The course of HIV disease in renal allograft recipients

The clinical course of HIV seropositive renal allograft recipients is ill defined. Thus, a retrospective analysis of mortality, morbidity and graft survival was performed in two groups of HIV-positive patients. Group 1 (nine patients), seropositive for an indefinite period of time prior to transplantation (eight IV drug abusers, one homosexual), all lost their grafts after a mean period of 23 ± 11 months from chronic rejection (six), complicated by focal glomerular sclerosis and nephrotic syndrome in three cases, sepsis (two) and death with a functioning graft (one). Four patients died, two from sepsis, one from Kaposi's sarcoma and one from fluid overload. Of the remaining five patients, all on hemodialysis, one had AIDS and four were asymptomatic after a mean period of 44 months following graft failure. Prolonged hospitalizations for both infections and acute rejection were common. Group 2 (six patients) seroconverted in the perioperative period, and two had functioning allografts at 78 and 100 months post-transplant. Causes of allograft loss, patient death and infection-related complications were similar to those of group 1, but acute rejection was rare. In conclusion, HIV infection in renal allograft recipients was associated with poor allograft survival due mainly to rejection, mostly chronic, often complicated by glomerular sclerosis and nephrotic syndrome. Infectious complications requiring hospitalization were also increased.     

Failure of acyclovir to prevent cytomegalovirus infection in renal allograft recipients

Cytomegalovirus (CMV) is the most common opportunistic pathogen following renal transplantation and remains a major concern in transplantation centers owing to its high morbidity and impact on renal allografts. Pending more effective antiviral drugs, efforts have been directed toward prevention strategies. We conducted a retrospective analysis to evaluate the efficacy of various prophylactic options used at our institution during the period April 1986 to August 1990. All CMV-negative patients with CMV-negative kidneys (D-R-) received screened, CMV-negative blood products (n=19). CMV-specific immunoglobulins (CMV Ig) were used in 6 patients at increased risk for primary CMV infection and acyclovir was administered to 21 patients at an initial intravenous dose of 5 mg/kg body weight; then oral doses of 800–3200 mg per day were given according to the patients' estimated creatinine clearance. Thirty-two patients did not receive any CMV prophylactic treatment and served as controls. CMV monitoring of the patients during the first 6 months after transplantation showed an overall infection and disease rate of 81% and 38.1%, respectively, in the acyclovir-treated group. Compared with controls, the incidences of infection and disease were higher in the acyclovir-treated patients, with a significant difference for CMV infection (P=0.002, generalized Wilcoxon test). Only 1 of the 19 D-R-patients presented with CMV infection. CMV Ig-treated patients tended to have less severe disease without any apparent reduction in infection incidence. Given the high rate of infection in patients at risk, we infer that high-dose acyclovir does not prevent CMV infection in our setting of renal transplantation. We advocate the use of screened, CMV-negative blood products in D-R-patients.Part of this study has already been published as a letter to the editor in the Annals of Internal Medicine     

肾移植受者巨细胞病毒感染及免疫抑制剂对其的影响

目的探讨肾移植受者巨细胞病毒(CMV)感染率及免疫抑制剂对其的影响.方法214例肾移植受者术后给予甲泼尼龙(MP)、抗淋巴细胞球蛋白(ALG)静脉滴注作为免疫诱导治疗.基础免疫抑制剂治疗为环孢素A+泼尼松+硫唑嘌呤.急性排斥反应时给予MP冲击治疗,无效时给予ALG或OKT3治疗.采用免疫细胞化学LSAB法测定外周血白细胞CMV-PP65抗原.结果CMV感染率为61.7%(126/214),初次检出CMV-PP65抗原的时间为术后(25.4±14.7)*!d,平均抗原阳性细胞数为每50000白细胞(9.2±7.9)个.CMV感染的肾移植受者在感染前急性排斥反应率为42.3%(52/126),明显高于无CMV感染受者的20.5%(P<0.01);使用ALG或OKT3治疗例数分别为23、15例,也高于无CMV感染的受者(P<0.05).CMV感染和无CMV感染的肾移植受者ALG免疫诱导治疗疗程分别为(4.7±1.32)*!d、(4.4±0.92)*!d,使用剂量分别为(14.1±1.32)支、(13.2±0.92)支,差异无显著性(P>0.05).结论肾移植术后CMV感染率高;术后短期的ALG免疫诱导治疗可能不增加CMV感染发生率;急性排斥反应发生后免疫抑制剂尤其是ALG或OKT3的使用与术后CMV感染密切相关.     

