Institutional Experience With New Antidiabetic Drugs in Kidney Transplant.

BACKGROUND: The recent introduction of new antidiabetic drugs, analogs of glucagon-like peptide-1 (GLP-1) and sodium-glucose cotransporter 2 inhibitors, has shown excellent results in the management of patients with diabetes with chronic kidney disease. However, documented results of these medications in the population that has undergone kidney transplant are sparse. We report our institutional experience with them, including occurrence of side effects and possible interactions with immunosuppressive medications. METHODS: A retrospective analysis of 15 patients (10 with diabetes and 5 without diabetes but with obesity) managed with these medications was carried out in the kidney transplant unit of Hospital Doctor Peset during the year 2019. Data acquired at baseline and 3, 6, and 12 months were analyzed. RESULTS: The median hemoglobin A1c at baseline was 6.7 (interquartile range [IQR] = 5.8-8.2) and at 12 months it was 6 (IQR = 5.3-8.1, P = .96). The mean weight difference at 12 months was a loss of 7.2 ± 6 kg; median body mass index at baseline was 31.2 kg/m2 (IQR = 29.7-35.5) and 29.5 kg/m2 (IQR = 27.6-31.6, P = .01) at 12 months. In addition to weight loss, a reduction in insulin and oral antidiabetic drug requirements was observed. No significant changes were detected in serum creatinine or proteinuria values and the immunosuppressant levels remained stable. No acute rejection episodes were observed. CONCLUSION: Based on our experience, the new antidiabetic drugs are safe, with no significant changes in renal function or immunosuppressant levels or clinically important adverse effects.

Disorders in bone-mineral parameters and the risk of death in persons with chronic kidney disease stages 4 and 5: the PECERA study.

BACKGROUND: Abnormalities of bone mineral parameters are associated with increased mortality in patients on dialysis, but their effects and the optimal range of these biomarkers are less well characterized in non-dialysis chronic kidney disease (CKD). METHODS: PECERA (Collaborative Study Project in Patients with Advanced CKD) is a 3-year, prospective multicenter, open-cohort study of 966 adult patients with non-dialyzed CKD stages 4-5 enrolled from 12 centers in Spain. Associations between levels of serum calcium (Ca) (corrected for albumin), phosphate (P), and intact parathyroid hormone (iPTH) with all-cause mortality (primary outcome) and cardiovascular mortality (secondary outcome) were examined using time-dependent Cox proportional hazards models and penalized splines analysis adjusted by demographics and comorbidities, treatments and biochemical values collected every 6 months for 3 years. RESULTS: After a median follow-up of 29 months (IQR: 13-36 months) there were 181 deaths (19%). The association of calcium with all-cause mortality was J-shaped, with an increased risk for all-cause mortality at levels > 10.5 mg/dL. For phosphate and iPTH levels, the association was U-shaped. The serum values associated with the minimum risk of mortality were 3.8 mg/dL for phosphate and 70 pg/mL for iPTH, being the lowest risk ranges between 2.8 and 5.0 mg/dL, and between 38 and 112 pg/mL for phosphate and iPTH, respectively. CONCLUSIONS: Our study provides evidence on the non-linear association of serum calcium, phosphate and iPTH levels with mortality in stage 4 and 5 CKD patients, and suggests potential survival benefits for controlling bone mineral parameters in this population, as previously reported for dialysis patients.

Randomized Controlled Trial Assessing the Impact of Tacrolimus Versus Cyclosporine on the Incidence of Posttransplant Diabetes Mellitus.

