Kidney transplantation from a living donor to a mentally disabled recipient with bilateral angiomyolipomas-A case report.

INTRODUCTION: Many centers do not perform transplantation in mentally disabled people. Our patient with progressive psychomotor developmental delay had bilateral angiomyolipomas. PRESENTATION OF THE CASE: Three years ago she underwent a right nephrectomy for massive spontaneous hemorrhage. The left kidney had a large, well-vascularized angiomyolipoma ready at any moment to bleed spontaneously was functioning normally. Two renal transplantation centers in Croatia refused to transplant from the patient's donor mother. The transplantation team had concerns whether to transplant a kidney to a person unable to care for herself, about who would take complete care of the patient, including regular immunosuppressive therapy, and whether it was ethically justified to explant a functioning kidney, although affected by angiomyolipomas, from a patient who required no renal replacement therapy at the time. CONCLUSION: We presented a successful kidney transplant in a mentally disabled person, clinical and ethical justifications for such a procedure, and a four-year post-transplant evaluation. Furthermore, in our opinion, renal transplantation in the mentally challenged needs to be referred to in literature exclusively as a relative contraindication instead of an absolute one, as has been practiced to date. This would facilitate transplantation teams deciding on kidney transplantation in mentally incapacitated individuals.

Effect of mycophenolate mofetil on progression of interstitial fibrosis and tubular atrophy after kidney transplantation: a retrospective study.

OBJECTIVES: Chronic transplant dysfunction after kidney transplantation is a major reason of kidney graft loss and is caused by immunological and non-immunological factors. There is evidence that mycophenolate mofetil (MMF) may exert a positive effect on renal damage in addition to immunosuppression, by its direct antifibrotic properties. The aim of our study was to retrospectively investigate the role of MMF doses on progression of chronic allograft dysfunction and fibrosis and tubular atrophy (IF/TA). SETTING: Retrospective, cohort study. PARTICIPANTS: Patients with kidney transplant in a tertiary care institution. This is a retrospective cohort study that included 79 patients with kidney and kidney-pancreas transplantation. Immunosuppression consisted of anti-interleukin 2 antibody induction, MMF, a calcineurin inhibitor±steroids. PRIMARY OUTCOME MEASURES: An association of average MMF doses over 1 year post-transplant with progression of interstitial fibrosis (Δci), tubular atrophy (Δct) and estimated-creatinine clearance (eCrcl) at 1 year post-transplant was evaluated using univariate and multivariate analyses. RESULTS: A higher average MMF dose was significantly independently associated with better eCrcl at 1 year post-transplant (b=0.21±0.1, p=0.04). In multiple regression analysis lower Δci (b=-0.2±0.09, p=0.05) and Δct (b=-0.29±0.1, p=0.02) were independently associated with a greater average MMF dose. There was no correlation between average MMF doses and incidence of acute rejection (p=0.68). CONCLUSIONS: A higher average MMF dose over 1 year is associated with better renal function and slower progression of IF/TA, at least partly independent of its immunosuppressive effects.

Expression of secreted frizzled-related protein 1 and 3, T-cell factor 1 and lymphoid enhancer factor 1 in clear cell renal cell carcinoma.

Frequency and mortality of renal cell carcinoma (RCC) are increasing for decades. However, the molecular background of RCC tumorigenesis is still poorly understood. In current study we investigated the expression of TCF/LEF and SFRP family members (SFRP1 and SFRP3) to gain a better understanding of biological signaling pathways responsible for epidemiology and clinical parameters of clear cell RCC (cRCC). Thirty-six pairs of paraffin-embedded clear cRCC and adjacent nontumoral tissues samples using immunohistochemistry (IHC) were analyzed and compared with corresponding clinicopathological parameters. Immunohistochemistry indicated statistically significant decreased SFRP3 expression in tumor tissues but no consistency in SFRP1 expression in analyzed normal and tumor tissue. The TCF1 expression level was significantly weaker in normal tissue compared to tumor samples while LEF1 protein levels were significantly weaker in tumor tissue. To our knowledge, this is the first report on analysis of the expression of transcription factors TCF1 and LEF1 in clear cell renal cell carcinoma and their comparison with Wnt signal pathway antagonists belonging to SFRP family.

