Early withdrawal of cyclosporine A improves 1-year kidney graft structure and function in sirolimus-treated patients

BACKGROUND: Chronic allograft nephropathy (CAN) represents the most common cause of late graft loss. Nephrotoxicity from chronic use of calcineurin inhibitors (CNI) has the potential to contribute to CAN. The present investigation aimed to evaluate the impact of early CNI withdrawal on kidney graft function and structure at 1 year in sirolimus (SRL)-treated patients. METHODS: Forty consecutive kidney transplant recipients were initially treated with corticosteroids, cyclosporine A (CsA), and SRL (2 mg/day). After 3 months, patients were randomly assigned to either continue the same treatment (group I) or to withdraw CsA and continue SRL (group II). All patients underwent kidney graft biopsy immediately after graft reperfusion (0-hr biopsy) and 12 months after engraftment. RESULTS: Baseline graft biopsy showed a higher degree of renal damage in group II patients (total score, 4+/-1.6 vs. 2+/-0.9; P<0.05). Twelve months after engraftment, CAN was diagnosed in 55% of all patients, of whom 64% were in group I and 36% in group II. CAN lesions were scored as moderate to severe in 90% of group I patients but only 32% of group II patients (P<0.05). A vascular score greater than or equal to 2 occurred in 90% of group I patients and in 38% of group II patients (P<0.05). At 1 year, group I patients showed a significantly worse kidney graft function (serum creatinine, 2.0+/-0.3 vs. 1.3+/-0.3 mg/dL; creatinine clearance, 54+/-14 vs. 66+/-17 mL/min; both P<0.002). CONCLUSIONS: These results suggest that early withdrawal of CsA is a safe option, which allows a significant reduction of chronic histologic damage, particularly vascular injury, of cadaveric kidney allografts.     

Impact of banff borderline acute rejection among renal allograft recipients

OBJECTIVE: This study was performed to determine the incidence, treatment, and outcomes of Banff borderline acute rejection (AR) among renal transplant recipients. PATIENTS AND METHODS: We reviewed the courses of adult kidney transplant recipients with borderline AR on clinically indicated biopsies performed at our center from January 2003 to July 2006. Patients with complete transplant records and serum creatinine values at 6 and 12 months were included in this study. The primary outcome measures were serum creatinine values at 1 to 2 weeks after treatment, and at 6 and 12 months after graft biopsy. RESULTS: Among 428 renal graft biopsies, borderline AR was observed in 100 cases (23%). Patients were maintained on the same immunosuppression. The 86 who had complete data were included in the study. Seventy-eight percent of the patients received treatment with 3 days of methylprednisolone, while 22% were untreated. Mean serum creatinine values in the treated group were 2.9 +/- 1.0, 2.6 +/- 2.5, and 3.0 +/- 2.9 mg/dL at the time of biopsy, and at 6 and 12 months thereafter, respectively. In the untreated group, mean serum creatinine values were 2.2 +/- 1.0, 1.9 +/- 0.8, and 2.3 +/- 1.2 mg/dL during biopsy, and at 6 and 12 months thereafter, respectively. There was no significant difference in the serum creatinine at any of the measured time points between the 2 groups. Twelve patients had repeat renal graft biopsies which showed AR (6%), chronic allograft nephropathy (2.4%), and borderline changes (3.8%). Nine of the patients in the treated group eventually developed graft loss. CONCLUSIONS: Patients with borderline AR showed a progressive increase in serum creatinine over time. They should be followed closely; immunosuppression may need to be intensified.     

Histologic findings in protocol biopsies performed in stable renal allografts under different immunosuppressive schedules

Protocol biopsies performed in stable renal allografts show different degrees of acute and chronic lesions. Histologic findings in protocol biopsies have been related to graft outcome. We evaluated histologic lesions observed in protocol biopsies performed in patients under different immunosuppression therapies. From June 1988 a protocol biopsy was performed at approximately 4 months in patients who fulfilled the following criteria: serum creatinine <300 micromol/L; stable renal function; and proteinuria <1 g/d. Histologic lesions were graded according to 1997 Banff criteria. For the present study we considered the following groups according to immunosuppressive schedule: (i) induction therapy with polyclonal or monoclonal antilymphocytic antibodies associated with cyclosporine and prednisone (n=201); (ii) cyclosporine, mycophenolate mofetil, and prednisone (n=127); and (iii) tacrolimus, mycophenolate mofetil, and prednisone (n=51). On protocol biopsy patients treated with tacrolimus displayed a lower acute score (0.61+/-1.01 vs 1.24+/-1.23 in group I, 1.28+/-1.41 in group II; P<.0001) and a higher proportion of normal biopsies (57.1% vs 41.9% in group I, 45.1% in group II; P=.016). A similar proportion of chronic lesions (chronic score of group I: 1.30+/-1.56; group II: 1.34+/-1.80; group III: 1.51+/-0.95; P=NS) was observed in the three groups. Protocol biopsies displayed fewer acute lesions in patients treated with tacrolimus. This result suggests that the efficacy of new immunosuppression schedules can be evaluated using the protocol biopsy as a surrogate marker of graft outcome.     

