Renin-angiotensin system blockade in biopsy-proven allograft nephropathy

Allograft nephropathy leads to progressive renal injury and ultimate graft loss. In native kidney disease, the use of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) is beneficial in retarding the decline of renal function. We reviewed a cohort of renal transplant recipients who were prescribed either an ACEi or ARB for biopsy-proven allograft nephropathy. Patients were followed from time of initiation of ACEi/ARB and were stratified based on biopsy findings. Outcomes of interest included safety, allograft survival, renal function, and rate of renal function decline pre- and post-ACEi/ARB. The 5-year allograft survival after biopsy was 83%. Mean serum creatinine was 2.2 +/- 1.1 mg/dL (range 1.0 to 4.3) at time of biopsy and 2.6 +/- 1.2 mg/dL (1.2 to 6.5) at last follow-up. The mean slope of the creatinine versus time (SD) was 2.43 (7.93) in the 12 months prior to therapy and 1.45 (3.66) following therapy, with the absolute difference in slope -3.38 (6.06) (P =.0004). We conclude that treatment with ACEi/ARB is beneficial in the management of allograft nephropathy.     

Correlation between endothelin expression in early post-transplant biopsy specimens and long-term allograft function in living-related renal transplantation

OBJECTIVE: We investigated whether degree of immunohistochemically evident endothelin (ET) expression in early post-transplant biopsy specimens could predict long-term allograft function in living-related renal transplantation. METHODS: Allograft biopsy specimens obtained from 40 patients with living-related transplants were studied. Cases with episodes of acute rejection or calcineurin inhibitor toxicity were excluded. We immunostained graft biopsy specimens obtained at pre-transplantation (PRE) and at 3 months (3M) afterward with anti-ET antibody. The number of stained tubular epithelial cells per 1000 tubular cells was defined as the staining index (SI). In the 21 patients whom we could assess at 3 yr (3Y) after transplantation, the correlation between ET expression and long-term graft function was examined. RESULTS: Anti-ET antibody staining was appreciable in tubular epithelium but not in glomeruli. Tubular SI at PRE and at 3M were 10.6 +/- 15.3 and 32.0 +/- 35.6 (mean +/- SD) respectively (p < 0.01). When patients were classified according to SI (group A, SI < 25; group B, SI > 25), declining ratio in creatinine clearance at 3Y after transplantation for groups A and B with respect was 21.8% +/- 15.4% and 41.9% +/- 21.6% (p < 0.05). CONCLUSION: High ET expression in early post-transplantation, biopsy specimens was related to poor long-term allograft function following living-related renal transplantation.     

Renin-angiotensin gene polymorphism in children with uremia and essential hypertension

The M235T polymorphism of the angiotensinogen (ANG) gene, the I/D polymorphism of the angiotensin converting enzyme (ACE) gene, and the A1166C polymorphism of the angiotensin II type 1 receptor (AT1R) gene were identified in 70 patients with end-stage renal disease [20 pediatric ESRD, aged 14.9+/-3.1, years blood pressure (BP) 139+/-14/91+/-13 mmHg, 50 adult ESRD, aged 48.7+/-18.7 years, BP 149.1+/-24/96.9+/-12 mmHg], 35 with juvenile essential hypertension (JEHT, aged 14.4+/-2.7 years, 24-h mean BP 135.37+/-7.37/72.4+/-7.68 mmHg), 130 adult healthy normotensive controls (aged 34.9+/-8.1 years, BP 117.8+/-8.7/78.7+/-8.5 mmHg), and 20 pediatric controls (aged 13.2+/-1.2 years, BP 109+/-6.5/71+/-5.9 mmHg). The ACE gene polymorphism was determined by polymerase chain reaction and the ANG and AT1R gene polymorphisms by single-step LightCycler technology. The ACE gene distribution of the Hungarian controls did not differ from the results of the other Caucasian populations. In JEHT and pediatric ESRD patients, the MT genotype of ANG was more frequent than in controls (JEHT 80%, pediatric ESRD 74% versus controls 50%, P<0.02). The DD genotype of ACE was over-represented in pediatric ESRD compared with controls (ESRD 45% versus controls 22%, P<0.05). There was a non-significant increase in the CC genotype frequency of AT1R in adult patients with ESRD compared with controls. In conclusion, there was an increased frequency of the ACE DD genotype in pediatric ESRD, which could be a genetic risk factor for the development of ESRD. Furthermore, there was a significant increase in MT genotype frequency of ANG M235T polymorphism in pediatric ESRD and JEHT. The role of AT1R gene polymorphism needs further investigation.     