Treatment of bleeding after kidney biopsy with recombinant activated factor VII.

Recombinant activated factor VII (rFVIIa) is approved for prevention and treatment of bleeding in hemophilia patients with inhibitors to FVIII (hemophilia A) or IX (hemophilia B), patients with congenital and acquired hemophilia and in patients with FVII deficiency or Glantzmann thrombasthenia (last indication is approved only in Europe). Off-labeled, the drug has been prescribed for prevention, or treatment of bleeding in severe hepatic disease, neonatal coagulopathies, high-risk surgical procedures, trauma, thrombocytopenia and platelet function disorders, as well as for urgent reversal of oral anticoagulation. Here we report a case of a 53-year-old female patient with delayed graft function after kidney transplantation, who had kidney biopsy complicated with prolonged bleeding. After unsuccessful treatment with desmopressin, the patient was treated with rFVIIa and the bleeding stopped immediately. Only few anecdotal reports of use of rFVIIa for treatment of bleeding in uremic patients have been published thus far. To our knowledge, this is the first case that describes use of rFVIIa for management of bleeding as a complication of renal biopsy in a uremic patient in the early kidney posttransplantation period.

[Effect of pretransplant dialysis modality on incidence of early posttransplant infections in kidney recipients]. / Utjecaj tipa dijalize na pojavnost ranih infekcija nakon transplantacije bubrega.

INTRODUCTION: Infection is one of the main causes of patient death and graft failure early after kidney transplantation. Effect of pretransplant dialysis modality on incidence of infections after kidney transplantation still remains controversial. The aim of the present study was to determine the impact of pre-transplant dialysis modality on incidence urinary tract infections (UTI) and sepsis in early posttransplant period in kidney transplant recipients. MATERIALS AND METHODS: In this case-control retrospective study a cohort of 72 kidney, kidney- pancreas or kidney-liver transplant recipients was included. Infection was defined by either clinical presentation or microbiological finding. Infections were categorized by localization and cause of infection. In patients on peritoneal dialysis peritoneal catheter was removed intraoperatively during transplantation. Infection rate during first three months posttransplant was analyzed. Difference in frequencies was calculated using nonparametric tests. Proportions were calculated using chi2 test. Time to first infection was analyzed using Kaplan-Meier survival analysis, p value < 0.05 criterion was used to decide statistical significance. RESULTS: The total number of infections per patient per day was not significantly different in peritoneal vs. hemodialysis modality (0,029 +/- 0.019 to 0,029 +/- 0,031, p=ns). Also, there was no significant difference in peritoneal vs. hemodialysis modality in the number of UTI (0.0156 +/- 0.0144 to 0,0165 +/- 0,0125, p=ns) and sepsis (0.0018 +/- 0.0044 to 0.0026 +/- 0.0019, p=ns) during first three months posttransplant. Similarly, no difference was noted between the groups in the location or cause of infection. Peritonitis prior to transplantation was not an independent risk factor for infections (p=0.37). In Cox regression PD was not an independent risk factor for either total infections, UTI, or sepsis. CONCLUSION: This study showed that there was not statistically significant difference in the risk for infection in first three months after kidney transplantation with respect to pretransplant dialysis modality. PD should be the first choice for renal replacement therapy in patients with end stage renal disease.

[The purpose of clinical laboratory accreditation in transplantation medicine]. / Znacenje akreditacije klinickih laboratorija u transplantacijskoj medicini.

