Assessment of Kidney Graft Function Evolution Measured by Creatinine and Cystatin C.

INTRODUCTION: The 2013 Kidney Disease Outcomes Quality Initiative Clinical Practice Guideline suggests measuring cystatin C (sCys) in adults with glomerular filtration rate (GFR) based on creatinine (sCr) between 45 and 59 mL/min/1.73 m2 if confirmation of chronic kidney disease (CKD) is required. There is not enough evidence to recommend the use of sCys or sCr to estimate GFR in kidney transplant recipients. OBJECTIVES: Our aims were to describe the evolution of sCr, sCys, and GFR in a group of kidney transplant patients and to determine their association with some markers of morbidity at 1 year. METHODS: A total of 54 patients were included. Analytical and clinical data were recorded. Renal function was analyzed using the CKD Epidemiology Collaboration (EPI) sCr equation and CKD-EPI sCys equation. RESULTS: sCys-estimated GFR was higher than estimated from sCr by CKD-EPI. The values of sCys have more variability than those of sCr. The agreement between the stages of CKD by sCr or sCys-estimated GFR measured by Cohen's kappa coefficient was only fair. One-year CKD-associated variables correlated differently with sCr and sCys-estimated GFR. Hemoglobin, uric acid, calcium, and phosphorus related to sCr-estimated GFR, whereas serum albumin was associated with sCys-estimated GFR. CONCLUSIONS: sCys values have a higher variability than sCr in kidney transplant recipients. sCys- or sCr-based GFRs have a nonsimilar behavior in these patients with weak agreement to stratify CKD stages and a different relationship to CKD-related comorbid conditions.

High regulatory T-cell levels at 1 year posttransplantation predict long-term graft survival among kidney transplant recipients.

INTRODUCTION: Regulatory T cells (Tregs) have gained an important role in mechanisms of tolerance and protection against the transplant rejection. However, only limited retrospective data have shown a relationship between peripheral blood Tregs and better long-term graft survival. The purpose of the present study was to investigate prospectively circulating Treg levels and their association with long-term graft survival. METHODS: Ninety kidney transplant recipients underwent measurement of Treg levels in peripheral blood before as well as at 6 months and 1 year posttransplantation. Receiver operating characteristic curves were applied to test the sensitivity and specificity of Treg levels to predict prognosis. RESULTS: Treg levels before transplantation correlated with those at 6 months and 12 months posttransplantation (P < .001 and P = .002, respectively). Patients who maintained high Treg levels (above 70th percentile) at both 6 and 12 months displayed better long-term graft survival at 4 and 5 years follow-up (P = .04 and P = .043 respectively). There was no effect on patient survival. CONCLUSION: Detection of high levels of peripheral blood Tregs was associated with better graft survival possibly using as a potential marker of prognosis.

Relation of urinary gene expression of epithelial-mesenchymal transition markers with initial events and 1-year kidney graft function.

INTRODUCTION: Renal dysfunction due to acute rejection (AR), acute tubular necrosis, or calcineurin inhibitors toxicity is related to development of interstitial fibrosis/tubular atrophy (IF/TA) and graft survival. Determination of serum creatinine (sCr) displays poor sensitivity as a marker for early detection of graft dysfunction. Kidney biopsy is an accurate but invasive procedure for the diagnosis. The levels of urinary mRNA of genes that regulate epithelial-mesenchymal transition (EMT) can reflect early damage and detect the development of IF/TA. Repeated studies of these genes can provide noninvasive information about the evolution of the graft, facilitating early diagnosis and treatment. OBJECTIVE: To analyze the relationships between early and 1-year graft evolution in relation to gene expression of EMT biomarkers. METHODS: Seventy-one kidney transplant recipients were monitored during 1 year recording analytical, clinical, and histological (if available) data. We determined RNA gene expression of EMT, angiotensinogen, E-cadherin, N-cadherin, transforming growth factor (TGF) beta and bone morphogenetic patients 7 (BMP7). RESULTS: At 3 months, angiotensinogen (mean [standard deviation]), (2.42 [.66] versus 8.58 [3.24]; P = .017) and N-cadherin (0.59 [0.26] versus 3.15 [1.35]; P = .016) discriminate a good evolution from AR episodes BMP-7 discriminated a good evolution versus AR (0.72 [0.29] versus 4.53 [2.23]; P = .006) and delayed graft function versus AR (1.14 [0.79] versus 4.53 [2.23]; P = .049). After 1 year, the ratio TGF-beta/BMP7 discriminated patients with an sCr > 1.5 mg/dL (6614.6 [1063.6] versus 3378.7 [1019]; P = .034). There was a positive correlation between urinary and tissue TGF-beta [r = 59; P = .003]. CONCLUSION: The expression of studied genes reverting EMT at 3 months postransplantation showed differences in initial graft evolution. At 1 year, the TGF-beta/BMP7 ratio suggested activation of EMT, possible early marker of renal dysfunction.

