using pulse doses of IgG. Diagnosis was established only by percutaneous ultrasonically-guided renal biopsy, as well as on the basis of typical immunofluorescence and light microscopy findings. Histopathologic changes were classified according to the World Health Organization classification for IgAN, by determination of average glomerular, vascular and interstitial fibrosis indices and the degree of tubular atrophy. IgG therapy was administered in three patients with nephrotic syndrome associated with IgAN characterized by minimal histological changes, i.e., by diffuse mesangioproliferative glomerulonephritis. Initial IgG pulse dose was 0.4 g/kg, given as slow intravenous infusion during three consecutive days in the course of the three-month period. Maintenance therapy consisted of intramuscular IgG in the doses of 2.5 g twice a month, for the next three months. After a six-month treatment, clinical and biochemical remission was achieved in patients with minimal histologic changes, but in other two patients with diffuse mesangioproliferative glomerulonephritis, the effect of the therapy consisted of reduced proteinuria by more than 50%, with the renal function restored to the level before therapy. Transient increase in the serum creatinine level was found in two patients. These preliminary results with IgG pulse therapy, although obtained on a small number of patients, suggest the drug's potent immunomodulatory properties, but its complexity and levels of actions should be further investigated.

[Histopathologic changes in the kidneys in patients with asymtomatic pathologic findings in urine]. / Histopatoloske promjene u bubrezima kod bolesnika sa asiptomatskim patoloskim nalazom u urinu.

The authors had analyzed histopathologic changes in the kidneys of patients with asymptomatic abnormalities of urine analyzing if they were correlated with the type of pathologic finding in urine. Retrospective study comprised a total of 76 patients with asymptomatic urine abnormalities. In all three groups of patients, formed upon the type of pathologic finding in urine, were determined heterogeneous histopathologic changes, and different types of glomerulonephritis, respectively. The most frequent histopathologic finding was IgA nephropathy, observed in 16.7% patients with isolated proteinuria, in 50% patients with isolated microscopic hematuria and in 55.9% patients with associated urine abnormalities. In distinction from the other two groups of patients, in the group of patients with isolated proteinuria normal histologic finding was very frequently found (25% patients), and in group of patients with associated urine abnormalities were observed more severe histopathologic forms of glomerulonephritis, such as membranoproliferative glomerulonephritis. It was concluded that different types of glomerulonephritis most frequently caused asymptomatic abnormalities of urine in younger patients.

[Treatment of nephrotic syndrome in IgA nephropathy with IgG pulsed doses]. / Lecenje nefrotskog sindroma u IgA nefropatiji pulsnim dozama IgG.

The preliminary results of nephrotic syndrome treatment in IgA nephropathy (IgAN) with pulse IgG doses have been presented. The diagnosis of IgAN has been made exclusively by percutaneous ultrasonically guided biopsy of kidneys, on the basis of characteristic finding of immunofluorescent and light microscopy. Histopathological changes were classified upon the Classification of World Health Organization for IgAN with the calculation of average glomerular, vascular and indices of interstitial fibrosis and tubular athrophy. The therapy with IgG was applied in 3 patients with nephrotic syndrome in complex of IgAN with minimal histologic changes, i.e. diffuse mesangioproliferative glomerulonephritis. Initial pulse dose of IgG was 0.4 g/kg and it was administered in slow intravenous infusion for three days running during three months. The therapy of maintenance consisted of intramuscular administration of IgG in the dose of 2.5 g, twice a month, for the next three months. After the six-month treatment, clinical and biochemical remission was achieved in the patient with minimal histologic changes, and in the other two patients with diffuse mesangioproliferative glomerulonephritis the effect of therapy was revealed in proteinuria decrease for over 50% and the preserved renal function on the level before the therapy has started. Temporary increase of creatinine serum concentration was registered in two our patients. Preliminary results of pulse therapy with immunoglobulin G, although obtained on the small patient number, imply its powerful immunomodulatory features, which complexity and action levels should be more investigated.

