Long-term beneficial effect of tacrolimus conversion on renal transplant recipients

OBJECTIVE: Acute rejection, chronic allograft nephropathy, and cyclosporine (CsA) toxicity remain serious problems for renal transplant recipients and may lead to graft loss. We retrospectively analyzed 34 patients whose biopsies revealed acute and/or chronic allograft rejection, or CsA nephrotoxicity, and who converted from CsA to tacrolimus. PATIENTS AND METHODS: From July 1996 through September 2003, CsA was converted to tacrolimus in 34 renal transplant recipients (26 male, 8 female) with renal biopsy at our hospital. Blood pressure and serum creatinine levels were checked monthly and serum cholesterol, triglyceride, and glutamic-pyruvic transaminase (GPT) levels were checked every three months. RESULTS: A consistently stable and better function after conversion was obtained in a significant portion (24, 71%) of patients. A statistically significant decline in serum creatinine and an improvement in the glomerular filtration rate were found at 3 m, 6 m, 12 m, 36 m, and 72 m after tacrolimus conversion. In 85.7% (12/14) of patients with acute rejection and in 35.7% (5/14) of patients with chronic allograft nephropathy (concomitant with acute rejection in 5), improved or stabilized graft function was noted. In addition, the systolic blood pressure and diastolic BP dropped significantly (P<0.05), while there was no significant change in cholesterol, triglyceride, and GPT levels. CONCLUSION: The beneficial effect of tacrolimus conversion on patients with acute rejection, chronic allograft nephropathy, or CsA nephrotoxicity was demonstrated in long-term follow up. The improvement in both renal function and blood pressure may be of paramount importance in reducing long-term cardiovascular morbidity and mortality.     

One-year routine renal transplant biopsies in children

In our institution, systematic renal graft biopsies are performed 1 year after transplantation before deciding to switch to alternate-day steroid therapy, which has been shown to be beneficial for statural growth. We analyzed the results of systematic graft biopsies in 145 children with a creatinine clearance > or =45 ml/min per 1.73 m2. Biopsies were classified according to Banff diagnostic categories. Normal parenchyma was observed in 19 cases (13%), non-specific lesions in 42 cases (29%), chronic allograft nephropathy grade 1-3 in 68 cases (49%), and acute rejection in 8 cases (5%). Clinicopathological correlations indicated that patients with chronic allograft nephropathy had received kidneys from older donors, with longer cold ischemia time and with a higher incidence of delayed graft function. There was a strong correlation between the donor age and the presence of vascular lesions. There was also a good correlation between the severity of histological lesions and the occurrence of acute rejection episodes during the 1st year after transplantation. Renal function remained stable for up to 10 years in patients with normal parenchyma or non-specific lesions, while serum creatinine levels increased after the 2nd year in patients with chronic allograft nephropathy.     

Stable kidney function in the second decade after kidney transplantation while on cyclosporine-based immunosuppression

BACKGROUND: Calcineurin inhibitors (CNIs) have been the mainstay of immunosuppressive protocols in kidney transplantation over the past 20 years. However, in some recipients, the adverse effects of CNIs contribute to chronic allograft nephropathy and death with function--the two leading causes of late graft loss. Other recipients maintain stable graft function. METHODS: We studied the impact of continuing CNI-based immunosuppression in the second decade after kidney transplantation. From 1984 through 1996, a total of 1,263 patients underwent a primary kidney transplant at the University of Minnesota and received cyclosporine-based immunosuppression. Antibody induction was used only in deceased donor recipients. RESULTS: The actuarial 20-year patient survival rate was 38%; graft survival, 30%; and death-censored graft survival, 60%. The annual mean serum creatinine level for recipients whose grafts survived > or =1 year remained stable, although recipients with a history of > or =1 acute rejection episode had a higher serum creatinine level vs. recipients who were rejection-free. The annual mean calculated creatinine clearance was also stable over time. In addition, for recipients who were acute rejection-free, chronic allograft nephropathy/chronic rejection was only responsible for 9% of graft losses. CONCLUSIONS: Our study suggests that some kidney transplant recipients tolerate long-term CNI-based immunosuppression with stable creatinine levels. Identifying certain recipients' predisposition to CNI toxicity and individualizing immunosuppressive therapy may be important in order to improve long-term kidney function, while simultaneously preserving low short-term acute rejection rates.     