New-onset diabetes after transplantation: drug-related risk factors.

INTRODUCTION: New-onset diabetes after transplantation (NODAT), an important complication of renal transplantation leads to reduced graft function and increased patient morbidity and mortality. Because of its high incidence and immense impact on clinical outcomes, prevention of NODAT is highly desirable. Several modifiable and nonmodifiable risk factors for NODAT have been described. The aim of this study was to analyze the influence of various drugs on the development of NODAT during the first year. METHODS: A retrospective analysis was performed on 303 adult kidney transplant recipients free of previously known diabetes. NODAT was defined as a fasting plasma glucose level ≥ 126 mg/dL confirmed by repeat testing on a different day. We excluded patients with transiently elevated fasting plasma glucose during the first 3 months. RESULTS: NODAT was diagnosed in 37 recipients (12.2%). Univariate analysis identified several variables related to NODAT: recipient age (P < .001), body mass index (P < .001), donor age (P = .005), family history of diabetes (P < .001), statin use (P = .005), diuretic use (P = .040) and tacrolimus therapy (P = .029). After multivariate analysis, recipient age (relative risk [RR] = 1.060, 95% confidence interval [CI] 1.019- 1.102, P = .004), family history of diabetes (RR = 3.562, 95% CI 1.574-8.058, P = .002), smoking habit (RR 2.514, 95% CI 1.118-5.655, P = .026) and diuretic use (RR = 2.496, 95% CI 1.087-5.733, P = .031) were independently associated with NODAT development. CONCLUSIONS: In our population of kidney transplant recipients, the main nonmodifiable risk factors for NODAT were recipient age and a family history of diabetes. Diuretic use was a modifiable risk factor associated with the development of NODAT. To reduce NODAT incidence, it is necessary to consider not only immunosuppressive therapy, but also concomitant drugs such as diuretics.

Prediction of delayed graft function by means of a novel web-based calculator: a single-center experience.

Renal failure persisting after renal transplant is known as delayed graft function (DGF). DGF predisposes the graft to acute rejection and increases the risk of graft loss. In 2010, Irish et al. developed a new model designed to predict DGF risk. This model was used to program a web-based DGF risk calculator, which can be accessed via http://www.transplantcalculator.com . The predictive performance of this score has not been tested in a different population. We analyzed 342 deceased-donor adult renal transplants performed in our hospital. Individual and population DGF risk was assessed using the web-based calculator. The area under the ROC curve to predict DGF was 0.710 (95% CI 0.653-0.767, p < 0.001). The "goodness-of-fit" test demonstrates that the DGF risk was well calibrated (p = 0.309). Graft survival was significantly better for patients with a lower DGF risk (5-year survival 71.1% vs. 60.1%, log rank p = 0.036). The model performed well with good discrimination ability and good calibration to predict DGF in a single transplant center. Using the web-based DGF calculator, we can predict the risk of developing DGF with a moderate to high degree of certainty only by using information available at the time of transplantation.

Early prediction of new-onset diabetes mellitus by fifth-day fasting plasma glucose, pulse pressure, and proteinuria.

