Biopsy-proven Chronic Allograft Nephropathy Research Articles

Long-term effect of eplerenone treatment in children with chronic allograft nephropathy.

Literature supports the protective role of mineralocorticoid antagonist (MRA) against the renal injury induced by aldosterone in kidney transplant recipients. However, there is limited data available regarding the safety and efficacy of MRAs in pediatric renal transplant patients. Therefore, we aimed to investigate the effect of long-term eplerenone administration in children with chronic allograft nephropathy (CAN). Twenty-six renal transplant children with biopsy-proven CAN, an estimated glomerular filtration rate (eGFR ) > 40 mL/min per 1.73 m2 and with a significant proteinuria were included. Selected patients were randomly divided into two groups as follows; Group 1 (n = 10) patients received 25 mg/day eplerenone and Group 2 (n = 16) patients did not receive eplerenone for 36 months. Patients were examined in the renal transplant outpatient clinic biweekly for the first month and once a month thereafter. The primary outcome of the patients was compared. Mean eGFR stayed stable in group 1 patients, but significantly decreased in group 2 at 36 months (57.53 ± 7.53 vs. 44.94 ± 8.04 mL/min per 1.73 m2 , p = .001). Similarly, spot protein-creatinine ratio was significantly lower in group 1 compared to group 2 patients at 36 months (1.02 ± 7.53 vs. 3.61 ± 0.53, p < .001). Eplerenone associated hyperkalemia was not observed in group 1 patients (4.6 ± 0.2 vs. 4.56 ± 0.3, p = .713). The long-term eplerenone administration blunted the chronic allograft nephropathy by maintaining a stable eGFR levels and decreasing urine protein-creatinine ratio. Eplerenone associated hyperkalemia was not observed in our study.

Vitamin D deficiency may predispose patients to increased risk of kidney transplant rejection.

BACKGROUNDVitamin D deficiency occurs in more than 80% of kidney transplant recipients. Its immunomodulatory effects can predispose transplant recipients to rejection and chronic allograft nephropathy (CAN). This study determined the association between serum 25 (OH) vitamin D, biopsy-proven allograft rejection, and CAN rates.AIMTo determine the relationship between serum 25 (OH) vitamin D level and biopsy-proven allograft rejection and CAN rate in renal transplant recipients.METHODSAdult renal transplant recipients followed at the clinic between January 2013 and 2018 were included. Recipients requiring graft biopsy due to declined function, hematuria, and proteinuria were reviewed. The two groups were compared regarding collected data, including the biopsy results, immunologic parameters, vitamin D, parathyroid hormone (PTH), phosphorus, albumin levels, and graft function tests.RESULTSFifty-two recipients who underwent graft biopsy met the inclusion criteria. In all, 14 recipients had a vitamin D level > 15 ng/mL (group 1) vs ≤ 15 ng/mL (group 2) in 38. In total, 27 patients had biopsy-proven rejection, and 19 had CAN. There was only 1 recipient with biopsy-proven rejection in group 1, whereas there were 24 patients with rejection in group 2. The rejection rate was significantly higher in group 2 than in group 1 (P < 0.001). Four patients were diagnosed with CAN in group 1 vs fifteen in group 2. There was no significant difference in the CAN rate between the two groups. PTH was higher at the time of graft biopsy (P = 0.009, P = 0.022) in group 1 with a mean of 268 pg/mL. Donor-specific antibodies were detected in 14 (56.0%) of the recipients with rejection. Vitamin D level was 9.7 ± 3.4 ng/mL in the rejection group vs 14.7 ± 7.2 in the non-rejection group; this difference was statistically significant (P = 0.003). The albumin levels were significantly lower in patients with rejection than in those without rejection (P = 0.001). In univariate regression analysis of risk factors affecting rejection, sex, serum vitamin D, phosphorus and albumin were found to have an impact (P = 0.027, P = 0.007, P = 0.023, P = 0.008). In multivariate regression analysis, the same factors did not affect rejection.CONCLUSIONThe serum 25 (OH) vitamin D level in kidney transplant recipients remained low. Although low serum vitamin D level emerged as a risk factor for rejection in univariate analysis, this finding was not confirmed by multivariate analysis. Prospective studies are required to determine the effect of serum vitamin D levels on allograft rejection.

