Predictors of Success in Conversion from Calcineurin Inhibitor to Sirolimus in Chronic Allograft Dysfunction

Chronic allograft dysfunction (CAD) is a major cause of graft loss in long-term kidney transplant recipients. To identify predictors of successful conversion from calcineurin inhibitor (CNI) to sirolimus (SRL) we investigated 59 renal transplant patients with CAD without histological signs of acute rejection. They received 12-15 mg SRL once, then 4-5 mg/day, target trough level 8-12 ng/mL. CNI dose was reduced by 50% simultaneously, and withdrawn at 1-2 months. Concomitant immunosuppression remained unchanged. After 1 year patient survival was 100% and graft survival 92%. In responders (54%) creatinine improved (2.75 +/- 0.75 to 2.22 +/- 0.64 mg/dL; p < 0.01). In nonresponders (46%) creatinine deteriorated (3.15 +/- 1.02 to 4.44 +/- 1.60 mg/dL; p < 0.01). Baseline renal function did not differ, however, baseline proteinuria (519 +/- 516 vs. 1532 +/- 867 mg/day, p < 0.01), histological grade of chronic allograft nephropathy (CAN) (1.2 +/- 0.5 vs. 1.9 +/- 0.6; p < 0.01), grade of vascular fibrous intimal thickening (1.2 +/- 0.7 vs. 1.7 +/- 0.7; p = 0.048) and number of acute rejections before conversion (0.73 +/- 0.69 vs. 1.27 +/- 0.96; p < 0.05) differed significantly between responders and nonresponders. In a multivariate analysis low proteinuria was the only independent variable. Proteinuria below 800 mg/day has a positive predictive value of 90%. Proteinuria at conversion below 800 mg/day is the only independent predictor for positive outcome in conversion from CNI to SRL in CAD.     

Evaluating the clinical course and prognostic factors of posttransplantation immunoglobulin A nephropathy

INTRODUCTION: Previous reports have suggested that posttransplantation immunoglobulin (Ig) A nephropathy displays a relatively benign course, hardly ever affecting graft function. However, more recent studies with longer follow-up have shown that posttransplantation IgA nephropathy may be a significant contributor to graft loss. Additionally, there may be other clinical or pathological factors that affect long-term graft outcome. We retrospectively analyzed 30 kidney transplant recipients with biopsy-proven IgA nephropathy in their allografts to determine the clinical course and prognostic factors in posttransplantation IgA nephropathy. The median duration of follow-up was 36 months (range, 1 month-17 years). The median onset of IgA nephropathy was 33.6 months posttransplantation (range, 5 days-103 months). The most common presentation was an abnormal urine examination (96.6%). Fifteen (50%) displayed microscopic hematuria with proteinuria more than 1 g/d. Fifteen patients (50%) lost their grafts at a median time of 24 months after the onset of disease (range, 1-93 months). Allograft loss was associated with a high serum creatinine level at the time of diagnosis (3.68 +/- 2.23 vs 1.79 +/- 0.34 mg/dL; P = .006), a greater level of proteinuria at the time of diagnosis (2.43 +/- 0.76 vs 1.29 +/- 1.07 g/d; P = .003), and more than 50% extracapillary proliferation (P = .05). Fibrinoid necrosis on allograft pathology impacted 1-year allograft survival (P = .025). CONCLUSION: Posttransplantation IgA nephropathy worsens allograft outcomes among patients with increased serum creatinine level or significant proteinuria at presentation or significant glomerular inflammation and/or tubulointerstitial damage.     

Prospective, Pilot, Open-Label, Short-Term Study of Conversion to Leflunomide Reverses Chronic Renal Allograft Dysfunction

