Early onset proteinuria after renal transplantation: a marker for allograft dysfunction

The objective of this study was to determine whether early proteinuria after renal transplantation affected long-term allograft survival. The 130 patients included 105 men and 25 women of overall mean age, 29.6 +/- 9.6 years. There were 105 living related and, 25 cadaveric donor transplants. Proteinuria was defined as a level in of more than 300 mg/d. Donor and recipient age at transplantation, duration of pretransplant dialysis, donor type (living related or cadaveric), the presence of delayed graft function or acute rejection, panel-reactive antibodies, the number of human leukocyte antigen mismatches, and the systolic blood pressure level were retrospectively recorded for the study subjects. Cox regression analysis was used to determine the effects of proteinuria on allograft survival. Patients with proteinuria demonstrated significantly lower graft survival rates than did those without proteinuria (54.17% vs 82.62%, respectively; P<.002). Proteinuria at the third month after transplantation (P<.004, odds ratio [OR]=3.26, confidence interval [CI]=1.46 to 7.29), donor age (P<.001, OR=1.06, CI=1.02 to 109), and panel-reactive antibodies (P<.041, OR=1.06, CI=1.00 to 1.12) were significantly associated with decreased allograft survival. Early proteinuria after renal transplantation was indicative of a high risk for allograft dysfunction. A reduction of proteinuria may be associated with improved graft survival.     

Early prediction of renal allograft loss beyond one year

Despite significant improvements in the results of renal transplantation since the introduction of cyclosporin, graft loss beyond the 1st year remains a significant and unresolved problem. In a retrospective analysis, 348 cyclosporin-treated renal transplant recipients with a functioning graft at 12 months were studied. Forty-eight patients in whom graft failure occurred in the 2nd and 3rd years were compared to 300 patients who maintained graft function beyond this time. Both groups were comparable with respect to donor and recipient features. Factors reflecting recipient immunological responsiveness —sensitization, previous transplantation and early rejection episodes-continued to affect graft survival beyond the 1st year. Surprisingly, there was a higher incidence of prior transfusion in the group with graft failure in the 2nd and 3rd years than in those with longer function (65% vs 24%). Serum creatinine levels at 3 and 6 months were also predictive of graft loss amongst patients with a functional graft at 1 year. It remains to be answered whether new immunosuppressive drugs and strategies will overcome these risks for late graft loss.     

The association of viral infection and chronic allograft nephropathy with graft dysfunction after renal transplantation

BACKGROUND: The long-term effect of viral infections on graft dysfunction and rejection after renal transplantation is uncertain. METHODS: A cohort of 37 renal transplant recipients was followed prospectively for 3 years. Creatinine clearance rate at 6 months and 3 years and chronic allograft nephropathy were correlated with the detection of cytomegalovirus (CMV), human herpesvirus 6 and human herpesvirus 7 and BK virus DNA, CMV disease, and acute rejection. RESULTS: CMV disease was significantly associated with poor graft function at 6 months, whereas chronic allograft nephropathy was associated with graft dysfunction at 3 years. Both CMV disease and detection of human herpesvirus 6 DNA were associated with chronic allograft nephropathy. CONCLUSIONS: CMV disease was a significant cause of early graft dysfunction, whereas the presence of chronic allograft nephropathy was the main determinant of poor long-term graft function. The role of viral infections in chronic allograft nephropathy deserves further investigation.     

An unusual cause of renal allograft dysfunction: graft papillary necrosis

A 43-year-old nondiabetic man, 5 years post-renal transplantation, presented complaining of oliguria, fever and dysuria of 1-day duration. Graft ultrasound did not reveal any obstructive changes. Graft function did not improve in spite of 3 days of antibiotics. On the fourth day he passed fleshy material in urine subsequent to which his urine output improved and fever recovered. His graft function settled near to the previous baseline. Histological analysis of the material revealed necrosed renal papillary tissue. Renal papillary necrosis in allograft is uncommon and generally reported in the immediate postoperative phase, but it can still occur later in transplant follow-up. It is a potentially treatable cause for acute allograft dysfunction and should be suspected in transplant patients presenting with acute pyelonephritis but not getting relief from antibiotic therapy.     

肾移植术后少尿或无尿的诊治体会

报告尸体肾移植术后发生少尿或无尿患者30例,其中有2例无尿时间长达8～12周。均采取严密观察肾脏血供、常规透析、仔细防治排斥反应等并发症的“积极等待”的方法予以治疗,大部分患者移植肾功能均恢复正常;2例长时间无尿的患者亦恢复了正常肾功能,取得了较好的效果。认为彩色多普勒超声对诊断移植肾少尿或无尿有较大帮助,采用“积极等待”的方法治疗肾移植术后的少尿或无尿可取得较好效果。     

Early renal transplantation after donor renal angiography affects initial graft function

Background

Renal angiography of a living donor is a common radiologic examination before transplantation. However, the contrast agent used during this procedure can cause contrast nephropathy. There are insufficient data regarding whether this radiocontrast exposure detoriates renal function and survival after transplantation. In this study, we analyzed the effects of radiocontrast exposure to donors before transplant surgery on the incidence of delayed graft function (DGF) and on the outcomes of recipients at 1 year posttransplantation.