INTRODUCTION: Despite the high incidence of posttransplant diabetes mellitus (PTDM) among high-risk recipients, no studies have investigated its prevention by immunosuppression optimization. METHODS: We conducted an open-label, multicenter, randomized trial testing whether a tacrolimus-based immunosuppression and rapid steroid withdrawal (SW) within 1 week (Tac-SW) or cyclosporine A (CsA) with steroid minimization (SM) (CsA-SM), decreased the incidence of PTDM compared with tacrolimus with SM (Tac-SM). All arms received basiliximab and mycophenolate mofetil. High risk was defined by age >60 or >45 years plus metabolic criteria based on body mass index, triglycerides, and high-density lipoprotein-cholesterol levels. The primary endpoint was the incidence of PTDM after 12 months. RESULTS: The study comprised 128 de novo renal transplant recipients without pretransplant diabetes (Tac-SW: 44, Tac-SM: 42, CsA-SM: 42). The 1-year incidence of PTDM in each arm was 37.8% for Tac-SW, 25.7% for Tac-SM, and 9.7% for CsA-SM (relative risk [RR] Tac-SW vs. CsA-SM 3.9 [1.2-12.4; P = 0.01]; RR Tac-SM vs. CsA-SM 2.7 [0.8-8.9; P = 0.1]). Antidiabetic therapy was required less commonly in the CsA-SM arm (P = 0.06); however, acute rejection rate was higher in CsA-SM arm (Tac-SW 11.4%, Tac-SM 4.8%, and CsA-SM 21.4% of patients; cumulative incidence P = 0.04). Graft and patient survival, and graft function were similar among arms. CONCLUSION: In high-risk patients, tacrolimus-based immunosuppression with SM provides the best balance between PTDM and acute rejection incidence.

Downregulation of miR-31 in Diabetic Nephropathy and its Relationship with Inflammation.

BACKGROUND/AIMS: There is a lack of reliable biological markers for the early diagnosis of diabetic nephropathy (DN) during type 2 diabetes. In this pilot study we aim to assess whether miR-31 levels are modulated by the presence of DN and whether the expression of this miRNA is related to leukocyte-endothelial interactions and inflammation. METHODS: Thirty-one T2D patients were enrolled in this pilot study; 18 with no diabetic complications and 13 with diabetic nephropathy. 24 non-diabetic subjects and 13 T2D patients with retinopathy (absent of other complications) were included to test the specificity of miR-31. Following anthropometric and biochemical evaluation, serum miR-31 levels were assessed by Real Time-PCR. Leukocyte-endothelial interactions were evaluated by a parallel flow chamber in vitro model. Serum TNFα, IL-6 and ICAM-1 levels were determined by XMAP-technology in a flow cytometry-based Luminex 200 instrument. RESULTS: Serum miR-31 levels were similar between control and T2D subjects. However, T2D patients with DN displayed reduced levels of miR-31 with respect to patients without complications. This decrease in miR-31 was more pronounced in patients with macroalbuminuria than in those with microalbuminuria and was specific for DN, since patients with retinopathy displayed unaltered miR-31 levels. The presence of DN involved a lower leukocyte rolling velocity and an increased rolling flux and adhesion. miR-31 levels were positively correlated with leukocyte rolling velocity and negatively associated to leukocyte adhesion, TNFα, IL-6 and ICAM-1 levels. CONCLUSION: Serum miR-31 may be a biomarker for DN in T2D patients. The regulation of this miRNA seems to be related to the recruitment of leukocytes to vascular walls induced by pro-inflammatory and adhesion molecules.

The effect of high-volume online haemodiafiltration on nutritional status and body composition: the ProtEin Stores prEservaTion (PESET) study.