Adult-size kidneys without acute tubular necrosis provide exceedingly superior long-term graft outcomes for infants and small children: a single center and UNOS analysis. United Network for Organ Sharing

BACKGROUND: Infants with end-stage renal disease are at highest risk for early graft loss and mortality of any subgroup undergoing renal transplantation. This study evaluates the influence of donor tissue mass and acute tubular necrosis (ATN) on graft survival and incidence of acute rejection episodes in infant and small child recipients of living donor (LD) and cadaver (CAD) adult-size kidneys (ASKs), pediatric CAD kidneys and combined kidney-liver transplants. Methods. Kidney transplants in infants and small children at a single center and those reported to the UNOS Scientific Renal Transplant Registry were analyzed. At Stanford, multi-variate analysis was conducted on 45 consecutive renal allograft recipients weighing < or = 15 kg, mean weight 11.2 +/- 2.6 kg. The UNOS Registry results in age groups 0-2.5 (n=548) and 2.5-5 years (n=743) were compared with age groups 6-12, 13-18, and the lowest risk adult group of 19-45 years. STANFORD RESULTS. Graft survival was 97.8 +/- 0.0 at 2 years and 84.6 +/- 0.1% at 8 years. The incidence of biopsy proven rejection was 8.8% in the first 3 months and 15.5% over the 8-year follow-up. None of the pediatric CAD kidneys had ATN. Rejection episodes were restricted to the pediatric CAD kidneys alone (3/3), with no kidney rejections in the combined pediatric CAD kidney-liver transplants (0/6; P=0.003). Four ASK transplants had ATN (1 postoperative and 3 late), and all predisposed to subsequent acute rejection episodes (4/4), whereas there were no rejection episodes in ASK transplants without ATN (0/32; P<0.001). At 3 years posttransplantation, mean serum creatinines were worse in ASKs with ATN (1.5 vs. 0.9 mg/dL; P<0.001) and in all grafts with rejection episodes (1.2 vs. 0.9 mg/dL; P<0.05). UNOS RESULTS: Among the 5 age groups studied, significantly better (P<0.001) long-term graft survival rates were observed in allograft recipients in the 2 youngest age groups with ASKs without ATN: 82 +/- 3% and 81 +/- 3% for LD and 70 +/- 7% and 78 +/- 4% for CAD recipients in the 0-2.5 and 2.5- to 5-year age groups, respectively, at 6 years after transplantation. Moreover, the projected graft half-lives after the 1st year in the LD groups without ATN were at least equivalent to those of HLA-identical sibling recipients ages 19-45 years: 26.3 +/- 5 and 29.3 +/- 6 years for the 0- to 2.5- and 2.5- to 5-year age groups, respectively, and 23.3 +/- 1 years for HLA-identical transplants. The graft half-lives for CAD recipients without ATN ages 0-2.5 and 2.5-5 yearswere equivalent or better than those for LD transplants without ATN in recipients aged 19-45 years: 15.4+/- 7 and 23.7 +/- 8 years versus 15.0 +/- 0.3 years. Mean serum creatinines were superior in the 2 younger recipient age groups compared with older age groups. CONCLUSIONS: Increased donor tissue mass of the ASK or kidney-liver transplants, in the absence of ATN, seems to confer a protective effect to infant and small child recipients of these allografts. This is manifested by a prolonged rejection-free state in the single center experience and enhanced graft survival and function in the UNOS analysis, comparable to HLA identical sibling transplants for LD infant and small child recipients and to LD adult results for CAD infant and small child recipients. To optimize this protective effect by whatever mechanism, absolute avoidance of ATN is essential in infant recipients of ASK or combined kidney-liver transplants.     

