Changes in Tumor Characteristics in Kidney Transplanted Patients Over the Last 40 Years.

BACKGROUND: Post-transplantation tumors (PTTs) are the greatest limiting factor for patient survival following organ transplantation. AIM: To describe the incidence and main characteristics of malignancies developed in patients who underwent kidney transplantation in Budapest between 1973 and 2014. METHODS: During this period, the essential data for PTTs were repeatedly evaluated. In this study, the results from 1990, 1995, 2000, 2006, and 2013 were evaluated. RESULTS: Incidence of PTTs increased from 2.3% to 11.1%. Male/female ratio was 2:1. Skin, native kidney, and lung cancers were the most common tumors during the entire observation period. Lymphoma was seen rarely at the beginning and became common in 2013. The same was observed in the most frequent general population tumors (colorectal, breast, hepatic, prostate, gastric cancer, and malignant melanoma) where the occurrence increased in the last 10 years. Mean age of patients increased from 35.7 to 56.5 years. During the last 20 years, age of recipients increased: above 50 years from 22.9% to 40.5%, and above 60 years from 8.2% to 23.1%. Patient survival was different according to tumor stage at discovering, i.e. renal cell carcinoma was usually discovered in stage I. resulting in a 66.1% 5-year survival rate, whereas 43.5% of colorectal cancers were diagnosed in stage IV, with a 13.9% 5-year survival rate. CONCLUSION: The frequency of PTTs and proportion of elderly persons undergoing transplants are continuously increasing. Tumor stage is a determining factor for patient survival. Recognition of precancerous conditions, diagnosis of tumors in early stage, and oncological screening can improve survival time.

Results and complications after living related kidney transplantation in Hungary: 30 years' experience.

The number of patients suffering from kidney disorders is increasing the need for kidney transplantation. Kidneys originating from living donors (LD) show substantially better results than those originating from cadaveric donors (CD). We performed 3000 kidney transplantations between November 1973 and December 2007, including 154 from LD (5.13%). The early kidney function as measured by the delta creatinine clearance was significantly better among the LD group (P < .001). There was no significant difference in the immunologic data between the LD and the CD groups (P = .047). Four years after transplantation the glomerular filtration rate (GFR) and the serum creatinine level treated to be better among the LD group with tacrolimus versus cyclosporine immunosuppression (P = .089). In the LD group, the acute rejection rate was lower with tacrolimus- versus cyclosporine based immunosuppression (P = .014).

Bourneville-Pringle disease for kidney transplantation: a single-center experience.

The Bourneville-Pringle disease is an autosomal-dominant disease affecting the kidneys in about 60%, causing end-stage renal disease in about 10% of the cases. Among more than 2800 renal transplant recipients during the last 33 years, we had two patients with this original disease. A third patient who underwent bilateral nephrectomy is currently awaiting a graft. The first patient was diagnosed at the age of 20 years after a few episodes of retroperitoneal bleeding. At the age of 26 years her left kidney was removed after a rupture; it measured 7500 g, and the histology described angiomyolipomatosis. A year later she underwent a cadaveric kidney transplantation. Subsequently her right kidney was removed due to bleeding. She is currently 5 years posttransplant with stable kidney function and good health. Our second patient was nephrectomized at the age of 35 years and 38 years because of angiomyolipomatosis. She underwent a cadaveric kidney transplantation 7 years later. After 5 years of excellent kidney function and a year after her arteriovenous fistula was ligated her upperarm had to be amputated because of uncontrollable bleeding. After another 6 months, she displayed rapid progression of a jejunal tumor and during operation received 54 U of blood transfusion but died at the age of 49 years with a well-functioning graft. Our third patient consecutively underwent two nephrectomies because of angiomyolipomatosis of her kidneys at the ages of 25 and 28 years. She has two children with the same disease. In addition she carries Leyden mutation, which has caused deep venous thromboses and pulmonary emboli. She is currently on our waiting list for kidney transplantation. The Bourneville-Pringle disease is a rare indication for kidney transplantation; the prognosis of the patient is dependent on the original disease.

A prospective, randomized, multicenter trial of tacrolimus-based therapy with or without basiliximab in pediatric renal transplantation.