Background: Compared with conventional haemodialysis (HD), online haemodiafiltration (OL-HDF) achieves a more efficient removal of uraemic toxins and reduces inflammation, which could favourably affect nutritional status. We evaluate the effect of OL-HDF on body composition and nutritional status in prevalent high-flux HD (HF-HD) patients. Methods: In all, 33 adults with chronic kidney disease (CKD) Stage 5 undergoing maintenance HF-HD were assigned to post-dilution OL-HDF (n = 17) or to remain on HF-HD (n = 16, control group) for 12 months. The primary outcome was the change in lean tissue mass (LTM), intracellular water (ICW) and body cell mass (BCM) assessed by multifrequency bioimpedance spectroscopy (BIS) at baseline and 4, 8 and 12 months. The rate of change in these parameters was estimated with linear mixed-effects models. Results: Compared with OL-HDF, patients assigned to HF-HD experienced a gradual reduction in LTM, ICW and BCM. These differences reached statistical significance at Month 12, with a relative difference of 7.31 kg [95% confidence interval (CI) 2.50-12.11; P = 0.003], 2.32 L (95% CI 0.63-4.01; P = 0.008) and 5.20 kg (95% CI 1.74-8.66; P = 0.004) for LTM, ICW and BCM, respectively. The normalized protein appearance increased in the OL-HDF group compared with the HF-HD group [0.26 g/kg/day (95% CI 0.05-0.47); P = 0.002], with a relative reduction in high-sensitive C-reactive protein [-13.31 mg/dL (95% CI -24.63 to -1.98); P = 0.02] at Month 12. Conclusions: OL-HDF for 1 year compared with HF-HD preserved muscle mass, increased protein intake and reduced the inflammatory state related to uraemia and dialysis, supporting the hypothesis that high convection volume can benefit nutritional status and prevent protein-energy wasting in HD patients.

Regression of vascular calcification in a parathyroidectomized patient on dialysis with untreated hypocalcemia over 12-year follow-up
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Although some experimental targets involved in calcium deposition are emerging, no intervention has been described to reliably reverse vascular calcification (VC). We report a case of severe VC regression in a parathyroidectomized patient on hemodialysis over 12-year follow-up, highlighting the use of calcium-free phosphate binders and a 2.5 mEq/L calcium dialysate for reducing calcium loading, despite persistent asymptomatic hypocalcemia occurrences. This case suggests that phosphate-binder choice and calcium dialysate concentration could be influenced by other components of CKD-MBD besides biochemical parameters, such as the presence of VC, so concluding that asymptomatic hypocalcemia may not be as harmful as once supposed, and conferring greater prognostic weight to the presence of VC than to calcium levels.
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What is the optimal level of vitamin D in non-dialysis chronic kidney disease population?

AIM: To evaluate thresholds for serum 25(OH)D concentrations in relation to death, kidney progression and hospitalization in non-dialysis chronic kidney disease (CKD) population. METHODS: Four hundred and seventy non-dialysis 3-5 stage CKD patients participating in OSERCE-2 study, a prospective, multicenter, cohort study, were prospectively evaluated and categorized into 3 groups according to 25(OH)D levels at enrollment (less than 20 ng/mL, between 20 and 29 ng/mL, and at or above 30 ng/mL), considering 25(OH)D between 20 and 29 ng/mL as reference group. Association between 25(OH)D levels and death (primary outcome), and time to first hospitalization and renal progression (secondary outcomes) over a 3-year follow-up, were assessed by Kaplan-Meier survival curves and Cox-proportional hazard models. To identify 25(OH)D levels at highest risk for outcomes, receiver operating characteristic (ROC) curves were performed. RESULTS: Over 29 ± 12 mo of follow-up, 46 (10%) patients dead, 156 (33%) showed kidney progression, and 126 (27%) were hospitalized. After multivariate adjustment, 25(OH)D < 20 ng/mL was an independent predictor of all-cause mortality (HR = 2.33; 95%CI: 1.10-4.91; P = 0.027) and kidney progression (HR = 2.46; 95%CI: 1.63-3.71; P < 0.001), whereas the group with 25(OH)D at or above 30 ng/mL did not have a different hazard for outcomes from the reference group. Hospitalization outcomes were predicted by 25(OH) levels (HR = 0.98; 95%CI: 0.96-1.00; P = 0.027) in the unadjusted Cox proportional hazards model, but not after multivariate adjusting. ROC curves identified 25(OH)D levels at highest risk for death, kidney progression, and hospitalization, at 17.4 ng/mL [area under the curve (AUC) = 0.60; 95%CI: 0.52-0.69; P = 0.027], 18.6 ng/mL (AUC = 0.65; 95%CI: 0.60-0.71; P < 0.001), and 19.0 ng/mL (AUC = 0.56; 95%CI: 0.50-0.62; P = 0.048), respectively. CONCLUSION: 25(OH)D < 20 ng/mL was an independent predictor of death and progression in patients with stage 3-5 CKD, with no additional benefits when patients reached the levels at or above 30 ng/mL suggested as optimal by CKD guidelines.