C4d as a significant predictor for humoral rejection in renal allografts

OBJECTIVE: To determine the diagnostic and clinical significance of C4d accumulation in renal allografts followed by acute rejection. METHODS: A total of 158 graft biopsies performed from December 1997 to December 2002 were classified, according to the Banff-97 criteria, into hyperacute rejection (HAR, three cases), acute vascular rejection (AVR, 27), acute cellular rejection (ACR, 24), borderline rejection (BR, 38), acute tubular necrosis (ATN, five), stable graft function (SGF, 30) and baseline kidney (31). Immunohistochemical technique was used to determine the C4d deposition level. RESULTS: The percentages of C4d positive in HAR, AVR, ACR, BR, ATN, SGF and baseline kidney groups were 100% (3/3), 77.8% (21/27), 37.5% (9/24), 23.7% (9/38), 0% (0/5), 3.3% (1/30), 0% (0/31), respectively. In acute rejection patients, the peak serum creatinine (sCr) level in C4d(ptc)-positive group (41 cases) was 334.82 +/- 238.37 micromol/L, with that of C4d(ptc)-negative group (47 cases) being 220.20 +/- 176.94 micromol/L (p < 0.01). After treatment, the trough sCr level in C4d(ptc)-positive group and C4d(ptc)-negative group were 176.87 +/- 111.80 and 121.75 +/- 34.59 micromol/L (p < 0.01), respectively. In each AVR, ACR and BR subgroups, the peak sCr level, the trough sCr level, after 3 or 6 months of AR, the sCr level in C4d(ptc)-positive subgroup was higher than that of C4d(ptc)-negative subgroup. There were more resistance against steroid therapy [65.9% (27/41) vs. 36.2% (17/47), p = 0.005] and a higher rate of graft loss [29.3% (12/41) vs. 6.4% (3/47), p = 0.001] in C4d(ptc)-positive group than those of C4d(ptc)-negative group. In each C4d(ptc)-positive subgroup of AVR, ACR and BR the complete reversion was 57.1, 56 and 66.7%, respectively, it is almost same. CONCLUSION: The C4d deposition level is of great value in diagnosis of acute rejection caused by humoral immune components. It is a significant predictor of graft survival and will be of great help when treating acute rejection.     

Endothelial nitric oxide synthase expression in ischemia-reperfusion injury after living related-donor renal transplantation

Ischemia-reperfusion injury during renal transplantation has been linked to early graft dysfunction and late graft failure. Nitric oxide (NO), produced by NO synthase (NOS), participates in the recovery from ischemia. We correlated the intensity of graft immunoreactivity for the endothelial NOS isoform (eNOS) during early reperfusion with graft function in 25 children receiving grafts from related donors. Renal allograft biopsy specimens were obtained before transplantation, 1 h after renal artery reperfusion, and 1 year after transplantation. Immunohistochemical staining for eNOS occurred mainly within the endothelium of glomerular capillaries and peritubular capillaries as well as in tubule cells. The mean intensity score for eNOS staining (0-9) was 3.0+/-1.4 before transplantation, 4.5+/-1.9 at 1 h, and 3.3+/-1.9 at 1 year (baseline vs 1 h, P<0.05). Creatinine clearance (ml/min) in patients with a 1-h eNOS score of below 5 and of at least 5, respectively, was 77.1+/-28.4 vs 104.3+/-25.3 at 1 month, 78.7+/-33.4 vs 105.2+/-24.4 at 3 months, 64.7+/-30.1 vs 100.1+/-25.3 at 1 year, 58.2+/-31.3 vs 84.7+/-18.8 at 3 years, and 71.2+/-19.7 vs 78.3+/-23.1 at 5 years ( P<0.05 for 1 month, 1 year, and 3 years). We concluded that elevated eNOS expression after reperfusion in living related-donor renal transplantation enhances the recovery from renal ischemia and, consequently, reduces late graft deterioration.     

Sequential use of Minnesota antilymphoblast globulin and cyclosporine in cadaveric renal transplantation

The use of Cyclosporine (CsA) immediately after renal transplantation may be associated with an increased incidence and duration of acute tubular necrosis (ATN) and permanent primary graft nonfunction. To avoid this potential interaction we treated recipients of primary cadaveric grafts initially with azathioprine (AZA), methylprednisolone (MP), and 5 daily doses of Minnesota antilymphoblast globulin (MAG) (postoperative days 3-7). AZA was discontinued and CsA started on day 6 if the graft was functioning by then. If ATN persisted beyond day 6, AZA and MAG (maximum 12 doses) were continued and CsA withheld until graft function was established (group 1-33 patients). This protocol is compared to our previous regimen of MAG (14 doses over the first 3 weeks), AZA and MP (group 2-68 primary cadaveric graft recipients). Improved one-year graft survival (81% vs. 60%, P less than 0.05) and patient survival (93% vs. 81%, P less than 0.05) were seen in group 1. The incidence and duration of ATN did not differ in the two groups. During the first year after transplantation more patients in group 1 were completely free of rejection episodes (40% vs. 20%, P less than 0.05) and the number of rejection episodes per patient was also lower in this group (1.0 +/- 15 vs. 1.6 +/- 49, P less than 0.05). The incidence of infections was not different in the two groups. No tumors have developed in either group. We conclude that in primary cadaveric renal transplantation the initial administration of a short course of MAG followed by CsA therapy results in excellent graft and patient survival while avoiding the potential adverse effect of CsA on an allograft already subjected to preservation injury.     