Leflunomide (LEF) is a synthetic isoxazole derivative with anti-inflammatory and antiviral properties, which has been reported to prevent acute rejection and delay progression of chronic allograft nephropathy (CAN) in animal models. We performed a pilot, crossover trial in 22 renal transplant recipients who were converted from azathioprine (AZA) or mycophenolate mofetil (MMF) to LEF in an effort to slow progression of renal dysfunction [deteriorating renal function (n = 5), cyclosporine (CyA) nephrotoxicity (n = 4) or biopsy-proven CAN (n = 13)]. Baseline maintenance immunosuppression consisted of CyA, AZA or MMF and prednisone. Six-month postconversion patient and graft survival was 100% and 91%, respectively. Mean serum creatinine 6months preconversion was 2.2 +/- 0.6mg/dL, at initiation was 3.0 +/- 1.1 mg/dL, and 6 months postconversion was 2.8 +/- 1.3 mg/dL. The rate of change in serum creatinine was 35 +/- 39%/6 months preconversion and -5 +/- 21%/6 months postconversion to LEF (p = 0.003). Two patients discontinued LEF for diarrhea and myalgia. No readmissions, increase in liver function tests, infections or acute rejection episodes occurred. Mean CyA levels did not change, 146 +/- 72 ng/ mL pre-LEF vs. 132 +/- 51 ng/mL post-LEF, p = NS. Conversion to LEF reversed progression of chronic renal allograft dysfunction with minimal toxicity.     

New aspects of posttransplant nephrotic syndrome: clinicopathologic correlations with outcomes

Although posttransplant nephrotic syndrome is frequent, its structural basis and prognosis have not been clearly defined. The biopsy findings of 54 patients with this disorder posttransplant, among 375 total renal transplant recipients engrafted during a 10-year period, were correlated with clinical follow-up data. The mean patient age was 41.7 +/- 12.3 years, female/male ratio 22/32, and cadaveric/living-related donor ratio 37/17. The nephrotic syndrome developed 3 to 91 months posttransplant. At the onset the mean values of serum creatinine was 2.9 +/- 1.8 mg/dL and proteinuria 4.5 +/- 0.8 g/d. The index biopsy findings showed chronic allograft nephropathy (CAN) in 33; de novo glomerulonephritis (GN) in 6, recurrent GN in 9, and undetermined GN in 6 who had an unknown primary renal disease. Among 21 follow-up biopsies during a mean of 44.3 +/- 28 months the CAN progressed but the GN remained the same. The treatment included augmented steroids alone (n = 1) or in combination with cyclophosphamide (n = 2) and with plasmapheresis (n = 1); angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) along (n = 5); calcium channel blockers (CCB) alone (n = 24); or the two types of drugs together (n = 22). Complete or partial remission was achieved in 8 and 5, respectively, but nephrotic syndrome recurred in 3 of these patients at 45.1 +/- 18 months later. Sustained remission was more likely in cases of GN (minimal change disease and IgA nephropathy) and ACEI-ARB treatment (P <.01). Graft failure, which occurred in 35 patients, correlated strongly with serum creatinine at onset, being significantly greater in patients with CAN (P <.005). Both remission of the nephrotic syndrome and graft survival were greater among patients with GN as compared to those with CAN.     

Prognostic factors associated with poor graft outcomes in renal recipients with post-transplant glomerulonephritis

BACKGROUND: Little data are available concerning post-transplantation glomerulonephritis (PTx-GN) and its prognostic factors associated with graft outcomes. METHODS: We retrospectively evaluated patients with de novo and recurrent PTx-GN to identify the factors associated with their negative impact on graft and patient outcomes. PTx-GN was diagnosed in 55 patients, wherein 17 (31%) had recurrent glomerulonephritis (GN) and 16 (29%) had de novo. RESULTS: Our enrolled population consisted of 34 +/- 13.7-yr-old male patients (72%), on hemodialysis for a median of 18 months (0-204) and mainly grafted from living donors (76%). The median onset time of proteinuria and hematuria was 50 d (10-2160) and 30 d (4-1170), respectively. One-yr graft survival rates after PTx-GN diagnosis was 64%. The most frequent de novo GN was membranous GN (26%), while focal segmental glomerulosclerosis was the most frequent recurrent GN (41%), with a very early onset (median of three months). One-yr graft survival was better in the recurrent disease than in the de novo patients, 76% vs. 55% (p = 0.24). The best predictor factors that correlated with graft survival were: proteinuria <3.5 g [relative risk (RR) = 0.24, p = 0.017], serum creatinine below 2.0 mg/dL (RR = 0.06, p = 0.016) at the time of biopsy and the use of angiotensin-converting enzyme inhibitors (ACEI) (RR = 0.12, p = 0.005). The use of ACEI markedly improved one-yr graft survival rates (92% vs. 47%, p < 0.001). CONCLUSION: PTx-GN has a strong negative impact on kidney graft survival. De novo GN appears to have a poorer prognosis than the recurrent type. Patients who used ACEI showed a better survival rate in the follow-up.     