Role of shear wave elastography in assessment of chronic allograft nephropathy

BackgroundThe principal cause of renal graft loss after the first year is chronic allograft nephropathy which is represented histologically by tubulo-interstitial fibrosis. Its early diagnosis and treatment are crucial to prevent late graft failure. Ultrasound is unequivocally the first-line imaging modality for the evaluation of renal transplants in the immediate postoperative period and for long-term follow-up. Ultrasound shear wave elastography is an imaging technique based on estimation of the elastic properties of tissues.Elastography is performed in the same clinical setting with conventional B-mode ultrasonography. Tissue elasticity is displayed as an absolute number and color-coded real-time estimation. So, it can be used in screening and diagnosing chronic allograft nephropathy. However, the accurate diagnosis and prognosis of renal parenchymal complications still relies on tissue biopsy. Many studies have proved the high specificity of ultrasound elastography in decreasing the number of unnecessary biopsies.ResultsIn our study, we included 36 patients with biopsy-proven chronic allograft nephropathy. All patients had a B-mode ultrasound examination and followed by ultrasound shear wave elastography in the same session. The results were compared to the histopathological results.Time since transplantation was directly correlated with mean renal stiffness, revealing that with longer time of transplantation renal stiffness and interstitial fibrosis and tubular atrophy (IF/TA) percentage increased with r = 0.72, 0.90 and p value < 0.001.Antero-posterior (AP) diameter of the renal graft was significantly correlated with mean renal stiffness as the larger the AP diameter, the higher the mean kidney stiffness with r = 0.47, 0.73 and p value 0.001.Sensitivity analysis showed that US shear wave elastography through mean kidney stiffness can significantly predict moderate Banff score of renal fibrosis using cutoff value 28.67 kPa with sensitivity 87.5%, specificity 90%, AUC 0.91 and p value < 0.001.ConclusionShear wave elastography (SWE) may be useful for the prediction of fibrosis in renal transplant patients, especially in the case of moderate Banff score, where the accuracy reached 87.5% using a cutoff value 28.67 kPa.We conclude that US SWE can be of great help during the regular follow-up of renal transplant patients. It can act as a screening tool to identify patients with stiffness values that suggest moderate tubulo-interstitial fibrosis, so eventually helping in the early diagnosis, management and help in selecting patients who are candidate for biopsy and in avoiding the repeated unnecessary biopsies for others.

Inferior Long-Term Outcomes for Kidney Transplant Recipients With an Immunologically Mediated Primary Renal Disease.

Recurrent glomerulonephritis can negatively affect kidney allograft survival. However, how primary renal disease affects transplant outcomes in the new era of immunosuppression remains unclear. We categorized 426 kidney transplant recipients (performed from 1996 to 2007) into 4 disease groups: (1) 99 recipients with biopsy-proven immunologically mediated kidney disease, (2) 40 recipients with urologic disease, (3) 67 recipients with polycystic kidney disease, and (4) 220 recipients with other causes of terminal renal failure/uncertain kidney disease. Long-term transplant outcomes were compared between groups at 1, 5, and 10 years of follow-up. Compared with the urologic, polycystic, and other diseases groups, the immunologic group showed significantly lower time of graft survival (9.5 ± 4 vs 8 ± 4 vs 8.5 ± 4 vs 7 ± 4 years, respectively) and estimated glomerular filtration rate (52.5 ± 32 vs 49 ± 22 vs 50 ± 32 vs 35.5 ± 30 mL/min; P < .05). Relative risk of 10-year graft loss for the immunologic group was 2.8 (95% confidence interval, 1.6-4.9). Recurrence rate was 12% in the immunologic group versus 1% and 0% in the other diseases and remaining groups (P < .05). The relative risk of 10-year graft loss for patients with recurrence was 2.7 (95% confidence interval, 1.2-6.3). Ten-year graft loss rates for patients with biopsy-proven acute rejection, chronic allograft nephropathy, and recurrent glomerulonephritis were 30%, 23%, and 42% (P < .05). For those with biopsy-proven recurrent glomerulonephritis, 10-year estimated glomerular filtration rate was significantly lower than for those with biopsy-proven acute rejection or chronic allograft nephropathy (14 ± 6 vs 18 ± 7 vs 30 ± 10 mL/min; P < .05). Kidney transplant recipients with immunologically mediated kidney diseases have inferior long-term allograft survival and function versus patients with other causes of renal failure. Recurrence represents the strongest risk factor for premature loss of function and transplant failure.

Randomized Controlled Trial of Mineralocorticoid Receptor Blockade in Children with Chronic Kidney Allograft Nephropathy.