Surgical approach to cases with multiple renal arteries in renal transplantation

AIM: To evaluate the effect of multiple renal artery (MRA) presence on the success and complication rate of renal allotransplantation. PATIENTS AND METHODS: We retrospectively analyzed 187 cases (128 men and 59 women) who were transplanted in our department from 1997 to 2005. 28 of these cases had MRA. Of MRA kidneys, 6 were obtained from cadavers and 22 from live donors. When the types of anastomoses for MRA cases were examined, 4 cases were anastomosed after being connected to the main polar artery with ex vivo bench surgery; the others had in vivo anastomosis. The patients were divided into two groups as single (group 1) and MRA (group 2) groups. Following the transplantation, creatinine levels, ATN ratios, development of hypertension, patient and graft survivals and vascular and urological complications were compared between the two groups. RESULTS: Patient and graft survival rates were compared between the two groups in the first and third post-operative years. In the first year, graft survival rates for groups 1 and 2 were 94.9 and 92.9% respectively, whereas in the third year these were calculated as 88 and 85.7%. Concerning patient survival, first year results for groups 1 and 2 were 92.5 and 89.2%, for the third year these were found to be 84.9 and 82.1%. Mean creatinine levels of both groups were compared in the first and third years. The results for groups 1 and 2 were 1.41 +/- 0.37 and 1.46 +/- 0.46 mg/dl respectively for the first year. In the third year these were found to be 1.60 +/- 0.43 and 1.69 +/- 0.49 mg/dl and there was no statistically significant difference between the groups. Vascular and urological complications were observed in only 6 out of 187 cases (3.2%). CONCLUSIONS: No significant difference has been observed between single and MRA kidneys considering the success and complication rates of renal allotransplantation.     

Double renal transplants from marginal donors: 2-year results

PURPOSE: Marginal cadaveric renal transplant donors represent a potential source for expansion of the donor pool but these kidneys have generally demonstrated significantly poorer survival compared to those from conventional donors. A strategy to provide sufficient renal mass for adequate nephron dosing and subsequent improved survival is the use of both kidneys for a single recipient. We present our 2-year experience with double renal transplants from marginal donors. MATERIALS AND METHODS: During an 8-year period 28 patients received double renal transplants (group 1) and 31 received a single transplant (group 2) from marginal donors. Donors were older than 55 years, or had diabetes mellitus, hypertension, greater than 15% glomerulosclerosis on biopsy, increasing creatinine or intrinsic renal parenchymal disease. RESULTS: Both groups were of similar age and the number of rejection episodes per year was similar but followup time differed (22.4+/-14.6 months for group 1 versus 43.7+/-20.5 for group 2). Male-to-female ratio, cold ischemia time, terminal creatinine and pre-transplant biopsy rates were similar for donors in both groups. Average donor age was younger in group 1 (48.9+/-15.8 versus 57.5+/-8.2 years, p = 0.01), and incidence of intrinsic renal disease and increasing donor creatinine was greater (12 versus 2, p = 0.002 and 4 versus 0, p = 0.04, respectively). Incidence of primary nonfunction (1 group 1 versus 5 group 2 patients) and delayed graft function (6 versus 7) was similar. The 1 and 2-year graft survival rates of 96% and 96%, respectively, for group 1 were significantly higher than those for group 2 (77% and 73%, p = 0.02). CONCLUSIONS: Our experience to date with double kidney transplants from marginal donors demonstrates acceptable 1 and 2-year survival rates significantly superior to the outcome using only 1 marginal kidney. This finding has important implications in the decision to use marginal donors in regard to cost-effectiveness and patient survival compared to the alternative of continued hemodialysis until an ideal donor organ becomes available.     

Prediction of chronic allograft damage index of renal allografts using serum level of plasminogen activator inhibitor‐1

Abstract: Background: Plasminogen activator inhibitor‐1 (PAI‐1) plays an important role in renal fibrosis. We conducted this study to examine whether serum PAI‐1 has a role in predicting chronic allograft nephropathy (CAN). Methods: Fifty kidney transplant recipients receiving graft biopsies were enrolled. The pathologic diagnoses were acute tubular necrosis (ATN; n = 12), borderline rejection (BR; n = 7), acute rejection (ACR; n = 12), CAN (n = 11), polyomavirus nephropathy (PVN; n = 3) and others (n = 5; glomerulopathy, n = 4; calcineurin inhibitor nephropathy, n = 1). The serum level of PAI‐1 and chronic allograft damage index (CADI) score of each patient were determined. Results: The CADI score of all patients was 4 (0–10) (median and range) and in each group was ATN 0.5 (0–4), BR 2.0 (1–4), ACR 4.0 (2–8), CAN 5.0 (4–10), PVN 7 (4–8) and others 2 (0–8). The serum PAI‐1 level of each group was ATN 9.38 (2.35–14.52) ng/mL, BR 10.09 (0.61–18.06) ng/mL, ACR 11.08 (2.32–20.68) ng/mL, CAN 14.51 (3.66–21.12), PVN 14.79 (13.94–21.94) and others 16.35 (4.05–21.01) ng/mL. CADI score is associated with serum PAI‐1 activity (r = 0.405, p = 0.003) and is inversely associated with serum creatinine (r = ?0.348, p = 0.011), but not with estimated glomerular filtration rate (p = 0.124). Conclusion: Serum PAI‐1 level has the potential to be a marker to predict CADI score, the quantitative score of CAN.     

