Association of polymorphisms in leptin and adiponectin genes with long-term outcomes in renal transplant recipients.

The effect of polymorphims in leptin and adiponectin genes on long-term outcomes of renal transplantation is unknown. In 349 renal transplant recipients (RTR), we aimed to determine associations between five SNPs in the leptin receptor (LEPR) and adiponectin (ADIPOQ) genes and these outcomes. Follow-up time ranged from 2 to 25 years (mean 10.29 ± 5.16 years). Two SNPs showed associations with long-term outcomes and their statistical significance greatly increased after 39 RTR with a history of cardiovascular events prior to transplantation were removed from the analysis. Adjusted odds ratios (OR) for LEPR rs1805094 and ADIPOQ rs1501299 and risk of graft loss were 0.35 (0.16-0.74) p = 0.006 and 2.37 (1.28-4.37) p = 0.006, respectively. The assessment of risk for global mortality revealed OR values of 0.20 (0.06-0.62), p = 0.005, and 2.43 (1.08-5.44), p = 0.031 for LEPR rs1805094 and ADIPOQ rs1501299, respectively. Our results show that polymorphism in genes involved in leptin and adiponectin function modify long-term outcomes in renal transplantation.

Iron deficiency in chronic kidney disease patients with diabetes mellitus.

BACKGROUNDS: Iron deficiency has been studied extensively in patients with chronic kidney disease on hemodialysis therapy. However, few studies looked at iron treatment in the non-dialysis chronic kidney disease population. METHODS: Five hundred and eighty patients were studied (247 were diabetic persons). Patients were divided into 4 groups: non-diabetic subjects without CKD, non-diabetic ones with GFR < 60 mL/min, diabetic persons without CKD and diabetic ones with GFR < 60 mL/min). Iron deficiency was diagnosed when serum ferritin level was <100 mg/dl. It was defined as diminished iron availability when ferritin was above 100 mg/dl and serum transferrin saturation (TSAT) was <20%. RESULTS: Anemia was more frequent in the diabetic CKD patients group (52.4%, p < 0.001). Anemia prevalence was also higher in all CKD patients as well as in diabetic patients compared with non-diabetic ones. Iron deficiency was more frequent in diabetic patients. Among CKD diabetic patients the prevalence of iron deficiency was higher than in non-diabetic CKD ones. Diminished iron availability prevalence was higher in non-diabetic patients. Logistic regression analysis showed that only sex and diabetes mellitus were independently associated with iron deficiency. CONCLUSIONS: Anemia was more common in diabetic CKD patients. Diabetes mellitus was independently associated with iron deficiency. Surprisingly, diminished iron availability was not more frequent in diabetic patients. The physio-pathological mechanisms that could explain these findings remain to be elucidated.

A comparison of cystatin C concentrations between patients with chronic interstitial nephritis and glomerular diseases.

AIMS: Cystatin C have shown to be a renal function parameter with higher sensitivity and specificity than serum creatinine. In tubular diseases, cystatin C degradation and an increase in its urinary elimination would be observed. We have tried to define if different kinds of kidney diseases may significantly affect the serum levels of cystatin C. DESIGN AND METHODS: Four hundred and four patients were studied: 249 men and 155 women, mean age was 64.3±10.1 years. Patients were classified into three groups: (1) Chronic interstitial nephropathy (CIN), (2) Glomerular nephropathy (GN), and (3) Non- CKD patients (control). GFR was estimated though the CKD-EPI equation and the Hoek formula. RESULTS: Median of serum creatinine levels was higher in CIN group than in GN and control groups. Median cystatin C levels were lower in control group compared with CIN and GN groups. No significant differences were found between CIN group and GN group. Nevertheless, the cystatin/creatinine rate was lower in the CIN group patients (0.94, 0.81-1.11) than in the GN group (1.02,I 0.85-1.25) as well as the control group (1.02, I 0.88-1.20). The cystatin C-estimated GFR/creatinine-estimated GFR rate was higher in the CIN group (1.18, 1.03-1.36) than in the GN patients (1.03, 0.88-1.21) and control ones (1.07, 0.88-1.20). CONCLUSIONS: Patients with CIN had lower serum levels of cystatin C defined as cystatin C/creatinine rate when they were compared with GN subject and control ones. In the same way, the index between cystatin C-estimated GFR and creatinine-estimated GFR was higher in CIN patients.

