Tomas Reischig

Effect of cytomegalovirus viremia on subclinical rejection or interstitial fibrosis and tubular atrophy in protocol biopsy at 3 months in renal allograft recipients managed by preemptive therapy or antiviral prophylaxis.

Background. Cytomegalovirus (CMV) is a risk factor for acute renal allograft rejection. The aim of this study was to determine the impact of CMV viremia on subclinical rejection (SCR) and interstitial fibrosis and tubular atrophy (IF/TA) in protocol biopsy at 3 months after transplantation. Methods. A total of 118 consecutive renal transplant recipients at risk for CMV (donor and recipient CMV seropositive) were included and followed up prospectively. Protocol biopsies with sufficient tissue were obtained in 102 patients. CMV activity was monitored using real-time polymerase chain reaction in whole blood. Three-month prophylaxis with valacyclovir or ganciclovir was given in 60 patients, whereas the remaining 42 patients were managed by preemptive therapy. Multivariate logistic stepwise regression analysis was used to estimate the effect of CMV viremia and other covariates on SCR and IF/TA. Results. CMV viremia occurred in 41% of the patients with a median peak viral load of 1300 copies/mL. The incidence of SCR and IF/TA was 29% and 28%, respectively. CMV viremia was not a risk factor for SCR (OR=0.77, P=0.551); however, viremia of more than or equal to 2000 copies/mL increased the risk of IF/TA (OR=3.83, P=0.023). Biopsy-proven acute rejection (OR=3.34, P=0.009) and sirolimus-based immunosuppression (OR=6.13, P=0.008) were independent predictors of SCR. Delayed-graft function (OR=6.02, P=0.001) and donor age (OR=1.53 per 10-year increase, P=0.009) were associated with IF/TA. Conclusions. CMV viremia is not an independent risk factor for SCR. CMV viremia with viral load of more than or equal to 2000 copies/mL is associated with increased risk of IF/TA in protocol biopsy at 3 months after transplantation.

Long-Term Outcomes of Pre-emptive Valganciclovir Compared with Valacyclovir Prophylaxis for Prevention of Cytomegalovirus in Renal Transplantation

Prevention of cytomegalovirus (CMV) is essential in organ transplantation. The two main strategies are pre-emptive therapy, in which one screens for and treats asymptomatic CMV viremia, and universal antiviral prophylaxis. We compared these strategies and examined long-term outcomes in a randomized, open-label, single-center trial. We randomly assigned 70 renal transplant recipients (CMV-seropositive recipient or donor) to 3-month prophylaxis with valacyclovir (n=34) or pre-emptive valganciclovir for significant CMV viremia detected at predefined assessments through month 12 (n=36). Among the 55 patients who had a protocol biopsy specimen available at 3 years to allow assessment of the primary outcome, 9 (38%) of 24 patients in the prophylaxis group and 6 (19%) of 31 patients in the pre-emptive therapy group had moderate to severe interstitial fibrosis and tubular atrophy (odds ratio, 2.50; 95% confidence interval, 0.74-8.43; P=0.22). The prophylaxis group had significantly higher intrarenal mRNA expression of genes involved in fibrogenesis. The occurrence of CMV disease was similar in both groups, but pre-emptive therapy improved 4-year graft survival (92% versus 74%; P=0.049) as a result of worse outcomes in patients with late-onset CMV viremia. In conclusion, compared with valacyclovir prophylaxis, pre-emptive valganciclovir therapy may lead to less severe interstitial fibrosis and tubular atrophy and to significantly better graft survival.