Immunohistochemical staining for proliferation antigen as a predictor of chronic graft dysfunction and renal graft loss

BACKGROUND: Assessment of proliferation rate (PR%) using monoclonal antibody for Ki-67 antigen has recently been found to have prognostic importance in lung and cardiac allografts. We ascertained whether the same might be true for renal allografts. METHODS: Newly cut sections from 20 archival paraffin blocks of renal allograft biopsy material showing acute cellular rejection and/or acute tubular necrosis (ATN) and absence of other pathology were stained using MIB-1 antibody and were further double-stained with anti-CD3, anti-CD20 or anti-CD68 antibodies. Counts of staining of mononuclear interstitial cells were correlated with clinical and pathological data. RESULTS: Mean PR% was significantly greater than that in control renal allografts (13.23 +/- 1.94 vs. 2.84 +/- 1.66, p < 0.01). PR% of cases with ATN and no or borderline rejection was significantly lower than that of the remaining cases with acute rejection pathology (6.68 +/- 1.15 vs. 14.31 +/- 1.62, p < 0.05). However, PR% was neither correlated to histological rejection grade nor to long-term graft outcome. Double labelling failed to identify the cell type of most infiltrating MIB-1 positive cells. CONCLUSIONS: Positive MIB-1 staining helps to identify the presence of rejection but does not appear to predict prognosis or correlate with the Banff classification of rejection pathology.     

Vascular endothelial growth factor expression and vascularity in renal allograft biopsies

BACKGROUND: Vascular endothelial growth factor (VEGF) expression influences tubular repair and promotes angiogenesis. The aim of the present study was to determine the relation of VEGF expression and cortical vascularity with renal pathological changes and clinical parameters in allograft biopsies. MATERIALS AND METHODS: Sections from 50 renal allograft biopsies were evaluated by streptavidine-biotin immunohistochemistry by primary antibodies against VEGF and CD34. Cortical tubulointersititial (TI) VEGF expression was scored by light microscopic examination considering intensity and density. Glomerular expression was scored as 0: no staining; 1: faint staining in less than 50% of glomeruli; 2: moderate to strong staining in more than 50% of glomeruli. We determined the number of vessels per cortical high power field (Nves) highlighted by CD34 staining. The clinical and pathological features were retrieved from patient files. RESULTS: Nves was decreased with interstitial fibrosis (IF): 56.3 +/- 3.7; 53.3 +/- 9.8, 46.6 +/- 10.5, 36.75 +/- 1.89 for cases with no IF to mild, moderate, and severe forms, respectively (P < .000). There was increased TI VEGF expression: 1.86 +/- 2.12, 5.8 +/- 3.1, 5.85 +/- 4.4, 10.25 +/- 2.06, respectively (P = .004). The NVes values were not different for cases with high and low to negative VEGF expression scores. There was a negative correlation between Nves values and creatinine at the time of biopsy and time from transplantation to biopsy (r = -.325, P = .024 and r = -.294, P = .038, respectively). Nves and VEGF scores were not different when acute rejection scores or cyclosporine toxicity were considered (P > .05), while Nves were significantly different for chronic allograft nephropathy scores (P = .05). CONCLUSIONS: Chronic renal changes seemed to be associated with decreased cortical vascularity in renal allografts, while the TI VEGF expression was increased. In contrast Nves was not increased with VEGF expression in this series. It seems that along with VEGF, other factors are required for protection against vascular reduction. The aging of the allograft is also a negative influence on cortical vascularity.     

Does infiltration of neutrophils in peritubular capillaries indicate humoral rejection? A case displaying a characteristic lesion of a significantly high amount of neutrophils in peritubular capillaries at 1-h graft biopsy during transplant operation

