Does Histopathology of Implanted Kidney According to Banff 07 Help Predict Long-term Transplantation Outcome?

Analyses of peritransplant biopsies of deceased-donor kidneys show high incidence of chronic abnormalities. The question arises whether chronic abnormalities present at implantation determine engrafted kidney fate regardless of other concomitant variables. The aim of this study was to identify risk factors of graft loss considering histopathological changes present at implantation scored according to Banff 07 criteria. PATIENTS AND METHODS: Inclusion criteria (n = 300) was engraftment between years 2000 and 2008 and availability of implantation biopsy. Analyzed abnormalities present in donor biopsy were arteriolar hyalinization, interstitial fibrosis, intimal sclerotization, tubular atrophy, total inflammation, and percentage of sclerotic glomeruli (Banff classification). Allograft function was estimated by abbreviated Modification of Diet in Renal Disease formula and proteinuria semi-quantitatively by standard dip-stick test. Kaplan-Meier estimate was used to assess graft survival. Searching for independent risk factors of graft survival was performed by means of Cox proportional hazards models (SAS System, SAS Institute Inc, Cary, NC, United States). RESULTS: In one-factor analyses, predictors of kidney allograft loss were donor age, donor history of diabetes, kidney allograft dysfunction within first posttransplant year, and recipient chronic hepatitis C. In terms of chronic abnormalities, arteriolar hyalinization of any intensity nearly doubled the risk of allograft loss. Independent risk factors of kidney allograft loss in multivariate analysis were donor age, posttransplant diabetes mellitus, proteinuria after engraftment, and recipient hepatitis C. CONCLUSION: The effect of arteriolar hyalinization on renal transplant survival is probably interwoven with other predictors of graft loss. Recognizing the negative impact of recipient chronic hepatitis C on graft survival, hepatitis C virus treatment should be provided to patients with advanced chronic kidney disease, patients on wait lists, or patients already transplanted.

Analysis of Health Behaviors in Patients After Liver Transplant.

Currently, transplantation is one of the most effective treatments for the failure of organs such as liver, kidneys, or heart. Keeping to specific recommendations by organ recipients is extremely important, as they are vital to the effectiveness of the transplant. Positive health behaviors (HBs) have significant impact on strengthening the recipient's health. AIM: The aim of this work is to indicate which HBs are exhibited by patients after liver transplants. MATERIALS AND METHODS: The study group consisted of 115 adult liver recipients, in various times after their transplants. The average age in the group was 53.83 years old. The major reason for transplant was post-inflammatory cirrhosis of liver originating from hepatitis B or C viral infection. A diagnostic survey was used in the study, as well as a tool in the form of an original questionnaire and Juczynski's standard Health Behavior Inventory (HBI) questionnaire. RESULTS: On the scale of general HBI index, patients achieved high results (M = 101), which shows that most recipients were disciplined in adhering to HBs. The worst results were achieved in the category of good eating habits, which proves that some respondents do not keep to the principles of healthy eating. The longer the time after the transplant, the lesser the extent in complying with HBs by recipients, in the first place in the scope of maintaining positive mental attitude. Specific behaviors were slightly worse, especially in residents of the countryside. CONCLUSIONS: Adherence to particular categories of health strengthening behaviors is conditioned by specified sociodemographic variables. Sex, level of education, and professional status significantly affect the implementation of pro-health activities. These are best implemented by women who had completed university and high school education who are on a pension or retired.

Prevalence of Cervical Infection With Human Papillomavirus of High Oncogenic Potential in Immunosuppressed Women on Renal Replacement Therapy With and Without Mammalian Target of Rapamycin Inhibitors.