Anemia as very late-onset cytomegalovirus disease after kidney transplantation.

Very late-onset cytomegalovirus (CMV) disease after solid organ transplantation is not associated with classic risk factors; therefore, it does not follow a pattern of predictable appearance. A high index of suspicion is necessary to make an accurate diagnosis. Anemia has multiple etiologies among kidney transplanted recipients, and CMV could be one of them. We report the case of a kidney recipient with anemia refractory to treatment which proved to be secondary to extremely late CMV digestive disease.

Mineral metabolism disorders, vertebral fractures and aortic calcifications in stable kidney transplant recipients: The role of gender (EMITRAL study).

BACKGROUND AND OBJECTIVES: The relationship between mineral metabolism disorders, bone fractures and vascular calcifications in kidney transplant recipients has not been established. METHOD: We performed a cross-sectional study in 727 stable recipients from 28 Spanish transplant clinics. Mineral metabolism parameters, the semi-quantification of vertebral fractures and abdominal aortic calcifications were determined centrally. RESULTS: Vitamin D deficiency (25OHD3<15ng/ml) was more common in female recipients at CKD-T stages I-III (29.6% vs 44.4%; p=0.003). The inverse and significant correlation between 25OHD3 and PTH was gender-specific and women exhibited a steeper slope than men (p=0.01). Vertebral fractures (VFx) with deformity grade ≥2 were observed in 15% of recipients. Factors related to VFx differed by gender; in males, age (OR 1.04; 95% CI 1.01-1.06) and CsA treatment (OR: 3.2; 95% CI: 1.6-6.3); in females, age (OR 1.07; 95% CI: 1.03-1.12) and PTH levels (OR per 100pg/ml increase: 1.27; 95% CI: 1.043-1.542). Abdominal aortic calcifications were common (67.2%) and related to classical risk factors but not to mineral metabolism parameters. CONCLUSIONS: Vitamin D deficiency is more common among female kidney transplant recipients at earlier CKD-T stages, and it contributes to secondary hyperparathyroidism. Prevalent vertebral fractures are only related to high serum PTH levels in female recipients.

Risk factors for post-transplant diabetes mellitus in renal transplant: Role of genetic variability in the CYP450-mediated arachidonic acid metabolism.

Arachidonic acid (AA) is metabolized by cytochrome P450 (CYP) enzymes to epoxyeicosatrienoic acids (EETs) and 20-hidroxyeicosatetraenoic acid (20-HETE), which play an important role both in renal transplant and diabetes mellitus (DM). We searched for associations between polymorphisms in this metabolic pathway and the risk of post-transplant diabetes mellitus (PTDM) in kidney recipients. One-hundred-sixty-four patients were genotyped for common SNPs in this route, namely CYP2C8*3, CYP2C8*4, CYP2C9*2, CYP2C9*3, CYP2J2*7, CYP4A11 F434S and CYP4F2 V433M. Demographic and clinical parameters were retrospectively collected at four time-points in the first year after grafting. Thirty-four patients (20.73%) developed PTDM, which was more prevalent among older patients [OR for older age = 1.06 (1.03-1.10), p < 0.001] and in those with higher body mass index (BMI) [OR for higher average BMI in the first year = 1.13 (1.04-1.23); p < 0.01]. Creatinine clearance [OR = 0.97 (0.95-0.99); p < 0.01] and exposure to tacrolimus [OR = 3.25 (1.15-9.19); p < 0.05] were also relevant for PTDM risk. With regard to genetic variants, logistic regression analysis controlling for significant demographic and clinical variables showed that the V433M polymorphism in CYP4F2, responsible for 20-HETE synthesis, was an independent risk factor for PTDM [OR = 3.94 (1.08-14.33); p < 0.05]. We have shown that a genetic variant in the CYP4F2 gene, the main gene implicated in 20-HETE synthesis, is associated with the risk for PTDM. Our findings suggest that genes in the metabolic pathways of AA may become good candidates in genetic association studies for PTDM.