Inagaki H, Takeda A, Sato T, Watanabe I, Katayama A, Haba T, Tominaga Y, Uchida K, Oikawa T, Morozumi K. Does infiltration of neutrophils in peritubular capillaries indicate humoral rejection? A case displaying a characteristic lesion of a significantly high amount of neutrophils in peritubular capillaries at 1-h graft biopsy during transplant operation. Clin Transplantation 2001: 15 (Supplement 5): 35–40. ©Munksgaard, 2001
We present a case report of a 50-yr-old Japanese woman with a significant accumulation of neutrophils in the peritubular capillaries (PTC) and severe acute tubular necrosis (ATN) at 1-h allograft biopsy during transplant operation from cadaver donor after a cardiac death. Significant accumulation of neutrophils in the PTC is usually valuable diagnostically for acute humoral rejection. However, the patient showed no clinical signs of acute rejection. A second graft biopsy performed on the fifth postoperative day (POD) revealed that both infiltration of neutrophils in PTC and ATN lesions were more aggravated. Neither clinical course nor other morphological findings were compatible with humoral rejection. After the third biopsy of POD 27 revealing acute vascular rejection of moderate degree, acute rejection therapy using methylprednisolone pulse therapy and OKT-3 therapy was performed. Consequently, after a period of delayed graft function requiring haemodialysis for approximately 4 wk, graft function was restored and serum creatinine decreased to 2 mg/dL. Later, we were able obtain information from a paired graft from the same donor. Significant accumulation of neutrophils in the PTC similar to our recipient was also noted in a 1-h biopsy specimen of the paired kidney. This confirmed that the accumulation of neutrophils in the PTC noted in two recipients was transmitted from the donor kidney. The pathogenesis and clinical significance of neutrophils in the PTC has been shrouded in mystery.     

Prospective study on renal outcome of IgA nephropathy superimposed on diabetic glomerulosclerosis in type 2 diabetic patients.

BACKGROUND AND METHODS: In order to examine the clinical outcome of IgA nephropathy (IgAN) superimposed on diabetic glomerulosclerosis in type 2 patients we studied 36 Chinese patients (26 men, 10 women), who were recruited for renal biopsy when they had proteinuria of more than 1 g/day. Twenty-seven had isolated diabetic glomerulosclerosis and nine had IgAN superimposed on diabetic glomerulosclerosis (combined). Renal function was assessed by serial serum creatinine, 24-h urine protein and creatinine measurements. Patient survival rate, incidence of end-stage renal disease (ESRD), blood pressure, and glycaemic control status were determined. RESULTS: The age at the time of renal biopsy was younger for the combined group when compared with the diabetic glomerulosclerosis group (44+/-3.6 vs 58+/-2.1 years, P=0.006). The duration of diabetes was, however, similar for the two groups (8.0+/-2.3 vs 6.7+/-1.2 years, P=NS). After a mean follow-up of 31.6+/-15.3 months, 15 patients (one in the combined group and 14 in the diabetic glomerulosclerosis group) developed ESRD. Nine patients (all in the diabetic glomerulosclerosis group) died during follow-up. With similar glycaemic and blood pressure control, the two groups had comparable rate of decline of creatinine clearance (CrCl) (-0.73+/-0.26 vs -0.73+/- 0.18 ml/min/1.73 m(2)/month, P=NS), final serum creatinine (363+/-134 vs 426+/-52 micromol/l, P=NS) and proteinuria levels (4.3+/-0.9 vs 4.4+/-0.6 g/day, P=NS), as well as CrCl (44.1+/-19.0 vs 33.4+/-6.9 ml/min/ 1.73 m(2), P=NS). CONCLUSION: It is concluded that the superimposed IgAN does not significantly alter the medium-term clinical outcome of patients with diabetic glomerulosclerosis.     

The effect of different immunosuppressive regimens on TGF-β1 expression in kidney transplant patients

Transforming growth factor (TGF)-beta1 is a key profibrogenic cytokine associated with the pathogenesis of chronic allograft nephropathy (CAN). The primary aim of this study was to evaluate TGF-beta1 expression in protocol kidney graft biopsy in patients treated with different immunosuppressive regimens. Protocol kidney graft biopsies were carried out in 77 patients with stable graft function at 1 year after kidney transplantation, treated with a triple-drug regimen based on cyclosporin A (CyA; n = 49) or tacrolimus (TAC; n = 28). Morphological findings were assessed using the Banff 97 classification. TGF-beta1 expression was analysed using immunochemistry, and semiquantitatively scored in different renal structures (total score 0-18). Clinical data were analysed at the time of biopsy, and 12 months thereafter. No significant relation was found between the used immunosuppressive regimen and the histomorphological picture in the graft. TGF-beta1 expression within graft tissue was significantly higher in patients treated with CyA when compared with TAC (9.94 +/- 4.2 vs. 5.0 +/- 3.2; P < 0.001). Serum creatinine and glomerular filtration rate (GFR; Cockroft-Gault calculation) were comparable in both groups but, in the course of the next 12 months, GFR significantly decreased only in the CyA-treated group (from 1.03 +/- 0.33 to 0.96 +/- 0.37 ml/s) while not changing in the TAC-treated group. Patients treated with TAC had significantly lower diastolic blood pressure and serum cholesterol. The significantly lower TGF-beta1 expression in 1-year protocol kidney graft biopsy in TAC-treated patients with stable renal function, and the different development of graft function in both groups suggest a possible benefit of TAC for long-term graft acceptance.     

The long-term effect of switching from cyclosporin A to mycophenolate mofetil in chronic renal graft dysfunction compared with conventional management.

