[Renal transplantation in patients with lupus nephritis]. / Transplantacija bubrega u bolesnika s lupusnim nefritisom.

Lupus nephritis (LN) is a severe complication of systemic lupus erythematosus (SLE), associated with high morbidity and mortality. Up to 60% of SLE patients develop LN, and despite novel and potent therapeutic regimens, 5 to 22% develop end-stage renal disease within 15 years of diagnosis. While LN primarily affects younger individuals, it is important to choose optimal method of renal replacement therapy for those who develop end-stage renal disease. Numerous studies were carried out trying to solve problems of treatment of patients with LN. Increased risk of infections, disease recurrence in renal allograft, undefined criteria for follow-up of disease activity after transplantation, as well as higher inci- dence of rejection episodes and thrombotic events are well known risks which have postponed and restricted access to transplantation for patients with LN for long-time. However, numerous studies have demonstrated similar long-term survival in patients treated with haemodialysis or peritoneal dialysis, with clear superiority of renal transplantation regarding the prolonged survival and better quality of life for SLE patients. Many questions are still waiting for answers. Close cooperation between nephrologists and immunologists provides the best treatment for SLE patients with end-stage renal disease.

[Consensus statement of the Croatian Society for Nephrology, Dialysis and Transplantation regarding the use of generic immunosuppressive drugs]. / Stav hrvatskog drustva za nefrologiju, dijalizu i transplantaciju bubrega prema uporabi generickih imunosupresiva u transplantaciji bubrega.

The use of generic immunosuppressive drugs may decrease the cost of immunosuppressive medication, although total cost sav- ings are still a matter of debate since patients need close monitoring after conversion from original to the generic formulation. A working group of the Croatian Society of Transplantation was established to develop recommendations on the use of generic immunosuppression in renal transplant recipients based on a review of the available data. Immunosuppressive drugs belong to the 'narrow therapeutic index' drugs, with huge pharmacokinetic variations secondary to the impact of food, other drugs, as well as of kidney and liver function. Failure to maintain an appropriate balance of immunosuppression seriously influences graft and patient survival. Published evidence supporting therapeutic equivalence of generic formulations is scarce or completely lacking. Different generic formulations may expose patients to uncontrolled product switching by pharmacists or general practitioners, which is very dangerous for patients, since generic preparations are not required to demonstrate bioequivalence with each other. The Croatian Society for Nephrology, Dialysis and Transplantation is not against the use of generic immunosuppressive drugs, but it requires close supervision of nephrologists and respecting the strict rules of their use. More efforts should be invested in education of primary care physicians as well as of patients to be aware of differences between the original and generic, as well as between different generic formulations.

[Outcome of renal transplantation after tacrolimus switch to cyclosporine]. / Ishod transplantacije bubrega nakon prevodenja s takrolimusa na ciklosporin.

Calcineurin inhibitors play the key role in current immunosuppressive therapy in transplantation medicine. We present our experience with tacrolimus as immunosuppressive therapy and the reasons for replacing tacrolimus with cyclosporine in some patients. We monitored graft function, serum lipid levels, and blood glucose concentration before and after immunosuppressant switch. The most common reason for change of immunosuppressive therapy was insulin dependent hyperglycemia; calcineurin inhibitor nephrotoxicity was the reason for switching immunosuppressive therapy in a small number of patients; and in one patient, the reason for immunosuppressive therapy switching was BK virus infection. Blood glucose normalized soon after the introduction of cyclosporine in the treatment. Monitoring of laboratory tests before and after immunosuppressive therapy switching showed the graft function to have remained unchanged.

[Outcome of renal transplantation in patients with chronic virus hepatitis]. / Ishod transplantacije bubrega u bolesnika s kronicnim virusnim hepatitisom.