BACKGROUND: Chronic immunosuppression constitutes a risk factor of human papillomavirus (HPV) related cervical cancer development. Maintenance immunosuppression with mammalian target of rapamycin (mTOR) inhibitors is associated with decreased incidence of de novo malignancies in kidney graft recipients. Recently published data suggest that mTOR inhibitors interfere with viral replication. The aim of the study was to assess if there is a difference in prevalence of HPV cervical infection in women on immunosuppressive regimens with or without mTOR inhibitors. MATERIAL AND METHODS: Cervical swabs taken from 64 immunosuppressed women on renal replacement therapy were analyzed for the presence of high-risk (HR) HPV DNA by means of an Amplicor HPV test and assessed taking into account the recorded data on mTOR inhibitor use. RESULTS: The testing revealed the presence of HR HPV DNA in none of the women that were treated with mTOR inhibitors and in 21.4% of patients that were administered immunosuppressive regimens without mTOR inhibitors (P = .08). Interestingly, 32% of women from the mTOR(-) group in contrast to 12.5% in the mTOR(+) group declared having had more than 2 lifetime sexual partners. CONCLUSIONS: Our results suggest that mTOR inhibitors might constitute a promising therapy modification in women at risk of HPV cervical malignancy development, but the effectiveness of such strategy requires further studies.

Malnutrition Risk in Kidney Recipients Treated With Mycophenolate Mofetil Is Associated With IMPDH1 rs2278294 Polymorphism.

BACKGROUND: Malnutrition is known to increase morbidity and mortality in renal transplant recipients, whereas little is known about genetic predisposition to low body mass index (BMI) in the transplant setting. Inosine monophosphate dehydrogenase (IMPDH) regulates intracellular fat accumulation, pre-adipicytes maturation, and is a target of mycophenolic acid (MPA) used as a standard immunosuppressant. We hypothesized that MPA may interfere with fat tissue formation and weight gain in kidney transplant recipients and this process may be modified by IMPDH1 or IMPDH2 (genes encoding constitutive and inducible IMPDH) small nucleotide polymorphism variants. STUDY DESIGN: In an observational longitudinal study of kidney transplant recipients treated with mycophenolate mofetil, genetic factors were IMPDH1 (rs2278294, rs2278293) and IMPDH2 (rs11706052) allelic variants, the main outcome was the time-dependent change in BMI, and secondary outcomes were occurrence of BMI below 18.5 or 20 kg/m2. RESULTS: In a study group of 190 patients, no association was found between BMI changes and rs11706052 and rs2278293 variants. In terms of rs2278294, we found that allele G was associated with significantly slower BMI gain in a dominant model of inheritance. Concerning secondary endpoints, none of the AA carriers were underweight at 6 months post-implantation, while at least 2% of G allele carriers were underweight. From the first post-transplant year, all AA carriers had BMI above 20 kg/m2, while among G allele carriers at least 10% had BMI < 20 kg/m2 by generalized estimating equations. CONCLUSION: Based on our results, we postulate that MPA derivates influence post-transplant BMI and potentially also body fat content. In consequence, genotyping rs2278294 would potentially allow clinicians to personalize MPA treatment.

In Vitro Fertilization and Pregnancy Outcomes Among Patients After Kidney Transplantation: Case Series and Single-Center Experience.

INTRODUCTION: Kidney transplantation (KTx) is the treatment of choice in patients with end-stage renal failure. Among various medical issues in female graft recipients, the need for maternity can become an overriding one. Gonadal dysfunction usually resolves within 6 months after transplantation; however, the prevalence of infertility is similar to this in the general population. MATERIALS AND METHODS: This case series describes the experience in infertility treatment and following perinatal care among KTx women who underwent successful in vitro fertilization (IVF). We followed three patients who previously received KTx and underwent IVF between 2014 and 2015. The 34-year-old (patient A) and 39-year-old (patient B) women received single KTx, and the 31-year-old (patient C) woman had received three previous transplantations. Patients A and C were diagnosed with primary tubal factor infertility, while patient B suffered from secondary idiopathic infertility. The stimulation protocols had no influence on their general condition nor graft function. Viable singleton pregnancies were confirmed in all cases. All newborns were born preterm, via cesarean section, as a consequence of severe preeclampsia. Patients A and C gave birth at 34th week of gestation (WG) (A: 1810 g and C: 2295 g), while patient B gave birth at 36th WG (2655 g). Other pregnancy complications were intrauterine growth restriction (patient A) and gestational diabetes mellitus (patient B). Although mild graft dysfunction was observed prior to delivery, all clinical measures and hypertension resolved during the puerperium. CONCLUSIONS: In these cases, pregnancy after KTx did not implicate persistent graft dysfunction. Regardless of the method of conception, pregnancy following KTx is associated with an increased incidence of complications, therefore it requires a multidisciplinary approach. IVF itself seems to be a safe procedure in KTx recipients if the pregnancy is advisable.