Although transplantation of solid organs has become a more standardized method of treatment, liver transplantation represents an exceptional multidisciplinary clinical procedure requiring understanding of specific pathophysiological changes that occur in the end stage of liver disease. Liver transplantation has been performed at Merkur University Hospital since 1998, with 360 transplantations performed to date. The most common indications are alcohol liver disease, cirrhosis caused by hepatitis B and C virus, hepatocellular carcinoma and cryptogenetic liver cirrhosis. Laboratory tests required for liver transplantation are performed at Department of Clinical Chemistry, Merkur University Hospital, accredited according to ISO 15189 in 2007 for the areas of clinical chemistry, laboratory hematology and coagulation, laboratory immunology-cell immunophenotyping, and molecular diagnosis. The complexity of liver transplant patients requires constant interaction between the anesthesiologist team and clinical laboratory, which has to ensure fast and efficient intraoperative monitoring of biochemical and liver profile: electrolytes and acid-base status, complete blood count, coagulation profile and monitoring of graft function according to the individual patient's health status. Dynamics of intraoperative changes is measured in whole arterial blood samples on a Nova Biomedical Stat Profile Critical Care Xpress mobile acid-base analyzer. Frequent monitoring of ionized calcium and magnesium levels is very important because of citrated blood transfusion and for appropriate therapeutic procedure. During anhepatic stage, there is a progressive increase in lactate level concentration. After reperfusion, a rapid increase in lactate clearance is an excellent indicator of stable graft initial function and its adequate size. During the transplantation procedure, there is usually a biphasic acid-base disturbance characterized by metabolic acidosis and then by metabolic alkalosis. The loss of base equivalents starts during the dissection stage and accelerates during the anhepatic stage. Fast and efficient intraoperative monitoring of hematological tests and coagulation status is of great help in detecting the cause of possible hemorrhage and consequential complications during transplantation procedure. The possibility of organ and tissue transplantation mostly depends on well regulated international cooperation in the areas of donating, transplanting and exchange of required organs and tissues, while laboratory test results must be comparable regardless of their geographical area, methodology employed or analytical equipment used, which is mainly warranted through accreditation according to the international ISO 15189 standard.

[Flow cytometry and acute renal rejection confirmed by histopathologic analysis]. / Protocna citometrija i akutno odbacivanje bubrega dokazano patohistoloskim nalazom.

Transplantation of solid organs, tissues or hematopoietic cells is now standard in the treatment of patients with terminal stage disease in order to cure and improve the recipients' quality of life. The study included 54 patients having undergone single or multiple organ transplantation. All patients received a combination of immunosuppressant therapy consisting of corticosteroids, calcineurin inhibitor (cyclosporine; tacrolimus), anti-CD25 (daclizumab) and mycophenolate-mofetil. In 24 patients, acute rejection was stratified by histopathologic analysis of renal biopsy. Fifteen highly sensitized patients were administered antithymocyte globulin (ATG) therapy. Absolute count and percentage of B/T lymphocyte subsets, NK cells and CD25+ or CD69+ activated T cells were measured on a flow cytometer (EPICS XL, Coulter) using single platform standardized protocol. Upon ATG therapy, rapid decline to a very low level of T and NK cell lymphocyte count was observed, as well of B lymphocytes, resulting in redistribution of lymphocyte compartment. Between consecutive measurements, kinetic changes of lymphocyte subset numbers (absolute count or percentage) did not differ in a large spectrum of immune parameters between the groups with and without rejection episode and having received quadruple immunosuppressive induction and maintenance therapy. Immunologic monitoring must be initiated prior to transplantation and continued consistently and frequently post-transplantation. Such a program is expensive and time-consuming and stressful for the patient, therefore, prospective studies should identify whether treatment decisions can be based reliably on these immune parameters. Serial measurement of immune cell counts is necessary for maintenance of ATG therapy and could be useful for monitoring patient recovery.

[Hepatocellular carcinoma initially diagnosed by fine needle aspiration cytology of the pelvic bone metastasis]. / Hepatocelularni karcinom primarno dijagnosticiran citoloskom punkcijom metastatskog procesa u zdjelicnoj kosti.