Tumours in End-Stage Kidney

OBJECTIVE Patients with end-stage kidney disease (ESKD) show a greater risk for renal cell carcinoma (RCC), which tends to be multifocal and bilateral. The malignant potential is unclear. The question is whether to remove both kidneys in patients with a tumor on one side only diagnosed by computed tomography (CT). MATERIALS AND METHODS Kidney tumors were found in 14 patients with ESKD from January 2002 to December 2006. One was unfit for surgery. Thirteen patients underwent nephrectomy and 6 a bilateral procedure of whom only 2 had bilateral tumors on CT, 3 multiple tumors on the contralateral side, and 1 uncontrollable hypertension with tumors as an incidental finding. Tumors were found in all 19 specimens. RESULTS In 13 kidneys (68.4%), the tumors were multiple; in 6 (31.6%), solitary. The types of tumor were: 13 (68.4%) papillary RCCs (PRCC), 9 (47.4%) clear RCCs (CRCC), a combination of PRCC and CRCC in 4 (21.0%), and myxoid liposarcoma (with solitary PRCC contralaterally). The mean follow-up was short (19 +/- 15 months; maximum, 54 months). Only 1 patient died due to a tumor at 16 months after operation. CONCLUSIONS There is a high risk for bilateral involvement. Patients who undergo unilateral nephrectomy must be regularly followed and contralateral nephrectomy carefully considered, mainly in transplanted patients on immunosuppression. Further studies are needed to give a definitive answer about the indications for surgery and the indications for contralateral nephrectomy as well. To date, prophylactic contralateral nephrectomy should not be a therapeutic standard.

Evaluation of three different methods to prevent dialyzer clotting without causing systemic anticoagulation effect.

Thrombogenicity is one of the most important biocompatibility markers of artificial material. Anticoagulation is commonly used to reduce thrombogenicity of the extracorporeal circuit (ECC) during intermittent hemodialysis (IHD). In some situations, systemic anticoagulants are contraindicated. The aim of our study was to compare thrombogenicity parameters during IHD with three different methods without a systemic anticoagulation effect. In a prospective, randomized, and crossover study, we examined 10 stable patients during IHD with (i) regular saline flushes of ECC; (ii) regional citrate anticoagulation (RCA); and (iii) AN69 ST membrane after ECC priming according to the manufacturers recommendations. Before IHD and after 10, 60, 120, and 240 min, we measured the platelet count and the plasma concentrations of platelet factor 4 (PF4) and thrombin/antithrombin complexes (TAT). All 10 procedures with RCA were successfully completed after 4 h, whereas 6/10 procedures with saline flushes and 5/10 procedures with AN69 ST were finished prematurely because of clotting (P < 0.05). The TAT production was significantly increased during saline flushes and AN69 ST compared with RCA (P < 0.05). Platelet activation demonstrated by rising PF4 was present during all three methods. Markers of coagulation cascade activation were progressively increasing during IHD with RCA, saline flushes, and AN69 ST. The activation was significantly lower during RCA, and according to thrombogenicity, RCA is the most effective among compared anticoagulation methods.

A randomized prospective controlled trial of oral ganciclovir versus oral valacyclovir for prophylaxis of cytomegalovirus disease after renal transplantation

Abstract.Oral ganciclovir and valacyclovir reduce the incidence of cytomegalovirus (CMV) disease after renal transplantation (RTx). Our study was designed to compare the efficacy, costs, and safety of oral ganciclovir and valacyclovir in the prophylaxis of CMV disease over the first 6 months after RTx. A total of 38 patients was randomized to 3-month treatment with either oral ganciclovir (1 g t.i.d., n=14, GAN group) or oral valacyclovir (2 g q.i.d., n=12, VAL group). A third group (C, n=12) received no prophylaxis. The patients were monitored by CMV-nested PCR in whole blood. No differences were found between the groups in their demographic characteristics, immunosuppressive protocols, or donor and recipient CMV serology. Thirty-six out of 38 (94.7%) recipients were CMV-seropositive. Over the 6-month post-RTx period, there were 13 episodes of CMV disease in eight (66.7%) patients of the C group compared with none in the GAN and VAL groups (P=0.0005, GAN vs C; P=0.001, VAL vs C). The incidence of CMV viremia was 30.8%, 50.0%, and 91.7% in the GAN, VAL, and C groups, respectively (P=0.004, GAN vs C; P=0.07, VAL vs C; P=NS, GAN vs VAL). Treatment failure (death, graft loss, CMV disease, or withdrawal from study) occurred in 14.3%, 0% and 66.7% in the GAN, VAL, and C groups, respectively (P=0.014, GAN vs C; P=0.001, VAL vs C; P=NS, GAN vs VAL). The average CMV-associated costs per patient (in 2001 euros) were 2,449±1,178, 2,485±581, and 4,259±4,616 in the GAN, VAL, and C groups, respectively. Ganciclovir and valacyclovir were well tolerated, with ganciclovir having had to be withdrawn shortly in one patient only because of thrombocytopenia. In conclusion, oral ganciclovir and valacyclovir are equally safe and effective in the prophylaxis of CMV disease after RTx. Both are cost-effective and help reduce CMV-associated costs by some 40% compared with patients without prophylaxis.