In a 6-month, multicenter, randomized, controlled, open-label, parallel-group trial, we investigated the efficacy and safety of adding basiliximab to a standard tacrolimus-based regimen in pediatric renal transplant recipients. Patients < 18 years received tacrolimus/azathioprine/steroids (TAS, n = 93) or tacrolimus/azathioprine/steroids/basiliximab (TAS + B, n = 99). Target tacrolimus levels were 10-20 ng/mL between days 0-21 and 5-15 ng/mL thereafter. Steroid dosing was identical in both groups. Basiliximab was administered at 10 mg (patients < 40 kg) or 20 mg (patients > or = 40 kg) within 4 h of reperfusion; the same dose was repeated on day 4. Biopsy-proven acute rejection rates were 20.4% (TAS) and 19.2% (TAS + B); steroid-resistant acute rejection rates were 3.2% and 3.0%, respectively. Patient survival was 100%; graft survival rates were 95% in both arms. The nature and incidence of adverse events were similar in both arms except toxic nephropathy and abdominal pain, which were significantly higher in the TAS + B arm (14.1% vs. 4.3%; p = 0.03 and 11.1% vs. 2.2%; p = 0.02; respectively). Median serum creatinine concentrations at 6 months were 86 micromol/L in the TAS and 91 micromol/L in the TAS + B arm; glomerular filtration rate was 79.4 and 77.6 (mL/min/1.73 m2), respectively. Adding basiliximab to a tacrolimus-based regimen is safe in pediatric patients, but does not improve clinical efficacy.

Tacrolimus combined with two different dosages of sirolimus in kidney transplantation: results of a multicenter study.

Tacrolimus combined with mycophenolate mofetil (MMF) is an effective regimen in kidney transplantation. This study compared the efficacy of combining tacrolimus and two different dosages of sirolimus with an established tacrolimus-MMF regimen. Each day in addition to tacrolimus, 325 patients received 2 mg sirolimus (TAC-SRL2 mg), 325 patients received 0.5 mg sirolimus (TAC-SRL0.5 mg) and 327 patients 1 g MMF (TAC-MMF). The initial tacrolimus dose was 0.2 mg/kg/day. Sirolimus patients received loading doses of 6 or 1.5 mg, and daily doses of 2 or 0.5 mg thereafter. Steroid administration was identical for all groups. The incidence of biopsy-proven acute rejection was lower in the TAC-SRL2 mg group (15.7%) compared with the TAC-SRL0.5 mg (25.2%, p = 0.003) and the TAC-MMF groups (22.3%, p = 0.036). Six-month graft survival was 91.0% (TAC-SRL2 mg), 92.6% (TAC-SRL0.5 mg) and 92.4% (TAC-MMF); the respective values for patient survival were 98.1%, 97.8% and 97.9%. Thirty-four patients (10.5%), 19 patients (5.8%) and 16 patients (4.9%) in the TAC-SRL2 mg, TAC-SRL0.5 mg and TAC-MMF groups, respectively, discontinued the study because of adverse events. Hyperlipemia was reported more often in the TAC-SRL2 mg group (24.0%) compared with 19.4% (TAC-SRL0.5 mg) and 11.0% (TAC-MMF; p < 0.05). Combining 2 mg sirolimus/day with tacrolimus results in lower rates of acute rejection, but a higher incidence of adverse events.

Is there any connection between the presence of kidney stones in primary hyperparathyroidism and the location of an underlying adenoma?

The majority of the patients with primary hyperparathyroidism (pHPT) recurrently produce kidney stones, while the rest have other clinical manifestations. The aim of this study was to examine the possibility of an association between the presence of kidney stones and the location of an underlying adenoma. This was a retrospective evaluation of the records of 91 patients (10 males, 81 females, mean age: 61.9 years [20 - 70 yrs]) operated for primary hyperparathyroidism between 1995 and 2000. One patient was excluded due to carcinoma. Kidney stones were found in 55 cases and other clinical symptoms in 35 cases. In 50 of the 55 patients (91 %) with kidney stones, the adenoma was located in the left inferior parathyroid gland (chi2 = 67.5, p < 0.00,001), while in 24 of the 35 patients (69 %) without kidney stones, the adenoma was in the right inferior parathyroid gland (chi2 = 43.9, p < 0.0001). These results suggest that the location of the adenoma may influence the presence of kidney stones in pHPT. It is proposed that the biologic effects of parathyroid hormone could differ depending on which of the four parathyroid glands it was secreted in, or the four glands may produce different biologically active fragments.