Renal transplant recipients are at high risk of cardiovascular disease (CVD). New-onset diabetes mellitus after transplantation (NODAT) contributes to the risk of CVD, reducing graft and patient survival. To improve outcome of kidney transplant recipients, it is of great interest to identify those patients who will develop NODAT. The aim of our study was to explore the predictive value of fifth-day fasting plasma glucose (FPG), third-month proteinuria, and pulse pressure (PP) for NODAT development. We analyzed 282 non-previously-diabetic kidney transplants in our center. Fifth-day FPG, PP, and third-month 24-hour proteinuria were collected. NODAT was defined at month 12 according to the "consensus guidelines": symptoms of diabetes plus casual glucose concentrations ≥ 200 mg/dL or FPG ≥ 126 mg/dL. Some 46 patients (16.3%) developed NODAT at month 12. Fifth-day FPG (133 ± 35 vs 108 ± 16 mg/dL, P < .001) and PP (57 ± 17 vs 49 ± 15 mm Hg, P = .007) were significantly higher in patients at risk for NODAT, but there was no difference in third-month proteinuria (652 ± 959 vs 472 ± 1336 mg, P = .390). A multivariate regression model showed an increased risk for NODAT associated with recipient age, body mass index, smoking habit, and a fifth-day FPG ≥ 126 mg/dL (relative risk 4.784, 95% confidence interval 2.121-10.788, P = .0002). The negative predictive value of a fifth-day FPG ≥ 126 mg/dL for predicting 1-year NODAT was 89.4%. Fifth-day FPG was independently related to NODAT development. The detection of a fifth-day FPG ≥ 126 mg/dL increases the risk of suffering NODAT more than 4 times. Fifth-day FPG < 126 mg/dL allows us to identify a transplant population with a low risk (near 10%) for NODAT.

Quantitative assessment of serum free light chains in renal transplantation.

Plasma cell dyscrasias can cause renal disease. Sensitive methods have recently been introduced to quantify serum free light chains (sFLCs). Renal function may influence the variability of these methods, as shown in chronic kidney disease (CKD) patients, but this problem has not been widely addressed in renal transplant patients. Herein, we examined the association between polyclonal sFLC concentrations and renal function among a population of renal transplant patients. We studied 102 kidney allograft recipients and 53 CKD patients classified according to KDOQI (Kidney Disease Outcomes Quality Initiative) stages. None of them had been diagnosed with monoclonal gammopathy. sFLCs were quantified by nephelometry. Both serum κ and λ free light chain concentrations rose progressively through each stage of KDOQI among both transplant and nontransplant patients (P<.0001). In the former setting, sFLC concentrations significantly correlated, using a Spearman coefficient, with serum creatinine, and serum cystatin concentrations as well as estimated glomerular filtration rate: namely, 0.723, 0.797, and -0.711 for sκFLC and 0.705, 0.759, and -0.694 for sλFLC, respectively (P<.0001 in all cases). Spearman correlation coefficients in nontransplant patients were: 0.559, 0.848, and -0.766 for sκFLC and 0.702, 0.875, and -0.855 for sλFLC, respectively (P<.0001 in all cases). In conclusion, sFLCs must be interpreted cautiously due to their clear association with renal function. Therefore, renal transplantation did not produce changes that were different from those dependent on renal function.

Number of peripheral blood regulatory T cells and lymphocyte activation at 3 months after conversion to mTOR inhibitor therapy.

BACKGROUND: Mammalian target of rapamycin (mTOR) inhibitors are effective for induction and maintenance of regulatory T cells (Tregs). OBJECTIVE: To assess the effects of conversion from calcineurin inhibitors (CNIs) to mTOR on the number of circulating Tregs and lymphocyte activation. PATIENTS AND METHODS: In 18 renal transplant recipients receiving CNI therapy (cyclosporine in 9, and tacrolimus in 9), treatment was converted to mTOR inhibitors (everolimus in 14, and rapamycin in 4). Peripheral blood samples were obtained before and 3 months after conversion. The number of circulating Tregs was measured using flow cytometry, and defined as CD4+/CD25high/CD127low/CD27+/CD62L+/CD45RO+/Foxp3+. Lymphocyte activation was assessed indirectly according to production of intracellular adenosine triphosphate (iATP) on polyclonal activation using a phytohemaglutinin assay (Immuknow; Cylex, Inc, Columbia, Maryland). RESULTS: In 15 patients (83.3%), the absolute number of Tregs increased significantly (P=.001) after conversion (median, 16.35 cells/mm3; 95% confidence interval [CI], 13.97-21.94) vs 3 months after conversion (32.03 cells/mm3; 95% CI, 26.25-41.66). The iATP production decreased from 326 ng/mL (95% CI, 302-419) to 248 ng/mL (95% CI, 196-318; P=.02), and increased in 4 patients (22.22%). No significant correlation was demonstrated between Treg concentration and change in iATP production. No rejection episodes were reported during follow-up. CONCLUSIONS: Despite the small number of patients in whom therapy was converted from CNI inhibitors to mTOR inhibitors, the data suggest an increase in the absolute number of Tregs after conversion. In addition, the concentration of activated peripheral CD4+ T cells decreased to nearly that associated with risk of infection due to overimmunosuppression.