The objective is to present results of renal transplantation in patients with end-stage renal disease and chronic virus C/B hepatitis. We retrospectively reviewed outcome of transplantation in patients having received renal allograft from 1985 to 2009 at Zagreb University Hospital Center: graft function, graft and patient survival, hepatic function, and complications of transplantation, i.e. episodes of acute rejection, manifestation of diabetes mellitus, and proteinuria. There were 91 patients, 50 men and 41 women, mean age 40.9. Patients were previously treated with dialysis for 7.8 years, with the mean follow-up after transplantation of 7.3 years. The most frequent diagnoses of end-stage renal disease were chronic glomerulonephritis, reflux nephropathy, tubulointerstitial nephritis, renal hypoplasia/aplasia, and polycystic renal disease. Good graft function (creatinine 200 micromol/L) was recorded in 59.5% of patients. One-year, 5-year and 10-year graft survival was 93%, 64% and 39%, and 1-year, 5-year and 10-year patient survival after transplantation was 98%, 72% and 42%, respectively. Normal values of liver chemistry (AST, ALT) were found in 59.5% and elevated values in 40.5% of patients. Episodes of acute rejection occurred in 56% of patients. Proteinuria was recorded in 27%, diabetes mellitus in 18% and elevated blood pressure in 66% of patients. Patients with chronic C/B virus hepatitis having undergone renal transplantation had worse graft function and worse graft and patient survival than patients without chronic hepatitis. The most common causes of death were cardiovascular diseases, cerebrovascular diseases and cirrhosis hepatitis.

[Association between viral infections and post-transplant malignancies in renal transplant recipients]. / Povezanost virusnih bolesti i tumora nakon transplantacije bubrega.

Immunosuppressive treatment is associated with an increased incidence of different malignant diseases. The etiology of posttransplant malignancies is multifactorial and includes decreased immune response to different viral infections, inappropriate removal of damaged cells, and impaired ability to repair DNA. EBV, HHV-8, Merkel cell virus, hepatitis B virus, hepatitis C virus and BK virus are all considered to be involved in the etiology of post-transplant malignancies. CMV has been considered as a potential causative factor in the development of colon cancer. However, current knowledge is mainly based on case reports. Further studies are needed to establish the causative role of different viruses in the etiology and pathogenesis of different malignant diseases in renal transplant population.

Head and neck malignancies in Croatian renal transplant recipients.

Renal transplantation is associated with increased incidence of cancer. We reviewed a large series of renal transplant recipients to determine the incidence and outcome of patients with malignant changes located at the head and neck. A total of 1232 renal transplant recipients have been followed at Department of Dialysis University Hospital Centre Zagreb from 1972 to 2009. Demographic data, localization and disease outcome were evaluated in patients who developed cancer. Twenty one patients (1.7%) developed 27 head and neck malignancies. The average time from transplantation to development of cancer was 56.8 months. The mean length of follow-up was 9.4+/-4.8 years. Eighteen malignancies were cutaneous in origin and 9 were noncutaneous. Of cutaneous malignancies, 88.9% were basal cell carcinoma; one patient had Merkell-cell carcinoma and one patient developed squamous cell carcinoma. Six cases of basocellular skin cancer were recorded in one fair-skin patient. Noncutaneous malignancies involved the oral cavity (2 cases of Kaposi's sarcoma and one pharyngeal cancer) and the thyroid gland in 3 patients each. Two patients had post-transplant lymphoproliferative disorder occurring at the head and neck. One patient had brain tumor. Radical surgery, radiation, and/or chemotherapy were necessary in 33.3% of patients. Immunosuppression was reduced in all patients, and 12 patients were switched from the calcineurin-based immunosuppression to sirolimus. They all have stable graft function. None of the patients died from cancer. Immunosuppression was ceased in one patient with Kaposi's sarcoma who returned to dialysis and died 10 years later from heart failure. An increased incidence of cancer occurring in the head and neck was recorded. Careful skin examination and oral examination is mandatory for discovering cancer before dissemination. Sirolimus is safe alternative to calcineurin-based immunosuppression in patients who developed head and neck malignancies.

[Thrombotic microangiopathy after kidney transplantation]. / Tromboticka mikroangiopatija nakon transplantacije bubrega.