Methods

We divided 80 living donor transplantations according to the duration between the renal angiography and the transplantation procedure: Group 1 as early transplantation at ≤20 days (n = 42) versus group 2 of late transplantation at ≥20 days (n = 38). We retrospectively collected acute rejection episodes and graft survival at 1 year, monthly serum creatinine values of, DGF, proteinuria at 1 month, GFR at posttransplant day 3 month 1, and 1 year.

Results

There were 10 group 1 recipients (23.8%) and 2 group 2 (5.3%) subjects who experienced ≥1 acute rejection episode in the 1st posttransplant year (P = .02); 1 patient in each group experienced graft loss at 1 year (P = .941). DGF was observed in 9 (22%) versus 1 patient (2.6%) in group 2 (P = .009). Posttransplant day 3 creatinine values were significantly higher (P = .005) with significantly lower GFR values (P = .043) in group 1. However, creatinine and GFR levels were similar at 1 month and 1 year. Month 1 proteinuria levels were significantly higher in group 1 (P = .014). There was a significant negative correlation between renal angiography time and month 1 proteinuria (P = .014).

Conclusions

Early renal transplantation (within 2 weeks after renal angiography) in living kidney donors can detoriate initial graft function and cause DGF.     

发生慢性移植肾功能不全者以西罗莫司替换环孢素A的临床疗效

目的 对采用以环孢素A(CsA)为基础免疫抑制剂的慢性移植肾功能不全(CRAD)患者,将CsA转换为西罗莫司(SRL),观察转换后的临床效果和安全性.方法 20例肾移植后出现CRAD的患者,采用突然转换法将CsA替换为SRL(3 mg/d),霉酚酸酯(MMF)和泼尼松(Pred)的剂量维持不变.另随机选取9例仍然使用CsA、MMF和Pred的CRAD患者作为对照.观察血肌酐(Cr)、肾小球滤过率(GFR)和24 h尿蛋白定量的变化情况以及SRL的不良反应.结果 对照组与转换组在患者年龄、性别构成比、移植后时间、转换时的血Cr水平和转换时免疫抑制剂用量等方面的差异均无统计学意义.随访1年,转换组有18例完成观察,其中11例(61.1%,11/18)转换有效,7例(38.9%,1/18)转换无效.转换有效者和转化无效者在转换时的血Cr、移植后时间、GFR及24 h尿蛋白定量等方面的差异有统计学意义.转换有效者的血Cr明显下降,GFR明显升高,而转换无效者的血Cr呈进行性升高,GFR呈进行性下降.转换治疗期间,1例出现急性排斥反应,经冲击治疗后逆转.完成随访的18例中,2例发生感染,3例出现皮疹,3例出现腹泻,2例出现口腔溃疡,8例出现骨髓抑制,6例转氨酶升高,10例出现高血脂,4例出现低血钾,没有患者因为上述不良反应而退出观察.结论 肾移植后采用以CsA为基础的免疫抑制方案者,若出现CRAD,可以将CsA替换为SRL,部分患者的肾功能得到改善,但转换应在移植肾功能发生严重损害前进行.     

Cyclosporine-induced renal dysfunction in human renal allograft recipients

Cyclosporine-treated renal allograft recipients frequently suffer CsA-related nephrotoxicity and hypertension. This study demonstrates that glomerular filtration rate is reduced acutely by 13% (P less than 0.02) and renal vascular resistance increased by 30% (P less than 0.05), immediately after patients take their CsA dose. The reduction in GFR is directly related to their trough CsA level (r = 0.82; P less than 0.01). The lower the trough CsA level the greater the fall in GFR after the CsA dose. Plasma renin activity does not increase after the CsA dose (pre-CsA 0.6 +/- 0.2 ng/L/sec vs. post-CsA 0.4 +/- 0.1 ng/L/sec; P = NS), and therefore cannot be responsible for the reduction in renal function. Short-term nifedipine treatment is effective in preventing the acute reduction in GFR (P less than 0.05). This occurred despite no apparent effect of nifedipine in altering trough or post-dose CsA levels. Furthermore nifedipine was effective in lowering both the mean arterial blood pressure (109 mmHg to 94 mmHg; P less than 0.01) and the elevated renal vascular resistance (25% reduction; P less than 0.02) observed in these patients. These results suggest that nifedipine may be a suitable agent for limiting acute CsA nephrotoxicity and for treating CsA-associated hypertension in renal allograft recipients.     

Histopathology of chronic renal allograft dysfunction

The rate of late allograft loss remains relatively constant, despite greatly improved success in the early management of renal transplants. The pathological changes encountered in kidneys undergoing late allograft dysfunction are the result of a variety of processes, both immune and nonimmune. The gradual appearance of interstitial fibrosis and tubular atrophy is a nonspecific finding, which characterizes late allograft dysfunction. Features that indicate chronic rejection include transplant glomerulopathy, vascular intimal hyperplasia, particularly in association with intimal lymphocytic infiltration. Both of these changes may be related to humoral rejection. Animal models provide important insights into the mechanism of chronic rejection. In a commonly used model, the Fisher to Lewis rat model, antidonor antibodies against matrix proteins are associated with the development of transplant glomerulopathy, and the appearance of antitubular antibodies and a granulomatous interstitial nephritis may indicate graft-host differences in tubular basement membrane structure.     