A prospective study of hepatitis C viremia in renal allograft recipients

In an attempt to study the impact of HCV viremia on renal transplant clinical course and outcome, we prospectively followed 133 HBsAg-negative end stage renal disease (ESRD) patients, in whom HCV-RNA-PCR results were available, from the pre- to post-transplant period. Eighty (60%) ESRD patients tested PCR-positive, of these, 12 (15%) were anti-HCV negative by second generation ELISA. The viremic patients had a longer time on dialysis (p < 0.001), received more blood units (p < 0.001) and had a higher frequency of pre-transplantation liver disease (p < 0.001). Further, 41% of PCR-positive patients gave a history of antischistosomal treatment compared with 23% of PCR-negative ones (p = 0.048). Recipients with and without HCV viremia were followed for a mean of 31.8 +/- 5.8 (range 6-42) months and 29.8 +/- 9 (range 6-41) months respectively, p = 0.14. While the prevalence of HCV viremia increased from 60 to 64% at the last follow-up, the anti-HCV seroprevalence decreased from 63 to 61%. PCR-positive patients had higher rates of both acute (p = 0.005) and chronic (p < 0.001) liver disease after transplantation compared with PCR-negative patients. However, none of our HCV RNA positive recipients developed a fulminant liver disease or hepatic failure until the last follow-up. Stepwise logistic regression analysis identified pre-transplant liver disease (Odds ratio = 2.4; p = 0.07) and a cumulative corticosteroid dose in excess of 15 g at the last follow-up (Odds ratio = 3; p = 0.03) as independent predictors of post-transplant hepatic dysfunction in PCR-positive patients. Azathioprine was discontinued due to hepatic dysfunction in a significantly (p = 0.005) higher proportion of viremic patients compared with the non-viremic ones. There were no significant differences between PCR-positive and -negative patients in terms of frequencies and individual causes of graft and patient losses. Our results demonstrate that HCV infection is extremely prevalent in Egyptian hemodialysis patients and is responsible for most hepatic dysfunctions after transplantation. Although HCV viremia did not negatively affect graft or patient outcome until 31 months post-transplantation, the authors would recommend that a viremic patient should have a liver biopsy before transplantation and be immunosuppressed with caution post-transplantation. A longer follow-up may be required to exclude increased rates of HCV-induced hepatic mortalities. Copyright Copyright 1999 S. Karger AG, Basel     

肾移植术后的巨细胞病毒感染及其对急性排斥反应的影响

目的 探讨肾移植受者术后活动性巨细胞病毒（ＣＭＶ）感染的发生率、感染的原因以及ＣＭＶ感染对急性排斥反应的影响。方法 检测１８７例肾移植受者和供者术前血清抗－ＣＭＶ抗体;受者术后定期检测体内ＣＭＶ ＤＮＡ、对ＣＭＶ ＤＮＡ阳性的部分患者给予抗ＣＭＶ治疗,并比较各组排斥反应的发生率。结果 无论是供者还是受者,术前如血清抗－ＣＭＶ抗体阳性,受者术后发生活动性ＣＭＶ感染者明显增多,这些患者急性排斥反应的发     

A prospective evaluation of leflunomide therapy for cytomegalovirus disease in renal transplant recipients

Aim

A preliminary observation suggests leflunomide is effective in the treatment of cytomegalovirus (CMV) disease in renal transplant recipients. A prospective evaluation was conducted in renal transplant recipients to study the efficacy of leflunomide in the treatment of CMV disease.

Patients and methods

With prior approval and informed consent for therapy and follow-up, 17 consecutive consenting renal transplant recipients with proven CMV disease were treated with leflunomide. CMV disease was defined as a clinical syndrome of fever and/or symptoms of organ involvement, leukopenia, and a positive nested CMV quantitative PCR test at 0.001 μg/5 μL template input, with or without histologic evidence of tissue invasion. Leflunomide metabolite concentrations (A77 1726) were monitored.

Results

Of the 17 patients, 14 patients were treated for 6 months for CMV disease the first time; the remaining 3 received leflunomide treatment for relapse after ganciclovir treatment, for a year. Seven patients had fever with viremia and no organ involvement, nine had viremia with involvement of gastrointestinal tract, and one had fever with CMV inclusions in the allograft, with no demonstrable viremia. The three patients with relapse treated with leflunomide responded. Overall, 15 patients (88%) clinically responded to leflunomide therapy and with viral clearance from blood and healing of involved organs. The cost of therapy with intravenous ganciclovir (Cymevene, Roche) for 2 weeks was US $721 while that of leflunomide (Cleft, Cipla Ltd) for 6 months was US $64.