We showed that mineralocorticoid receptor blockade (MRB) prevented acute and chronic cyclosporine nephropathy (CsA-Nx) in the rat. The aim of this translational study was to investigate the effect of long-term eplerenone administration on renal allograft function in children with biopsy-proven chronic allograft nephropathy (CAN). Renal transplant children <18 years, biopsy-proven CAN, and a GFR>40 ml/min per 1.73 m2 were included. Patients with BK virus active nephritis, recurrence of renal disease, GFR decline in previous 3 months, or treated with calcium antagonists or antifungal drugs were excluded. They were randomized to receive placebo (n=10) or eplerenone 25 mg/d for 24 months (n=13). Visits were scheduled at baseline, 6, 12, and 24 months. At each period, a complete clinical examination was performed and blood and urine samples were taken. Urine creatinine, 8-hydroxylated-guanosine, heat shock protein 72 (HSP72), and kidney injury molecule (KIM-1) levels were also assessed. In kidney biopsy samples, the tubulo-interstitial area affected by fibrosis (TIF) and glomerulosclerosis were measured at baseline and after 24 months. The baseline eGFR was 80±6 in the placebo and 86±6 ml/min per 1.73 m2 in the eplerenone group; at 24 months it was 66±8 and 81±7 ml/min per 1.73 m2, respectively (P=0.33; 95% confidence intervals, -18 to 33 at baseline, and -11 to 40 after 24 months). The albumin-to-creatinine ratio was 110±74 in the placebo, and 265±140 mg/g in the eplerenone group; and after 24 months it was 276±140 and 228±88 mg/g, respectively (P=0.15; 95% confidence intervals, -283 to 593, and -485 to 391, respectively). In addition, the placebo exhibited a greater TIF, glomerulosclerosis, and urinary HSP72 compared with the eplerenone group. Although this study was underpowered to provide definitive evidence that long-term eplerenone administration attenuates the progression of CAN in pediatric transplant patients, it encourages testing the potential benefit of MRB in this pediatric population.

Noninvasive diagnostic and predictive value in renal transplant recipients with acute rejection by measurement of urine Fractalkine

Objective: To investigate the relationship between early-stage renal acute rejection(AR) and the level of Fractalkine in urine, explore the diagnostic and noninvasive monitoring value in early stage after transplantation by measurement of urine Fractalkine. Methods: Urine samples were examined from renal transplant patients between January 2006 and October 2009. A total of 155 patients were enrolled, including 49 with biopsy-proved AR, 58 patients with stable renal function and no abnormal histological findings, 10 patients with subclinical rejection in protocol biopsy, 9 patients with biopsy-proven acute tubular necrosis and 29 patients with biopsy-proven chronic allograft nephropathy. Additionally, urine samples were also collected from 40 healthy controls. Fractalkine was measured in urine samples using a commercial human Fractalkine enzyme-linked immunosorbent assay (ELISA) kit. Immunohistochemistry for Fractalkine expression was performed on biopsies from renal transplant patients with AR and non-AR. Results: Forty-nine patients with AR excreted urinary Fractalkine at a significantly higher level than levels in patients with stable renal function and healthy controls[(429.1±56.1)vs (94.6±8.4), (84.5±8.9)ng/mmol creatine, both P<0.001]. Patients with AR excreted urinary Fractalkine at a significantly higher level than levels in patients with acute tubular necrosis and chronic allograft nephropathy[(429.1±56.1)vs(133.0±9.8), (183.0±18.9)ng/mmol creatine, both P<0.001]. Receiver operating characteristic(ROC)curve was constructed to determine the discriminatory power of Fractalkine levels for diagnosis of AR. The area under ROC curve was 0.920(95% CI: 0.875-0.969, P<0.001), which showed that Fractalkine was a suitable marker for the diagnosis of AR. At a cut-off point of 157.5 ng/mmol creatinine, the sensitivity was 83.7% and the specificity was 84.5% (P<0.001). The dynamic level of urinary Fractalkine in AR patients within 3 weeks after transplantation fluctuated above 300 ng/mmol creatine, which is remarkably higher than patients with stable renal function (below 200 ng/mmol creatinine). Conclusions: As a noninvasive monitoring method, Fractalkine in urine may be a new approach for detection of AR as well as useful to predict response to antirejection therapy. It has good sensitivity and specificity. Besides, measurement of Fractalkine in urine is a simple, inexpensive method for the routine clinical monitoring after kidney transplantation.

Rapamycin induces ILT3highILT4high dendritic cells promoting a new immunoregulatory pathway

ILT3(high)ILT4(high) dendritic cells (DCs) may cause anergy in CD4(+)CD45RO(+)CD25(+) T cells transforming them into regulatory T cells (Tregs). Here, we tested whether chronic exposure to rapamycin may modulate this immunoregulatory pathway in renal transplant recipients. Forty renal transplant patients with biopsy-proven chronic allograft nephropathy and receiving calcineurin inhibitors were randomly assigned to either calcineurin inhibitor dose reduction or withdrawal with rapamycin introduction. At conversion and 2 years thereafter, we measured the rapamycin effects on circulating DCs (BDCA1/BDCA2 and ILT3/ILT4 expression), CD4(+)/CD25(high)/Foxp3(+) Tregs, CD8(+)/CD28(-) T cells, and the Th1/Th2 balance in graft biopsies. In rapamycin-treated patients, peripheral BDCA2(+) cells were significantly increased along with ILT3/ILT4(+) DCs. The number of circulating CD4(+)/CD25(high)/Foxp3(+)/CTLA4(+) Tregs, CD8(+)CD28(-) T cells, and HLA-G serum levels were higher in the rapamycin-treated group. The number of ILT3/ILT4(+)BDCA2(+) DC was directly and significantly correlated with circulating Tregs and CD8(+)CD28(-) T cells. ILT3/ILT4 expression was increased in kidney biopsies at the end of the study period along with a significant bias toward a Th2 response within the graft only in the rapamycin-treated patients. Thus, rapamycin induces the upregulation of ILT3 and ILT4 on the DC surface, and this effect is associated with an increase in the number of Tregs and expansion of the CD8(+)CD28(-) T cell population. This suggests that mTOR inhibition may promote a novel immunoregulatory pathway.