Effect of thymoglobulin in graft survival and function 1 year after kidney transplantation using deceased donors

This study evaluated 1-year graft function and survival among kidney transplantations from deceased donors using thymoglobulin (Thymo) as an induction strategy. PATIENTS AND METHODS: Fifty-seven percent of patients were men and overall mean age was 42 +/- 15 years. Cold ischemia time was 20.1 +/- 4.8 hours. The primary outcome was defined as survival not censored for death after 1 year. The secondary outcome was defined as a comparison of function and survival among patients who received more or less then six doses of Thymo. RESULTS: Four patients experienced acute rejection episodes and the other three died during follow-up. One-year graft survival was 91% with a mean serum creatinine of 1.28 +/- 0.43 mg/dL. Cytomegalovirus infection occurred in 56%. Forty-two (64%) patients displayed acute tubular necrosis of mean duration of 6.89 +/- 7.48 days. Patients who received lower doses showed better serum creatinine values 3 months (1.45 vs 1.86 mg/dL, P = .013) and 12 months (1.05 vs 1.50 mg/dL, P = .04). The difference was probably due to acute tubular necrosis that produced a RR of 1.7 (P = .02; CI 1.04-2.97) when compared with patients with Scr values above 1.30 mg/dL. When censored for death, graft survival was not different between the two groups (< or =6 doses 93% vs >6 doses 97%, P = .43). CONCLUSION: Immunologic induction with Thymo produced excellent graft survival after 1 year with preservation of graft function. Delayed graft function was the most important determinant of graft function after 1 year.     

Effect of mycophenolate mofetil on kidney graft function and body weight in patients with chronic allograft nephropathy

BACKGROUND: Chronic allograft nephropathy (CAN) is the most common cause of late graft loss. A beneficial effect of mycophenolate mofetil (MMF) on CAN was observed, although, due to the loss of body weight (BW) under MMF, serum creatinine (sCr) and reciprocal sCr may be unsuitable markers of graft function. METHODS: In 17 kidney transplant patients with CAN, azathioprine (Aza) was replaced by MMF. The remaining therapy was not changed; specifically, the cyclosporine (CsA) dose was not decreased. The mean values and regression coefficients of reciprocal sCr, CCr, urinary creatinine excretion (uCr x V), proteinuria, BW, blood pressure (BP), serum cholesterol (sChol), and serum triglycerides (sTG) versus time were analyzed 12 months before and after institution of MMF by a paired-comparison t test. RESULTS: The mean regression coefficient of reciprocal sCr differed significantly before and after conversion to MMF (mean -0.01 +/- 0.01 vs +0.012 +/- 0.029 mg/dL per month), suggesting improved graft function. However, the mean values of BW (74 +/- 15 vs 71 +/- 15 kg, P <.001) and uCr x V (1152 +/- 321 vs 1065 +/- 266 mg per 24 hours, P=.0897) decreased, making the increase in CCr less significant (mean -1.16 +/- 2.69 vs 0.40 +/- 1.79 mL/min per month, P <.05). BP, sChol, sTG, and proteinuria before and after conversion did not differ significantly. Among patients with long-term stable graft function at 36.5 +/- 16.9 months after conversion to MMF there was an almost significant improvement in renal protein excretion. CONCLUSIONS: MMF improved graft function, although this effect was overestimated using reciprocal sCr. Other risk factors, such as BP, sChol, and sTG, showed no significant differences, suggesting that MMF accounted for the improvement in CAN. The course of proteinuria under MMF seems to be of prognostic significance.     