Mutation scanning of the p53 tumor suppressor gene in renal and liver transplant patients in Hungary.

INTRODUCTION: The increased incidence of malignancies among transplanted patients is well known. Abnormal function of the p53 tumor suppressor gene has been reported in more than half of all tumors. The aim of our study was to detect point mutations of p53 gene in transplanted patients because the presence of mutations may be a predictive factor for tumor development. An earlier diagnosis can help to develop new strategies for immunosuppressive therapies. METHODS: Three point mutations were chosen based on the literature: exon5-codon175, exon7-codon248, exon8-codon273. Genomic DNA from the plasma of 60 liver, 362 renal transplants, and 45 nontransplanted patients with different tumors and 20 suspected healthy patients were analyzed with a real-time PCR method using the Roche LightCycler. The mutations were evaluated by melting curve analysis. RESULTS: We elaborated a special protocol for scanning the above mentioned p53 point mutations, which were proved by sequencing as well. Among 487 patients, 486 showed a wild-type genotype. The only patient carrying a mutation at codon 273 (heterozygous) was a liver transplant patient, who developed pancreas carcinoma and had already died. CONCLUSION: Our data suggest that mutations of the targeted codons in leukocyte DNA seem to be rare, but a mutation could be lethal. The evaluated three point mutations of p53 gene were not predictive for tumor development.

Improving results of renal transplantation with the use of elderly donors: the Budapest experience.

The use of elderly donors has become a necessity with the increasing demand for deceased donor organs resulting in transplant centers worldwide expanding their donor criteria. We, therefore, thought it appropriate to review our experience using elderly (>60 years) brain-dead donors for kidney transplantation. We investigated the influence of donor parameters on early graft function and survival. A retrospective comparative analysis of three periods was performed: 1994 to 1998 (P1) n = 40; 1999 to 2000 (P2) n = 28; and 2001 to 2002 (P3) with n = 31 donors. Mean donor age in each period was 63.4 +/- 3.3, 64.5 +/- 3.4, and 63.8 +/- 2.7 years; mean diuresis was 473 +/- 450, 307 +/- 316, and 276 +/- 185 mL/hour; and the need for vasopressors during donor management was 81%, 85%, and 70% respectively. The number of kidney recipients was 59, 30, and 37, mean age was 49 +/- 13, 53 +/- 11 and 54 +/- 8 years, the recipient ratio of patients >60 years was 17%, 33%, and 27% respectively, and no differences among the groups in the HLA mismatch. Primary nonfunction occurred in 8.5%, 0%, and 2.8%; acute rejection ratio at 1 year was 35%, 36%, and 32%, the mean serum creatinine at 12 months was 183.7 +/- 66.0, 157.8 +/- 41.2 and 160.7 +/- 46.5 mumol/L. The 1-year graft survival was 71.2%, 91.0% and 92.0% and the 1-year patient survival 88.2%, 96.6%, and 97.2%, respectively, for periods 1, 2, and 3. There has been a considerable improvement in the 1-year graft and patient survivals. With careful donor and recipient evaluation, individualized immunosuppression, and age matching the results of renal transplantation from elderly deceased donors can be comparable to the results of the "optimal" deceased donor kidney transplantation.

De novo tumors after kidney transplantation: the Budapest experience.