The Impact of ICAM1 and VCAM1 Gene Polymorphisms on Chronic Allograft Nephropathy and Transplanted Kidney Function

ICAM-1 and VCAM-1 adhesion molecules play important roles in the immune response and emergence of chronic allograft nephropathy (CAN). The several polymorphisms of ICAM1 and VCAM1 genes are associated with changes in molecular expression therefore affecting allograft function and immune responses after kidney transplantation. The aim of this study was to examine the impact of polymorphisms in ICAM1 and VCAM1 genes on biopsy-proven CAN and renal allograft function. The 270 Caucasian renal transplant recipients (166 men and 104 women) were genotyped for the rs5498 ICAM1 and rs1041163 and rs3170794 VCAM1 gene polymorphisms using real-time polymerase chain reaction. There was no correlation between polymorphisms and CAN. Creatinine concentrations in the first month after transplantation differed between the rs5498 ICAM1 genotypes (P = .095), being higher for GG carriers (AA + AG vs GG, P =.07) albeit not with statistical significance. Creatinine concentrations at 12, 24, and 36 months after transplantation differed significantly among rs5498 ICAM1 genotypes (P = .0046, P =.016, and P = .02) and were higher among GG carriers (AA + AG vs GG, P = .001, P = .004, and P = .006). Rs5498 ICAM1 GG genotype and receipient male gender were independent factors associated with higher creatinine concentrations. These results suggest that the rs5498 ICAM1 GG genotype may be associated with long-term allograft function.

Chronic Allograft Nephropathy - an Indian Study

Introduction: Chronic allograft nephropathy(CAN) is a major cause of late graft loss. Multiple factors have been implicated in the pathogenesis of CAN thus making the treatment of this entity equally difficult. Recent evidence has suggested involvement of Aldosterone in progression of Renal fibrosis. Hence this study was carried out for Aldactone (Spironolactone) as a novel form of therapy. Material and methods: A total of 72 patients during the study period from Aug 2004 to May 2011 with biopsy proven Chronic Allograft Nephropathy were randomized to receive Aldactone(Spironolactone) -(group A) & placebo-(group B) in addition to immunosuppressive & other medication. Group A received 25 mg of Aldactone. Investigations in the form of biochemical parameters including serum creatinine, proteinuria, GFR, C-reactive protein were studied in both the groups at the beginning and after 6 months and yearly thereafter. Follow up allograft biopsy could not be done in all the cases because of various reasons. The patients were followed up (minimum 1 year and maximum 6 years) on continued treatment from Aug 2004 to May2011. Results: Serum creatinine remained stable in Group A patients(p=0.020). GFR as measured with DTPA renal allograft scintigraphy showed a significant improvement (p=0.003) as compared to Group B patients. Changes in GFR correlated positively with decline in proteinuria & albuminuria (p=0.04) in Group A patients. The graft function progressively deteriorated in Group B patients (p=0.04). There was no significant hyperkalemia noted in thegroup A patients. There was no significant correlation of CRP levels with level of GFR(p=0.65), noted. The base line characterstics of both the groups were similar. Conclusions: The present study reveals benefit of using Aldactone (Spironolactone) in patients having Chronic Allograft Nephropathy resulting in significant improvement of graft function. It was well tolerated without any significant hyperkalemia.It is a novel, easily acceptable & cost effective form of therapy for CAN. This is the first Double blind, placebo controlled, randomized, prospective study using Aldactone for CAN from India & is a part of ongoing study.