The term thrombotic microangiopathy (TMA) encompasses different disturbances that are usually classified as thrombotic thrombocytopenic purpura (TTP) or haemolytic-uraemic syndrome (HUS). These syndromes are characterized by thrombocytopenia, microangipathic haemolytic anaemia, neurological deficits and renal failure. Etiology of TMA include exotoxins, drug toxicity (cyclosporin, tacrolimus, ticlopidine, clopidogrel, mitomycin), but also familiar forms associated with deficiency of factor H (HUS) or vWF protease activity (TTP). TMA in renal transplant recipients may evolve de novo or may recur in patients who were diagnosed with TMA as the primary renal disease. We present a case of renal transplant recipient with ESRD of unknown etiology, who was diagnosed with TMA 3 years after transplantation. After discontinuation of cyclosporine, she was treated with therapeutic plasma exchange (TPE). Cytomegalovirus reactivation demanded discontinuation of the chronic program of TPE, what was followed by worsening of graft function and demand for dialysis one year after the diagnosis of TMA. Patients with TMA should be carefully followed-up after renal transplantation for the signs of disease recurrence. Withdrawal of precipitating factors is of outstanding importance. TPE is used to limit the endothelial damage and to limit the microangiopathic process. However, its efficacy is unclear. Our case demonstrates that TPE may improve graft survival, with the possibility of inducing opportunistic infections. International registries are needed to establish the guidelines for follow-up and treatment of renal transplant recipients with TMA.

[Renal impairment induced by nonselective prostaglandin inhibitor]. / Ostecenje bubrega izazvano neselektivnim inhibitorom prostaglandina.

The role of kidney function is of utmost importance in the maintenance of constant body fluid amount. However, kidneys are at a great risk of exposure due to high intrarenal blood flow and the existing concentrate system. Different damage can originate from renal clearance of various drugs, while metabolites or xenobiotics may be associated with potential nephrotoxic effects, particularly in the presence of additional risk factors. For analgesics such as nonsteroidal antirheumatics (NSARs), it is possible that they inhibit renal production of prostaglandins, potent vasodilators, resulting in tissue ischemia and direct toxicity. Therefore, the aim of this study was to evaluate changes in the cellular potential response of proximal tubules first in the presence of prostaglandin type E (PGE2) and then in the presence of Na-diclofenac, a nonselective prostaglandin inhibitor, and their effects on transport process of substrate (glucose), by using electrophysiological studies in experimental animals. PGE2 was found to play specific role at local intrarenal level, where they directly stimulated the processes of sodium and substrate (glucose) cotransport through luminal membrane of proximal tubules, without changing the control cell potential response. Results with diclofenac as a nonselective cyclooxygenase inhibitor and thus prostaglandin synthesis inhibitor revealed it to cause concentration-dependent depolarization of the cellular potential. It also reduces cotransport of the substrates and ions involved in intracellular equilibrium. At concentrations higher than therapeutic, diclofenac became nonspecific and therefore caused permanent depolarization. Accordingly, the results of these experimental studies may be useful to specialists treating patients suffering from renal dysfunction or kidney diseases. This can also contribute to rationalization of the therapeutic use of analgesics, greater caution and better recognition of the associated risk factors, in elderly or renal patients in particular.

[Arterial hypertension in renal transplant recipients]. / Hipertenzija nakon transplantacije bubrega.