Kidney transplant recipients show an increase in the ratio of T-cell effector memory/central memory as compared to nontransplant recipients on the waiting list.

Studies of allotolerance in animal models do not usually consider the presence of preexisting memory T cells and activated immune status. However, humans are exposed throughout life to a multitude of external agents that enhance the immune memory. In this article, we consider the effect that a previous kidney transplant has on the number of regulatory T cells (Tregs), effector memory T cells (TEM), and central memory T cells (TCM). Sixty-three patients with end-stage renal disease were studied just before being transplanted (51 first transplants and 12 retransplants). The numbers of Tregs (CD4+ CD25highCD127lowCD27+CD62L+CD45RO+FOXP3+), TEM (CD3+CD45RO+CD62L+), and TCM (CD3+CD45RO+CD62L-) cell subsets were quantified in peripheral blood by flow cytometry. The absolute number of Tregs was slightly lower in patients with previous allografts (median, 95% confidence interval [CI]: 16.7 cells/mm3, 12-20.5) than in those who received their first transplants (median, 95% CI: 19.6 cells/mm3, 19.3-29.6; P-NS). Clearer differences were found with the number of CD3+ TCM, since the transplanted patients had lower numbers (238 cells/mm3, 153-323) than those who had not yet received transplants (378 cells/mm3, 317-439; P=.029). As a result, the TEM/TCM ratios of both CD4+ and CD8+ T cells in patients with previous allografts were higher than in those who received first transplants. In conclusion, the assessment of just the number of Tregs in renal transplant patients is not enough and must be read together with the number of TEM and TCM. The TEM:TCM ratio increases in patients with previous allografts, probably due to activation of the immune response in renal transplantation.

Analysis of urinary gene expression of epithelial-mesenchymal transition markers in kidney transplant recipients.

INTRODUCTION: Renal graft dysfunction due to acute rejection, acute tubular necrosis, or anticalcineurin toxicity with development of interstitial fibrosis or tubular atrophy are the primary causes of graft failure. Determination of kidney function using the serum creatinine concentration demonstrates low sensitivity as a marker for the diagnosis, and kidney biopsy is an invasive procedure. The levels of urinary messenger RNA of genes that regulate epithelial-mesenchymal transition (EMT) can reflect early kidney damage. Thus, repeated transcriptome studies of these genes can provide information about the evolution of the graft, and possibly enable early diagnosis and treatment. OBJECTIVE: To analyze the temporal relationships between early graft evolution and gene expression of EMT biomarkers. METHODS: Of 70 kidney transplant procedures performed between January 1, 2007 and December 31, 2008, 42 were analyzed prospectively for 3 months. Analytical and clinical data were recorded, as well as histologic findings if available. Urine mRNA extraction was performed using a commercially available kit. RNA gene expression of EMT, angiotensinogen, epidermal growth factor receptor, E-cadherin, N-cadherin, transforming growth factor-ß, and bone morphogenetic protein 7 was determined at real-time quantitative polymerase chain reaction. ß2-Microglobulin was used as a reference gene. RESULTS: At 75 days posttransplantation, analysis revealed that angiotensinogen (mean [SD], 2.91 [0.70] vs 6.04 [1.24]; P=.04) and N-cadherin (1.01 [0.43] vs 4.31 [0.92]; P=.01) discriminate good evolution from acute rejection. Epidermal growth factor receptor (2.78 [0.66] vs 6.02 [1.09]; P=.33) and bone morphogenetic protein 7 (0.85 [0.33] vs 3.07 [1.37]; P=.04) discriminate good evolution vs delayed graft function. CONCLUSION: Differential gene expression at 75 days posttransplantation reflects differences related to initial histologic damage. This observation encourages design of a long-term longitudinal analysis with multiple markers to obtain early diagnosis and forecast the prognosis of graft dysfunction.