A 3'-UTR Polymorphism in Soluble Epoxide Hydrolase Gene Is Associated with Acute Rejection in Renal Transplant Recipients.

BACKGROUND AND PURPOSE: Epoxyeicosatrienoic acids (EETs) are arachidonic acid metabolites that play a protective role against damaging processes that may occur after re-oxygenation of the graft. We aimed to investigate whether the presence of functional polymorphisms in the gene encoding soluble epoxy hydrolase (EPHX2), which metabolizes EETs to less active compounds, may play a role in the outcome of renal transplantation. METHODS: In a group of 259 Caucasian renal transplant recipients and 183 deceased donors, we determined the presence of three common EPHX2 SNPs, namely rs41507953 (K55R), rs751141 (R287Q) and rs1042032 A/G. Associations with parameters of graft function and the incidence of acute rejection were retrospectively investigated throughout the first year after grafting by logistic regression adjusting for clinical and demographic variables. RESULTS: Carriers of the rs1042032 GG genotype displayed significantly lower estimated glomerular filtration rate (eGFR) (38.15 ± 15.57 vs. 45.99 ± 16.05; p = 0.04) and higher serum creatinine values (1.57 ± 0.58 vs. 1.30 ± 0.47 g/dL; p=0.02) one year after grafting, compared to patients carrying the wildtype A-allele. The same GG genotype was also associated to increased risk of acute rejection. Interestingly, this association was observed for the genotype of both recipients [OR =6.34 (1.35-29.90); p = 0.015] and donors [OR = 5.53 (1.10-27.80); p=0.042]. A statistical model including both genotypes along with other meaningful demographic and clinical variables resulted in an increased significance for the association with the recipients' genotype [OR=8.28 (1.21-74.27); p=0.031]. CONCLUSIONS: Our results suggest that genetic variability in the EETs-metabolizing gene, EPHX2, may have a significant impact on the outcome of deceased-donor renal transplantation.

Polymorphisms in CYP-mediated arachidonic acid routes affect the outcome of renal transplantation.

BACKGROUND: Arachidonic acid (AA) is metabolized by cytochrome P450 (CYP) enzymes to vasoactive metabolites (mainly epoxyeicosatrienoic acids) which are known to play a protective role against damaging processes that may occur after re-oxygenation of the graft. We aimed to investigate whether the presence of functional polymorphisms along these metabolic routes may play a role in the outcome of renal transplantation. DESIGN: One-hundred and forty Caucasian renal transplant recipients and 137 donors were included. We determined the presence of seven common functional polymorphisms in the five genes governing the CYP-mediated AA metabolic pathway (CYP2C8, CYP2C9, CYP2J2, CYP4A11 and CYP4F2). Associations with parameters and events related to graft function and survival were retrospectively investigated throughout the first year after grafting. RESULTS: The CYP2J2*7 allele of the donor was significantly associated with higher risk for delayed graft function [OR = 4·40 (1·45-13·37), P < 0·01] and lower death-censored graft survival [107·90 (84·19-131·62) vs. 176·89 (166·47-187·32) months for CYP2J2*1/*1 grafts; log-rank P = 0·015]. In addition, patients whose donors carried the CYP4A11 434S variant of the F434S polymorphism displayed impaired creatinine clearance, with statistically significant differences vs. 434FF subjects throughout the whole period of study (P < 0·05, P < 0·01, P < 0·001 and P < 0·05 for 1 week, 1 month, 5 months and 1 year after grafting, respectively). CONCLUSIONS: Taken together, these results indicate that variability in the CYP450 genes involved in the synthesis of eicosanoids from AA may have a significant impact on graft function and survival in renal transplantation.