[Ultrasound guided percutaneous biopsy of the kidney]. / Perkutana biopsija bubrega vodena ultrazvukom.

In the course of 5 years, 582 ultrasound guided percutaneous renal biopsies were performed in 558 patients. Kidney tissue was obtained in 507 patients (90.9%), and in 485 (86.9%) the obtained sample was sufficient to establish the diagnosis. Complications following renal biopsies were observed in 221 patients, or 38% of total biopsies. There were 212 (36.4%) clinically moderate complications. The most frequent ones were asymptomatic hematomae (32.6%), and infrequently lumbar pain (2.4%) and hematuriae lasting less than 12 hours (1.4%). In 9 patients 10 (1.7%) serious clinical complications in the form of hematuria lasting more than 12 h (1%), large perirenal hematomae (0.5%) and urinary infections (0.2%). In the older age group and in patients with pronounced renal failure no significant difference in the incidence of complications was observed. Ultrasound guided percutaneous renal biopsy is a safe diagnostic method, and the associated complications do not seriously curb its use. The therapy of complications is primarily conservative, and only rarely surgical.

[Pathologic changes in the interstitium in IgA nephropathy]. / Patohistoloske promene intersticijuma u IgA-nefropatiji.

Some of tubulointerstitial changes are frequently found in glomerular disorders. A wide range of interstitial lesions have also been observed in patients with IgA nephropathy. Percutaneous biopsy specimens taken from 74 kidneys of IgA nephropathy patients have been analysed. Obtained tissues were examined by LM, If and EM. Light microscopy, immunofluorescence and electron microscopy Morphologic changes have been classified into 5 groups according to WHO classification. Interstitial changes, cellular infiltrations, fibrosis and other lesions from all renal tissues have been analysed and according to their intensity semiquantitatively graded into 4 groups. Histopathologic analysis has most frequently revealed interstitial fibrosis and less frequently mononuclear cellular infiltration particularly in patients with more prominent glomerular changes. Therefore, we have as well as other authors, confirmed that interstitial changes represent an important prognostic factor in the IgA nephropathy development. However, analysis of repeated biopsy specimens to confirm this hypothesis is necessary.

[Correlation of inflammatory cytokines in the urine and serum with clinico-laboratory and pathohistologic features in patients with IgA nephropathy]. / Korelacija koncentracije inflamacionih citokina u urinu i serumu s klinicko-laboratorijskim i patohistoloskim odlikama kod bolesnika s IgA nefropatijom.

Complete examination of 21 patients with IgA nephropathy included determination urine and serum IL-6, TNF alpha and INF gamma levels by ELISA (Luzernachen, Luzern Switzerland). Control group included 15 healthy volunteers. Urine IL-6 levels ranging 37-274.1 pg/ml were detected in 15 (71.2%) patients with IgA nephropathy. IL-6 serum levels were undetectable. In the control group serum and urine levels were also undetectable. Correlation between the IL-6 level and proteinuria degree and endogenous creatinine clearance rate has not revealed statistically significant relationship. In relation to histologic groups (minimal changes, focal glomerulonephritis, mesangial proliferative, diffuse sclerosing) patients with minimal changes had (statistically) significantly higher IL-6 urine levels than the third and fourth group. Average the urine levels were 145.8 +/- 166.6 pg/ml and the serum ones were 148 +/- 101 pg/ml. In relation to the control group (statistically) significant difference was not found. Correlation between TNF alpha level and proteinuria degree and creatinine clearance rate has revealed (statistically) significant relationship (p < 0.05). Average interferon gamma serum levels in lgA nephropathy patients were 312.0 +/- 111.8 and in comparison with the control group (statistically) significant difference was found (p < 0.01). The obtained results suggest the important role of cytokine production disregulation associated with the pathogenesis of IgA nephropathy.