Risk of cardiovascular disease associated with refractory hypertension in renal transplant recipients.

BACKGROUND: Hypertension is common after renal transplantation, affecting as many as 80% of recipients. It is generally accepted that hypertension is associated with poor graft survival and reduced life expectancy because of increased cardiovascular risk factors. The prevalence of refractory hypertension in renal transplant recipients is unknown, and could be associated with a poor prognosis. OBJECTIVE: To investigate the effects of refractory hypertension on cardiovascular disease (CVD) after renal transplantation in 486 patients with grafts functioning for longer than 1 year. PATIENTS AND METHODS: Patients were classified into 2 groups: (1) 57 with refractory hypertension, that is, systolic blood pressure 130 mm Hg or greater or diastolic blood pressure 80 mm Hg or greater, and receiving treatment with at least 3 drugs, one of which was a diuretic; and (2) the remaining 429 patients. Patient and graft survival, and posttransplantation CVD were analyzed. RESULTS: Refractory hypertension was associated with male sex (82.5% vs 66.5% [P<.01]), poor renal function (mean [SD] serum creatinine concentration 2.2 [1.2] mg/dL vs 1.6 [0.6] mg/dL; Modification of Diet in Renal Disease score 39.2 [20.0] mL/min/1.73 m2 vs 49.2 [18.0] mL/min/1.73 m2 [P=.000]; and steroid therapy (94.7% vs 79.0% [P=.001]). In the group with refractory hypertension, 5-year patient and graft survival rates were lower, and the incidence of posttransplantation CVD was greater (relative risk, 1.7; 95% confidence interval, 1.05-2.18; P=.03). CONCLUSION: Refractory hypertension is an independent risk factor for increased cardiovascular morbidity and mortality in renal transplant recipients.

Elevated serum gamma-glutamyltransferase and hypomagnesemia are not related with new-onset diabetes after transplantation.

BACKGROUND: New-onset diabetes mellitus after transplantation (NODAT) contributes to the risk of cardiovascular disease (CVD) and infection, reducing graft and patient survival in kidney transplant recipients. To reduce CVD and improve outcomes of kidney transplant recipients, it is of great interest to more precisely elucidate the risk factors that contribute to the development of NODAT. A previous study reported that hypomagnesemia is an independent predictor of NODAT. Elevated gamma-glutamyltransferase (GGT) activity increases the risk of incident type 2 diabetes in the general population. The objective of this study was to determine whether magnesium (Mg) and GGT were risk factors for NODAT among our population of kidney transplant recipients. METHODS: We retrospectively analyzed 205 non-previously diabetic kidney transplant recipients. GGT was measured before transplantation as well as at months 1, 2, and 12. Mg was measured at months 1, 2, and 12. NODAT was defined at month 12 and at the end of follow-up according to the "2003 international consensus guidelines." RESULTS: Although 36 patients (17.5%) developed NODAT at month 12, 55 patients (26.8%) displayed it at the end of follow-up. We did not observe any significant difference, either in mean Mg (month 1, 1.73±0.24 vs 1.75±0.30 [P=.824]; month 2, 1.71±0.22 vs 1.68±0.26 [P=.565]; month 12, 1.77±0.27 vs 1.80±0.24 [P=.596]) or GGT values (pretransplantation, 32 ± 27 vs 33±85 [P=.866]; month 1:39±24 vs 48±70 [P=.452]; month 2, 53±96 vs 48±83 [P=.739]; month 12, 40±37 vs 38±53 [P=.830]) between NODAT and non-NODAT patients at month 12 or at the end of follow-up. CONCLUSION: Hypomagnesemia and high GGT activity were not risk factors for NODAT development in kidney transplant recipients.

Erythropoietin resistance as surrogate marker of graft and patient survival in renal transplantation: 3-year prospective multicenter study.