肾移植术后患者血清半胱氨酸蛋白酶抑制物水平与肾功能的关系

目的 探讨肾移植术后患者血清半胱氨酸蛋白酶抑制物(CyC)的水平变化与移植肾功能的相关性.方法选择193例使用他克莫司(FK506)加霉酚酸酯(MMF)加泼尼松(Pred)三联免疫抑制剂肾移植患者术后的血、尿标本,测定血清CyC和血、尿肌酐.经统计学分析,与常规的血清肌酐(SCr)浓度及尿肌酐清除率(CCr)和内生肌酐清除率(CkCCr)作相关性比较,评估CyC判断移植肾肾小球滤过功能的敏感性和特异性.结果 193例肾移植患者术后第5天血清CyC、SCr和CCr、CkCCr分别为(1.91±1.28)mg/L、(174.2±129.1)μmol/L、(67.9±27.3)ml/min、(68.1±27.8)ml/min.其中CyC浓度＜1.25 mg/L者42例,1.25～2.00 mg/L者102例,＞2.0 mg/L者49例;SCr浓度＜125/μmol/L者62例,125～200μmol/L者83例,＞200/μmol/L者48例;CkCCr＞80ml/min者52例,80～60 ml/min者96例,＜60 ml/min者45例.CyC与SCr呈正相关(r=0.886,P＜0.001),与CkCCr呈负相关(r=-0.907,P＜0.001);SCr与CkCCr呈负相关(r=-0.889,P＜0.001).非参数受试者工作特征曲线分析CyC、SCr、CCr、CkCCr曲线下面积分别为0.877、0.771、0.832、0.909,其诊断敏感性和特异性分别为91.6%、69.3%,52.2%、96.1%,67.5%、77.1%和84.6%、71.3%. 结论 肾功能轻度损害时,血清CyC比SCr先一步增高,有可能成为评定肾移植患者移植肾功能的敏感性标志物.     

Oxidative stress and nitric oxide system in post-transplant hypertension

BACKGROUND: CsA-induced endothelial dysfunction and CsA-induced hypertension have been attributed to CsA effects on the endothelial-derived factors controlling vasomotor tone, but the mechanisms responsible are unclear. Endothelial nitric oxide (NO) is known to maintain a state of basal vasodilation and recently a NO mediated counterregulatory mechanism protective from CsA-induced vasoconstriction has been suggested. PATIENTS AND METHODS: Our study evaluates ecNOS gene status and NO metabolites in kidney transplanted patients under chronic CsA treatment with CsA-induced hypertension. Since CsA increases superoxide production, which metabolizes NO, plasma hydroperoxides and peroxynitrite were also evaluated as index of the presence of "oxidative stress". RESULTS: Quantification of monocyte ecNOS mRNA and NO metabolites plasma level from patients and control subjects (C) demonstrated NO system up regulation in patients notwithstanding hypertension. The mean ecNOS to beta-actin ratio was 2.00 +/- 0.87 vs 0.29 +/- 0.08 in C, p < 0.04. NO metabolite plasma level was 30.03 +/- 9.62 mM vs 9.37 +/- 3.86, p < 0.001. Hydroperoxides were also increased in patients: 3.6 +/- 1.6 i.a.u. vs 1.4 +/- 0.8, p < 0.007 (from cholesterol esters) and 10.8 +/- 6.6 vs 1.5 +/- 0.9, p < 0.008 (from triglycerides) as well as peroxynitrite plasma level: 0.36+/- 0.14 mM/L vs undetectable in C. CONCLUSIONS: This study confirms a NO system up-regulation in transplanted patients. However, the counterregolatory system to CsA-induced vasoconstriction, could be cancelled by CsA induced superoxide and free radicals production which, increasing NO metabolism could contribute to CsA induced vasoconstriction and hypertension.     