Post-transplant nephrotic syndrome: A comprehensive clinicopathologic study

BACKGROUND: Post-transplant (Tx) nephrotic syndrome (NS) is not well defined. METHODS: Seventy-four renal transplant recipients with NS were studied. RESULTS: Biopsies showed chronic allograft nephropathy (CAN) in 31 patients; recurrent glomerular disease (GN) in 15, de novo GN in 18, and undetermined GN in 9. NS developed 0.25 to 384 months post-Tx and was treated with angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) in 18 patients; calcium channel blockers in 25; or both drugs in 31. NS remitted in 24% of cases 2 to 28 months after onset, and this persisted in all except 3 patients. The remission rate was lowest (9%) for CAN and highest (47%) for de novo GN. Compared with persistent NS, those with remission showed higher prevalence of de novo GN (53% vs. 17%), lower prevalence of CAN (18% vs. 50%), earlier onset of NS (39 vs. 59 months), lower serum SCr at onset (2.3 vs. 2.9 mg/dL), and higher incidence of treatment with ACE or ARB. The 5-year graft loss rates for CAN, recurrent and de novo GN were 57%, 36%, and 23%, respectively. Compared with the functioning grafts, the failed grafts showed higher prevalence of CAN (60% vs. 16%), lower prevalence of de novo GN (12% vs. 46%), earlier onset of NS (47 vs 65 months post-Tx), higher serum SCr at onset (3.3 vs. 2.0 mg/dL), lower prevalence of remission of NS (5% vs. 48%), and higher proteinuria at follow-up (5.1 vs. 2.5 g/day). Graft survival improved with NS remission (88% vs. 18%). CONCLUSION: Post-Tx NS displays distinctive clinicopathologic features with pathogenetic and therapeutic implications.     

Proteinuria after conversion to sirolimus in renal transplant recipients

Sirolimus (SRL) is a new, potent immunosuppressive agent. More recently, proteinuria has been reported as a consequence of sirolimus therapy, although the mechanism has remained unclear. We retrospectively examined the records of 25 renal transplant patients, who developed or displayed increased proteinuria after SRL conversion. The patient cohort (14 men, 11 women) was treated with SRL as conversion therapy, due to chronic allograft nephropathy (CAN) (n = 15) neoplasia (n = 8); Kaposi's sarcoma, Four skin cancers, One intestinal tumors, One renal cell carsinom) or BK virus nephropathy (n = 2). SRL was started at a mean of 78 +/- 42 (15 to 163) months after transplantation. Mean follow-up on SRL therapy was 20 +/- 12 (6 to 43) months. Proteinuria increased from 0.445 (0 to 1.5) g/d before conversion to 3.2 g/dL (0.2 to 12) after conversion (P = 0.001). Before conversion 8 (32%) patients had no proteinuria, whereas afterwards all patients had proteinuria. In 28% of patients proteinuria remained unchanged, whereas it increased in 68% of patients. In 40% it increased by more than 100%. Twenty-eight percent of patients showed increased proteinuria to the nephrotic range. Biopsies performed in five patients revealed new pathological changes: One membranoproliferative glomerulopathy and interstitial nephritis. These patients showed persistently good graft function. Serum creatinine values did not change significantly: 1.98 +/- 0.8 mg/dL before SRL therapy and 2.53 +/- 1.9 mg/dL at last follow-up (P = .14). Five grafts were lost and the patients returned to dialysis. Five patients displayed CAN and Kaposi's sarcoma. Mean urinary protein of patients who returned to dialysis was 1.26 (0.5 to 3.5) g/d before and 4.7 (3 to 12) g/d after conversion (P = .01). Mean serum creatinine level before conversion was 2.21 mg/dL and thereafter, 4.93 mg/dL (P = .02). Heavy proteinuria was common after the use of SRL as rescue therapy for renal transplantation. Therefore, conversion should be considered for patients who have not developed advanced CAN and proteinuria. The possibility of de novo glomerular pathology under SRL treatment requires further investigation by renal biopsy.     

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.     