Delivery Method in Patients After Liver or Kidney Transplantation.

Pregnancy following renal or liver transplant is safe for the mother, fetus, and allograft if standard practice guidelines are strictly followed. Cesarean delivery is often required for the safety of the mother and child. The aim of this paper was the evaluation of delivery method in patients after liver (G1) and kidney transplantation (G2) in comparison with the population of healthy pregnant women (G0). MATERIALS: Retrospective analysis included 51 (G1) and 59 (G2) women who delivered between 2000 and 2016. Control group (G0) consisted of 170 nontransplanted patients, who delivered between 2014 and 2016. The results were compared using nonparametric and parametric tests (Fisher exact test, t test). The SAS 9.2 was used for the analysis. RESULTS: The rate of cesarean delivery was high in all pregnancies following kidney (G1 = 80.4%) or liver transplantation (G2 = 67.8%) compared with control group (G0 = 44.1%; P < .05). The most common indication for cesarean delivery in G1 was gestational hypertension/preeclampsia (n = 18; 43.9%), threatening intrauterine asphyxia (n = 12; 29.3%), and failure to progress (n = 2; 4.9%). The most common indications for cesarean delivery in G2 were threatening intrauterine asphyxia (n = 14; 35%), failure to progress (n = 9; 22.5%), and gestational hypertension/preeclampsia (n = 2; 5%). CONCLUSION: Cesarean delivery in patients after kidney or liver transplantation is performed mainly for obstetric reasons. The reported incidence of cesarean delivery in pregnancy following transplant is high, reflecting the high degree of clinical caution exercised in these patients.

Posttransplantation glomerulonephritis: risk factors associated with kidney allograft loss.

AIM OF THE STUDY: Chronic glomerulonephritis (GN) is reported as a common cause of late kidney allograft loss. The aim of this study was to identify risk factors associated with kidney allograft loss in the course of posttransplantation GN. PATIENTS AND METHODS: The study analyzed 75 kidney allograft recipients with biopsy-confirmed posttransplantation GN, including 27 cases of immunoglobulin (Ig)A nephropathy (IgAN), 30 of membranous GN (MGN), 6 of mesangiocapillary GN (MCGN); and 12 of focal segmental GN (FSGS). The risk factors for kidney allograft loss, defined as dialysis reintroduction after GN onset, were identified through are historical cohort study. CLINICAL FINDINGS: After the onset of posttransplantation GN, the median time to dialysis introduction was 46 months. The risk factors for kidney allograft loss were as follows: male gender (hazard ratio [HR] = 1.92; 95% confidence intervall [CI] 1.0-3.70; P = .052), initial unsatisfactory kidney function (HR = 1.86 per 1 mg/dL serum creatinine increment; 95% CI 1.0-3.46; P < .05), graft dysfunction at diagnosis (HR = 1.65 per 1 mg/dL serum creatinine increment; 95% CI 1.32-2.07; P < .001), nephrotic syndrome (HR = 2.3; 95% CI 1.13-4.99; P < .05) late-onset GN (HR = 1.1 per each additional year of observation, 95% CI 1.0-1.21; P < .05), and MPGN as a type of GN. Enhanced immunosuppression increased and ACEI and/or statin treatment decreased the risk of return to dialysis, respectively: HR = 1.56, 95% CI 0.76-3.18, P = .22; HR = 0.39, 95% CI 0.16-0.98, P = .0037; and HR = 0.367, 95% CI 0.15-0.88, P = .025. CONCLUSIONS: Identification of risk factors can help discover patients who will have a faster progression to kidney allograft loss due to GN. In posttransplantation GN, statins and/or ACEI should be prescribed, if there are no contraindications.