Long-term mTOR inhibitors administration evokes altered calcium homeostasis and platelet dysfunction in kidney transplant patients.

The use of the mammal target of rapamycin (mTOR) inhibitors has been consolidated as the therapy of election for preventing graft rejection in kidney transplant patients, despite their immunosuppressive activity is less strong than anti-calcineurin agents like tacrolimus and cyclosporine A. Furthermore, as mTOR is widely expressed, rapamycin (a macrolide antibiotic produced by Streptomyces hygroscopicus) is recommended in patients presenting neoplasia due to its antiproliferative actions. Hence, we have investigated whether rapamycin presents side effects in the physiology of other cell types different from leucocytes, such as platelets. Blood samples were drawn from healthy volunteers and kidney transplant patients long-term medicated with rapamycin: sirolimus and everolimus. Platelets were either loaded with fura-2 or directly stimulated, and immunoassayed or fixed with Laemmli's buffer to perform the subsequent analysis of platelet physiology. Our results indicate that rapamycin evokes a biphasic time-dependent alteration in calcium homeostasis and function in platelets from kidney transplant patients under rapamycin regime, as demonstrated by the reduction in granule secretion observed and subsequent impairment of platelet aggregation in these patients compared with healthy volunteers. Platelet count was also reduced in these patients, thus 41% of patients presented thrombocytopenia. All together our results show that long-term administration of rapamycin to kidney transplant patients evokes alteration in platelet function.

CYP2C8*3 polymorphism and donor age are associated with allograft dysfunction in kidney transplant recipients treated with calcineurin inhibitors.

Epoxieicosatrienoic acids (EETs) play a protective role against damaging processes in the kidney. We have assessed the effect of polymorphisms in EETs-producing enzymes (CYP2C8 and CYP2J2) and other proteins involved in calcineurin inhibitors (CNIs) disposition (CYP3A4, CYP3A5, and ABCB1) on graft function and clinical outcome in 166 renal transplant recipients treated with CNIs. Both CYP2C8*3 and donor age greater than 48 years were associated to a higher incidence of delayed graft function (DGF) [OR = 2.01 (1.1-4.1), P = .04 and 5.14 (2.4-10.9), P < .0001; respectively] and worse creatinine clearance 1 year after grafting (P < .05 and P < .001, respectively). In addition, carrying 4-6 variants in the 3 ABCB1 loci and older donor age were individually associated to higher incidence of calcineurin-inhibitor-induced nephrotoxicity [OR = 2.38 (1.1-5.4), P = .03 and OR = 1.03 (1.01-1.06), P = .038]. Regression analyses confirmed the relevant effect of both CYP2C8*3 and donor age on graft dysfunction. Carrying the 2C8*3 allele and having a donor older than 48 years was defined as a high-risk status and observed to be highly related to DGF [OR = 3.91 (1.46-10.48), P < .01] and worse creatinine clearance (P = .033). Our results show that genetic and clinical parameters can be combined to identify risk factors for allograft dysfunction in renal transplant recipients.

ABCB1 polymorphisms are associated with cyclosporine-induced nephrotoxicity and gingival hyperplasia in renal transplant recipients.