Effects of angiotensin-converting enzyme inhibitor and steroid therapy on proteinuria in FSGS: a retrospective study in a single clinic

We retrospectively evaluated the response to steroids (S) +/- angioten-sin-converting enzyme inhibitors (ACEI) vs. ACEI in nephrotic patients with FSGS seen in our clinic from 1992 - 1999. Of 48 patients with biopsy-proven FSGS, 30 had pre-therapy and follow-up evaluations of proteinuria. Of these, 22 were nephrotic (> or = 3 g protein/24 h). Twelve/22 were treated with S and 10/22 with ACEI +/- HMG-CoA reductase inhibitor (statin) alone. 92% of S patients received ACEI during follow-up, 83% concurrently with steroid treatment. The two cohorts (S vs. ACEI) were not different in age (34 +/- 12 vs. 33 +/- 12), sex (75% vs. 78% male), or ethnicity (83% vs. 83% African American). Mean follow-up time was 16 (range 4 - 61 months) vs. 23 months (range 6 - 56 months). Mean S dose was 70 mg qd (range 60 - 100 mg), with mean treatment duration of 4 months. Nephrotic patients were compared with regard to degree of proteinuria at follow-up. There were no complete remissions (proteinuria < or = 200 mg/24 h) in either group. There was no difference in partial remissions (> 200 mg to < 3 g proteinuria/24 h) between the two groups - 5/12 vs. 6/10 (p = 0.434). There was no difference in the proportion of patients progressing to ESRD. Although proteinuria decreased significantly with time in both groups, there was no significant treatment effect. There was no significant time or treatment effect on serum creatinine. Mean arterial pressure and serum cholesterol were not significantly different between the groups. Thus, treatment with S +/- ACEI is no more effective in reducing proteinuria in FSGS than treatment with ACEI alone.     

Study of mRNA growth factors in urinary cells of kidney transplant recipients as predictors of chronic allograft nephropathy

BACKGROUND: Chronic allograft nephropathy (CAN) is responsible for a significant proportion of graft loss. Current diagnostic methods for CAN are inadequate, and noninvasive assays for detecting allograft dysfunction/rejection and predicting long-term outcomes are a priority in transplantation. METHODS: Urine samples were collected from 48 kidney transplant recipients (KTR): 18 recipients with stable graft function (creatinine levels<2.0 mg/dL) and proteinuria of less than 500 mg/24 hr (Group 1); 18 recipients with stable graft function and proteinuria of greater than 500 mg/24 hr (Group 2); and 12 recipients with biopsy confirmed CAN. Urinary cell levels of transforming growth factor-beta1 (TGF-beta1) mRNA or epidermal growth factor (EGF) mRNA were measured using real-time quantitative PCR assay, and levels were correlated with renal allograft status. The integrity of RNA isolated from urine sediments was also assessed using the Agilent 2100 Bioanalyzer. RESULTS: Urinary cell TGF-beta1 mRNA levels were higher in the CAN group compared to Group 1 (P<0.0001) or Group 2 (P<0.0001). Urinary cell EGF mRNA levels were higher in Group 1 compared to Group 2 (P<0.0001) or the CAN group (P<0.0001). There were no significant differences in the urinary cell levels of EGF mRNA between patients with greater than 500 mg/24 hr proteinuria (Group 2) and the CAN group (P=0.75). CONCLUSION: These results demonstrate that urinary cell TGF-beta1 mRNA levels distinguish CAN patients from long-term transplant patients with stable renal function and varied levels of proteinuria. Urinary cells may be a good resource for the noninvasive diagnosis of CAN.     

Sirolimus conversion experience in a single center

OBJECTIVE: One major cause of graft loss is chronic allograft nephropathy (CAN), which may relate to calcineurin inhibitors (CNIs). We converted CAN cases from CNIs to sirolimus and observed the outcomes. METHOD: From January 2004 to August 2007, there were 28 kidney recipients in our center with creeping creatinine levels compatible with CAN. We started sirolimus at 2 mg/d and reduced the CNIs gradually. Sirolimus trough levels were kept between 5 and 8 ng/mL. Mycophenolic acid was cut in half; there was no adjustment on prednisolone dose. RESULTS: The mean switch time was 47.3 months after transplantation. One case discontinued sirolimus due to severe drug-induced pneumonitis. Twelve of the 27 (45%) patients showed improvements in graft function. The most frequent complications were anemia (13/28), hyperlipidemia (13/28), and pneumonitis (4/28). A baseline serum creatinine level less than 2.2 mg/dL seemed to forecast a response to sirolimus conversion. Most of the graft functional improvement occurred within 6 months after the switch. No graft or patient loss was encountered. CONCLUSION: Our experience suggested that 45% of patients with sirolimus conversion showed improved graft function. Among patients within 1 year after transplantation, those with a creatinine level less than 2.2 mg/dL, no proteinuria, and no hyperlipidemia seemed to be better candidates for Sirolimus conversion.     