Oral and transdermal hormonal contraception in women after kidney transplantation.

AIM: The aim of the study was to assess the safety of low-dose oral or transdermal hormonal contraception in kidney recipients. MATERIALS AND METHODS: Twenty-six kidney recipients, aged 18 to 44 years (mean, 31.0) took low-dose contraceptive pills, and 10 kidney recipients, aged 22 to 36 years (mean, 31.4) used transdermal contraceptive systems. Contraception was administered for a period not shorter than 18 months. At the onset of therapy all patients showed stable graft function. The main indication for therapy was effective contraception. Additional indications were mild ovarian cysts and irregular or profuse menstruations. The pills consisted of 20 to 35 microg of etinyl estradiol and generation III progestogen. The contraceptive patch released 20 microg of etinyl estradiol and 150 microg of norelgesromin daily. RESULTS: No case of pregnancy was noted. Oral contraception was discontinued in two cases, in one case due to profound thrombophlebitis of the lower extremity and in the other case deterioration of liver function. No other side effects or symptoms of intolerance were reported. Hormonal contraception did not significantly influence body mass index, mean blood pressure, serum creatinine, or other biochemical parameters. CONCLUSION: Despite the presence of relative contraindications, mainly arterial hypertension and impaired liver function, hormonal contraception should be considered in female kidney recipients to be a highly effective contraceptive method that additionally regulates menstrual bleeding, protects from development of mild ovarian cysts and seems to positively influence women's well-being. The transdermal mode of administration may diminish the chance for drug interactions and therefore be safer for patients.

C4d complement split product in diagnosis of immunological activity of chronic allograft nephropathy.

INTRODUCTION: Activation of the humoral branch of the immunological response is currently believed to play an important role in pathogenesis of chronic allograft nephropathy. The impact of humoral alloreactivity, indicated by the presence of C4d deposits in peritubular capillaries of a renal allograft, on the development of chronic allograft nephropathy is a significant problem in transplantation. The aim of the study was to assess and correlate C4d expression in patients with chronic allograft nephropathy, with clinical and morphological variables, as well as to assess the impact of a change in immunosuppression regimen on posttransplant course and renal allograft morphology. PATIENTS AND METHODS: Twenty-six patients with chronic allograft nephropathy underwent biopsies to correlate C4d expression with clinical parameters and morphological findings. In all patients azathioprine was replaced with mycophenolate mofetil with additional CsA dose reduction in 12 patients. After 1 year, 14 protocol biopsies were performed. RESULTS: The frequency of C4d peritubular capillary deposition among patients with chronic allograft nephropathy was 30%. C4d expression appeared later after transplantation, was correlated with chronic allograft glomerulopathy and proteinuria but not other clinical or histological variables. C4d deposits displayed no independent impact on serum creatinine level. Proteinuria was significantly more reduced in the C4d(+) group. Progression of chronic morphological changes was significantly accelerated in the C4d(+) group. CONCLUSION: C4d peritubular capillary expression did not differentiate patients after immunosuppression enhancement, but it predisposed to progression of chronic morphological findings during 1-year observation.

Thrombotic nephropathy and pulmonary hypertension following autologous bone marrow transplantation in a patient with acute lymphoblastic leukemia: case report.

Thrombotic microangiopathy is a severe and life-threatening complication following allogeneic or autologous bone marrow transplantation (BMT). Herein we describe a case of microangiopathic hemolytic anemia with progressive renal failure and pulmonary hypertension subsequent to autologous BMT due to acute lymphoblastic leukemia.