Conclusion

Leflunomide treatment for CMV disease in renal transplant recipients is effective, simple, and economical.     

A longitudinal prospective study of cytomegalovirus pp65 antigenemia in renal transplant recipients

Cytomegalovirus (CMV)-encoded pp65 antigen in peripheral blood leukocytes (CMV antigenemia) was investigated in 1017 serial samples from 64 patients for 16 weeks after renal transplantation in a prospective study. In 110 samples from 24 patients, at least one antigen-positive leukocyte was identified. The median number of stained cells was 4 (range 1–1000) per 4×10⁵ leukocytes. Twenty-one of 24 patients with serological signs of an active CMV infection were antigen-positive (sensitivity 87.5%), whereas 3 patients with antigenemia did not show serological signs of infection during the observation period (specificity 92.5%). Positive results were obtained 19 days (median) before serological response and 9 days (median) before the onset of CMV syndrome. The sensitivity in defining a CMV syndrome was 100% (n=8). In all patients who presented with CMV syndrome, antigenemia was present prior to the onset of symptoms or on the same day. In contrast, serological monitoring rendered the diagnosis of CMV infection possible at the onset of clinical symptoms in only two of eight patients. We conclude that (1) insufficient results obtained with the CMV antigenemia assay by other investigators are mainly due to technical problems that can easily be overcome by the protocol presented and (2) the detection of CMV pp65 antigen in peripheral blood leukocytes is an excellent tool for rapid and early diagnosis of CMV infection.     

Therapeutic use of ganciclovir for invasive cytomegalovirus infection in cadaveric renal allograft recipients.

Between November 1987 and September 1989, 419 cadaveric renal transplants were performed at our university. Of the patients 36 (8.6%) had invasive cytomegalovirus infection documented by gastric or duodenal mucosal biopsy in 23 (64%), bronchoalveolar lavage in 12 (33%), allograft biopsy or nephrectomy specimen in 5 (14%) and/or liver biopsy in 1 (3%). Cytomegalovirus severity was defined as mild in 27 patients, moderate in 6 and severe in 3. Ganciclovir [9-(1,3-dihydroxy-2-propoxymethyl)-guanine] was begun once the diagnosis was confirmed by histology or culture at a median of 56 days from transplantation (range 28 to 133 days). Duration of ganciclovir therapy was a minimum of 7 days or until fever was absent for 5 consecutive days (mean 12.2 +/- 3.5 days, range 4 to 21). Ganciclovir was well tolerated and side effects were limited to de novo neutropenia (7 patients), thrombocytopenia (2) and rash (1). Initial clinical improvement was observed in all patients. Two patients had recurrent cytomegalovirus infections that responded to a second course of ganciclovir. The 1-year actuarial patient survival was 100%. At a mean followup of 12.7 +/- 6.2 months 19 patients retained allograft function with a mean serum creatinine of 2.5 mg./dl. (range 1.2 to 4.6). Ganciclovir appears to be a safe and effective drug for the treatment of tissue invasive cytomegalovirus infection in cadaver renal transplant recipients. Prompt institution of this drug at diagnosis of invasive cytomegalovirus may lower the mortality rate formerly associated with this disease.     

更昔洛韦预防肾移植术后巨细胞病毒感染的前瞻性随机对照研究

目的研究更昔洛韦对肾移植术后巨细胞病毒(CMV)感染的预防作用。方法选取2004年行首次肾移植的55例患者,所有患者术后均常规应用环孢素A+霉酚酸酯+激素的免疫抑制方案。将患者随机分为2组,A组27例,从肾移植术后第2周起静脉滴注更昔洛韦5mg.kg-1.d-1,共30d,预防CMV感染;B组28例,没有针对CMV感染进行预防性用药。所有患者肾移植术后均随访6个月,检测其血清中CMV-IgG、CMV-IgM及CMV-DNA的表达,统计肾移植术后6个月时CMV感染率、CMV病的患病率、CMV感染时间、CMV病临床缓解时间、急性排斥反应发生率以及药物不良反应等项目。结果A、B两组患者的CMV感染率分别为37%和25%,CMV患病率分别为22.2%和14.3%,两组相比,差异无统计学意义。A组术后发现CMV感染时间较B组明显延迟(P<0.05),且发生CMV病后的临床缓解时间较B组显著缩短(P<0.05)。A、B两组急性排斥反应发生率分别为11.1%和21.4%,两组比较,差异无统计学意义。1例患者应用更昔洛韦后发生白细胞数减少,经集落刺激因子治疗后恢复。结论肾移植术后静脉滴注更昔洛韦对降低CMV感染率及发病率无明显作用,但可明显延迟肾移植术后CMV感染的发生时间,并显著缩短CMV发病后的临床症状缓解时间。提示肾移植术后CMV感染的预防性用药可能需要更长的时间。     