Hepatocellular carcinoma mostly develops in patients with liver cirrhosis due to chronic hepatitis C virus (HCV) infection. A case is presented of a patient with hepatorenal syndrome as a sequel of liver cirrhosis due to HCV infection. Primary tumor of the liver was not diagnosed by routine procedures, but by fine needle aspiration cytology of the extensive osteolytic lesion of the pelvic bone, performed as part of the pre-transplantation workup. Transplantation procedure was abandoned because of inappropriate donor liver (hepatic artery thrombosis), and palliative pain-relieving irradiation was recommended. However, hepatic coma developed very rapidly and the patient died within a month of the diagnosis of metastatic hepatocellular carcinoma. Although hepatocellular carcinoma metastases are not rare, massive bone infiltration from a primary tumor undetectable by routine methods is not frequently encountered.

[Multifocal epithelioid hemangioendothelioma treated by liver transplantation--case report]. / Multifokalni epiteloidni hemangioendoteliom jetre lijecen ortotopnom transplantacijom jetre--prikaz bolesnika.

Multifocal epithelioid hemangioendothelioma of the liver is a rare primary tumor with a variable course of disease. A case is presented of a 27-year-old female patient with multiple hepatic lesions on ultrasonography, suspect of metastatic tumor of the liver. Serum tumor markers were not elevated, while clinical examination of the lungs, gastrointestinal and gynecologic systems did not confirm the presence of a primary tumor process. Metastatic tumor and primary hepatocellular tumor were ruled out by fine needle aspiration cytology. Along with a characteristic immunophenotype of the vascular cell endothelium (positive for CD31 and CD34), high proliferation demonstrated by the analysis of argyrophilic nucleolar organization regions (AgNOR) and DNA aneuploidy, cytomorphological pattern suggested the diagnosis of angiosarcoma. Histopathologic finding corresponded to epithelioid hemangioendothelioma. Ten years after orthotopic liver transplantation, the patient is free from disease relapse, with regular follow up testing. Hemangioendothelioma of the liver is characterized by multifocality, which excludes resection; thus, liver transplantation is the method of choice. Therefore, preoperative diagnostic workup is of utmost importance to differentiate it from other primary and metastatic tumors of the liver.

Polyomavirus associated nephropathy after kidney and pancreas transplantation: case report.

Polyomavirus virus associated nephropathy (PVAN) is an important cause of graft failure in the renal transplant population. The prevalence of PVAN has increased from 1% to 10% in the past decade, leading to loss of transplanted organ in 30% to 80% of cases. In the absence of specific antiviral drugs, early detection of disease and modification/reduction of immunosuppressive regimen is currently the cornerstone of therapy. In the setting of multiorgan transplantation, like simultaneous pancreas and kidney transplantation (SPKT), diagnosis and therapy of PVAN can be even more challenging problem. We report a first described case of PVAN in patient after SPKT in Croatia. Patient is a 32 years old Caucasian male with type 1 diabetes mellitus and end stage renal failure, diagnosed for PVAN 6 month after SPKT. Patient was treated with reduced immunosuppressive regimen. At 32 month follow up, patient has preserved kidney and pancreas function with estimated glomerular filtration (eGFR) rate of 91 mL/min and no signs of PVAN on his 2 year protocol kidney biopsy.

Fine needle aspiration cytology of adrenocortical carcinoma--case report.