IgA nephropathy in kidney allograft recipients-therapeutic perspective.

INTRODUCTION: A growing number of patients are losing their kidney allografts due to glomerulonephritis. Although posttransplant IgA nephropathy (IgAN) is regarded as benign, it may lead to late allograft loss in a substantial number of patients. The aim of this study was to evaluate the influence of posttransplant IgAN on long-term transplantation outcomes, risk factors for progression of graft dysfunction, and effectiveness of therapeutic interventions. PATIENTS AND METHODS: We evaluated, potential risk factors for accelerated graft loss among 27 kidney allograft recipients with posttransplant IgAN, comparing graft survival in a control group matched for population and transplantation-related parameters. We evaluated the effectiveness of therapeutic interventions regarding immunosuppressive regimen, and hypertension control including angiotensin converting enzyme inhibitor (ACEI) usage with Kaplan-Meier, Cox proportional hazard plots, and log-rank tests in statistical analyses. RESULTS: Compared with the control group, patients with IgAN experienced a 6.57 higher risk for dialysis dependence (P < .01, 95% CI 1.4 to 30.83). The risk for accelerated graft loss in the course of IgAN was associated with graft dysfunction (RR = 2.16 for additional 1 mg/dL of serum creatinine at glomerulonephritis presentation; P < .03, 95% CI 1.2 to 4.36) and intense proteinuria as evidenced by a RR = 4.67 for the presence of the nephrotic syndrome (P < .05, 95% CI 0.95 to 22.8). Immunosuppression enhancement resulted in a significantly decreased risk of dialysis dependence, namely, RR = 4.76 (95% CI 1.12 to 20, P < .04). With ACEI treatment there was a tendency for a 2.8-fold decreased risk of dialysis dependence, without reaching statistical significance (P = .14). CONCLUSIONS: Patients with posttransplant IgAN may benefit from intensifying maintenance immunosuppression, which slows progression to end-stage graft dysfunction.

Genetic analysis of liver tumorigenesis in SV40 T antigen transgenic mice implies a role for imprinted genes.

Liver tumors from interspecific hybrid, transgenic mice containing the SV40 early region linked to a mouse major urinary protein enhancer/promoter were analyzed for loss of heterozygosity to identify chromosomal regions which potentially contain genetic loci involved in multistep tumorigenesis. A broad pattern of complete and partial loss of heterozygosity or allelic imbalance was observed with frequent loss of heterozygosity/partial loss of heterozygosity of loci on chromosomes 1, 5, 7, 8, and 12. In tumors from Mus domesticus x Mus spretus F1 mice a strong preference for loss of the domesticus allele of H19 on chromosome 7 was observed, whereas loss of heterozygosity/partial loss of heterozygosity on chromosome 8 involved preferential loss of spretus alleles. In tumors from reciprocal crosses with Mus castaneus, the maternal chromosome 7 H19 allele was preferentially lost irrespective of whether it was domesticus or castaneus, strongly suggesting the involvement of an imprinted gene(s) in tumor progression.

Genomic DNA-based hMSH2 and hMLH1 mutation screening in 32 Eastern United States hereditary nonpolyposis colorectal cancer pedigrees.

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant cancer syndrome characterized by early age of onset colorectal cancer (mean 45 years) as well as endometrial, urinary tract, and upper gastrointestinal adenocarcinomas. The HNPCC phenotype has been shown to segregate with germline mutations in the human homologues of the DNA mismatch repair genes MSH2, MLH1, PMS1, and PMS2. However, the majority of published DNA mismatch repair gene mutation surveys associated with HNPCC kindreds report multiple levels of preselection, including 2p and 3p chromosomal linkage analysis and the evaluation of microsatellite instability of proband colorectal cancers prior to mutation analysis. For this reason, the concise contribution of each of the known DNA mismatch repair genes to the HNPCC phenotype remains unknown. We report the results of a genomic DNA-based analysis of hMSH2 and hMLH1 germline mutations in 32 unrelated Eastern United States HNPCC kindreds. These families were selected for study on the basis of phenotype only. We identified three hMSH2 and six hMLH1 mutations in eight families, for a positive mutation rate of 25%. Two mutations were identified in one of the families. Four of the mutations detected have not been reported in the literature previously. One of the mutation-positive families is African American; the others were of European-American ancestry. These results provide a clarification of the contribution of hMSH2 and hMLH1 to the HNPCC phenotype and suggest that in the majority of Eastern United States HNPCC kindreds selected by phenotype alone, the molecular genetic basis for the disease remains unknown.