BACKGROUND: To overcome toxicity of calcineurin inhibitors, recent trials have proposed substituting cyclosporin (CysA) with mycophenolate mofetil (MMF). No data concerning the long-term side effects and long-term renal outcome of this strategy have been published. METHODS: We retrospectively compared 39 renal transplant patients with chronic graft dysfunction who were subjected to CysA to MMF substitution (group 1) with 39 matched renal transplant patients who were continued on conventional management (group 2). The mean serum creatinine and the slope of deterioration of renal function before the date of the therapeutic intervention (T(0)) were similar in both groups. Follow-up in both groups was 76 +/- 42 months before T(0) and 44 +/- 11 months after T(0). RESULTS: In group 1, conversion was associated with a decrease of mean serum creatinine concentrations from 192 to 172 micro mol/l at 1 year (P = 0.004) and 159 micro mol/l at 3 years (P < 0.003) after T(0), whereas it remained unchanged in group 2. The systolic blood pressure decreased in group 1 from 155 mmHg before T(0) to 145 mmHg at 1 year (P < 0.01) and 133 mmHg at 3 years (P < 0.001) without any increase of the antihypertensive drug, whereas it did not change in group 2. Lipid profile tended to improve in group 1 after T(0) and was unchanged in group 2. None of the patients in group 1 developed acute rejection after T(0), whereas two acute rejections occurred in group 2. Graft survival, however, was similar in both groups. In group 1, several side effects occurred related to MMF treatment, and led to its discontinuation in two cases and the reduction of its dose for 18 patients (64%). CONCLUSION: CysA/MMF substitution improves renal function and blood pressure in chronic allograft dysfunction when compared with conventional management. However, CysA/MMF substitution is associated with a high rate of MMF-related side effects, requiring modulation of its dose.     

The pathologic impact of tacrolimus on protocol biopsy in renal transplant patients with basiliximab-based immunosuppression

Forty-two ESRD patients underwent renal transplantation using basiliximab (mean age: 30.6 +/- 18.6 years at transplantation; male: 50%; ESRD duration: 51.6 +/- 13.0 months) between February, 2000 and July, 2003. All patients had a protocol biopsy on the day of transplant, on discharge from the hospital (35.5 +/- 13.2 days), and at 1 year after transplant. The immunosuppression included a calcineurin inhibitor, basiliximab, mycophenolate mofetil (MMF), and methylprednisolone. While 16 patients used tacrolimus (FK group: 29.4 +/- 16.6 years old), 26 patients used cyclosporine (CsA group: 31.4 +/- 20.1 years old). Protocol biopsies were graded according to the Banff 97 classification. The incidence of acute rejection episodes within 1 year was greater in the CsA (15%) than the FK group (6%). Serum creatinine at hospital discharge was similar (CsA: 1.01 +/- 0.59 mg/dL, FK: 0.97 +/- 0.49, p = .18); however creatinine at 1 year differed significantly (CyA: 1.22 +/- 0.88 mg/dL, FK: 0.92 +/- 0.39, P = .03). There was a trend toward an increase in the score of interstitial inflammations in the CsA group, while it remained constant in the FK cohort (P = .05 at 1 year between the two groups). Other pathologic scores (t, ci, ct, cv, ah) did not differ between the groups at 1 year. Although there were no differences in the demographics between the two groups, there were several trends toward better renal function in the FK group.     

Clinicopathological correlation in biopsy-proven atherosclerotic nephropathy: implications for renal functional outcome in atherosclerotic renovascular disease.

BACKGROUND: Atherosclerotic renovascular disease (ARVD) is commonly associated with renal failure. It is now recognized that intrarenal damage, (ischaemic or atherosclerotic nephropathy) is a major contributor to the renal impairment in these patients. In this study the impact of histological changes upon renal functional outcome was investigated in patients with atherosclerotic nephropathy. METHODS: The Hope Hospital renal biopsy database (1985-1998) was interrogated for patients with histology compatible with atherosclerotic nephropathy. Case-note review enabled the assessment of several clinical parameters and outcomes, including change in creatinine clearance per year (DeltaCrCl (ml/min/year)), blood pressure control, dialysis need, and death. Renal parenchymal damage was analysed by morphometric analysis (of interstitial fibrosis and glomerulosclerosis) and a semi-quantitative chronic damage score (score 0-3 (normal-severe) for each of glomerulosclerosis, interstitial fibrosis, tubular atrophy, and arteriolar hyalinosis; maximum=12). Patients were stratified into two groups who had either deteriorating (group 1) or stable (group 2) renal function during follow-up. RESULTS: Twenty-five patients (age 64.7+/-10.5, range 43-83 years; 17 male, eight female) were identified. Sixteen patients had undergone angiography; two had significant (>50%) renal artery stenosis. Mean follow-up was 25.6+/-14.8 (range 5-50) months. Group 1 patients had DeltaCrCl -7.4+/-6.8 ml/min/year, n=14 and group 2 patients had DeltaCrCl 4.8+/-7.0 ml/min/year, n=11. Four patients in group 1 developed end-stage renal disease and five patients died (three in group 1 and two in group 2). At study entry, group 1 patients had worse renal function (CrCl 27.6+/-17.6 vs 36.0+/-33.9, NS), greater proteinuria (1.2 vs 0.5 g/24 h, NS), and higher systolic blood pressure (167.1+/-30.8 mmHg vs 150.6+/-37.8, NS) compared with group 2 patients. Group 1 patients showed more glomerulosclerosis (51.6 vs 24.9%, P:<0.01), greater proportional interstitial volume (44.9 vs 33.9%, P:<0.02), and higher overall chronic damage score (P:<0.05) than those in group 2. There was a significant correlation between renal functional outcome and chronic damage score, glomerulosclerosis and proportional interstitial volume for the entire patient cohort. CONCLUSION: In patients with atherosclerotic nephropathy the severity of histopathological damage is an important determinant and predictor of renal functional outcome.     