Arterial hypertension develops in up to 80% of renal transplant recipients. Uncontrolled hypertension induces left ventricular hypertrophy, heart failure and death, but also promotes deterioration of allograft function. Cadaveric transplantation, delayed graft function, renal artery stenosis, presence of native kidneys, increased body weight and therapy with calcineurin inhibitors and steroids have been associated with an increased incidence of hypertension after kidney transplantation. Cyclosporine increases both systemic and renal vascular resistance, enhances sympathetic activation, endothelin production and, possibly, decreases vascular relaxation by decreasing the generation of nitric oxide. Tacrolimus has less pronounced prohypertensive role after renal transplantation. Corticosteroids contribute to the development of hypertension, since their withdrawal results in a significant decrease of blood pressure in the majority of patients. Renal artery stenosis occurs in almost 12% of hypertensive renal transplant recipients. It is a correctable cause of hypertension, and for this reason should be investigated in all suspected patients. Doppler ultrasonography is used as the screening method that is highly sensitive and specific in the hands of a well-experienced investigator. However, dependence of the method on the experience of the investigator is its major drawback. Magnetic resonance angiography and spinal computed tomography angiography are useful noninvasive methods, but arteriography remains a method for establishing the definitive diagnosis. Percutaneous balloon angioplasty, with or without placement of the stent, is successful in the majority of patients, but with a high incidence of restenoses (20%). Surgery is indicated for stenoses that cannot be treated with angioplasty or that recur. Auto-transplantation of the kidney with complex stenoses of graft arteries is useful in selected cases. Posttransplant hypertension should be aggressively treated to prevent the development of end-organ damage. Every effort should be invested in reducing immunosuppression when appropriate, together with salt restriction and weight reduction. Calcium channel blockers have good antihypertensive properties accompanied with minimization of cyclosporine-induced renal vasoconstriction. Angiotensin-converting enzyme inhibitors (ACEi) should be used in patients with proteinuria. Renal function should be carefully monitored after their introduction since they may cause transitory deterioration of glomerular filtration and/or hyperkaliemia. ACEi can induce anemia in renal transplant recipients, side effect that is often used in the treatment of posttransplant erythrocytosis. All other antihypertensive drugs could be used, with minoxidil being the most potent one. Patients with resistant hypertension should be investigated for the presence of renal artery stenosis. After exclusion of rejection, renal artery stenosis and recurrent disease, in cases of severe hypertension, native kidneys laparoscopic nephrectomy should be considered.

Treatment of thrombotic microangiopathies with plasma exchange.

Thrombotic microangiopathy (TMA) is a syndrome characterized by thrombocytopenia, microangiopathic hemolytic anemia, neurologic abnormalities, fever and renal dysfunction. This retrospective analysis sought to determine the clinical characteristics and outcome of patients with TMA treated with plasma exchange at the Department of Dialysis, University Hospital Zagreb. From 1982 to July 2005, 17 patients (10 male and 7 female, age ranging from 18 to 74 years) have been diagnosed with TMA. The most common presenting symptom was purpura in 76.5%, followed by neurologic disturbance in 70.5%, renal function abnormality in 41.1%, and fever in 29.4% of patients. Patients were treated with a daily plasma exchange, which was continued until the normalization of platelet count with minimal hemolysis. Plasma exchange treatment was first tapered and later discontinued with careful monitoring of laboratory parameters. Of the 17 patients, 13 achieved complete remission after 5-32 sessions, two had partial response, and two had no response and died of progressive disease. Four patients developed chronic relapsing TMA, and three of them progressed to end-stage renal disease. Survival at 1 year in our series exceeds 88%, but decreased with duration of follow-up. Overall, with the median follow up of 5 years, 6 patients died from consequences of TMA (35.3%); three with chronic TMA, and 2 in the acute phase of progressive disease. A 74-year old male who developed TMA after prostate cancer died from disseminated malignant disease. Our results demonstrate a high incidence of renal function abnormalities in patients with TMA at presentation, but also during long term follow-up. Development of end-stage renal disease was associated with poor prognosis. Further studies, long term follow-up and establishment of international registries are needed to clarify many dilemmas associated with the diagnosis, treatment and outcomes of patients with TMA.

Complications of therapeutic plasma exchange: experience with 4857 treatments.

Plasma exchange (PE) is a technique of extracorporeal blood purification which removes large molecular weight substances from plasma. The Department of Dialysis, Zagreb University Hospital Center's database, which includes data on 509 patients, or 4857 PE treatments, was retrospectively analyzed to test the safety of PE. A total of 231 adverse reactions were recorded (4.75% of treatments). The most common complications were paresthesias (2.7%), hematoma at the puncture site (2.4%), clotting (1.7%), mild to moderate allergic reactions (urticaria; 1.6%) and bleeding (0.06%). True anaphylactoid reactions were recorded in five procedures. The incidence of severe, potentially life-threatening adverse reactions was 0.12%. The prophylactic use of calcium and potassium was responsible for a low incidence of electrolyte disturbances. There was no lethal outcome associated with PE. When carried out by experienced staff, PE is a relatively safe procedure. The use of fresh frozen plasma is associated with a higher rate of adverse reactions.