PURPOSE: There is a great deal of controversy regarding the clinical impact of genetic variants in patients receiving cyclosporine (CsA) as immunosuppressant therapy. We have investigated the effect of polymorphisms in the CYP3A and ABCB1 genes on CsA pharmacokinetics, acute rejection incidence and drug-related side effects in renal transplant recipients METHODS: The presence of CYP3A5*3, CYP3A4*1B and ABCB1 C1236T, G2677T/A and C3435T polymorphisms was assessed in 68 patients and retrospectively associated with pharmacokinetic and clinical parameters at 1 week and 1, 5 and 12 months after transplantation. RESULTS: Only minor associations were found between the tested polymorphisms and CsA pharmacokinetics. Most notably, CYP3A5 expressers showed lower blood trough levels than non-expressers in the first week after grafting (32.5 ± 14.7 vs. 55.1 ± 3.8 ng/ml per mg/day per kilogram). In terms of CsA-induced adverse effects, the incidence of nephrotoxicity was higher in carriers of the ABCB1 3435TT genotype and in those patients carrying four to six variants in the three ABCB1 loci [odds ratio (OR) 4.2, 95 % confidence interval (CI) 1.3-13.9, p = 0.02 and OR 3.6, 95 % CI 1.1-11.8, p = 0.05, respectively]. These subjects with four to six ABCB1 variants were also at higher risk for gingival hyperplasia (OR 3.29, 95 % CI 1.1-10.3, p = 0.04). Renal function and the incidence of neurotoxicity and of acute rejection did not vary across the different genotypes. CONCLUSIONS: ABCB1 polymorphisms may be helpful in predicting certain CsA-related side effects in renal transplant recipients. Our results also suggest that the mechanisms underlying these genetic associations are most likely independent of the drug's trough blood concentrations.

Hematocrit, urea and gender: the Hematocrit, Urea and GEnder formula for prognosing progressive renal failure in diabetic nephropathy.

OBJECTIVE: Diabetic nephropathy is a common cause of end stage renal disease. Notwithstanding, wide inter-individual variations in the speed of progression of diabetic nephropathy are frequent. We have used the score of the HUGE formula to predict progression of kidney disease in a group of diabetic nephropathy patients. DESIGN AND METHODS: The sample consisted of 84 type 2 diabetic patients. At treatment entry, the mean age was 62.1 ± 12.5 years and 59.5% were male. Blood pressure was measured at office at each visit. Serum creatinine, urea, hematocrit and 24h proteinuria were analyzed every 6 months. HUGE score was calculated from gender, urea and hematocrit. RESULTS: Mean HUGE score was 0.99 ± 3.88. Using as cut off point 1.5, those patients who had a score equal or higher (n=31) showed a bigger increase in serum creatinine after one year (41.8 ± 62.1%) than those subjects with score<1.5 (n=53) (18.7 ± 38.6%, p=0.041). 5 patients with low HUGE score reached end stage renal failure (9.4%) and 10 patients in the high HUGE score group (32.3, p=0.008). When logistic regression analysis was performed only a HUGE score higher than 1.5 (p=0.003) and proteinuria higher than 2g/day (p=0.041) were independently associated to CRF progression (creatinine increment>25%). CONCLUSIONS: In diabetic nephropathy patients the HUGE equation may be useful to detect the subjects prone to progressive renal failure. Wider samples will be needed to confirm this finding and, most important, its applicability to other kinds of nephropathy.

Impact of genetic polymorphisms on tacrolimus pharmacokinetics and the clinical outcome of renal transplantation.

We retrospectively examined the association of polymorphisms in the CYP3A, CYP2J2, CYP2C8, and ABCB1 genes with pharmacokinetic (PKs) and pharmacodynamic (PDs) parameters of tacrolimus in 103 renal transplant recipients for a period of 1 year. CYP3A5 expressers had lower predose concentrations (C(0) )/dose and higher dose requirements than nonexpressers throughout the study. Among CYP3A5*1 carriers, those also carrying the CYP3A4*1B allele showed the lowest C(0) /dose, as compared with CYP3A4*1/CYP3A5*3 carriers (54.28±26.45, 59.12±24.00, 62.43±41.12, and 57.01±17.34 vs. 112.37± 76.60, 123.21±59.57, 163.34±76.23, and 183.07±107.82 at 1 week, 1 month, 5 months, and 1 year after transplantation). In addition, CYP3A4*1B/CYP3A5*1 carriers showed significantly lower dose-corrected exposure than CYP3A4*1/CYP3A5*1 carriers 1 year after transplantation (57.01±17.34 vs. 100.09±24.78; P=0.016). Only the ABCB1 TGC (3435-2677-1236) haplotype showed a consistent association with PDs (nephrotoxicity; OR=4.73; CI: 1.3-16.7; P=0.02). Our findings indicate that the CYP3A4*1B-CYP3A5*1 haplotype may have a more profound impact in tacrolimus PKs than the CYP3A5*1 allele. This study does not support a critical role of the CYP450 or ABCB1 single nucleotide polymorphisms in the occurrence of toxicity or acute rejection in renal transplant recipients treated with tacrolimus.

