Cytomegalovirus infection complicating renal transplantation and its relationship to acute transplant glomerulopathy

The incidence of cytomegalovirus (CMV) infection was established, using laboratory criteria, in 298 patients receiving 362 renal allografts (164/298 = 55%). The incidence of CMV infection did not differ between azathioprine/prednisolone-treated and cyclosporine-treated patients (55% vs. 57% NS). The use of antithymocyte globulin (ATG) increased the incidence of CMV infection (78% vs. 51%: P less than 0.01). Donor and recipient CMV status, known for 116 allografts, did not correlate with the incidence of CMV infection (recipient CMV-positive = 50%; recipient CMV-negative = 54%: NS). CMV infection was responsible for 8 patients' deaths (2.7% mortality). Thirty-three patients with acute transplant glomerulopathy were identified (11%). There was no correlation between acute transplant glomerulopathy and CMV infection. Glomerulopathy was associated with poor graft survival (22/33 patients with a graft survival of less than 6 months). Thus CMV infection, although a common complication of renal transplantation with significant morbidity and mortality, is not closely associated with acute transplant glomerulopathy. Further, the lack of correlation of donor-recipient CMV serologic status with graft outcome limits the usefulness of pretransplantation donor screening.     

Acute transplant glomerulopathy is associated with antibody-mediated rejection and poor graft outcome

Transplant glomerulopathy (TG) is traditionally considered to be a chronic entity. However, in our practice we observed patients who presented with features of TG as early as 14 days posttransplantation. We investigated the clinicopathological features of these cases. During a 4-year period, all patients with acute rejection were identified. Charts were reviewed to identify patients with antibody-mediated rejection and biopsy features of TG within 6 months posttransplantation. Three patients met the above- mentioned criteria. All of them had diffuse margination of inflammatory cells in peritubular capillaries in the setting of acute renal failure or delayed graft function. Monocyte (CD68-positive) margination in peritubular capillaries was a common feature. All 3 patients had donor-specific antibodies and features suggestive of antibody-mediated rejection. C4d stain in peritubular capillaries was focal and mild or absent in serial biopsies. Occlusive endothelial swelling of glomerular capillary loops (endotheliosis) preceded TG. None of the patients had evidence for other causes of similar glomerular changes in a transplant, such as calcineurin inhibitor toxicity, ischemia, hepatitis C, or immune complex glomerulonephritis. They did not have other biopsy features of chronicity when TG appeared and as it progressed. TG can occur as an acute phenomenon. We propose that endotheliosis is a more accurate and specific precursor of TG than mere glomerulitis. These cases of acute TG may represent a form of antibody-mediated rejection associated with proteinuria and poor response to treatment.     

Diabetic ketoacidosis following development of de novo diabetes in renal transplant recipient associated with tacrolimus

Although drugs used in renal transplant recipients such as steroids, cyclosporine, and particularly, tacrolimus have diabetogenic potential, diabetic ketoacidosis is uncommon. There are few data concerning the long-term follow-up of these patients. Diabetic ketoacidosis occurred in a renal transplant recipient following de novo development associated with tacrolimus.     

De novo malignancy is associated with renal transplant tourism

Despite the objections to transplant tourism raised by the transplant community, many patients continue travel to other countries to receive commercial transplants. To evaluate some long-term complications, we reviewed medical records of 215 Taiwanese patients (touring group) who received commercial cadaveric renal transplants in China and compared them with those of 321 transplant recipients receiving domestic cadaveric renal transplants (domestic group) over the same 20-year period. Ten years after transplant, the graft and patient survival rates of the touring group were 55 and 81.5%, respectively, compared with 60 and 89.3%, respectively, of the domestic group. The difference between the two groups was not statistically significant. The 10-year cumulative cancer incidence of the touring group (21.5%) was significantly higher than that of the domestic group (6.8%). Univariate and multivariate stepwise regression analyses (excluding time on immunosuppression, an uncontrollable factor) indicated that transplant tourism was associated with significantly higher cancer incidence. Older age at transplantation was associated with a significantly increased cancer risk; however, the risk of de novo malignancy significantly decreased with longer graft survival. Thus, renal transplant tourism may be associated with a higher risk of post-transplant malignancy, especially in patients of older age at transplantation.     