Rapid Resolution of Proteinuria of Native Kidney Origin Following Live Donor Renal Transplantation

To assess the contribution of the protein content of urine from the native kidneys to post-transplant proteinuria, we prospectively studied 14 live donor transplant recipients with a pre-transplant random urine protein to creatinine ratio (UPr:Cr) >0.5. Seven patients received preemptive transplants, and seven patients were on dialysis pre-transplant (with residual urine output). Resolution of proteinuria was defined as UPr:Cr < 0.2. Immunosuppression consisted of tacrolimus, mycophenolate mofetil and corticosteroids. Anti-hypertensive drugs that might reduce proteinuria were avoided during the study. The serum creatinine was 8.7 +/- 0.7 mg/dL pre-transplant, and the nadir post-transplant serum creatinine was 1.4 +/- 0.1 mg/dL. The pre-transplant UPr:Cr ranged between 0.5 and 9.2 (mean = 2.9 +/- 0.6). The UPr:Cr decreased to <0.2 in all 14 patients at a mean of 4.5 weeks post-transplant (range 1-10 weeks). In conclusion, in live donor renal transplant recipients with immediate graft function, proteinuria of native kidney origin resolves in the early post-transplant period. After the immediate post-transplant period, proteinuria cannot be attributed to the native kidneys, and work up for proteinuria should focus on the allograft.     

Detection of B lymphocytes (CD20+) in renal allograft biopsy specimens

Acute allograft rejection represents an important complication after transplantation with significant impact on long-term graft survival. The involvement and relevance of B lymphocytes in this process is still not clear. The aim of this study was to quantify in renal allograft biopsy specimens the number of cells positive for CD20, a specific marker for B lymphocytes. Immunohistochemical techniques using monoclonal anti-CD20 antibody was used on paraffin sections from 38 renal allograft biopsy specimens. The biopsy specimens were classified into 3 groups, according to clinical and histological criteria: normal kidney, acute rejection, and chronic allograft nephropathy (CAN). In the normal kidney, no CD20(+) cells were detected. In contrast, in all cases of acute rejection and CAN, there were CD20(+) cells. The CD20(+) cells occurred in the infiltrate in 2 distinct patterns: scattered or nodular. In cases of acute rejection, the number of CD20(+) cells was significantly higher than in CAN cases (137.0 +/- 57.2 vs 45.4 +/- 9.8 cells/mm(2); P < 0.05). The nodular pattern was observed in 4 of 11 cases (36%) in the acute rejection group, and in 4 of 20 cases (20%) in the CAN cohort. In the acute rejection group, the presence of B-cell clusters tender to be associated with a higher level of serum creatinine (3.7 +/- 1.8 mg/dL vs 2.8 +/- 0.1 mg/dL in the scattered pattern group; not significant [ns]). In conclusion, these preliminary results demonstrated B lymphocytes in cases of renal allograft dysfunction, which were more pronounced in acute allograft rejection. Further analyses are required to determine whether the detection of CD20(+) cells in renal allograft biopsy specimens can be used as a prognostic marker.     

Renoprotective effect of early inhibition of the renin-angiotensin system in renal transplant recipients

The aim of this work was to study the effect of early administration of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II type-I receptors blockers (ARB) on renal function and proteinuria in renal transplant recipients with good, stable renal function and mild proteinuria. Twenty four patients started ACEI/ARB therapy within 14 months after surgery (RAS-). Before (T0) and every month for 2 years after the initiation of ACEI/ARB we evaluated creatinine clearance (CrCl), proteinuria/day (UP), UP/CrCl (FUP), arterial blood pressure, and serum lipid levels. Twenty-eight patients who never received ACEI/ARB (RAS+) were studied in the same fashion. In the RAS+ CrCl was reduced after 2 years compared with T0 (64.5 +/- 2.6 vs 75.0 +/- 3.2 mL/min, P < .003); UP and FUP were both significantly increased (666 +/- 65 vs 132 +/- 20 mg/day 8.8 +/- 1.2 vs 2.6 +/- 0.6 mg/mL x 10(3); P < .001 and .002) compared with T0. Moreover, UP (P < .04), FUP (P < .03), and the percentage reduction of CrCl (11.4% +/- 5% vs 4.6% +/- 1.8%; P < .05) were greater in RAS+ than RAS- subjects at 2 years of the study. The values of other parameters did not show significant differences between the two groups. In conclusion, this study suggested that ACEI/ARB have renoprotective effects, when used in patients with good stable renal function and mild proteinuria. These drugs may play a role to prevent chronic allograft nephropathy.     