Long-term graft function changes in kidney transplant recipients.

Background. Monitoring changes in glomerular filtration rate (GFR) is the recommended method for assessing the progression of kidney disease. The aim of this study was to assess the decline of graft function defined by the annualized change in GFR and the factors which affect it.Methods. Four thousand four hundred and eighty-eight patients, transplanted during the years 1990, 1994, 1998 and 2002 in 34 centres in Spain with allograft survival of at least 1 year, were included in the study. GFR was estimated using the four-variable equation of the Modification of Diet in Renal Diseases (MDRD) study. Linear mixed effects model was applied to determine the relation between the covariates and the annualized change in GFR after transplantation.Results. The average GFR at 12 months was 51.4 +/- 18.9 mL/min/1.73 m(2); most patients were in stage 3 of chronic kidney disease classification. The average patient slope, calculated in a linear model with varying-intercept and varying-slope without covariates, was -1.12 +/- 0.05 mL/min/year (slope +/- standard error). Some variables were related to both the 12-month GFR (intercept) and the slope: recipient gender, hepatitis C virus (HCV) status, estimated GFR (eGFR) at 3 months and proteinuria at 12 months. Some variables were only related to the slope of eGFR: time on dialysis, primary renal disease and immunosuppression. Others affected only the 12-month GFR: donor age, delayed graft function, acute rejection and systolic blood pressure at 12 months. Higher graft function at 3 months had a negative impact on the GFR slope. Cyclosporine-based immunosuppression had a less favourable effect on the rates of change in allograft function.Conclusions. There was a slow decline in GFR. Poor graft function was not associated with an increased rate of decline of allograft function. Immunosuppression with cyclosporine displayed the worst declining GFR rate.

Angiotensin-converting enzyme inhibitors versus angiotensin receptor blockers for diabetic nephropathy: a retrospective comparison.

INTRODUCTION: There are no adequate head-to-head comparisons of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) in type 2 diabetic patients in spite of some interesting attempts. Furthermore, there are no adequate studies about the effects of ACE inhibitors in type 2 diabetic patients, who are the great majority of diabetic individuals. This study has retrospectively compared the effects of ACE inhibitors and ARBs used to treat diabetic nephropathy in a group of type 2 diabetic subjects. DESIGN AND METHODS: Patients (n=154) were treated with ACE inhibitors (mean age 59.5+/-13.3 years, 52.6% were male). Eighty-five patients had been treated with ARBs from 1999 until now (mean age 62.6+/-10.9 years, 56.0% were male, differences not significant). Kaplan-Meier survival analysis was used to calculate survival before reaching end-stage renal disease (ESRD) (glomerular filtration < 15 ml/min, stage V of renal disease as defined by KDOQI clinical guidelines) or starting renal replacement therapy. Only patients treated for more than six months were included in the survival analysis. Comparison of survival was made at three, five and seven years after starting treatment. RESULTS: Pre-ESRD survival was 91.9% at three years, 81.6% at five years and 61.9% at seven years of follow-up for patients treated with ACE inhibitors. For patients treated with ARBs, pre-ESRD survival was 95.3% at three years, 82.1% at five years and 78.2% at seven years of follow-up (p=0.02, log-rank test). At 36 months, the comparative odds ratio for having started renal replacement therapy or reaching end-stage renal failure was 0.246 (95% confidence interval 0.114-0.531, p<0.001 for chi-square and likelihood ratio tests). The risk for the ARB cohort was 0.682 (95% confidence interval 0.578-0.804), meanwhile for ACE inhibitor patients it was 2.768 (95% confidence interval 1.481-5.172). CONCLUSIONS: The effects of ACE inhibitors and ARBs seem to be different, favouring the use of ARBs. These results may have been influenced by the different circumstances when each kind of drug was indicated, since ARBs were used with the specific recommendations for control of blood pressure in diabetic patients. An earlier referral of these patients may also have had some effect on these results. The need for a well-designed prospective study on type 2 diabetic patients with heavy proteinuria is warranted.