The autoimmune response to vimentin after renal transplantation in nonhuman primates is immunosuppression dependent

BACKGROUND: Chronic allograft nephropathy (CAN) is a common late complication of kidney transplantation. Antibodies to both human leukocyte antigen and nonhuman leukocyte antigen antigens have been implicated in the development of this condition. Here we investigated the presence of antivimentin antibodies in nonhuman primate recipients of kidney allografts as a possible predictor of CAN and the effects of immunosuppression. METHODS: Thirty seven rhesus monkeys received a kidney allograft to study the potency of several different immunosuppressive regimens (conventional immunosuppression, n=19, vs. costimulatory blockade, n=18). Monkeys were tested for antivimentin antibody by enzyme-linked immunosorbent assay and for anti-donor antibody by staining donor spleen cells with recipient serum. The appearance of antibodies was correlated with the graft pathology in biopsy and necropsy material. RESULTS: Antivimentin antibodies were found in 31 of 37 animals, whereas only 15 of 32 animals made anti-donor antibodies. Conventional immunosuppression did not prevent antivimentin antibody formation. Costimulation blockade, in particular blocking CD40 and CD86, significantly delayed or prevented antivimentin antibody formation, but did not prevent CAN. Antivimentin antibodies were not significantly associated with development of CAN. CONCLUSIONS: We postulate that vimentin acts as an autoantigen after renal transplantation; it elicits an autoimmune response that is not regulated by cyclosporine. This autoimmune response may be part of the complex immunologic events occurring posttransplantation and may contribute to the development of CAN, but cannot be considered as a major cause of CAN because this condition also develops without antivimentin antibodies.     

肾移植术后乙型肝炎病毒相关性纤维化淤胆性肝炎

目的 探讨肾移植术后乙型肝炎病毒相关性纤维化淤胆性肝炎的临床及组织学特征。方法 回顾观察了3例肾移植术后乙型肝炎病毒相关性纤维化淤胆性肝炎患者的临床特点，并对其肝穿刺组织进行HE、浸银染色及乙型肝炎病毒核心抗原（HBcAg)免疫组织化学染色观察。结果 3例患者均表现为进行性肝功能衰竭，血清转氨酶仅轻度上升；汇管区广泛纤维化，毛细胆管及肝细胞内胆汁淤积明显，炎性细胞浸润轻，肝细胞乙型肝炎病毒核心抗原（HBcAg)强表达。结论 肾移植术后的乙型肝炎病毒相关性纤维化淤胆性肝炎是一种特殊的、致死性病毒性肝炎；乙型肝炎病毒无症状携带者肾移植术后应密切监测肝功能的变化。     

Membranous glomerulopathy following kidney transplantation. Association with renal vein thrombosis in two of nine cases

The association of renal vein thrombosis and membranous glomerulopathy in native kidneys has been well documented. However, this association has only occasionally been described following renal transplantation. A review of 693 renal transplant recipients revealed 77 (11%) in whom persistent, heavy proteinuria (greater than 2 g/24 hr) developed. Renal histology was available in all 77 patients. A diagnosis of membranous glomerulopathy was made in 7 patients. Two further cases were added on the basis of biopsy findings--1 patient had a protein excretion of 1.7 g/24 hr, the other had microscopic hematuria and red cell casts in the urine. Renal venography was performed in 4 cases. The decision to perform venography was based on clinical criteria (thrombophlebitis or marked edema of the leg on the side of the allograft), and/or histological criteria (associated interstitial edema and venous congestion). Renal vein thrombosis was present in 2 patients. Three of the 9 patients had membranous glomerulopathy as the cause of their end-stage renal disease; 2 of these patients had received kidneys from living-related donors. Four of the patients were classified as having de novo membranous glomerulopathy on the basis of having a different cause for their end-stage renal disease. Two patients were classified as having unspecified membranous glomerulopathy; both of these patients had had chronic glomerulonephritis, but there was lack of characterization of the original glomerular disease. Seven of the 9 patients continued to have stable allograft function 1-12 months after the diagnosis of membranous glomerulopathy was made in the renal allograft. The remaining 2 patients both had associated renal vein thrombosis; 1 had progressive deterioration of renal function and returned to dialysis 24 months after the diagnosis of membranous glomerulopathy had been made, while the other died of unrelated causes 27 months after the diagnosis had been made.     