Cytomegalovirus-associated renal allograft rejection: new challenges for antiviral preventive strategies

The adverse impact of cytomegalovirus (CMV) infection after solid organ transplantion is currently believed to be mediated primarily by its immunomodulatory effects. There is a large body of evidence showing that both CMV disease and asymptomatic viremia are independent risk factors for the development of allograft rejection. The aim of this article is to summarize mechanisms whereby CMV is involved in the development and progression of allograft rejection, with particular emphasis on renal transplant recipients. The article will also address the potential of anti-CMV preventive protocols designed to favorably affect the incidence of allograft rejection.

TSC2/PKD1 contiguous gene syndrome: a report of 2 cases with emphasis on dermatopathologic findings.

The association of tuberous sclerosis complex (TSC) and autosomal dominant polycystic kidney disease (ADPKD), termed TSC2/PKD1 contiguous gene syndrome, is a result of molecular defect demonstrating by deletion disrupting TSC2 and PKD1. Dermatopathology of this syndrome has never been addressed. We report 2 sporadic cases form of TSC2/PKD1 contiguous gene syndrome, with emphasis on dermatopathologic findings. Both patients presented with a typical phenotype of TSC and early-onset renal polycystic requiring kidney transplantation in one of the patients. Of a total of 13 cutaneous lesions studied, there were 7 facial angiofibromas, 2 shagreen patches, 1 periungual fibroma, 1 hypopigmented macule, 1 epidermoid cyst, and 1 intradermal melanocytic nevus. The histological features were basically similar to those occurring in TSC, but some unusual features were identified. In both patients, deletions in the region of TSC2 and PKD1 were revealed performing by multiplex ligation probe amplification test. It is concluded that the histopathological features of skin lesions in this syndrome are similar to those encountered in TSC. Clinical awareness and appropriate molecular investigation of TSC2/PKD1 contiguous gene syndrome is necessary in all patients with a typical phenotype of TSC in infancy, adolescence, or adult age, because of severity of the renal alterations.

Prospective Comparison of Valacyclovir and Oral Ganciclovir for Prevention of Cytomegalovirus Disease in High-Risk Renal Transplant Recipients

Aims: To compare the efficacy, costs and safety of oral ganciclovir and valacyclovir in the prophylaxis of cytomegalovirus (CMV) disease in renal transplant (RTx) recipients at high risk of CMV disease. Methods: A total of 83 patients were prospectively randomized to 3-month treatment with either oral ganciclovir (3 g/day) or oral valacyclovir (8 g/day). A 3rd group received no prophylaxis. Forty-nine patients were considered to be at high risk of CMV disease due to D+R– serologic status, OKT3/ATG treatment and/or acute rejection within 12 months after RTx. Twenty-three high-risk patients were treated with ganciclovir (GAN group), 17 patients with valacyclovir (VAL group), and 9 patients received no prophylaxis (C group). Results: No significant differences were found among the groups in their demographic characteristics, immunosuppressive protocols, D/R CMV serology, or CMV risk factors. The 12-month incidence of CMV disease was 89% in the C group compared with 9% in the GAN group and 6% in the VAL group (p < 0.001, GAN or VAL vs. C; p = 0.713, GAN vs. VAL). Treatment failure (death, graft loss, CMV disease or withdrawal from study) occurred in 17, 6, and 89% in the GAN, VAL, and C groups, respectively (p < 0.001, GAN or VAL vs. C; p = 0.285, GAN vs. VAL). The average CMV-associated costs per patient were EUR 3,161, 3,757, and 7,247 in the GAN, VAL, and C groups, respectively (p = 0.027). Conclusion: Valacyclovir and oral ganciclovir are equally effective in the prophylaxis of CMV disease in high-risk RTx patients. Both regimens are cost-effective and help reduce CMV-associated costs by nearly 50% compared with patients without prophylaxis.