The effect of graft nephrectomy on long-term graft function and survival in kidney retransplantation

We retrospectively evaluated the long-term results of 53 (3.5%) recipients who received second allograft among 1486 kidney transplants between November 3, 1975 and June 30, 2004. Two study groups were patients in Group 1 (n = 21) who underwent allograft nephrectomy and those in Group 2 (n = 32) who did not. We assessed demographic features, rejection rates throughout the follow-up period, and serum creatinine levels at 12 months as well as graft and patient survival rates, postoperative complications, time interval between transplantations, and HLA matches. Forty-three patients who underwent retransplantation received kidneys from living-related donors and the remaining 10 from cadaveric donors. Mean serum creatinine levels of Group 1 versus Group 2 were 1.8 mg/dL (range, 0.8 to 6.6 mg/dL) versus 2.1 +/- 1.1 mg/dL (range, 1.1 to 7.1 mg/dL). HLA-AB and HLA-DR mismatches were 1.9 +/- 1.1 versus 1 +/- 0.6, respectively (P = .01). Acute rejection rates were not significantly different between Groups 1 (9/21, 43%) and 2 (12/32, 38%) (P < .05). The average intervals between the first and the second transplantations were 62 +/- 26 months in Group 1 (P = .02) and 32 +/- 11 months in Group 2. One-, 3-, and 5-year graft survival rates in Group 1 versus Group 2 were 83% versus 89% (P > .05); 64% versus 79% (P > .05), and 45% versus 68% (P = .04), respectively. In conclusion, we did not observe any advantage of graft nephrectomy before retransplantation. The length of the interval between the first and the second transplantations may have a negative correlation with second graft survival.     

Clinical results of immunosuppressive triple therapies in living-related renal transplantation--a single center experience

We reviewed the outcome of three methods employed for living-related renal transplantation (RTx) in our institution to assess triple immunosuppressive regimens. Between January 1989 and July 2003, a total of 35 living-related RTxs were performed at our institution. The immunosuppressive regimen given to 16 patients (group A) was cyclosporine (CsA), steroid and azathoprine (AZ) that given to 9 patients (group B) was tacrolimus (TAC), steroid and AZ and that given 9 patients (group C) was TAC, steroid and mycophenolate mofetil (MMF). Graft survival rate, serum creatinine, proteinuria, acute rejection, chronic allograft nephropathy (CAN), cytomegalovirus (CMV) infection and drug-induced nephropathy were investigated. There was no significant difference in graft survival rate among the three groups. Although serum creatinine levels (mg/dl) at 3 months post-transplant were 1.22+/-0.37 in group A, 1.43+/-0.14 in group B, 1.30+/-0.34 in group C, respectively (p<0.05; A vs. B), there was no significant difference at 1 year post-transplant. Frequency of proteinuria in groups A, B and C was 75.0, 50.0, 25.0%, respectively (p<0.05; A vs. C). The incidences of acute rejection and CAN within 1 year post-transplant were, respectively, 56.3% and 43.8% in group A, 37.5% and 37.5% in group B; and, 25.0% and 12.5% in group C (NS). The incidence of drug-induced nephrotoxicity was 12.5, 50.0% and 37.5% in groups A, B and C, respectively (p<0.05; A vs. B). The triple immunosuppressive therapy including calcineurin inhibitors, especially the regime of TAC, MMF, and steroids decreased the frequencies of proteinuria and rejections, which deteriorated the long-term outcome in living-related RTxs.     