Severe tubulo-interstitial disease in a renal allograft due to cytomegalovirus infection

A 34 year old female developed impaired function of her renal allograft 21 months post-transplant. This was associated with lethargy, pyrexia, tenosynovitis, pancytopenia and a colonic ulcer. Severe tubulo-interstitial changes with intranuclear inclusion bodies and intracytoplasmic herpes type viral particles were seen on renal biopsy. There was no evidence of rejection. Cytomegalovirus was cultured from the urine and there was a rise in CMV antibody titer. These findings suggested the renal impairment was due to a direct cytopathic effect of the CMV. Despite treatment with transfer factor and adenine arabinoside, there was progressive loss of graft function.     

Determinants of the source of cytomegalovirus in murine renal allograft recipients

Cytomegalovirus is present in a latent state in renal allografts and may be reactivated in recipients. While human and murine strains are alike in that a primary infection occurs in seronegative recipients of a kidney from a seropositive donor, they may differ when the recipient is seropositive. In a murine transplant model, superinfection of a seropositive recipient with a second strain is unusual. Reports in human transplantation indicate that superinfection of a seropositive recipient does occur, however the frequency is unknown. Our studies examine the potential importance of specific viral strains in host and recipient, the contribution of prior humoral immunity in the recipient, and the technical ability to identify distinctive strains of virus in the presence of each other. Our results indicate that reversal of the viral strains in donor or recipient animals does not alter our previous observation that reactivation of the endogenous recipient viral strain predominates as the infecting strain in the posttransplant period. Further, the presence of antibody in nearly all donors and recipients confirms that all animals were originally infected prior to transplantation. Finally, we demonstrated the technical ability to detect one virus in the presence of the other, thus excluding this variable as possibly confounding. We conclude that the endogenous, latent recipient strain of cytomegalovirus in the murine model is preferentially reactivated in the posttransplant interval.     

The adverse impact of cytomegalovirus infection on clinical outcome in cyclosporine-prednisone treated renal allograft recipients

Cytomegalovirus (CMV) infection was diagnosed in 28% (n = 144) of 516 renal allograft recipients treated with cyclosporine-prednisone (CsA-Pred) immunosuppressive therapy. The majority of infections produced either asymptomatic (n = 37) or mild-to-moderate (n = 75) clinical disease, while 10% were lethal (n = 14). Transplantation from a seropositive donor to a seronegative recipient was associated with an increased incidence of (CMV) infection but did not predispose to more severe clinical disease. Similarly, donor source (cadaver [CAD] vs. living-related donor [LRD]), age greater than or equal to 45 years, and antecedent pulse steroid therapy for the treatment of acute rejection were not correlated with clinically more severe disease. An increase in serum creatinine to greater than or equal to 25% of preinfection nadir values occurred in association with CMV infection in 106 patients, returning to nadir values or below in 74.5% of these individuals. CMV infection did not impact on actual patient survival among recipients of LRD or CAD allografts or on actual 1-year HLA-haploidentical or HLA-identical LRD graft survival. In contrast, actual 1-year cadaveric graft survival was significantly lower among CMV-infected (n = 95) vs. uninfected (n = 198) patients (75.8% vs. 87.8%, P = .01). In association with the finding of reduced actual 1-year CAD graft survival, CMV-infected patients were found to be more predisposed to develop acute rejection episodes. Of the CMV-infected CAD graft recipients, 48.4% developed greater than or equal to 1 acute rejection episode during the first year following transplantation vs. 25.3% of their uninfected counterparts (P less than .001). The impact of CMV infection in CsA-Pred treated renal transplant recipients does not differ substantially from that reported historically in association with prednisone-azathioprine immunosuppressive therapy.     