Sirolimus for the Treatment of Kaposi Sarcoma After Renal Transplantation: A Series of 10 Cases

The incidence of Kaposi sarcoma (KS) has substantially increased among immunocompromised patients, suggesting a role for immunosuppressive drugs. The aim of this study was to evaluate the incidence, features, and outcome of KS among 307 kidney transplantation patients at our center between January 1994 and June 2010. During the study period, the 10 patients who developed KS (3.25%) showed a mean age at transplantation of 35.8 ± 8.7 years (range, 22 to 49 years). The mean interval between transplantation and occurrence of KS was 24.7 ± 21.36 months (range, 6 to 64 months). The mean time of antithymocyte globulin induction was 9.5 days (range, 6 to 13 days). KS was restricted to the skin in 7 cases, among which, one presented with associated Hodgkin lymphoma. Visceral involvement (one lung and one colon) was observed in two cases. One patient presented with a gastric KS without skin lesions. Immunosuppressive treatment was reduced, then withdrawn in three cases, resulting in regression of KS a few weeks later, but with graft loss requiring hemodialysis at 1, 3 and 4 months. Among the remaining 7 cases, we stopped mycophenalate mofetil (MMF) and switched from calcineurin inhibitors to sirolimus. Allograft function remained stable after the switch. Only one patient who already had allograft dysfunction due to biopsy-proven chronic allograft nephropathy. Deteriorated progressively, undergoing hemodialysis at 2 years after KS diagnosis. In conclusion, we observed a relatively high incidence of KS among our cases. The introduction of sirolimus resulted in complete regression of KS lesions with preserved graft function.

Outcome of Kidney Transplantation Following End-Stage Renal Disease Due to Reflux Nephropathy

Background Reflux nephropathy (RN) has an important place among the etiologies of end-stage renal disease (ESRD). In this retrospective study we sought to analyze posttransplantation complications among renal transplant recipients whose primary disease was RN. Methods Seven hundred forty-five patients who underwent transplantation in our institution between 1983 and 2006 were included in the study. The outcomes of patients with RN (Group 1) were compared with a control group (Group 2) that consisted of age-matched, nondiabetic patients whose primary disease was chronic glomerulonephritis or unknown etiologies. Results Group 1 consisted of 52 patients, including 20 males with a mean overall age of 25 years. Group 2 included 47 patients, including 21 males with a mean age of 27 years. There was no significant difference with regard to age, gender, donor type, donor age, modality of hemodialysis, or HLA match between the 2 groups. Group 1 graft survival rates in the first and fifth years were 95% and 90%, respectively, and in Group 2 they were 86% and 70%, respectively ( P = .302 and P = .072, respectively). There was no significant difference with respect to follow-up duration, hospital stay, or incidence of biopsy-proven or clinically suspected acute rejection episodes between the groups. During the 6-year follow-up, the incidence of biopsy-proven chronic allograft nephropathy was the same in both groups. One patient in Group 1 and 2 in Group 2 died of cardiovascular issues; 1 Group 2 patient died of infection. The frequency of urinary tract infection in Group 1 was greater than that of Group 2 (40% vs, 23%; P = NS). Conclusion Despite the higher incidence of urinary tract infections, there was no significant difference in posttransplantation complications or patient and graft survival rates between RN patients compared with the control group.

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.

Immunohistochemical characterization of glomerular and tubulointerstitial infiltrates in renal transplant patients with chronic allograft dysfunction

The term chronic allograft nephropathy (CAN) was deleted in the Eighth Banff Classification and two new categories were introduced: chronic T-cell-mediated rejection (CTMR) and chronic active humoral rejection (CAHR). The aim of this study was to revise our CAN cases diagnosed in the last 4 years, analyse allograft survival rates and identify types of infiltrating cells in the different settings. Seventy-nine patients with biopsy-proven CAN were examined and classified into four groups according to the Banff 2005 criteria: CTMR, CAHR, chronic calcineurin inhibitor toxicity (CNITOX) and interstitial fibrosis and tubular atrophy not otherwise specified (NOS). CD4, CD8, CD20, CD68, CD103, Foxp3 and IL-17 protein expression and C4d deposits were investigated. We diagnosed 20 CTMR, 13 CAHR, 28 CNITOX, and 18 NOS. Death-censored graft survival at 4 years from renal biopsy was worse in CAHR compared with the other types of chronic injury. Glomerular CD8(+) cells were increased in CTMR vs CNITOX and NOS. Interstitial CD4(+) and CD8(+) cells were increased in CTMR vs CNITOX. CD68(+) cells in glomerular and peritubular capillaries were higher in CAHR vs CNITOX, CTMR and NOS. CD103(+) cells were higher in cases with tubulitis than in those without. T regulatory and T helper 17 cells were rarely observed in the different settings. Graft survival was worse in patients with CAHR. The presence of any grade transplant glomerulopathy and chronic allograft vasculopathy are poorer prognostic factors. Infiltrating CD8(+), CD103(+) and CD4(+) cells may help to differentiate CTMR from other types of chronic injury, thus improving diagnostic/prognostic features of biopsy in patients with chronic allograft dysfunction.