IgA nephropathy in kidney allograft recipients-therapeutic perspective

INTRODUCTION: A growing number of patients are losing their kidney allografts due to glomerulonephritis. Although posttransplant IgA nephropathy (IgAN) is regarded as benign, it may lead to late allograft loss in a substantial number of patients. The aim of this study was to evaluate the influence of posttransplant IgAN on long-term transplantation outcomes, risk factors for progression of graft dysfunction, and effectiveness of therapeutic interventions. PATIENTS AND METHODS: We evaluated, potential risk factors for accelerated graft loss among 27 kidney allograft recipients with posttransplant IgAN, comparing graft survival in a control group matched for population and transplantation-related parameters. We evaluated the effectiveness of therapeutic interventions regarding immunosuppressive regimen, and hypertension control including angiotensin converting enzyme inhibitor (ACEI) usage with Kaplan-Meier, Cox proportional hazard plots, and log-rank tests in statistical analyses. RESULTS: Compared with the control group, patients with IgAN experienced a 6.57 higher risk for dialysis dependence (P < .01, 95% CI 1.4 to 30.83). The risk for accelerated graft loss in the course of IgAN was associated with graft dysfunction (RR = 2.16 for additional 1 mg/dL of serum creatinine at glomerulonephritis presentation; P < .03, 95% CI 1.2 to 4.36) and intense proteinuria as evidenced by a RR = 4.67 for the presence of the nephrotic syndrome (P < .05, 95% CI 0.95 to 22.8). Immunosuppression enhancement resulted in a significantly decreased risk of dialysis dependence, namely, RR = 4.76 (95% CI 1.12 to 20, P < .04). With ACEI treatment there was a tendency for a 2.8-fold decreased risk of dialysis dependence, without reaching statistical significance (P = .14). CONCLUSIONS: Patients with posttransplant IgAN may benefit from intensifying maintenance immunosuppression, which slows progression to end-stage graft dysfunction.     

Ten years of treatment with tacrolimus is related to an excellent renal function, allowing monotherapy in a large proportion of cases: unicentric results of the tacrolimus versus cyclosporine A European Multicentric Study in kidney transplant patients

Tacrolimus (Tac) is the most frequently used base inmunosuppressant for transplantation in Spain and the United States. However, long-term data on its use in renal transplant patients are lacking. The aim of this study was to analyze the 10-year outcome of patients from our institution treated with Tac or cyclosporine (CsA) who were included in the European Multicenter Study of kidney transplantation (1993 to 1994). This trial compared the efficacy and safety of steroids + Tac + azathioprine versus steroids + CsA + azathioprine at 1 year, showing a significantly lower acute rejection rate in Tac patients, with no differences in graft or patient survival. In our long-term analysis, we included patients with a functioning graft after the first year: 15 patients on Tac and 11 on CsA. In the "intent-to-treat" (ITT) analysis, patient survival was 14/15 (93%) versus 9/11 (82%) and death noncensored graft survival was 10/15 (67%) versus 8/11 (73%) in Tac and CsA, respectively. Analyzing patients "into treatment" (TT), death/noncensored graft survival was 11/16 (69%) versus 6/9 (67%), respectively. Serum creatinine tended to be lower in Tac group (ITT 1.26 +/- 0.42 vs 1.63 +/- 1.16 mg/dL, P = NS; TT 1.23 +/- 0.4 vs 1.86 +/- 1.28 mg/dL, P = NS). However, in the TT analysis, Tac patients exhibited a significantly better creatinine clearance (89.3 +/- 40 vs 46.8 +/- 21 mL/min, P = .037) and lower systolic blood pressure (125 +/- 5 vs 140 +/- 12 mm Hg, P = .007) at 10 years. No other significant differences were observed in blood pressure, lipid profile, or glucose metabolism. Outstandingly, Tac monotherapy was the most frequently used regimen after 10 years: ITT 6/9 (67%) versus 1/8 (12.5%), P = .05, TT 7/10 (70%) versus 0/6 (0%), P = .011. Patients under Tac monotherapy exhibited an excellent graft function (serum creatinine 1.08 +/- 0.14 mg/dL) and negative proteinuria, with Tac trough levels of 7.9 +/- 1.3 ng/mL. In summary, our results suggest that Tac-based immunosuppression provides an excellent kidney function 10 years after transplantation and allows monotherapy in a high percentage of kidney transplant patients.