主要组织相容性一类相关链A基因抗体与慢性移植肾功能减退的相关性研究

目的 探讨肾移植术后主要组织相容性一类相关链A基因(MICA)抗体对稳定期移植肾功能的影响.方法 采用免疫荧光液相芯片技术检测57例肾移植术后超过半年患者的MICA抗体水平及特异性.并同时检测SCr水平,分析MICA抗体对移植肾功能的影响. 结果 57例患者中HLA抗体和MICA抗体均为阴性者38例,HLA抗体阳性、MICA抗体阴性者11例,HLA抗体阴性、MICA抗体阳性者5例,HLA抗体和MICA抗体均阳性者3例.在MICA特异性抗体不同类型中,MICA019抗体5例、MICA027抗体3例、MICA018抗体2例、MICA004和017抗体各1例,MICA抗体阳性值≥6分者9例,占75%(9/12).MICA抗体阳性组8例与MICA抗体阴性组49例在术前输血史、淋巴毒试验、冷缺血时间、术后时间方面差异均无统计学意义(P＞0.05);而在术时年龄方面差异有统计学意义[(32.5±7.9)岁与(43.0±10.4)岁(P=0.008)3.MICA抗体阳性HLA抗体阴性组SCr水平[(117.20±12.30)μmol/L]及SCr异常比例(5/5)均高于HLA抗体和MICA抗体均阴性组[(89.40±28.95)μmol/L及23.7%(9/38),P＜0.05].结论 肾移植术后监测MICA抗体可作为肾移植HLA阴性患者预后重要的标志物,并且MICA抗体与慢性移植肾功能减退存在明显的相关性.     

First-year renal function predicts long-term renal allograft loss

Purpose

We performed a retrospective study to examine the impact on long-term graft survival of first-year posttransplantation renal function, as evaluated by serum creatinine.

Patients and Methods

We analyzed data from 1,273 adult kidney transplants performed between 1983 and 2008. All recipients >18 years old were included if their grafts had survived beyond 1 year, excluding patients simultaneously transplanted with other organs. Cox proportional hazards multivariable analysis was used to examine the relationship between first-year posttransplantation renal function and death-censored graft loss, adjusted for other variables. Renal function in the first year was expressed as serum creatinine levels at 1, 6, and 12 months as well as the change in creatinine between those 3 periods.

Results

Posttransplantation 1-month serum creatinine levels and change between 1 and 6 months were independent predictors of long-term graft loss. Multivariable analysis also identified donor age (increasing), acute rejection episode occurrence, recipient age at transplantation (decreasing), and gender (female) as independently predictive of graft failure, adjusting for other factors usually associated with graft loss, namely, pretransplantation time on dialysis, HLA mismatches, and delayed graft function. The predictive effect of creatininemia was sustained at 6 and 12 months, after adjusting for these covariates.

Conclusions

Posttransplantation serum creatinine levels at 1, 6, and 12 months were independent predictors of graft survival, suggesting that they could be considered as surrogate endpoints for long-term death-censored graft loss.     

Persistent post-transplant autonomous hyperparathyroidism despite 23 years of excellent renal allograft function

Hyperparathyroidism is a common problem for patients on renal replacement therapy programs. Many long-term dialysis patients require parathyroidectomy while on dialysis. Some patients, however, despite severe renal osteodystrophy, are transplanted, and in these a large proportion show a slow resolution of bony problems, in the context of the removal of the uremic stimulus to abnormal bone metabolism. A proportion of these patients become hypercalcaemic after renal transplantation, sometimes with symptoms. There is not a consensus on how these patients should be managed, with opinions varying from early parathyroidectomy to later parathyroidectomy and to conservative treatment. We present the case of a lady who underwent 23 years of conservative management of her post-transplant hyperparathyroidism. She was hypercalcaemic for almost all of that period, despite excellent renal transplant function. Finally, after 23 years she underwent surgical parathyroidectomy with autografting with prompt sustained resolution of her symptomatic hypercalcaemia.     

Chronic allograft nephropathy score before sirolimus rescue predicts allograft function in renal transplant patients

Chronic allograft nephropathy (CAN) is a major indication for initiation of sirolimus (SRL) in renal transplantation (TX) to prevent deterioration of renal function. We evaluated whether the CAN score at time of sirolimus rescue (SRL-R) predicts renal allograft function. CAN score is the sum of the following 4 categories: glomerulopathy (cg, 0-3), interstitial fibrosis (ci, 0-3), tubular atrophy (ct, 0-3), and vasculopathy (cv, 0-3). This is a retrospective cohort study of renal transplant recipients from July 2001 to March 2004. Immunosuppression consisted of preconditioning with rabbit anti-thymocyte globulin or alemtuzumab and maintenance with tacrolimus (TAC) monotherapy with spaced weaning, if applicable, SRL-R was achieved by conversion from TAC, or by addition to reduced doses of TAC. Ninety patients received SRL. Thirty-three of these patients met the inclusion criteria of the following: (1) receipt of SRL for >6 months, and (2) follow-up of > or =6 months. There were 16 patients in the low-CAN (0-4) group and 17 patients in the high-CAN (>4) group. Cockcroft-Gault (C-G) glomerular filtration rate (GFR) was calculated at SRL-R and at 1, 3, 6, and 12 months. The DeltaGFR was significantly better in the low-CAN group at 1, 3, and 6 months. A trend toward an improved DeltaGFR was present at 12 months in the low-CAN group (P = .16). CAN scoring at the time of SRL-R predicts recovery of renal allograft function (as measured using DeltaGFR), and should be used in preference to biochemical markers (Cr and C-G GFR), which may not be reliable predictors.     