Prediction of Chronic Allograft Nephropathy Using Classification Trees

Introduction For its intrinsic potential to mine causal relations, machine learning techniques are useful to identify new risk indicators. In this work, we have shown two classification trees to predict chronic allograft nephropathy (CAN), through an evaluation of routine blood and urine tests. Methods We retrospectively analyzed 80 renal transplant patients with 60-month follow-up (mean = 55.20 ± 12.74) including 52 males and 28 females of overall average age of 41.65 ± 12.52 years. The primary endpoint was biopsy-proven CAN within 5 years from transplantation ( n = 16). Exclusion criteria were multiorgan transplantations, patients aged less than 18 years, graft failure, or patient death in the first 6 months posttransplantation. Classification trees based on the C 4.8 algorithm were used to predict CAN development starting from patient features at transplantation and biochemical test at 6-month follow-up. Model performance was showed as sensitivity (S), false-positive rate (FPR), and area under the receiver operating characteristic curve (AUC). Results The two class of patients (no CAN versus CAN) showed significant differences in serum creatinine, estimated Glomerular Filtration Rate with Modification of Diet in Renal Disease study formula (MDRD), serum hemoglobin, hematocrit, blood urea nitrogen, and 24-hour urine protein excretion. Among the 23 evaluated variables, the first model selected six predictors of CAN, showing S = 62.5%, TFP = 7.2%, and AUC = 0.847 (confidence interval [CI] 0.749–0.945). The second model selected four variables, showing S = 81.3%, TFP = 25%, and AUC = 0.824 (CI 0.713–0.934). Conclusions Identification models have predicted the onset of multifactorial, complex pathology, like CAN. The use of classification trees represent a valid alternative to traditional statistical models, especially for the evaluation of interactions of risk factors.

Sirolimus-based calcineurin inhibitor withdrawal immunosuppressive regimen in kidney transplantation: a single center experience

This observational study was conducted to evaluate the safety and efficacy of the conversion from calcineurin inhibitors (CNIs) to sirolimus (SRL)-based immunosuppressive therapy in kidney transplantation. Sixty-four kidney recipients of mean age 38.3 +/- 14.6 years were converted to SRL. The main reasons for conversion were elective in 45 (70.3%) and biopsy-proven chronic allograft nephropathy in 11 (17.2%). The primary CNI used was cyclosporine A in 51 patients. Mean time to conversion was 50.5 months. After conversion, 61 patients received mycophenolate mofetil. We evaluated the impact of conversion on renal function for 5 years post-conversion. The overall mean follow-up time was 72.8 months. The analysis showed significant improvement in renal function at month 3 post-conversion (P < 0.05) with stabilization thereafter. Lipid parameters and blood sugar levels were similar pre- and post-conversion. Abnormal liver function test was transient in 12.8%. Reasons for SRL discontinuation were nephrotic range proteinuria in two patients and mouth ulceration in one. We compared patients with serum creatinine <140 micromol/l and those with serum creatinine > or = 140 micromol/l, and found that serum creatinine was an independent risk factor for chronic allograft dysfunction (P = 0.02). Graft loss occurred in three patients because of cardiovascular death in two and an acute rejection episode in one. We concluded that conversion from CNIs to SRL is an option and of benefit without significant acute rejection episodes or chronic allograft dysfunction especially in well-selected kidney transplant recipients with good graft function.

High within-patient variability in the clearance of tacrolimus is a risk factor for poor long-term outcome after kidney transplantation

We hypothesized that a high within-patient variability in clearance of tacrolimus and mycophenolate mofetil (MMF) would put patients at risk for periods of over- or underimmunosuppression and would thus lead to long-term chronic allograft nephropathy and graft loss after transplantation. From 297 patients transplanted between 1 January 2000 and 31 December 2004, the within-patient variability in clearance was calculated from tacrolimus whole-blood concentrations and mycophenolic acid (MPA) plasma concentrations drawn between 6 and 12 months post-transplantation. As a primary outcome, a composite end point consisting of graft loss, biopsy-proven chronic allograft nephropathy and 'doubling in plasma creatinine concentration in the period between t = 12 months post-transplantation and last follow-up' was used. In the study population of 297 patients, 34 patients reached the primary end point of graft failure. The within-patient variability in the clearance of tacrolimus and three other covariates are significant risk factors for reaching the composite end point of failure [P-values for intraindividual tacrolimus variability = 0.003, biopsy-proven acute rejection (BPAR) = 0.003, recipient age at transplantation = 0.005]. The mean tacrolimus concentration for controls [7.4 (+/- 2.9) ng/mL] and for failures [6.9 (+/- 2.5) ng/mL] was similar. Within-patient variability in the clearance of MPA was not related to reaching the composite end point of failure. This study shows a significant relationship between the high within-patient variability in the clearance of tacrolimus, but not for MPA, and long-term graft failure.