Value of pretransplantation cytokine profiles for predicting acute rejection in renal transplant recipients

Episodes of acute rejection may represent an important risk factor for the development of chronic allograft nephropathy. Various studies have shown that pretransplant cytokine profiles in recipient blood are associated with transplant outcome. Serum samples were collected 24 hours before transplantation from 57 patients (38 men and 19 women of age 36 +/- 5 years) receiving kidneys from unrelated living donors. Additional samples were collected at 1 and 2 weeks after transplantation, as well as during every rejection episode. The immunosuppression consisted of a cyclosporine, prednisolone, and mycophenolate mofetil. Among the transplanted patients, 19 (33.3%) individuals experienced an acute rejection episode based on an increased level of serum creatinine and blood urea nitrogen during the first 14 days after transplantation. TGF-beta, IL-2 and IFN-gamma serum levels were determined by an ELISA method using Bindermed system kits. The mean concentration of TGF-beta before transplantation tended to be lower among patients with acute rejection episodes compared to those with stable graft (75,265 versus 85,394 pg/mL; P = .34) and at 1 week after transplantation (77,558 versus 84,390 pg/mL), although the differences were not significant. Among patients with rejection the mean IL-2 concentration was significantly higher before, at 1 week, and at 2 weeks after transplantation (15.0 versus 6.8 pg/mL, P = .005; 19.0 versus 4.9 pg/mL, P = .001; and 21.1 versus 4.7 pg/mL, P = .0001). The mean concentration of IFN-gamma was significantly higher pre- and at 1 and 2 weeks posttransplantation in patients with acute rejection episodes (161.1 versus 65.2, 175.6 versus 66.5 and 173.7 versus 77.1 pg/mL, all P < .001). In conclusion, evaluation of Th1 cytokines before transplantation may represent valuable predictive marker for an acute rejection episode.     

Interleukin-6 and neopterin in renal transplant recipients: a longitudinal study

Serum and urine interleukin-6 (IL-6) levels and serum neopterin/creatinine ratios were longitudinally studied in 86 renal transplant recipients until 4 months after transplantation. During acute rejection and acute tubular necrosis (ATN), serum and urine IL-6 levels were elevated compared to during stable transplant function (P<0.001). During acute rejection, serum IL-6 levels increased at least 2 days before plasma creatinine started to rise (P<0.05), indicating its early involvement in the rejection process. During cytomegalovirus (CMV) disease, serum, but not urine, IL-6 levels were higher (P<0.01), and serum neopterin/creatinine values were higher than during stable transplant function, ATN, or acute rejection (P<0.01). No significant differences with stable transplant function occurred during cyclosporin A toxicity. Measurement of serum IL-6 provided a sensitivity of 84% and a specificity of 85% for the diagnosis of acute rejection episodes not coinciding with ATN. All cases of CMV disease could be diagnosed by measurement of serum neopterin/creatinine, which provided a specificity of 73%.     

Analysis of urinary donor-derived DNA in renal transplant recipients with acute rejection