BACKGROUND: Some transplant recipients demonstrate an inadequate response to erythropoiesis-stimulating agents, or so-called erythropoietin (Epo) resistance. The cause is multifactorial. Resistance to EPO may entail a poor prognosis for the graft and the patient, although results in the literature are inconsistent, and long-term follow-up is lacking. OBJECTIVE: To evaluate whether the presence of Epo resistance at the beginning of the study was a predictive factor for graft and patient survival. MATERIALS AND METHODS: From 482 renal transplant recipients (Kidney Disease Outcomes Quality Initiative stage 3-4T) receiving Epo-stimulating agents in the Anemia and Renal Transplantation in Spain study, 101 were selected for the present study. Erythropoietin resistance was defined as a ratio of weekly Epo dosage/hemoglobin concentration>486,94 U/g/dL with a hemoglobin/<11 g/dL. Darbepoetin dosage was calculated in Epo equivalent units, with a 1:200 conversion factor. Patients were grouped as Epo-resistant (ER+) or not Epo-resistant (ER-), to assess whether Epo resistance was predictive of patient and graft survival. RESULTS: There were no differences in demographic data between the 2 groups except for a higher incidence of vascular, interstitial, and diabetes-related causes of chronic renal failure in the ER+ group. At 3 years posttransplantation, graft survival was 33% in the ER+ group vs 58% in the ER- group (P=.06), and patient survival was 52% in the ER+ group vs 88% in the ER- group (P=.008). Using a Cox regression model, at 3 years, the relative risk of graft failure was 1.96 in the ER+ group (95% CI, 0.93-3.12; P=.07), and of patient death was 3.9 (95% confidence interval, 1.30-11.63; P=.01). CONCLUSION: Erythropoietin resistance is an independent risk factor for death after renal transplantation.

Comparative analysis of adverse events requiring suspension of mTOR inhibitors: everolimus versus sirolimus.

BACKGROUND: Inhibitors of mammalian target of rapamycin (mTORi) have been suggested as an alternative to calcineurin inhibitors (CNIs) to treat stable renal transplant recipients. However, their use has been significantly limited owing to a high incidence of side effects. OBJECTIVE: To compare the rate of dropout (mTORi elimination and CNI reintroduction) caused by side effects among renal transplant patients converted to everolimus (EVL) or sirolimus (SRL). METHODS: Between October 1999 and February 2010, 409 subjects were converted to an mTORi at least 3 months after transplantation, including 220 (53.8%) to EVL and 189 (46.2%) to SRL. Most patients were under CNI therapy. Patients were followed for a median of 35 months (interquartile range [IQR], 18-50 months). RESULTS: mTORi treatment was prematurely eliminated due to adverse events in 112 patients. The median time between the initiation of mTORi and discontinuation was 5.7 months (IQR, 1.9-15.7 months; range, 0.2-48 months): 5.5 (IQR, 1.6-16.3) in the EVL group and 7.4 (IQR, 2.6-15.6) in the SRL group. In the EVL group, the drug was stopped in 69 patients (31.4%), and in the SRL group in 43 patients (22.8%; P=.051). The most important causes of discontinuation were severe infections (2.3% in EVL group and 4.8% in SRL group; P=.17), pneumonitis (6.8 % in EVL group and 4.8 in SRL group; P=.38), acute rejection episode (4.1% in EVL group and 1.6% in SRL group; P=.13), proteinuria (4.1% in EVL group and 1.6% in SRL group; P=.13), renal function deterioration (2.3% in EVL group and 2.1% in SRL group; P=.91), and severe dermal eruption (2.3% in EVL group and 0.5% in SRL group; P=.14). CONCLUSIONS: Although the overall incidence discontinuations due to side effects was higher in the EVL group, there was no greater frequency of severe side effects, such as pneumonitis, proteinuria, acute rejection episodes, renal function deterioration, or dermal eruptions.

Determinants of resistive index shortly after transplantation: independent relationship with delayed graft function.

Measurement of the vascular resistive index (RI) by Doppler ultrasonography has been proposed as a non-invasive method to evaluate renal allograft dysfunction, but there are conflicting reports about its clinical utility. The aim of our study was to analyse the donor and recipient characteristics related to RI measured at days 2 and 3 after renal transplantation and the relationship between RI and allograft outcome. RI was measured by Doppler ultrasonography in 333 patients at days 2 or 3 post-transplantation. Donor and recipient variables and allograft outcome were collected from a prospectively maintained institutional database. In patients with RI higher than 0.7, donor age, recipient age, duration of renal replacement therapy, incidence of diabetes, hypertension and atherosclerosis in the recipient, pulse pressure, initial creatinine and the incidence of delayed graft function (DGF) were higher. After multivariate analysis, the only variables that remained significant for an increased risk of higher RI were recipient age over 55 years, presence of diabetes in the recipient and DGF. Recipient age, previous diabetes mellitus and DGF are the most important determinants of transplant kidney RI in the first days after transplantation. So both the graft recipient and the graft itself, but not the donor, determine intra-renal Doppler indices.