[Impact of advanced kidney disease on transplanted patients and their return to dialysis]. / Impacto de la enfermedad renal avanzada del trasplantado renal y su vuelta a diálisis.

Although long-term outcomes also improved, graft loss caused by chronic allograft nephropathy remains an important obstacle. This situation, together with the progressive increase in the number of renal transplant patients, means that the population of transplant patients readmitted to a dialysis program will be progressively greater. The mortality rate in patients starting dialysis after graft loss has been reported as variable, though higher than that observed in patients with a functioning graft and that observed in patients on dialysis treatment. However, it is not known how the management of chronic kidney disease patients in the transplant setting differs from that of patients with native kidney disease with a similar degree of renal dysfunction. Many patients in stages 4T-5T have chronic kidney disease related complications that fall below targets established for nontransplant chronic kidney disease patients. A limited number of studies have evaluated patients returning to dialysis after graft failure and the different guidelines in the setting of transplantation have not analyzed this crucial aspect so important. Parting from this premise, a working group of the Spanish Society of Nephrology in the field of kidney transplantation and dialysis has reviewed in-depth each of the clinical aspects of care of patients with kidney transplant failure coming back to dialysis and drawn up a consensus document in order to optimize the management of this condition.

[Progression factors in chronic kidney disease. Immunological mechanisms]. / Factores de progresión de la enfermedad renal crónica. Mecanismos inmunológicos.

In kidney transplantation patient and graft survival are excellent in short-term and mid-term, although they remain stable in the long-term.The incidence of acute rejection has decreased to 8%-15%.Despite marked progress in understanding immunologic mechanisms involved in transplantation, new tools are required to detect early changes that could affect allograft function allowing us to anticipate histological lesions and providing a more accurate use of immunosuppressive drugs.From an immunologic point of view, efforts should be directed to avoid interstitial fibrosis and tubular atrophy (IF/TA) and to prevent antibody-mediated rejection.The most frequent cause of late graft loss is IF/TA.Improvement in kidney transplant results have been achieved with calcineurin inhibitors -CNI- (cyclosporin and tacrolimus), antiproliferative agents (mycophenolate mofetil and enteric-coated mycophenolic acid) and T-cell depleting antibodies. The combination of tacrolimus + mycophenolate mofetil + steroids has been the gold standard in kidney transplant immunosuppression. An adequate balance in order to maintain the appropriate immune response is essential to the patient to avoid infections or neoplasias as well to prevent rejection.In renal transplant recipients with chronic kidney disease stage 4T in which renal function remains stable,immuno-suppressive drugs can be continued at the usual maintenance doses. As GFR declines, CNI and antiproliferative drugs should be reduced.

[Definitive removal of immunosuppressors]. / Retirada definitiva de la inmunosupresión.

There's no controlled and prospective studies which show the safest and most effective way to reduce or suspend immunosuppression drugs dosage, and only few groups have published their own protocols. There are reasons to discontinue the immunosuppression therapy; the high incidence of infections is the most important. However, a fast withdrawal is not free of problems, like are residual renal function decline and graft intolerance signs, which could take to nephrectomy, a high risk intervention. Most recommended guidelines for immunosuppression use are: - Antimetabolites immediately cancellation and corticoesteroids slow drop (level C recommendation). - Calcineurin inhibitors could be discontinued but if residual renal function is still significant, it is recommended to maintain a low dosage over three to six months; then, withdrawal may be done slowly (level C recommendation). We have not found information supporting the immunosuppression use beyond six months.