A 49-year-old woman presented for hirsutism, deep voice and hypertension. Ultrasonography (US) revealed a solitary tumor mass, eight cm in size, of the right adrenal gland. Laboratory tests showed it to be a hormonally active, androgen secreting tumor (elevated testosterone level), which was consistent with the clinical picture of the disease. After histopathological analysis tumor was signed out as adrenocortical carcinoma, a low risk carcinoma according to Weiss' classification. One year later on regular follow up, US revealed a suspicious growth measuring 65 x 43 mm in the projection of the lower pole of the right kidney. The finding was verified by computerized tomography and the patient was reoperated on. Exploration revealed secondary growth in the region of greater omentum, without infiltration of adjacent organs. Histopathologic analysis confirmed metastatic ACC. 8 months after the second operation and after 6 chemotherapy cycles according to EAP protocol, control CT showed enlarged para-aortic lymph nodes and a node along the upper pole of the right kidney. Cytologic puncture was performed. Cytologic opinion was recidive of primary malignant disease. ACC is a rare malignant epithelial tumor of adrenal cortical cells, with high malignant potential. Morphologically (histopathology and cytology), differential diagnosis includes adenoma on the one hand, and renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC) on the other hand. A combined evaluation of clinical features, size or weight, microscopic appearance, immunohistochemical and molecular genetic data is necessary to ensure a correct diagnosis. The purpose of this case report is to present clinical and cytomorphologic features of our case of adrenocortical carcinoma which is very rare in cytology practice.

Dual kidney transplantation: case report.

Chronic shortage of kidney transplants worldwide has led to the use of organs from so called marginal or borderline donors, now termed "expanded-criteria donors". There has been an emerging practice of dual kidney transplantation (DKT) to compensate for sub optimal nephron mass of such kidneys. We performed DKT in "Merkur" University Hospital in August 2005. The donor was a 72-year old female with a history of long-term hypertension, aneurysm of the posterior cerebral artery, cerebrovascular insult (CVI), and with normal creatinine values and kidney function at the time of explantation. Initial biopsy of donor kidneys revealed acute tubular damage, with connective changes in 22% and 11% of glomeruli in the left and the right kidney, respectively. The recipient was a 60-year old male diagnosed with the IgA nephropathy on the last biopsy in 1999, and on dialysis since November 2003. Postoperative course was uneventful without any surgical complications. A triple immunosuppressive protocol was used. On follow-up ultrasonography 4 years posttransplantation both kidneys appeared of normal size and parenchymal pattern and with no signs of dilatation of the canal system, and color Doppler examination demonstrated normal flow in both kidneys. In conclusion, the use of DKT ie. donors by the expanded-criteria will continue to increase, and further studies of the results will, with no doubt, support this method.

Polymorphisms in Toll-like receptor genes--implications for prostate cancer development.

Toll-like receptors are key players in initiation of innate immune response of the host. In addition to innate immunity they can also induce adaptive immune responses. The concept that inflammation can promote chronic prostatic diseases, such as benign prostatic hyperplasia or prostate carcinoma is supported by several new findings. Epidemiological data have correlated prostatitis with an increased risk of prostate cancer, while PCR-based analyses of bacterial colonization in prostate cancer specimens and normal prostate tissue showed high correlation of bacterial colonization and chronic inflammation with a diagnosis of prostate carcinoma. Even evidence from genetic studies support the hypothesis that prostate inflammation may be a cause of prostate cancer. From these points of view identification of factors, such as SNPs in TLR genes, associated with risk for prostate carcinoma development seems reasonable. Consequently, there are many investigations showing the connection between SNPs in TLR genes and pronounced susceptibility to different diseases. In this article we review the key findings about the genetic variability of TLR genes and prostate cancer risk.

Accreditation of medical laboratories in Croatia--experiences of the Institute of Clinical Chemistry, University Hospital "Merkur", Zagreb.

Since 2003 when the international norm for implementation of quality management in medical laboratories (EN ISO 15189, Medical laboratories--Particular requirements for quality and competence) was established and accepted, accreditation has become practical, generally accepted method of quality management and confirmation of technical competence of medical laboratories in the whole world. This norm has been translated into Croatian and accepted by the Croatian Institute for Norms as Croatian norm. Accreditation is carried out on voluntary basis by the Croatian Accreditation Agency that has up to now accredited two clinical medical biochemical laboratories in the Republic of Croatia. Advantages of accredited laboratory lie in its documented management system, constant improvement and training, reliability of test results, establishing users' trust in laboratory services, test results comparability and interlaboratory (international) test results acceptance by adopting the concept of metrological traceability in laboratory medicine.

Urine immunocytology as a noninvasive diagnostic tool for acute kidney rejection: a single center experience.