Abstract: In renal transplantation we usually diagnose an acute rejection by based on the results of a needle biopsy; however, this takes time and findings in some cases are not definite. We analysed the urine of renal recipients for the presence of donor DNA in an attempt to establish a diagnostic means of acute rejection. Sixty-four renal transplant recipients were examined. Thirty-seven patients had no trouble after transplantation and 22 patients developed acute rejection, diagnosed based on serum creatinine levels and/or needle biopsy findings of the graft. Five patients had drug-induced renal dysfunction. In female recipients with a male graft we examined urine for the presence of Y-chromosome (SRY and DYZ-1) and in recipients receiving a HLA mismatched graft we investigated the HLA-DR gene (DRB1) by the polymerase chain reaction (PCR) method. Among female recipients with a male graft there were 14 patients with stable renal function and SRY and DYZ-1 on Y-chromosome were negative in 13 (93%) and positive in one, whereas SRY and DYZ-1 of urine were positive in the four female patients with acute rejection and these DNA fragments disappeared in three after rejection therapy. One patient was subjected to haemodialysis. Among 23 recipients of a graft from HLA mismatched donors with stable renal function, DRB1 was negative in 21(91%). Among 18 patients with acute rejection DRB1 was positive in 16 (93%) and negative in two. These DNA fragments disappeared in 13 patients after rejection therapy. In all patients with drug-induced renal dysfunction donor-derived DNA was negative. Presence of donor-specific DNA in the urine of the recipient is associated strongly with acute rejection and analysis of DNA derived from donor cells in urine might be an effective and accurate method for the diagnosis of acute rejection of a renal transplant.     

排斥反应时血清可溶性白细胞相关免疫球蛋白样受体1的水平及意义

目的 探讨可溶性白细胞相关免疫球蛋白样受体1(sLAIR-1)与移植物排斥反应的相关性.方法 采用双抗体夹心酶联免疫吸附试验测定23例肝移植、139例肾移植患者的血清sLAIR-1水平,并以健康志愿者为对照.结果 健康志愿者的血清sLAIR-1水平为(4.3±2.3)μg/L,移植器官功能正常者(肝移植11例,肾移植87例)的sLAIR-1为(6.3±3.7)μg/L,二者比较,差异无统计学意义(P>0.05).肝移植后发生急性排斥反应的6例患者,其血清sLAIR-1水平为(47.2±25.9)μg/L;肾移植后后发生急性排斥反应的20例患者,其血清sLAIR-1水平(36.3±14.7)μg/L;移植肾功能丧失的5例患者,其血清sLAIR-1水平为(28.8±9.4)μg/L,上述三者的血清sLAIR-1水平均明显高于移植物功能正常者和健康志愿者(P<0.01).移植肝重度排斥反应的1例,其血清sLAIR-1高达117.3μg/L,为正常人的27倍.移植肝慢性排斥反应者(5例)和移植肾慢性排斥反应者(27例)的血清sLAIR-1水平分别为(16.1±6.4)μg/L和(13.1±5.5)μg/L,也明显高于移植物功能正常者和健康志愿者(P<0.05).结论 发生排斥反应者的血清sLAIR-1水平升高,其水平的升高可能是发生排斥反应的重要风险因素.     

Chronic renal allograft nephropathy

Chronic rejection/chronic allograft nephropathy is the most prevalent cause of renal graft loss after the first year post-transplant. Chronic rejection/chronic allograft nephropathy is characterized by a slow progressive deterioration of graft function, often in combination with proteinuria and hypertension. 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 delayed graft function, nephron-dosing mismatch, repeated acute rejection episodes, and pathologically severe rejection. However, the precise pathogenesis of chronic allograft nephropathy remains elusive. The differential diagnosis of immunologically mediated chronic rejection and chronic rejection caused by non-immunologic factors is usually not possible using clinical parameters. The histopathologic findings of chronic allograft nephropathy are progressive interstitial fibrosis and remodelling of the vascular wall, and these findings are nonspecific. However, typical chronic transplant glomerulopathy, which affects glomerular tufts, as well as the multilayering of the peritubular capillary basement membrane, are characteristic of immunologic chronic rejection. Furthermore, in long-surviving patient with an allograft treated with a potent immunosuppressive agent, a calcineurin inhibitor, two or more concomitant independent lesions often develop. Therefore, the term "chronic allograft nephropathy" may be clinically preferable to "chronic rejection" to describe the gradual decline in graft function months or years after transplantation, in the absence of a well defined mechanism of graft dysfunction. The most effective way to prevent chronic allograft nephropathy is to avoid any kind of graft damage via either immunologic or non-immunologic mechanisms. Received: April 1, 2000 / Accepted: May 2, 2000     