Pathogenesis of chronic renal allograft dysfunction

The pathogenesis of chronic renal allograft dysfunction was reviewed. Chronic rejection/chronic renal allograft nephropathy is the most prevalent cause of renal graft loss after the first year post-transplant. Both immunologic and non-immunologic factors play key roles in the pathogenesis of chronic allograft nephropathy. Acute rejection episodes are the most prevalent risk factor for chronic rejection. Many risk factors for chronic allograft nephropathy have been identified, such as glomerular hyper-filtration, delayed graft function, repeated acute rejection, systemic hypertension and hyperlipidemia. However, the precise pathogenesis of chronic allograft nephropathy remains obscure. The differential diagnosis of immunologically mediated chronic rejection and chronic allograft dysfunction caused by non-immunologic factors is usually impossible using clinical parameters. The histopathologic findings of chronic allograft nephropathy are progressive interstitial fibrosis with tubular atrophy and thickening of vascular intima, and these findings are non-specific. Therefore, the term chronic allograft nephropathy may be clinically preferable to chronic rejection to describe the gradual decline in graft function. The most effective way to prevent chronic allograft dysfunction is to avoid any kind of graft damage via immunologic or non-immunologic pathway.     

CD103+ CTL accumulate within the graft epithelium during clinical renal allograft rejection.

BACKGROUND: We have previously reported that activated CD8+TCRalphabeta+ cells that express high levels of the beta7 integrin CD103 (formerly alphaE, MLA) are present at the graft site during clinical renal allograft rejection. This observation potentially provides new insight into the mechanisms underlying renal allograft destruction because the ligand of CD103 is the epithelial cell-specific molecule E-cadherin, which is known to be expressed by critical graft functional elements such as the renal tubular epithelium. We herein used combined fluorescence-activated cell sorter (FACS) and immunohistochemical (IHC) analyses of transplant nephrectomy (TN) specimens to demonstrate that CD103+ cytolytic T lymphocytes (CTLs) specifically home to the graft epithelium during rejection episodes. METHODS: Serial sections of TN specimens undergoing histologically confirmed cellular rejection (n=7) were stained with anti-CD8 or anti-CD103 and were scored for the presence of positively stained cells within the tubular basement membrane. Freshly isolated graft-infiltrating lymphocytes were subjected to three-color FACS analyses to define the extended phenotypic characteristics of CD103+ cells detected by IHC. RESULTS: CD103+ cells in all specimens were biased towards an intratubular localization. On average, the percentage of CD103+ cells with an intraepithelial localization was 52.2+/-13.1 compared to 12.0+/-3.5 for pan CD8+ cells (mean+/-SE, n=5). FACS analyses confirmed that CD103+ cells detected by IHC exhibited the salient characteristics of CD8+ CTLs (large CD8+TCRalphabeta+CD62L-CD11a(hi)perforin+). The CD103- subset of graft-infiltrating CD8 cells also exhibited a CTL phenotype, but these were predominantly restricted to the graft interstitium. CONCLUSIONS: These data implicate CD103 as a homing receptor that targets graft-infiltrating CD8+ CTLs to the graft epithelium. Given the strong association of tubulitis with clinical rejection, these data are consistent with a role for the CD103+ CTL subset as an effector mechanism in renal allograft destruction.     

The role of C-reactive protein in graft dysfunction after renal transplantation

PURPOSE: We investigated whether serial daily measurements of serum C-reactive protein could help differentiate episodes of transplant dysfunction due to rejection, infection, cyclosporin A nephrotoxicity or acute tubular necrosis in renal allograft recipients. MATERIALS AND METHODS: Morning serum was obtained daily from 134 patients during the first 30 days after renal transplantation. All episodes of graft dysfunction were recorded and compared to transplant biopsies. C-reactive protein concentrations were correlated with postoperative graft function and the various causes of graft dysfunction. RESULTS: All patients demonstrated an increase in C-reactive protein in response to surgery and a maximum level was reached on day 2 after transplantation. Mean C-reactive protein concentration was significantly increased for delayed (61.50 microg./ml.) compared to primary (mean 38.01) graft function (p = 0.001, Mann-Whitney U test). There were significant increases in C-reactive protein for bacterial infections other than asymptomatic bacteriuria (33.98 microg./ml), interstitial graft rejection (16.43) and acute tubular necrosis (30.50) compared to uneventful courses. C-reactive protein was unchanged for viral infections or cyclosporin A toxicity. CONCLUSIONS: Serial C-reactive protein measurements help to identify renal transplant dysfunction of different origins. However, rejection, infection and acute tubular necrosis show similar patterns of C-reactive protein increase. Thus, C-reactive protein is unable to discriminate the causes of renal graft dysfunction. Biopsy remains the gold standard for the differential diagnosis of renal allograft dysfunction.