Renal biopsy is a gold standard for establishing diagnosis of acute rejection of the renal allograft. However, being invasive, renal biopsy has potential significant complications and contraindications. Therefore, possibility to noninvasively diagnose acute rejection would improve follow-up of kidney transplant patients. The purpose of this study was to evaluate urine immunocytology for T cells as a method for noninvasive identification of patients with acute renal allograft rejection in comparison to renal biopsy. In this prospective study a cohort of 56 kidney, or kidney-pancreas transplant recipients was included. Patients either received their transplant at the University Hospital "Merkur", or have been followed at the "Merkur" Hospital. Patients were subject to either protocol or indication kidney biopsy (a total of 70 biopsies), with simultaneous urine immunocytology (determination of CD3-positive cells in the urine sediment). Acute rejection was diagnosed in 24 biopsies. 23 episodes were T-cell mediated (6 grade IA, 5 grade IB, 1 grade IIA, 1 grade III and 10 borderline), while in 1 case acute humoral rejection was diagnosed. 46 biopsies did not demonstrate acute rejection. CD3-positive cells were found in 21% of cases with acute rejection and in 13% of cases without rejection (n.s.). A finding of CD3-positive cells in urine had a sensitivity of 21% and specificity of 87% for acute rejection (including borderline), with positive predictive value of 45% and negative predictive value of 68%. Although tubulitis is a hallmark of acute T cell-mediated rejection, detection of T cells in urine sediment was insufficiently sensitive and insufficiently specific for diagnosing acute rejection in our cohort of kidney transplant recipients.

The value of urinary decoy cells finding in patients with kidney transplantation.

Childhood infection with polyomaviruses leads to a life-long latent infection of renal and urinary tract epithelia. Replication in the reno-urinary epithelium is associated with viral cytopathic changes such as nuclear inclusions and decoy cells. During the 2005-2009 period, cytological urine analysis was performed in 154 samples (94 male and 60 female) from patients with kidney transplantation (n = 19), simultaneous pancreas-kidney transplantation (SPKT) (n = 9) and simultaneous kidney and liver transplantation (n = 2). Urine samples were analyzed monthly following transplantation according to the protocol. The period from transplantation to the first occurrence of decoy cells in the urine and the period of decoy cell persistence in the urine were assessed. The presence of decoy cells (< 10 and > 10 decoy cells) and red blood cells (< 20 E, 20-100 E and > 100 E) per cytospin smear was semiquantitatively determined, along with analysis of inflammatory cells (neutrophilic granulocytes) and fungi. In patients with decoy cells detected, their sensitivity, specificity, and negative and positive predictive value for BK virus nephropathy were calculated. Correlation of the study parameters was estimated by use of Kruskal-Wallis test (Statistica 7.1, StatSoft Inc., Tulsa, USA). Decoy cells were found in 30 patients (20 male and 10 female), age median 40 (range 16-69) years, at a mean of day 115 (range day 5-747) post transplantation, whereas their presence was recorded for a mean of 141 (range 77-771) days. Immunohistochemical staining of kidney biopsy sample for polyomavirus (SV40 large T-antigen) yielded positive reaction in 2/30 (7%) patients. Erythrocyturia was present in 29/30 patients with decoy cells. The number of decoy cells per cytospin smear generally ranged less than 10 in 25/30 patients, whereas more than 10 decoy cells per cytospin smear were only recorded in 5/30 patients. Immunohistochemistry produced positive finding for BK virus in one patient with SPKT and simultaneous kidney and liver transplantation each, which was statistically significantly more common as compared with patients with kidney transplantation alone (p = 0.0244). Immunohistochemical positivity for BK virus was more significant in cases with more than 10 decoy cells detected in cytospin smear (p = 0.013). In BK nephropathy, the finding of urinary decoy cells showed a 100% sensitivity, 84% specificity, 100% negative predictive value and 6% positive predictive value. BK virus nephropathy remains a significant post transplantation complication.