Conversion to Sirolimus for Chronic Allograft Nephropathy and Calcineurin Inhibitor Toxicity and the Adverse Effects of Sirolimus After Conversion

Chronic allograft nephropathy and calcineurin inhibitor toxicity may cause graft loss. After kidney transplantation, especially among those patients with chronic allograft nephropathy, sirolimus may be a good alternative to calcineurin inhibitors. Unlike calcineurin inhibitors, sirolimus is devoid of significant nephrotoxicity, but approximately 30% to 50% of patients on sirolimus therapy display mild or severe adverse effects. We sought to report our experience with sirolimus conversion among patients with chronic allograft nephropathy as well as the mild versus severe adverse effects that limit the drug's use. We analyzed the outcomes of 88 patients (64 men and 24 women) of overall mean age of 35.9 +/- 9.9 years (range, 21-59 years) who had undergone kidney transplantation. Immunosuppressive therapy had been converted from a calcineurin inhibitor to sirolimus because of biopsy-proven chronic allograft nephropathy, calcineurin inhibitor toxicity, or presence of malignancy. We excluded patients with prior acute rejection episodes. Subjects were divided into two groups with respect to their creatinine levels: Group A < 2 mg/dL and Group B >or= 2 mg/dL. After conversion to sirolimus, possible adverse effects of sirolimus were evaluated at the follow-up inset. Each patient underwent a physical examination, and estimation of serum lipid and electrolyte levels as well as hemoglobin concentration. At the time of conversion of the 88 renal transplant patients, their mean duration after grafting was 48 +/- 15 months (range, 4-296). The prior treatment consisted of a calcineurin inhibitor, prednisolone, and mycophenolate mofetil. After conversion, the calcineurin inhibitor was stopped and sirolimus was begun. The 48 Group 2 patients (34 men, 14 women) of overall mean posttransplant time of 22.7 +/- 14.6 months who underwent conversion displayed a mean serum creatinine increase to 3.2 +/- 1.4 mg/dL, including 17 subjects who underwent rejection. The 40 Group 1 patients (30 men, 10 women) with a mean overall posttransplant period of 67.6 +/- 49.9 months showed an fall in serum creatinine level to 1.4 +/- 0.5 mg/dL among only 3 patients. While 5/88 patients showed no increase in proteinuria (5.6%); 83 (94.4%) did experience it. Proteinuria increased from a mean of 192 +/- 316 to 449 +/- 422 mg/d. Only three patients displayed heavy proteinuria (>3 g/d); sirolimus was discontinued for this reason. Proteinuria was well controlled in the other patients with angiotensin-converting enzyme and/or angiotensin II receptor inhibitor agents. After sirolimus conversion, serum cholesterol levels increased from 187 +/- 42 to 214 +/- 52 mg/dL, and serum triglyceride levels increased from 161 +/- 61 to 194 +/- 102 mg/dL. All but four patients responded to statin therapy, with serum lipid levels falling to acceptable levels. Another four patients developed unilateral lower extremity edema with sirolimus discontinued for this reason. One patient displayed generalized arthralgia. Chronic allograft nephropathy or calcineurin inhibitor toxicity can lead to loss of graft kidney function. Calcineurin inhibitor toxicity can lead to chronic allograft nephropathy. Patients with a low baseline serum creatinine level who undergo sirolimus conversion showed stabilized kidney function. Late conversion of patients with a serum creatinine above 2 mg/dL face a risk of graft failure. Sirolimus displayed a limited incidence of serious adverse effects; mild or moderate adverse effects, such as hyperlipidemia and proteinuria, were easily controlled with countermeasure therapy.

Clinical Implications of Proteinuria in Renal Transplant Recipients Switching to Rapamycin for Chronic Allograft Dysfunction