Role of poly (ADP-ribose) polymerase in kidney transplant and its relationship with delayed renal function: multivariate analysis

Kidney allografts undergo pretransplant cold ischemia and consequent ischemia-reperfusion injury (IR). Poly (ADP-Ribose) polymerase (PARP-1) overactivation leads to massive NAD+ consumption and ATP depletion with induction of cellular necrosis under ischemic conditions, which may lead to an increase in acute tubular necrosis (ATN) and a delay in total recovery of renal function (RFR) of the transplanted organ. MATERIALS AND METHODS: Nuclear PARP-1 immunohistochemical expression (clone: PARP01) was studied in 155 paraffin-embedded renal biopsies from suboptimal donors and 95 kidney allograft biopsies with histopathological diagnosis of ATN. RESULTS: In 50% of ATN biopsies, more than 50% of tubular nuclei were immunostained for PARP-1. PARP-1 expression was higher in ATN biopsies than in those from suboptimal donors (2.40 +/- 0.74 vs 0.92 +/- 1.13, P = 0.0001 Mann-Whitney). PARP-1 showed a statistically significant relationship with the time required to achieve effective diuresis (Rho:0.779), with serum creatinine, and with duration of cold ischemia (Rho:0.803). These relationships were stronger in the biopsies with ATN. In conclusion, multivariate analysis demonstrated that PARP-1 expression and cold ischemia duration in kidney biopsies with ATN predicted the short-term delay in total recovery of renal function and serum creatinine in the first month.     

Urinary N-acetyl-beta-D-glucosaminidase and neopterin aid in the diagnosis of rejection and acute tubular necrosis in initially nonfunctioning kidney grafts

AIM: The study aimed at investigating urinary neopterin, a marker of cellular immune response, and urinary N-acetyl-beta-D-glucosaminidase (NAG), a marker of tubular damage, as noninvasive means to differentiate between acute tubular necrosis (ATN) and rejection in initially nonfunctioning (INF) human renal transplants. METHODS: Seventy-two renal transplant patients were studied. Forty-five of them experienced an uncomplicated early posttransplant course, 27 patients suffered from INF. Twenty-two patients experienced ATN, 5 patients had a total of six biopsy-proven rejections. The NAG activity was measured by a colorimetric assay, neopterin by high-performance liquid chromatography. Receiver operating characteristics (ROC) analysis was applied to compute diagnostic performance and an optimal discriminating threshold. RESULTS: Demographic characteristics (age, gender, cold and warm ischemia periods, HLA mismatches) and posttransplant urinary NAG and neopterin excretions did not differ between ATN and rejection groups. Both urinary NAG and neopterin excretions were lower in the control group (NAG 1.8 +/- 1.0 U/mmol urinary creatinine; neopterin 270 +/- 126 nmol/mmol urinary creatinine; mean +/- SD) as compared with the ATN group (NAG 12 +/- 10 U/mmol, p < 0.001 vs. control group; neopterin 303 +/- 195 nmol/mmol, n.s.) and the rejection group (NAG 7 +/- 8 U/mmol, p < 0. 01; neopterin 508 +/- 419 nmol/mmol, p < 0.01). The ratio of urinary neopterin to NAG excretion (uNNR; dimension nmol neopterin/U NAG activity) increased during rejections as compared with ATN (139 +/- 74 vs. 50 +/- 38 nmol/U, p < 0.01). The area under the ROC curve for uNNR was 0.88 +/- 0.07 (p < 0.001). Applying a ROC-estimated optimal discriminator of uNNR (80 nmol/U), 16 patients with ATN and all six rejection episodes were classified correctly. CONCLUSION: The uNNR provides a noninvasive means to aid in the differential diagnosis of rejection and ATN in INF human renal transplants.