In vitro immunoglobulin production in long-term renal transplant recipients

The difference in immunoregulation between stable renal transplant recipients and patients undergoing chronic rejection is unknown. In stable transplant recipients humoral responses to the allograft are controlled, but in patients with chronic rejection this control appears to be lost. In this study we evaluate B cell function in 24 stable transplant recipients and 5 patients with chronic rejection, using pokeweed mitogen (PWM)-stimulated in vitro lymphocyte production of immunoglobulin (Ig). Stable patients and patients with chronic rejection were similar with respect to time posttransplant, age, degree of HLA-A and B matching and immunosuppressive therapy. Unstimulated immunoglobulin production and serum immunoglobulin levels were similar in both groups and within the normal range. PWM stimulated IgG, and IgM production was significantly depressed in stable patients compared with normal controls and patients with chronic rejection. Patients with chronic rejection had normal PWM-stimulated Ig production. Mononuclear cell subsets--as determined by the monoclonal antibodies T4, T8, T11, B1, and M02, as well as the ratio of T4 to T8--were similar in the two patient groups and within the normal range. There was no correlation between decreased Ig production and decreased T4/T8 ratio. We conclude that stable renal transplant recipients have impaired in vitro humoral responses that may be important in maintaining allograft tolerance. In patients with chronic rejection PWM-stimulated responses have escaped control, and this may be important in the pathogenesis of antibody-mediated graft damage. Impaired Ig production in stable patients may be due to a suppressor cell mechanism--however, quantitative measurements of suppressor cells and the T4/T8 ratio do not predict humoral unresponsiveness.     

Long-Term Beneficial Effect of Tacrolimus Conversion on Renal Transplant Recipients

Objective. Acute rejection, chronic allograft nephropathy, and cyclosporine (CsA) toxicity remain serious problems for renal transplant recipients and may lead to graft loss. We retrospectively analyzed 34 patients whose biopsies revealed acute and/or chronic allograft rejection, or CsA nephrotoxicity, and who converted from CsA to tacrolimus. Patients and Methods. From July 1996 through September 2003, CsA was converted to tacrolimus in 34 renal transplant recipients (26 male, 8 female) with renal biopsy at our hospital. Blood pressure and serum creatinine levels were checked monthly and serum cholesterol, triglyceride, and glutamic-pyruvic transaminase (GPT) levels were checked every three months. Results. A consistently stable and better function after conversion was obtained in a significant portion (24, 71%) of patients. A statistically significant decline in serum creatinine and an improvement in the glomerular filtration rate were found at 3 m, 6 m, 12 m, 36 m, and 72 m after tacrolimus conversion. In 85.7% (12/14) of patients with acute rejection and in 35.7% (5/14) of patients with chronic allograft nephropathy (concomitant with acute rejection in 5), improved or stabilized graft function was noted. In addition, the systolic blood pressure and diastolic BP dropped significantly (P< 0.05), while there was no significant change in cholesterol, triglyceride, and GPT levels. Conclusion. The beneficial effect of tacrolimus conversion on patients with acute rejection, chronic allograft nephropathy, or CsA nephrotoxicity was demonstrated in long-term follow up. The improvement in both renal function and blood pressure may be of paramount importance in reducing long-term cardiovascular morbidity and mortality.     