Association of MYH9 rs3752462 and rs5756168 Polymorphisms With Transplanted Kidney Artery Stenosis.

Allelic variants of the MYH9 gene, encoding myosin nonmuscle heavy chain type IIA, have been shown to correlate with diminished glomerular filtration rates and end-stage kidney disease in individuals of Caucasian ancestry. Myosin nonmuscle heavy chain type IIA is expressed during development as well as in injured vessels and kidney structures. We hypothesized that MYH9 risk variants may correlate with kidney artery injury and dysfunctional healing, such as transplant renal artery stenosis (TRAS). Our study aimed at evaluating the association of MYH9 risk allelic variants (rs4821480, rs4821481, rs3752462, rs11089788, rs136211, rs5756168, rs2032487, and rs2239784) with TRAS, defined as >50% renal artery lumen reduction. Genotyping was performed with the use of custom Taqman genotyping assays on DNA samples (n = 295) from white deceased-donor kidney transplant recipients and genomic DNA from the corresponding donors. Statistical analysis was performed with the use of Kaplan-Meier estimates, log-rank tests, and proportional hazard Cox models. Recipients carrying TT in rs5756168 experienced diminished risk of TRAS (hazard ratio [HR], 0.31; P < .009), whereas organs carrying CC in rs3752462 were exposed to excessive TRAS risk (HR, 2.54; P < .047). In multivariate stepwise analysis TRAS was 10.9-fold increased in kidneys originating from rs3752462 CC, whereas the risk was decreased 3.45-fold (adjusted HR, 0.29) in recipients carrying rs5756168 TT (P < .007 and P < .033, respectively). Intracranial bleeding or trauma compared with other mechanisms of donor death diminished TRAS risk by 87% and 91%, respectively (P < .030 and P < .017). Our study is the first to identify genetic predisposition to transplant renal artery stenosis.

Serum TGF-beta1 correlates with chronic histopathological lesions in protocol biopsies of kidney allograft recipients.

INTRODUCTION: Transforming growth factor-beta (TGF-beta) is a well-known profibrotic factor playing a role in chronic kidney allograft nephropathy. Cyclosporine (CsA)-sparing immunosuppressive regimens may improve long-term graft function. Our aim was to study the influence of immunosuppressive treatment with versus without calcineurin inhibitors on serum TGF-beta levels and histological changes in protocol biopsies of kidney allograft recipients. PATIENTS AND METHODS: In this prospective, randomized study of 42 low-rejection risk patients we randomized two groups: group A: mycophenolate mofetil (MMF), prednisone, daclizumab, and reduced CsA dose for 7 months (5 mg per kg per day) followed by complete withdrawal (n = 21); and group B: normal CsA dose (10 mg per kg per day adjusted according to C2 levels), MMF, prednisone, and no daclizumab (n = 21). METHODS: In both groups we performed histological assessments (Banff 97) and measured serum TFG-beta levels before as well as, at 3 and 12 months after transplantation. RESULTS: We found a relationship between immunosuppressive regimen and the TGF-beta concentration over 1 year of observation. Before transplant the TGF-beta1 levels did not differ between the groups (P = .29); at 3 months they were 33 +/- 9 vs 49 +/- 15 pg per mL, respectively, in groups A and B (P = .08), and at 12 months they were 39.5 +/- 4 versus 55.5 +/- 11 pg per mL, respectively, in groups A and B (P = .03). Protocol biopsies at 12 months in group B showed chronic tubular lesions more pronounced than in group A. TGF-beta1 concentrations were significantly higher among group B than A. We conclude that TGF-beta1 concentration may predict the development of kidney graft fibrosis; early CsA withdrawal may achieve a reduction in chronic tubular and interstitial injury of cadaveric kidney allografts.