In a retrospective study we analyzed the incidence and characteristics of de novo tumors developing in renal transplant recipients treated in our center. The 5% incidence de novo tumors developing among patients treated with azathioprine and prednisolone (n = 241) was similar to the 5.4% incidence of de novo tumors developing among patients treated with calcineurin-based immunosuppression (n = 1918). The most common malignancies among our patients were basal cell (21.7%) and squamous cell (13.9%) carcinomas of the skin, followed by urogenital (10.4%) and lung malformations (9.6%). A high incidence of Kaposi's sarcoma (9.6%; half cutaneous and half visceral) and a lower than expected incidence of posttransplant lymphoproliferative disorder (PTLD; 3.5%) was found. Among patients developing de novo tumors, the incidence of death with a functioning graft was higher than among recipients without tumors. Moreover, the incidence of tumor-related death was high among the de novo tumor recipients. Among our recipients, the most aggressive tumors were Kaposi's sarcoma, lung tumors, lymphomas, and gastrointestinal tumors, which occurred relatively early after transplantation and were the cause of death in most cases. Compared to tumor registry data, we found an inverse basal-to-squamous cell carcinoma ratio, a lower incidence of PTLD, and a higher incidence of Kaposi's sarcoma.

Freedom from rejection and stable kidney function are excellent criteria for steroid withdrawal in tacrolimus-treated kidney transplant recipients.

OBJECTIVES: This prospective, randomized, multicentre study investigated the efficacy and safety of two tacrolimus-based regimens and their potential to withdraw steroids. METHODS: In total 489 patients were randomised to receive either tacrolimus and MMF (n = 243) or tacrolimus and azathioprine (n = 246) concomitantly with steroids in both treatment groups. The initial oral dose of tacrolimus was 0.2 mg/kg/day, MMF dose was 1 g/day, azathioprine was administered at 1-2 mg/day. Steroids were tapered from 20 mg/day to 5 mg/day. From month 3 onwards, steroids were withdrawn in patients who were free from steroid-resistant rejection and who had serum creatinine concentrations < 160 mumol/L. Study duration was 6 months. RESULTS: Patient survival at month 6 was 98.3% (Tac/MMF/S) and 98.4% (Tac/Aza/S), graft survival at 6 month was 95.0% (Tac/MMF/S) and 93.5% (Tac/Aza/S). The 6-month incidences of biopsy-proven acute rejection were 18.9% (Tac/MMF/S) compared with 26.8% (Tac/Aza/S), p = 0.038. The 6-month incidences of steroid-resistant acute rejection were 2.1% (Tac/MMF/S) and 4.9% (Tac/Aza/S), p = ns. At the end of month 3, steroid withdrawal was performed in 60.5% (Tac/MMF/S) and 48.8% (Tac/Aza/S) of patients, p < 0.01. During months 4-6, 2.7% of patients in the Tac/MMF group had a biopsy-confirmed acute rejection compared with 0.8% of patients in the Tac/Aza group. In patients who continued to receive steroids, the incidences of biopsy-proven acute rejections during months 4-6 were 3.5% (Tac/MMF/S) and 7.1% (Tac/Aza/S). At study end, the steroid-free patients had an excellent kidney function, the median serum creatinine concentration was 119.5 mumol/L (Tac/MMF) and 115.1 mumol/L (Tac/Aza); the median serum creatinine of the total study group was 130.5 mumol/L (Tac/MMF/S) and 132.8 mumol/L (Tac/Aza/S). CONCLUSION: Both tacrolimus regimens are efficacious and safe. The combination of Tacrolimus and MMF achieved a lower rejection rate and permitted a higher proportion of steroid-free patients. The overall incidence of acute rejection was low and kidney function was good.

Angiography effectively supports the diagnosis of hepatic metastases in medullary thyroid carcinoma.