造血干细胞移植后慢性移植物抗宿主病相关的膜性肾病一例

目的 总结造血干细胞移植后慢性移植物抗宿主病（cGVHD）相关的膜性肾病的诊疗体会。方法 为1例急性淋巴细胞白血病患者施行HLA全相合的无关供者外周血造血干细胞移植，术后应用甲氨喋呤和他克莫司（FK506）预防GVHD。术后第19d发生急性GVHD，经甲泼尼龙治疗逆转。分别于术后182d、235d停用FK506和泼尼松，5d后患者出现cGVHD表现，肝功能异常，并伴肾病综合征的相关表现，病理诊断为膜性肾病Ⅱ期，遂给予FK506和泼尼松治疗，同时辅以利尿、降脂等措施。结果发生膜性肾病时，患者的尿蛋白＋＋＋＋，白细胞75个／μl，上皮细胞359．5个／pl，病理性管型＋，管型计数为167个／μl，24h尿蛋白定量为4．28g；肾组织活检，无肾小球硬化，肾小球体积稍大，部分血管袢受压，开放欠佳，肾小球基底膜轻微增厚，外观呈僵硬感，系膜基质轻、中度增殖；间质区部分肾小管扩张，肿胀、变性，未见明显间质纤维化和炎症细胞浸润；Masson染色可见基底膜上皮侧嗜复红物沉积；免疫荧光检查，IgG＋＋＋，C3＋＋＋，IgA＋＋，沿毛细血管袢呈颗粒状节段性分布，系膜区呈团块状分布；IgM、Clq、CA均阴性。电镜下可见肾小球基底膜上皮下沉积物，并有基膜增厚，毛细血管系膜基质轻度增生。经泼尼松和FK506治疗，2个月后尿蛋白转阴。结论 造血干细胞移植后出现肾病综合征或蛋白尿，应考虑GVHD相关膜性肾病的可能，肾穿刺活检有助于诊断，糖皮质激素和FK506治疗有效。     

Immunoglobulin class and specificity of antibodies causing positive T cell crossmatches. Relationship to renal transplant outcome

A group of 42 renal transplants performed in the presence of a T-cell-positive crossmatch were analyzed to determine the class and specificity of the donor-reactive cytotoxic antibodies. Dithiothreitol (DTT) was used to reduce IgM antibodies and a monoclonal antibody directed at a monomorphic determinant present on all HLA class I antigens (PA2.6) was used to inhibit cytotoxicity of anti-HLA class I antibodies. Sera from 26 of the positive crossmatches were considered to be autoreactive, and the positive crossmatch proved to be due to IgM and not directed at HLA class I in each case. One year graft survival was 100% in the 5 living-related and 60% in the 21 cadaver donor transplants, of which 10 were regrafts. Of the 42 positive crossmatches, 16 were not due to autoantibody. One was positive in the current serum taken at the time of transplantation, and this graft was rejected hyperacutely, while 15 were positive with peak but not current serum samples. Of the positive crossmatches, 12 were inhibited by PA2.6 demonstrating that they were directed at HLA class I antigens. PA2.6 inhibition could not be shown in 3 and in 1 DTT reduction was technically unsatisfactory. While 4 of the 7 positive crossmatches due to IgM antibodies were successful, the 7 transplants performed with positive crossmatches due to IgG antibodies all failed. DTT reduction and inhibition of cytotoxicity by PA2.6 helps to define positive crossmatches with donor T cells that are not associated with graft failure. Transplantation in the presence of a peak positive T cell crossmatch due to an anti-HLA antibody might only be successful if the antibody in the peak serum is of the IgM class.     