Inhibition of mammary carcinogenesis in rats by dietary restriction.

Mammary tumors were induced by 7,12-dimethylbenz[a]anthracene (DMBA) in Sprague-Dawley female rats kept under different dietary restrictions. Starting at 40 days of age, 4 groups of rats were either full-fed or fed 25%, 50% or 80% of their daily ration. At 55 days of age DMBA was given by intravenous injection. Rats were continued on the restricted diet until 150 days after carcinogen treatment. Rats on 25% diet lost weight rapidly and the experiment had to be terminated. Rats on the 50% diet maintained a lower body weight throughout the experiment; only 12% developed tumors. Rats on the 80% diet lost weight initially, but at the termination of the experiment, there was no significant difference in body weight between this group and the full-fed controls. Of the rats on 80% diet, 34% developed tumors, compared to 92% tumor incidence in the full-fed controls. Vaginal smears were normal in the animals fed the 80% diet, while some irregularity was observed in the 50% group. Breeding capability in rats on the 80% diet was not affected, since there was no observable difference in the pregnancy rate between these animals and their controls. There was also no difference in plasma level of estrogen between the 80% diet group and the full-fed controls at the time of carcinogen treatment. [3H]Thymidine labelling index was significantly affected by 50% restriction of diet while there was no significant change in the 80% group.

Differential regulation of TGF-beta 2 by hormones in rat uterus and mammary gland.

Previous work from this laboratory has shown that transforming growth factor beta 2 (TGF-beta 2) mRNA is abundant in the pregnant uterus. In the present study, we examined the synthesis and secretion of TGF-beta 1,2 and 3 in the rat uterus and mammary gland and show differential secretion and expression of TGF-beta 2 in a tissue specific manner. Elevated levels of TGF-beta 2 were detected in late pregnant maternal plasmas (> 100 pM), and in the milk (> 500 pM) during early lactation. High concentrations of TGF-beta 2 (> 200 pM) were also detected in uterine fluids collected from ovariectomized adult rats after high dose estrogen treatment. TGF-beta 2 mRNA levels were elevated in lobuloalveolar epithelial cells isolated from pregnant mammary gland. Three major transcripts of 3.5, 4.0, and 4.7 kb were seen, of which the 4.7 kb, dominates. Mammary glands of estrogen treated ovariectomized rats showed a similar pattern of TGF-beta 2 transcripts. In contrast, four major TGF-beta 2 mRNA transcripts of 5.7, 4.7, 4.0, and 3.5 kb, with the dominant species of 4.0 and 5.7 kb, were observed in uteri from the estrogen treated animals up to 48 h after the last estrogen injection. This suggests that TGF-beta 2 is regulated in a tissue specific manner. We conclude that the secretion of TGF-beta 2 is tightly regulated by hormones and that estrogen and prolactin are critical factors in the tissue-specific regulation of the local production of TGF-beta 2 in the mammary gland and female reproductive tract.

C4d complement split product expression in chronic rejection of renal allograft.