There is evidence that treatment with m-TOR inhibitors can be beneficial in cases of chronic renal allograft dysfunction. However, some authors have reported poor outcomes of renal function if the switch to m-TOR inhibitors is made in the presence proteinuria > 0.8 g/d. The present study sought to provide a retrospective analysis of the clinical outcome of 63 kidney recipients diagnosed with chronic allograft dysfunction whose therapy was converted to rapamycin including 35 subjects with renal biopsy-proven chronic allograft nephropathy. At the time of conversion, patients were divided into three groups: group I (negative proteinuria), group II (proteinuria between 0.3 and 0.8 g/d), and group III (proteinuria > 0.8 g/d). On conversion, 21 recipients had no proteinuria (group I). After a follow-up of 24.6 +/- 12.8 months, they showed a significant improvement in renal function (previous MDRD4 = 39.9 +/- 11.5 mL/m/1.73 m(2), current MDRD4 50.3 +/- 13.3 mL/m/1.73 m(2), P < .05). Fifteen patients (71.4%) developed proteinuria, which was generally mild (0.8 +/- 0.7 g/d) and controlled with angiotensin-converting enzyme inhibitors (42.8%). In group II (n = 18), renal function clearly stabilized after a follow-up of 23.2 +/- 14.4 months (previous MDRD4 = 30 +/- 8.8 mL/m/1.73 m(2), current MDRD4 = 37 +/- 12.2 mL/m/1.73 m(2), NS), although there was a progressive deterioration of previous proteinuria levels (previous proteinuria 0.4 +/- 0.15 g/d, current proteinuria 1.2 +/- 2 g/d, P < .05), which was more frequent and intense in patients whose treatment with calcineurin inhibitors (CNIs) was suspended (with CNI 0.9 +/- 1.7 g/d, without CNI 1.6 +/- 2.2 g/d, P < .05). Group III (n = 24) had a greater degree of renal insufficiency and a worse outcome after 25.9 +/- 18 months of follow-up, with a frank and progressive deterioration in renal function (previous MDRD4 = 38 +/- 17 mL/m/1.73 m(2), current MDRD4 = 32.5 +/- 19.2 mL/m/1.73 m(2), P < .05) and proteinuria (previous proteinuria = 1.5 +/- 0.7 g/d, current proteinuria = 2.5 +/- 2.2 g/d, P < .05) after conversion. Again, the deterioration in proteinuria was more intense in the patients whose previous CNIs were suspended (with CNI = 1.1 +/- 0.9 g/d, without CNI = 4.2 +/- 2.3 g/d, P < .05). In conclusion, for patients with chronic allograft dysfunction who do not present with proteinuria or whose proteinuria is less than 0.8 mg/d, switching to rapamycin is useful, since it clearly improves or stabilizes renal function, although there may be a discrete increase in proteinuria in the second case. However, among patients with proteinuria greater than 0.8 mg/d accompanied by a greater degree of renal insufficiency, conversion to rapamycin leads to deterioration of proteinuria levels and renal function. These data show that conversion to rapamycin in cases of chronic allograft dysfunction must be made early when there is no proteinuria or it is minimal, and that proteinuria is a predictor of the outcome of allograft function.

Synergistic effect of mycophenolate mofetil and angiotensin-converting enzyme inhibitor in patients with chronic allograft nephropathy

Experimental data and few clinical non-randomized studies have shown that inhibition of the renin-angiotensin system by angiotensin-converting enzyme (ACE) associated or not with the use of mycophenolate mofetil (MMF) could delay or even halt the progression of chronic allograft nephropathy (CAN). In this retrospective historical study, we investigated whether ACE inhibition (ACEI) associated or not with the use of MMF has the same effect in humans as in experimental studies and what factors are associated with a clinical response. A total of 160 transplant patients with biopsy-proven CAN were enrolled. Eighty-one of them were on ACE therapy (G1) and 80 on ACEI_free therapy (G2). Patients were further stratified for the use of MMF. G1 patients showed a marked decrease in proteinuria and stabilized serum creatinine with time. Five-year graft survival after CAN diagnosis was more frequent in G1 (86.9 vs 67.7%; P < 0.05). In patients on ACEI-free therapy, the use of MMF was associated with better graft survival. The use of ACEI therapy protected 79% of the patients against graft loss (OR = 0.079, 95%CI = 0.015-0.426; P = 0.003). ACEI and MMF or the use of MMF alone after CAN diagnosis conferred protection against graft loss. This finding is well correlated with experimental studies in which ACEI and MMF interrupt the progression of chronic allograft dysfunction and injury. The use of ACEI alone or in combination with MMF significantly reduced proteinuria and stabilized serum creatinine, consequently improving renal allograft survival.

Management of Chronic Allograft Nephropathy

Despite improving immunosuppressive protocols in renal transplantation, chronic allograft nephropathy (CAN) remains a major impediment to long-term graft survival. The optimal immunosuppressive regimen for a patient with CAN is unknown. The aim of this study is to evaluate the various immunosuppressive management strategies of biopsy-proven CAN and of chronic allograft dysfunction (CAD) (no biopsy). A systematic review of randomized trials (n = 12 trials with 635 patients) was conducted. Studies included patients who were >6 mo post-transplant. All patients were on a calcineurin inhibitor (CNI), most often cyclosporine, and were randomized to convert to mycophenolate mofetil (MMF), tacrolimus, or sirolimus (Rapa) or to add azathioprine, MMF or Rapa to their current regimen. Follow-up time was 6 to 36 mo. The outcome measures evaluated were renal function in 11 of 12 studies and repeat renal biopsy results in one study. The methodological quality scores of the trials were generally low, using the Jadad scale (median value 2/5). Results varied between studies but suggested that CNI withdrawal is safe and that conversion to MMF or Rapa may be beneficial. The incidence of adverse effects ranged from 0% to 68% between the studies, and medication withdrawal occurred in 0% to 24% of patients. The review did not result in a consensus regarding the management of CAN and CAD. Further studies are required to determine the best therapeutic option for patients with CAD and CAN.