Statin use is associated with prolonged survival of renal transplant recipients

The efficacy of statins for the prevention of cardiovascular events is well established in the general population but remains unknown in renal transplant recipients. In this study, the association of statin use with patient and graft survival was investigated in a cohort of 2041 first-time recipients of renal allografts between 1990 and 2003. Multivariable Cox regression demonstrated that statin use was independently associated with lower mortality rates. Twelve-year survival rates were 73% for statin users and 64% for nonusers (P = 0.055). The adjusted hazard ratio for all-cause mortality associated with statin use was 0.64 (95% confidence interval 0.48 to 0.86). Graft survival rates during the same time period were 76% for statin users and 70% for nonusers (P = 0.055). The adjusted hazard ratio for graft survival associated with statin use was 0.76 (95% confidence interval 0.55 to 1.04). Results from marginal structural models were virtually identical. In summary, statin use was associated with prolonged patient survival, but no difference in graft survival was detected. Although these results are encouraging, a definitive causal relationship can be determined only from randomized clinical trials.     

Hemoglobin variability after renal transplantation is associated with mortality

Anemia is a common problem after renal transplantation. Therefore, the patients are treated with erythropoietin stimulating agents (ESAs). The varying response to treatment contributes to hemoglobin variability, which might be associated with mortality. We conducted a retrospective cohort study of first kidney allograft recipients between 1990 and 2008 represented in the Austrian Transplant Registry. We included 1441 patients of whom 683 received ESAs at any time after transplantation. Cox regression with cubic splines and linear estimates and the purposeful selection algorithm of covariables were used. The measure of variability was the moving standard deviation computed at three monthly intervals for the entire graft life. The hazard ratio (HR) of mortality and graft loss in the spline models increased with hemoglobin variability. The linear HR for mortality was 2.35 (95% confidence interval 1.75-3.17, P<0.001) and functional graft loss 2.45 (1.76-3.40, P<0.001). In an adjusted Cox model (ESA use, hemoglobin, age, diabetes, days on dialysis, eGFR, biopsy confirmed acute rejection and year of transplantation), hemoglobin variability was associated with mortality (HR: 2.11; 1.51-2.94; P<0.001). No association with functional graft loss could be detected (HR: 1.34; 0.93-1.93; P=0.121). These findings suggest that hemoglobin variability is associated with mortality of renal allograft recipients.     

Histopathologic features of transplant glomerulopathy associated with response to therapy with intravenous immune globulin and rituximab

Transplant glomerulopathy (TG) is associated with poor long‐term allograft survival and is often accompanied by microcirculation inflammation. Histopathologic scoring may inform prognosis and help guide therapy. We retrospectively assessed 33 patients with biopsy‐proven TG. All biopsies were given a glomerulitis (g) and peritubular capillaritis (ptc) score. We determined allograft survival and serum creatinine stability in three different score groups: g < 2 and ≥ 2, ptc < 2 and ≥ 2, and (g + ptc) < 4 and ≥ 4. We assessed the impact of treatment with intravenous immune globulin (IVIG) and rituximab on outcomes. Graft survival and serum creatinine stability did not differ in each of the histopathologic score groups. Higher‐score groups were associated with the presence of concomitant antibody‐mediated rejection and were more likely to receive IVIG and rituximab. Treatment with IVIG and rituximab resulted in stability of serum creatinine within the higher‐score groups, but not in the lower‐score groups. Stabilization of serum creatinine was associated with an improvement in donor‐specific antibody. Histopathologic scoring in kidney allograft biopsies with TG may help guide treatment. The combination of IVIG and rituximab appears to be beneficial in patients whose biopsies have moderate or severe microvascular injury.