Chronic allograft rejection remains the major cause of late renal graft loss. Its pathogenesis is complex, depending on both immunological and nonimmunological factors. An important role in development of chronic rejection is ascribed to an ongoing immunological reaction mainly of the humoral type. C4d complement split product, as a stable fragment of complement degradation activated by antigen-antibody complexes, is considered to be an indicator of humoral activity in allografts. The aim of the present study was to establish a correlation between C4d expression and morphological findings specific for chronic rejection among biopsy specimens from patients with deteriorating graft function versus protocol biopsy specimens versus biopsy specimens of native kidneys with glomerular diseases. C4d deposits in peritubular capillaries and glomeruli were observed in 83% of patients with morphological changes of chronic rejection. No C4d expression was found in the protocol biopsy group. C4d deposits in glomeruli localizations were found in kidneys from patients with glomerulopathies; the pattern of distribution was similar to that for antibodies characteristic for glomerulonephritis. There was a positive correlation between C4d expression and morphological features of chronic rejection. In our opinion, only peritubular capillary localization is specific for a rejection process; glomerular localization is nonspecific and probably secondary to antigen-antibody complex deposition in course of some types of glomerulopathies.

36-month follow-up of 75 renal allograft recipients treated with steroids, tacrolimus, and azathioprine or mycophenolate mofetil.

OBJECTIVES: The aim of this retrospective study was to assess the incidence of acute rejection episodes (AR), diabetes mellitus (DM), and serum creatinine (SCr) among renal transplant recipients treated with tacrolimus (Tac), steroids (S), and mycophenolate mofetil (MMF) or azathioprine (Aza). METHODS: Seventy-five renal allograft recipients enrolled in the COSTAMP study were followed for a period of 3 years. Patients were randomized to receive either Tac and MMF (n = 41) or Tac and Aza (n = 34) concomitantly with steroids. Follow-up assessments were performed at 3, 6, 12, 24, and 36 months. RESULTS: Patient survival at month 36 was 91.18% in the Tac/Aza/S group and 97.56% in the Tac/MMF/S group. Graft survival at month 36 was 82.35% and 85.37%, respectively. During the study period, 22 cases of biopsy-proven AR were diagnosed in 17 patients (22.6%). After 36 months the total number of AR was 11 in the Aza-treated group (32.4%) and 11 in the MMF-treated group (26.8%). DM was diagnosed de novo in 17 individuals (22.6%). During 36 months, 10 patients from Aza-treated group (29.4%) and seven from MMF-treated group developed DM (17.1%). Serum creatinine values were not significantly different in both arms of the study. Comparison of arterial blood pressure and total cholesterol revealed no significant changes in any of the studied groups. CONCLUSIONS: We conclude that combinations of steroids, tacrolimus, and azathioprine or MMF provide good results with regard to renal function.

Human herpesvirus-6 in renal transplant recipients: potential risk factors for the development of human herpesvirus-6 seroconversion.

Herpesviruses, including human herpesvirus-6 (HHV-6), reactivate and have the potential to be pathogenic in immunocompromised patients. Little information is available regarding the correlation between immunosuppressive therapy and HHV-6 seroconversion after organ transplantation. Serum samples obtained from 120 kidney and kidney/pancreas transplant recipients were tested to explore the potential risk factors for developing HHV-6 infection including types of immunosuppression and induction/rejection therapy. Stored serum samples obtained prior to and at the 2nd, 4th, 12th and 48th weeks after transplantation were tested for anti-HHV-6 immunoglobulin (Ig)M antibodies using indirect immunofluorescence assay. Prior to transplantation and 48 weeks after transplantation the sera were additionally tested for anti-HHV-6 IgG using enzyme-linked immunoassay. Ninety-one percent of 120 recipients were HHV-6 IgG-positive before transplantation. One hundred seven of 120 patients were anti-HHV-6 IgM-negative before transplantation. Primary/secondary HHV-6 seroconversion occurred in sera of 46.6% of these 107 patients. HHV-6 seroconversion most frequently occurred 2 to 4 weeks after transplantation. There was no significant relationship between HHV-6 seroconversion and the treatment with methylprednisolone (MP). The incidence of HHV-6 seroconversion was significantly higher in subjects who were treated with the regimens including Daclizumab or Sirolimus as compared with those who were on other protocols. HHV-6 seropositivity in the Polish population of organ transplant recipients is very high. We demonstrated a trend toward association of HHV-6 seroconversion with type of immunosuppressive therapy.