The phenomenon of hemoglobin variability with erythropoiesis stimulating agents in renal transplant patients.

Treatment with erythropoiesis-stimulating agents (ESA) is often associated with fluctuation in hemoglobin (Hb) levels that has been considered a factor that influences morbidity/mortality in hemodialysis patients. Our aim was to describe the hemoglobin variability during ESA treatment and to study associated factors in kidney transplants. Hb variability (defined as fluctuations of Hb +/- 1.5 g/dl) was assessed in 85 renal transplant patients treated with ESA for at least 3 months and with a minimum of 6 Hb measurements along 1 year. 58% of patients experienced Hb variability during follow-up. Although 71.3% of patients maintained Hb levels greater than 11 g/dl along the whole follow-up, only 3% of patients maintained stable Hb levels within the target range all the time (11 - 13 g/dl). By multivariate analysis, clinical factors associated with variability were changes in ESA dose (RR 2.92, p = 0.04), infectious events with hospitalization (RR 1.95, p = 0.03) and the use of sirolimus (RR 1.1, p < 0.05). Excluding dose changes and hospitalization in the analysis variability was an independent predictor of graft function deterioration. In conclusion, Hb variability is common in renal transplants treated with ESA. Only few patients maintained Hb levels in the therapeutic range (11 - 13 g/dl). Dose changes, inflammatory status and graft function deterioration are the determining factors.

Clinical and epidemiological characteristics of refractory hypertension in renal transplant patients.

Hypertension is common following renal transplantation, affecting up to 80% of recipients. It is generally accepted that hypertension is associated with poor graft survival and reduced life expectancy, contributing to increased cardiovascular risk factors and mortality rates. The prevalence of refractory hypertension among renal transplant patients is unknown; it may be associated with a worse prognosis. The aim of our study was to determine the prevalence of refractory hypertension among 529 stable renal transplant recipients and to describe its clinical and epidemiological features. We divided this population into 4 groups to make comparisons: normotensive (n = 82), controlled hypertension (n = 228), uncontrolled hypertension but not refractory (n = 183), and refractory hypertension (n = 36) as defined by a systolic blood pressure >or= 140 mm Hg and/or a diastolic blood pressure >or= 90 mm Hg among patients treated with 3 or more drugs (1 of them being a diuretic). The proportion of patients with refractory hypertension in our transplant unit was 6.8%. The main characteristics of patients with refractory hypertension versus normotensive patients were: mainly systolic hypertension (152.5 +/- 10.32 vs 121.6 +/- 9.26 mm Hg; P < .012), elderly age (59.47 vs 48.33 years; P < .000), diabetes (36.2% vs 1.2%; P < .000), poorer renal function as measured by glomerular filtration rate (36.15 +/- 20.41 vs 56.12 +/- 15.75 mL/min/1.73 m(2); P < .004), higher 24-hour urinary protein excretion (2.55 +/- 2.61 vs 0.5 +/- 0.8 g; P < .003), and steroid treatment (47.2% vs 23.2%; P < .000). The results of this study may help identify the clinical and epidemiological factors which correlated with refractory hypertension for future interventional applications to reduce the morbidity/mortality among the renal transplant population.

Correlation of C0 and C2 levels with cyclosporine side effects in kidney transplantation.