Elevated numbers of circulating endothelial cells in renal transplant recipients

BACKGROUND: Damage of microvascular endothelial cells is a salient feature of acute vascular rejection and chronic allograft nephropathy, yet specific blood markers of ongoing endothelial injury are currently unavailable. Circulating endothelial cells have recently been established as a novel marker of endothelial damage in a variety of vascular disorders. METHODS: We studied 129 renal transplant recipients who underwent percutaneous graft biopsy. Circulating endothelial cells were isolated with immunomagnetic anti-CD146-coated Dynabeads. Cells were stained with acridine and counted. To verify their endothelial origin, staining for Ulex europaeus lectin 1 (UEA-1) was performed in parallel. Twenty-one healthy controls were also studied. RESULTS: On biopsy, seven patients had acute vascular rejection, 15 patients had acute tubulointerstitial rejection, 14 patients had borderline rejection, and 93 patients had no rejection. Patients with acute vascular rejection had the highest cell numbers (72+/-39 cells/mL) when compared with all other patients (P<0.02). Regardless of their biopsy findings, however, all other renal transplant recipients had significantly higher numbers of circulating endothelial cells (25+/-20 cells/mL) than healthy controls (7+/-5 cells/mL, P<0.001). Finally, there was a significant correlation of cell numbers and serum cyclosporine A trough levels. By contrast, there was no correlation with serum creatinine, age, or the number of immunosuppressive drugs. CONCLUSIONS: The number of circulating endothelial cells is a novel marker of endothelial damage in renal transplant recipients. Further studies must now evaluate the origin of these cells, corroborate the clinical significance of our findings, and delineate the influence of calcineurin inhibitors.     

Donor antigen-specific regulatory T-cell function affects outcome in kidney transplant recipients

Chronic transplant dysfunction, a major impediment to long-term allograft survival, is caused by several factors including an ongoing alloimmune response termed chronic rejection. To define some of these factors further, we selected 107 patients mismatched to their donors from 623 patients transplanted at a single center. Patients were categorized according to their immunosuppressive treatment and further divided into those with stable or chronic allograft dysfunction. Donor human lymphocyte antigen allopeptide-specific T-cell lines were then generated from stable patients and those with biopsy-proven chronic allograft nephropathy. Increased amounts of CD4+CD25+ regulatory T cells (Tregs) and Treg-associated gene expression profiles were found in cell lines derived from the patients with stable compared with those with chronic allograft dysfunction. Furthermore, a higher percentage of Tregs was found in patients with stable graft function on tacrolimus-based compared with cyclosporine-based immunosuppression protocols. Patients with stable graft function had a significantly higher expression of interleukin (IL)-4 and IL-10, whereas the cytokines IL-2, IL-17, and interferon-γ were significantly higher in patients with allograft dysfunction in vitro. Thus, enhancing the operational role of naturally occurring donor-specific Tregs in allograft recipients by adjusting the immunosuppression protocol may be advantageous particularly for patients with ongoing chronic rejection.     

Selective use of mycophenolate mofetil in renal transplant patients in Indian scenario

PURPOSE: Although mycophenolate mofetil (MMF) has emerged as a valuable immunosuppressive in renal transplantation, its high cost demands that it be used selectively. MATERIALS AND METHODS: This retrospectively study included 55 renal transplant patients on MMF for rescue therapy after treatment of acute vascular rejection (n = 45), acute/chronic liver disease with elevated transaminases (n = 4), early chronic rejection (n = 2), cyclosporine toxicity (n = 3), and cyclosporine-induced hemolytic-uremic syndrome (n = 1). The patients were given 1.5 to 2 g MMF in divided doses for at least 6 months, depending upon the tolerability, adverse effects, and finances, and followed for 1 year. The patients on MMF following treatment of acute rejections were compared with controls who received azathioprine-based triple immunosuppression after treatment of an acute rejection episode. RESULTS: The incidence of recurrent acute rejection in the first year was 18% in the MMF group compared to 42% in the control group (P < .005). The serum transaminases in the acute/chronic liver disease group reached normal levels at 3 to 6 months. The serum creatinine remained stable for a mean duration of 8 months in the early chronic rejection patients. The patients with cyclosporine toxicity showed stable graft function on low-dose cyclosporine. The patient with hemolytic-uremic syndrome showed stable graft function for 4 years. The MMF-based triple regimen is two times more expensive than an azathioprine-based regimen. CONCLUSION: MMF significantly decreases the recurrence of acute rejection. It is a good alternative agent in special situations like acute/chronic liver diseases with elevated transaminases, early chronic rejection, cyclosporine toxicity, and cyclosporine-induced hemolytic-uremic syndrome. Because of the high cost it should be used selectively in our population.     