BACKGROUND: Medullary thyroid carcinoma (MTC) belongs in the group of neuroendocrine tumors with early lymphatic and hepatic dissemination. A high rate of undetectable metastases is hypothesized to be responsible for the frequent mismatch between the apparent relatively small tumor burden and the elevated plasma tumor marker level. METHODS: Thirty-six MTC patients with residual/recurrent biochemical signs (elevated basal calcitonin level) and/or characteristic general symptoms (diarrhea and/or flushing) were systematically examined by conventional radiology, whole-body 18F-deoxyglucose positron emission tomography (PET), dynamic liver computed tomography and magnetic resonance imaging, and hepatic angiography. RESULTS: Conventional diagnostic imaging revealed lymph node (LN) involvement in the cervical, mediastinal, supraclavicular, and axillary regions (16 cases), and multiple pulmonary (3 cases), bony (1 solitary and 1 multiple case), and breast (1 case) metastases. (18)F-deoxyglucose PET identified all these extralymphatic metastatic lesions (except 2 cases with multiple pulmonary metastases), and also supradiaphragmatic LN involvement in 34 (94%) patients. In 32 (89%) cases, multiple small (generally < or = 1 cm) hypervascular, hepatic metastases undetectable by other imaging methods were localized angiographically. Of the 23 original pathologic specimens investigated, 18 (78%) exhibited LN involvement. The smallest primary tumor in patients with hepatic metastases was 1 cm. CONCLUSIONS: Hepatic angiography is recommended for primary staging in MTC patients with a primary tumor measuring 1 cm or larger, and/or pathologically proven LN involvement, and also during restaging for suspected recurrences to avoid unnecessary extensive surgical LN dissection in the neck and mediastinum.

[Qualitative and quantitative detection of hepatitis C virus RNA by PCR technique. Monitoring of viral copies after liver transplantation]. / Hepatitis C-vírus (HCV)-RNS kvalitatív és kvantitatív kimutatása PCR technikával. A HCV-RNS-kópiaszám monitorozása májtranszplantációt követóen.

The authors demonstrate the HCV nucleic acid amplification method is not wide-spread in Hungary yet. The HCV-RNA is usually detectable 2-4 weeks after infection independently the immunostate of the patients. The authors help to select the adequate measurement(s) in logical order when HCV infection is suspected. The benefit of the PCR method is emphasized. Monitoring of the HCV-RNA titer of the liver transplanted patients promotes to establish the fluctuation of HCV-RNA copies and the effectivity of therapy following transplantation. The detection of HCV-RNA by PCR method is a proof of an acute or chronic infection and rules out past infection. The quantitative PCR measurement is useful for determination of indication and control of efficacy of antiviral therapy.

Optimization of hepatocyte spheroid formation for hepatic tissue engineering on three-dimensional biodegradable polymer within a flow bioreactor prior to implantation.

We hypothesize that in vitro conditioning of hepatocytes within biodegradable poly-L-lactic acid (PLLA) polymer matrices prior to implantation may increase hepatocyte survival and function after transplantation. The purpose of this study was to optimize the culture conditions of hepatocytes in a pulsatile flow bioreactor. PLLA discs were seeded with rat hepatocytes in a concentration of 2.5, 5, 10, 20 and 40 x 10(6) cells/ml. Seeded discs were exposed to recirculated perpendicular flow of 0, 7, 15, 24, 32, 52 ml/min of supplemented Williams' Medium E and harvested after 6 days in flow culture. Only under flow conditions the hepatocytes formed spheroidal aggregates (SphA) of 50-260 microm in diameter with a liver-like morphology and active metabolic function. The number of SphA was examined by phase contrast microscopy and the reductive enzyme function of the hepatocytes was tested using MTT. Hematoxylin and eosin histology showed vital hepatocytes within the SphA less than 200 microm in diameter but central necrosis in the SphA exceeding this size. Immunohistochemical staining confirmed albumin production of hepatocytes within the SphA. The optimal cell seeding concentration was 10 x 10(6) cells/ml with a flow speed of 24 ml/min. SphA of hepatocytes cultured with this flow bioreactor method may prove useful as a functional unit for tissue engineering of an in vivo liver substitute.

Renal tubular cell necrosis and apoptosis in transplanted kidneys.

Renal wedge biopsies were taken from donors' kidneys immediately at the end of cold ischaemia and 30 min after transplantation in 11 cases. Five renal grafts showed immediate and six showed delayed renal function clinically. The ratio of apoptotic and necrotic renal tubular cells and Ki67 activity was determined in both biopsies. Necrotic and apoptotic as well as proliferating renal tubular cells were seen in all samples. Both apoptotic and proliferative activity was decreased in samples taken 30 min after transplantation in cases of immediate renal function compared to the samples taken before transplantation. This phenomenon was not observed in cases of delayed renal function.