[Interleukin-2 receptor blockers in renal transplantation]. / Blokatori receptora za interleukin-2 u transplantaciji bubrega.

The last two decades have witnessed significant advances in the renal transplantation immunosuppressive protocols. The introduction of mycophenolate mofetil, tacrolimus, sirolimus and polyclonal antibodies has significantly improved graft survival. However, intensification of immunosuppression results in complications such as malignant diseases, opportunistic infections and metabolic disturbances with consequential increase in cardiovascular mortality. Advances in molecular engineering have made possible the development of monoclonal humanized or chimeric antibodies, which will not induce the host immune response with production of neutralizing antibodies or serum sickness. Antibodies directed against the alpha chain of human IL-2 receptor have recently been introduced into immunosuppressive protocols. Daclizumab is a humanized antibody, and basiliximab is a chimeric antibody, engineered by cloning segments of the murine immunoglobulin sequence into the human-immunoglobulin gene. It decreases immunogenicity while maintaining high specificity for IL-2R alpha chain. The efficacy and safety of both preparations have been reported in large randomized studies. Their use in induction resulted in a significant decrease in acute graft rejections after renal transplantation. The possibility of decreasing the dose or complete withdrawal of certain immunosuppressive agents with the use of IL-2R blockers seems promising for further improvement in the longterm graft survival. Longterm follow-up is necessary to determine their role in solid organ transplantation.

[Long-term monitoring of children with focal segmental glomerulosclerosis and a transplanted kidney]. / Dugotrajno pracenje djece s fokalnom segmentalnom glomerulosklerozom i presadenim bubregom.

INTRODUCTION: Focal segmental glomerulosclerosis (FSGS) is an important cause of nephrotic syndrome and end-stage renal disease. Children with FSGS are at a risk of recurrence of disease following renal transplantation. The rate of recurrence has been estimated to range from 15% to 50%, having a potentially detrimental course towards the loss of renal function. The factors associated with an increased probability of recurrence are not well known. PATIENTS: The authors followed 8 pediatric patients (3 girls and 5 boys) with FSGS who had undergone renal transplantation (16% of all transplanted pediatric patients) over a long period (1982-2001). The mean age of the children at the time of disease onset was 4 years and 8 months (range: 2 months-12 years). Children were monitored from 10 months to 4 years before the first dialysis. On average, the first dialysis was performed at 7 years of age (range: 12 months-16 years). Time elapsed between the first dialysis and transplantation ranged from 1 to 3 years (mean 1.5 year), and mean age at transplantation was 8 years and 6 months (range: 4-18 years). The grafts were from 2 living-related and 6 cadaveric donors. Five recipients were immunosuppressed with cyclosporin A (CsA) -steroids-azathioprine (Aza), 2 with CsA-steroids-mycophenolate mofetil (MMF), and 1 with CsA-steroids regimen. Follow-up period after transplantation ranged from 2 to 15 years (mean time 7 years and 8 months). RESULTS: Creatinine values, proteinuria range and blood pressure were monitored every 3 months after transplantation, and were as follows: creatinine 41-386 mumol/l (mean value 153 mumol/l), proteinuria 0.01-3,14 g/l (mean 0.27 g/l, median 0.03 g/l), systolic blood pressure 90-140 mm Hg (mean 110 mm Hg), diastolic blood pressure 60-90 mm Hg (mean 80 mm Hg). Two patients developed hypertension grade I and III after renal transplantation. There were 5 (0.6 per patient) acute rejection episodes. Two grafts (25%) were rejected 5 and 9 years after transplantation, but recurrence of FSGS was not confirmed by renal biopsy. CONCLUSION: Due to the small sample size no firm conclusions about recurrence of FSGS could be made. However, the fact that none of 8 children developed recurrence of FSGS after renal transplantation speaks against the relatively high recurrence rates in our pediatric population.