Mast Cells Tryptase in Patients After Renal Transplantation

Mast cells (MC) are involved in the pathogenesis of interstitial fibrosis, acute renal transplant rejection, and chronic allograft nephropathy. The aim of this study was to evaluate MC tryptase concentrations in the sera of 58 renal transplant recipients at various times after surgery in relation to graft function. We observed that kidney transplantation patients showed much higher serum tryptase concentrations than healthly controls. We demonstrated a positive correlation between serum tryptase concentration and hemoglobin, hematocrit, red blood cell count, and hepatic cell damage. We were not able to show any direct correlation between serum tryptase concentration and graft function. The clinical relevance of these findings demand further investigation.     

Serum and urinary neopterin as markers in renal transplant patients

For monitoring neopterin levels, serial serum and urinary samples were obtained from 21 renal transplant patients. In renal transplant patients, serum neopterin levels were significantly higher than in healthy volunteers, even though in a clinically stable state urinary neopterin levels were also higher than in healthy volunteers, but statistically not significantly. In cases with rejection, both serum and urinary neopterin levels were significantly more elevated than in the stable state. In contrast, serum and urinary neopterin levels were not clevated in nephrotoxicity events. These results suggest that serum and urinary neopterin levels might be valuable indicators of acute rejection. Moreover, they could be useful for differentiating acute rejection from nephrotoxicity episode.     

High urine sIL-6R as a predictor of late graft failure in renal transplant recipients

BACKGROUND: Chronic allograft nephropathy is an important cause of late renal transplant failure. Although numerous studies on cytokines have been carried out, the pathogenetic role of cytokines in chronic renal allograft nephropathy remains unclear. METHODS: In a retrospective study, the authors compared posttransplant plasma and urine cytokine levels (interleukin [IL]-1alpha, IL-1beta, soluble [s] IL-1 receptor [R] antagonist [A], IL-2, sIL-2R, IL-3, IL-4, IL-6, sIL-6R, IL-10, tumor necrosis factor-alpha, transforming growth factor-beta2, and interferon-gamma) in 34 matched pairs of patients with or without late graft failure and in 50 matched pairs with either normal or increased serum creatinine levels and continued stable graft function. RESULTS: Twelve and 6 months before late graft failure, urine levels of sIL-6R were significantly increased (P=0.003 and P=0.01, respectively). Serum creatinine levels were not associated with increased urine sIL-6R. CONCLUSION: High urine sIL-6R appears to be predictive of late graft failure in renal transplant recipients.     

De novo sirolimus-based regimen in Thai renal transplant recipients

BACKGROUND: Calcineurin inhibitor (CNI) toxicity is a common cause of chronic allograft nephropathy. Although de novo sirolimus (SRL) with CNI minimization may provide better graft function, studies in Asian recipients are lacking. AIM: We sought to determine the 1-year outcomes of renal transplant patients who received a de novo SRL-based regimen with CNI minimization. PATIENTS AND METHODS: A single-center, prospective study of de novo SRL-based, reduced-dose cyclosporine regimen was performed from 2004 to 2007. The control group was a historical cohort of a cyclosporine-based regimen (cyclosporine, prednisolone, and mycophenolate mofetil). The 1-year outcome parameters included renal function, rate of acute rejection, biopsy-proven CNI toxicity, graft and patient survivals. RESULTS: The SRL-based regimen achieved 100% 1-year graft and patient survivals. The renal function was comparable between the SRL-based and CNI-based regimens (serum creatinine 1.32 +/- 0.45 and 1.45 +/- 0.43 mg/dL; P = .27). The rate of biopsy-proven acute rejection was comparable (9.5% and 13%; P = .68). The SRL-based regimen had a higher rate of biopsy-proven CNI toxicity (28.5% and 9.7%; P = .03). CONCLUSIONS: De novo SRL-based regimen with CNI minimization provides excellent transplant outcomes. The strategy to minimize or withdraw CNIs may achieve excellent graft function. A prospective study targeting lower CNI trough levels in Asian transplant recipients is required.     