Renin-angiotensin system component gene polymorphisms in Japanese maintenance haemodialysis patients

Summary: The renin-angiotension system (RAS) component gene polymorphisms was examined in 216 patients undergoing maintenance haemodialysis (HD) therapy and in 208 control subjects. the RAS polymorphisms selected for analysis were angiotensin I converting enzyme (ACE) I/D, angiotensinogen (Agt) T235/M235, angiotensin II type 1 receptor (AGT1R) A1166/C1166. the control allelic frequencies was ACE I/D (0.63/0.37), Agt T235/M235 (0.16/0.84), and AGT1R A1166/C1166 (0.94/0.06). Recently, relationships between ACE I/D and the progression of renal disease attract great attention in Japanese and Caucasian populations. ACE D allele was expected to be more frequent in HD population. However, no accumulation of ACE D allele or Agt T235 allele, AFT1R C1166 allele in Japanese end-stage renal disease (ESRD) subjects was detected. to explain the paradoxical result of positive association of ACE D allele with progression of renal disease and no bias of ACE genotype in ESRD subjects, further investigation with systematic prospective study regarding the change of ACE genotype distribution around the period of entering dialysis therapy is required.     

The effect of ATG on cytokine and cytotoxic T-lymphocyte gene expression in renal allograft recipients during the early post-transplant period

BACKGROUND: Despite the long history of ATG use, the exact in vivo mechanism of action remains unclear. In the present study, we analyzed the effect of ATG-induction therapy on expression of 10 immunologically relevant genes in the early post-transplant period. METHODS: Eight renal allograft recipients received post-transplant prophylactic ATG treatment on 10 consecutive days and an additional three patients received treatment on 5, 6, or 7 consecutive days, respectively. Gene expression was measured at the beginning and the end of therapy and normalized to a control gene using Taqman real-time PCR methodology. Results were compared with those of matched control patients. No patients were diagnosed with rejection. RESULTS: ATG-treated patients showed decreases in the expression of cytotoxic T cell genes perforin (-56%, p = 0.03) and granzyme B (-45%, p = 0.01) and cytokine gene IFN-gamma (-75%, p = 0.005), and significant increases in the expression of cytokine genes IL-7 (550%, p = 0.04), IL-10 (275%, p = 0.01), IL-15 (417%, p = 0.03), TNF-alpha (615%, p = 0.01), and TGF-beta (235%, p = 0.02). No significant changes were observed in the control group, with the exception of a decrease in IL-10 expression (-42%, p = 0.01). There were no significant changes in IL-12 or Fas-L expression in either group. CONCLUSION: ATG-induced decreases in the expression of IFN-gamma, perforin, and granzyme B and increases in IL-10 and TGF-beta might be considered beneficial to the recipient, whereas increases in the expression of IL-7, IL-15, and TNF-alpha genes might be involved in immunological processes not effected by ATG that may harm the transplant in the long term.     

Macrophage index predicts short-term renal allograft function and graft survival

The ability to predict renal allograft dysfunction in the short term and predict graft survival by quantifying the macrophage infiltrate in allograft renal biopsies is described. Renal allograft biopsies performed for cause in 41 consecutive patients were scored for macrophages (macrophage index, MI) by use of a modified Banff score of inflammation (BSI), and the impact of the MI on serum creatinine (SCr) levels 3 months post-biopsy (post-Bx) and on graft survival was quantified. Biopsies were stained for macrophages, individual lesions semiquantified and MI, BSI and chronic allograft damage index (CADI) obtained. The effects of pathologic indices on 3 month post-Bx SCr and graft survival were quantified by multivariate analysis and Cox regression. Glomerular and interstitial macrophage scores correlated inversely with graft survival. MI predicted an increase in SCr 3 months post-Bx (P=0.02). MI >3 (hazard ratio 23.13, P=0.003) also had a powerful negative predictive value on graft survival.     

肾素－血管紧张素系统在骨关节炎发病中的研究

骨关节炎是一种以关节软骨退变为主的慢性疾病，但其具体发病机制目前仍不清楚。肾素－血管紧张素系统在维持人体内部环境的稳定中起着重要作用，近年来也被认为在骨关节炎的发生、发展中发挥重要的调控作用。本文针对肾素－血管紧张素系统信号通路调控骨关节炎及退变的分子机制进行综述。