Cyclosporine has a narrow therapeutic window requiring close monitoring to ensure adequate immunosuppression while avoiding nephrotoxicity and other side effects. Pharmacokinetic studies have suggested that cyclosporine levels at 2 hours postdose (C2) is the best single time point to predict area under the concentration curve (AUC) in kidney transplant recipients. C2 also predicted acute rejection episodes and nephrotoxicity better than trough levels (C0). Targeting cyclosporine levels to minimize side effects while maintaining adequate immunosuppressive effects is of clinical interest. There are conflicting evidence and few reports about whether cyclosporine-related side effects are a dose-dependent phenomenon. The aim of this single center study was to ascertain whether cyclosporine side effects were dose-dependent and which single time point level (C0 or C2) was more closely related to them. We analyzed 225 patients on Neoral-based immunosuppression with C0 and C2 levels measured on the same day of 2 different visits. Serum creatinine, glucose, uric acid, potassium, total cholesterol, triglycerides, and 24-hour urinary sodium elimination were measured by routine biochemical analyses. Blood pressure was measured at each visit. A significant positive correlation was observed between C2 and C0 concentrations and levels of potassium (P < .001), total cholesterol (P < .001), systolic blood pressure (P < .001), and pulse pressure (P < .01). There was a significant negative correlation between C2 and uric acid (P < .001). AUCs of receiver operating characteristic (ROC) curves for both C2 and C0 levels were significant as predictors of hyperkalemia (P < .001), hyperuricemia (P = .001), hypercholesterolemia (P < .05), and high systolic blood pressure (P < .05). There were no significant differences between the capacities of C2 or C0 to predict these variables. In conclusion, potassium, total cholesterol, uric acid, and systolic hypertension were influenced by cyclosporine in a dose-dependent manner. Both C2 and C0 were useful to predict cyclosporine side effects.

Chronic renal disease in renal transplant patients: management of cardiovascular risk factors.

Kidney transplantation is the treatment of choice for patients with end-stage renal disease. Despite improvements in short-term patient and graft outcomes, there has been no major improvement in long-term outcomes. The aim of this study was to determine the prevalence of cardiovascular risk factors, such as hypertension, dyslipidemia, diabetes, chronic kidney disease, and obesity, and the impact of their control among 526 stable renal transplant recipients according to the guidelines in the general population. Mean blood pressure was 133 +/- 16/81 +/- 9 mm Hg. The proportion of patients on antihypertensive therapy was 75%, and on ACE inhibitors or angiotensin II receptor blockers, 26%. The mean cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides were 195 +/- 41, 115 +/- 32, 51 +/- 17, and 137 +/- 75 mg/dL, respectively. The proportion of patients on statin treatment was 49.7%, and those with body mass indices between 25 and 30, 30 and 35, and >35 kg/m(2) were 35%, 15%, and 4%. We observed a high prevalence of chronic kidney disease, hypertension, dyslipidemia, and obesity among renal transplant patients. Suboptimal control was frequent and control of some of these complications was far below targets established for nontransplant patients despite progressive intensification of therapy with functional graft decline. The findings of this study may have an impact on the management of renal transplant recipients.

[Changes in the pre-transplant bone-mineral metabolism do not affect the initial progress of the renal graft]. / Las alteraciones del metabolismo óseo-mineral pretrasplante no influyen en la evolución inicial del injerto renal.

BACKGROUND: Abnormalities in serum calcium, phosphate, and Parathyroid Hormone (PTH) concentrations are common in patients with chronic kidney disease and have been associated with increased morbidity and mortality. One of the most common problems in the first weeks after renal transplantation is Delayed Graft Function (DGF). There are several well-known risk factors for DGF development, but the role of calcium phosphate-PTH homeostasis as a risk factor for early graft dysfunction is controversial. This issue was addressed in the current study. METHODS: Pretransplant PTH, calcium and phosphate values were gathered in 449 patients that received a renal transplant in our center between 1994 and 2007. Other variables expected to influence the risk for delayed graft function were included from the clinical charts. RESULTS: The incidence of DGF was 27.3%. DGF development was significantly associated with recipient age, type and need of renal replacement therapy, peak panel reactive antibodies, transfusion number and donor age. There were no significant differences in the mean pretransplant values of calcium (9.4 +/- 1.0 vs. 9.5 +/- 0.9 mg/dl, p = 0.667), phosphate (5.7 +/- 1.8 vs. 5.5 +/- 1.5 mg/dl, p = 0.457), calcium-phosphate product (53.5 +/- 17.2 vs. 51.8 +/- 14.6 mg(2)/dl(2), p = 0.413) and PTH (315 +/- 312 vs. 340 +/- 350 pg/ml, p = 0.530) between patients with and without DGF. CONCLUSIONS: In our study population pretransplant serum PTH, calcium and phosphorus levels have no influence on the risk for DGF.