Polyomavirus infection of renal allograft recipients: from latent infection to manifest disease

Polyomavirus (PV) exceptionally causes a morphologically manifest renal allograft infection. Five such cases were encountered in this study, and were followed between 40 and 330 d during persistent PV renal allograft infection. Transplant (Tx) control groups without PV graft infection were analyzed for comparison. Tissue and urine samples were evaluated by light microscopy, immunohistochemistry, electron microscopy, and PCR. The initial diagnosis of PV infection with the BK strain was made in biopsies 9+/-2 mo (mean +/- SD) post-Tx after prior rejection episodes and rescue therapy with tacrolimus. All subsequent biopsies showed persistent PV infection. Intranuclear viral inclusion bodies in epithelial cells along the entire nephron and the transitional cell layer were histologic hallmarks of infection. Affected tubular cells were enlarged and often necrotic. In two patients, small glomerular crescents were found. In 54% of biopsies, infection was associated with pronounced inflammation, which had features of cellular rejection. All patients were excreting PV-infected cells in the urine. PV infection was associated with 40% graft loss (2 of 5) and a serum creatinine of 484+/-326 micromol/L (mean +/- SD; 11 mo post-Tx). Tx control groups showed PV-infected cells in the urine in 5%. Control subjects had fewer rejection episodes (P<0.05) and stable graft function (P = 0.01). It is concluded that a manifest renal allograft infection with PV (BK strain) can persist in heavily immunosuppressed patients with recurrent rejection episodes. PV mainly affects tubular cells and causes necrosis, a major reason for functional deterioration. A biopsy is required for diagnosis. Urine cytology can serve as an adjunct diagnostic tool.     

Posttransplant diabetes mellitus in renal allograft recipients: A prospective multicenter study at 2 years

The purpose of this study was to investigate the incidence and risk factors for the development of diabetes mellitus after kidney transplantation (PTDM). A total of 1783 nondiabetic renal allograft recipients transplanted from January 2000 to December 2002 were included. Diabetes was diagnosed following American Diabetes Association criteria. While 1276 patients were treated with tacrolimus (Tac), mycophenolate mofetil (MMF), and steroids, 507 patients received cyclosporine-ME (CsA), MMF, and steroids. PTDM incidence at 6, 12, and 24 months was 14.2%, 12.8%, and 13.3%, respectively. Cumulative incidence during the follow-up was 21.6%. Only 121 of the diabetic patients (47.6%) at 6 months remained diabetic at 24 months. Furthermore, 60 patients of 116 patients on insulin at 6 months (51.7%) remained on treatment at 24 months. The cumulative incidence of PTDM was similar in the two immunosuppressive treatments (19.7% on CsA-MMF vs 22.3% on Tac-MMF; P = NS). However, at 24 months, 14 of 50 diabetic patients on CsA-MMF (28%) and 74 of 161 patients on Tac-MMF (45.9%) were on insulin treatment (P < .05). By Cox regression analysis, age older than 60 years (RR 1.61; 95%CI 1.28-2.04; P < .001), body mass index (BMI) > 30 kg/m2 at transplantation (RR 1.66; 95%CI 1.27-2.16; P < .001), and immunosuppression with Tac (RR 1.30; 95%CI 1.02-1-66; P = .033) were associated with PTDM. In conclusions, the incidence of PTDM at 24 months in immunosuppressive protocols including MMF is about 22%, and it is associated with older age, increased BMI, and immnunosuppression with Tac.     

Long-term oral ganciclovir prophylaxis for prevention of cytomegalovirus infection and disease in cytomegalovirus high-risk renal transplant recipients

BACKGROUND: Although specific therapy is available with ganciclovir, cytomegalovirus (CMV) disease remains a major problem after renal transplantation especially in CMV seronegative recipients of organs of seropositive donors (D+R-). METHODS: In an open-labeled prospective controlled trial we evaluated the effect of long-term oral ganciclovir prophylaxis (3 g/day for 3 months posttransplantation) in a cohort of 31 CMV-high risk (D+R-) renal transplant recipients (GC) compared with a cohort of 28 high-risk patients with targeted CMV prophylaxis (CO) receiving i.v. ganciclovir during antirejection therapy. Primary end-points were CMV infection, diagnosed by pp65 antigenemia assay or serologic method, and CMV disease. Additionally severity of CMV disease quantified by a scoring system was evaluated. RESULTS: CMV prophylaxis significantly reduced the incidence of CMV infection (CO: 75%, GC: 45%; P<.05) and CMV disease (CO: 60%, GC: 29%; P<.05) without relevant side effects and without any clinical suspicion of ganciclovir resistance. Severity of CMV disease as quantified by a scoring system was reduced from 8.3+/-6.7 points in controls to 3.3+/-2.6 points in ganciclovir-treated patients (P<.05). Mortality did not differ significantly between the two groups (CO: n=3, GC: n=1; NS). However, there was one lethal CMV disease and a second death possibly attributable to CMV disease in the control group, whereas in ganciclovir-treated patients there was no CMV-associated fatal outcome. CONCLUSION: Long-term oral ganciclovir prophylaxis is effective and safe in CMV high-risk renal transplant recipients.