Effect of histological damage on long-term kidney transplant outcome

BACKGROUND: Chronic renal allograft failure remains a major challenge to overcome. Factors such as donor quality, delayed graft function (DGF), acute rejection, and immunosuppression are known to affect long-term outcome, but their relationship to histological damage to graft outcome is unclear. METHODS: Protocol kidney biopsies (n=112) obtained at 3 months after transplantation yielded 102 with adequate tissue. Histology was scored by the Banff schema, and compared with implantation biopsies (n=91), repeat 12-month histology (n=39), decline in serum creatinine and serial isotopic glomerular filtration rate, onset of chronic allograft nephropathy (CAN), and actuarial graft survival censored for death with a functioning graft. RESULTS: At a median follow-up of 9.3 years, 20 patients had graft failure and 26 died with a functioning graft. Banff chronic nephropathy was present in 24% of 3-month biopsies, and was predicted by microvascular disease in the donor, cold ischemia, DGF, and acute vascular rejection (P<0.001). Acute glomerulitis at 3 months correlated with segmental glomerulosclerosis at 12 months, subsequent recurrent glomerulonephritis, and graft failure (P<0.01). Subclinical rejection at 3 months occurred in 29% of biopsies, correlated with prior acute rejection and HLA mismatch, and led to chronic histological damage by 12 months (r=0.25-0.67, P<0.05-0.001). Subclinical rejection, arteriolar hyalinosis, and tubulitis present at 3 months had resolved by 12 months. The 10-year survival rates for Banff chronic nephropathy were 90.4% for grade 0, 81.0% grade 1, and 57.9% for grades 2 or greater (P<0.01). Early tubulointerstitial damage at 3 months profoundly influenced graft survival beyond 10 years. CAN was predicted by kidney ischemia, 3-month chronic intimal vascular thickening, tubular injury, proteinuria, and late rejection. Chronic fibrointimal thickening of the small arteries and chronic interstitial fibrosis at 3 months independently predicted graft loss and decline in renal function (P<0.05-0.001). CONCLUSIONS: Early transplant damage occurs in the tubulointerstitial compartment from preexisting donor kidney injury and discrete events such as vascular rejection and DGF. Subsequent chronic damage and graft failure reflect accumulated previous injury and chronic interstitial fibrosis, vascular impairment, subclinical rejection, and injury from late rejection. CAN may be conceptualized as the sequelae of incremental and cumulative damage to the transplanted kidney. The duration of graft survival is dependent and predicted by the quality of the transplanted donor kidney combined with the intensity, frequency, and irreversibility of these damaging insults.     

Impact of HLA antibodies on transplant glomerulopathy

The influence of humoral rejection on the development of chronic allograft nephropathy (CAN) is controversial, especially in relation to transplant glomerulopathy. The aim of our study was to analyse the influence of anti-HLA antibodies on the development of transplant glomerulopathy (cg0, cg1, cg2, and cg3; Banff'97). We selected all renal transplants patients from 1975 to 2003 who had a functioning graft for at least 6 months and a clinically indicated graft biopsy with CAN and chronic glomerular changes (case group). We studied the presence of anti-HLA antibodies (Ab) in the last serum taken while the graft was functioning and divided them into three groups according to the severity of glomerular lesions. We also selected 52 contemporary and comparable cases without transplant glomerulopathy (control group). A total of 77 case had transplant glomerulopathy: 39 cg1, 29 cg2, and 9 cg3. Pretransplant Ab titers and number of previous blood transfusions were higher among the subgroup with the most severe glomerulopathy. Patients who developed posttransplant anti-HLA Ab more frequently showed transplant glomerulopathy. Serum creatinine and proteinuria were higher among cases with chronic glomerulopathy, and more grafts were lost in that group. Thus, the presence of HLA-Ab is a key factor in the development of transplant glomerulopathy and chronic allograft rejection.