Intragraft cytomegalovirus infection: a randomized trial of valacyclovir prophylaxis versus pre-emptive therapy in renal transplant recipients.

BACKGROUND In a randomized study, we observed a higher incidence of biopsy-proven acute rejection with pre-emptive valganciclovir therapy as compared with valacyclovir prophylaxis for prevention of cytomegalovirus (CMV) disease after renal transplantation (RTx). Persistence of the virus within the allograft could stimulate the alloimmune response. The aim of our study was to evaluate intragraft CMV infection in patients randomized to the trial. METHODS RTx recipients at risk of CMV were randomized to pre-emptive therapy with valganciclovir (n=36) for significant CMV viraemia (> or =2,000 copies/ml by quantitative PCR in whole blood samples) or 3-month prophylaxis with valacyclovir (n=34). Renal biopsies performed during 12 months post-RTx were analysed for the presence of CMV by real-time PCR and immunohistochemical staining. RESULTS A total of 35 patients (59 biopsies) in the pre-emptive group and 31 patients (57 biopsies) with valacyclovir prophylaxis had > or =1 biopsy specimen with sufficient material for intragraft CMV determination. Cumulative incidence of intragraft CMV infection was 14% and 7% (P=0.315) with pre-emptive therapy and prophylaxis, respectively. Patients at risk for primary CMV infection (CMV serological donor-positive and recipient-negative) were at higher risk for intragraft CMV infection (40% versus 5%; P=0.008). CMV viraemia at the time of biopsy was associated with the presence of CMV within the allograft (P<0.001). CONCLUSIONS During the first year after RTx, the incidence of intragraft CMV infection was relatively low with comparable rates in patients managed by pre-emptive valganciclovir therapy and valacyclovir prophylaxis.

End-stage kidney disease: gains of chromosomes 7 and 17 and loss of Y chromosome in non-neoplastic tissue.

The aim of this study was to determine the copy number changes of chromosomes 7, 17, 3p, and Y in a non-neoplastic tubular epithelium in end-stage kidney disease (ESKD). Seventeen kidneys from 11 patients with ESKD were retrieved from the archive files. Non-neoplastic kidney tissue in these cases was examined separately. Tissues containing papillary adenomas (PA), clear (CRCC) and papillary renal cell carcinomas (PRCC), and myxoid liposarcoma (LPS) were examined using the same probes and compared with non-neoplastic tissue. Tubular changes in the kidney parenchyma were classified into three types: (1) The vast majority of tubules were entirely atrophic; (2) Several tubules were hyperplastic, i.e., tubules with undifferentiated large epithelial cells, in which it was impossible to establish the specific type of a renal tubulus; (3) Dysplastic tubules were dilated, sometimes wrinkled. The basal membranes were lined by large eosinophilic epithelial cells with polymorphic nuclei and pseudostratification. Nucleoli were clearly visible. These tubular changes were multifocal with a haphazard distribution within the atrophic parenchyma. PA were detected in nine patients, of whom eight patients also revealed an additional tumor type(s) (4x CRCC, 3x PRCC, 1x PRCC, and CRCC). One patient had a CRCC only, another had a combination of PRCC and LPS. Chromosomal abnormalities were found in the second and third group of tubular changes, i.e., in hyperplastic and dysplastic tubules. Trisomy of chromosome 7 was detected in six cases, whereas trisomy of chromosome 17 in eight cases. A combination of both trisomies was found in five cases. Loss of chromosome Y was found in two cases. Fluorescence in situ hybridization on tissues containing papillary adenomas, renal cell carcinomas, and liposarcoma revealed expected results, i.e., trisomy of chromosomes 7 and 17 in all PAs and PRCC. No gains were present in CRCC and LPS. Loss of Y was found in six PA, five PRCC, and one LPS; loss of X was found in two CRCCs. We suggest that chromosomal changes typical of the papillary renal cell lesions, i.e., trisomies of chromosomes 7 and 17, are very frequent in non-neoplastic parenchyma of the end-stage kidney, and they have a tendency to a multifocal occurrence.