Nephroprotection by Hypoglycemic Agents: Do We Have Supporting Data?

Current therapy directed at delaying the progression of diabetic nephropathy includes intensive glycemic and optimal blood pressure control, renin angiotensin-aldosterone system blockade and multifactorial intervention. However, the renal protection provided by these therapeutic modalities is incomplete. There is a scarcity of studies analysing the nephroprotective effect of antihyperglycaemic drugs beyond their glucose lowering effect and improved glycaemic control on the prevention and progression of diabetic nephropathy. This article analyzes the exisiting data about older and newer drugs as well as the mechanisms associated with hypoglycemic drugs, apart from their well known blood glucose lowering effect, in the prevention and progression of diabetic nephropathy. Most of them have been tested in humans, but with varying degrees of success. Although experimental data about most of antihyperglycemic drugs has shown a beneficial effect in kidney parameters, there is a lack of clinical trials that clearly prove these beneficial effects. The key question, however, is whether antihyperglycemic drugs are able to improve renal end-points beyond their antihyperglycemic effect. Existing experimental data are post hoc studies from clinical trials, and supportive of the potential renal-protective role of some of them, especially in the cases of dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors. Dedicated and adequately powered renal trials with renal outcomes are neccessary to assess the nephrotection of antihyperglycaemic drugs beyond the control of hyperglycaemia.

Quality of life and stressors in patients with chronic kidney disease depending on treatment.

This study evaluated health-related quality of life (HRQOL) in a Spanish sample of chronic kidney disease patients (n = 90) undergoing different renal replacement therapies, considering the influence of treatment stressors, mood, anxiety and quality of sleep. While all patients had worse physical functioning than controls (p < .01), only those undergoing haemodialysis (HD) showed worse physical well-being, occupational functioning, spiritual fulfillment and more health interference with work (p < .05). They also obtained higher depression scores than renal transplant patients (TX) (p = .005). Those TX receiving the immunosuppressor sirolimus exhibited more cardiac/renal, cognitive and physical limitations than the rest (p < .05). Dialysis vintage correlated positively with sleep disturbances and depression scores and negatively with total Quality of Life (QLI) (p < .05). HD patients experienced more psychological distress than peritoneal dialysis patients (PD) (p = .036). Regression models including sleep, anxiety and depression were estimated for subscales of HRQOL. In TX patients, low depressive scores related to an optimal QLI in almost all subscales, while in HD patients they explained part of the variability in psychological well-being, interpersonal functioning and personal fulfillment. HD condition results in a QLI more distant to the standards of controls.

Vascular calcification in patients with nondialysis CKD over 3 years.

BACKGROUND AND OBJECTIVES: Vascular calcification (VC) is common in CKD, but little is known about its prognostic effect on patients with nondialysis CKD. The prevalence of VC and its ability to predict death, time to hospitalization, and renal progression were assessed. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The Study of Mineral and Bone Disorders in CKD in Spain is a prospective, observational, 3-year follow-up study of 742 patients with nondialysis CKD stages 3-5 from 39 centers in Spain from April to May 2009. VC was assessed using Adragao (AS; x-ray pelvis and hands) and Kauppila (KS; x-ray lateral lumbar spine) scores from 572 and 568 patients, respectively. The primary end point was death. Secondary outcomes were hospital admissions and appearance of a combined renal end point (beginning of dialysis or drop >30% in eGFR). Factors related to VC were assessed by logistic regression analysis. Survival analysis was assessed by Cox proportional models. RESULTS: VC was present in 79% of patients and prominent in 47% (AS≥3 or KS>6). Age (odds ratio [OR], 1.05; 95% confidence interval [95% CI], 1.02 to 1.07; P<0.001), phosphorous (OR, 1.68; 95% CI, 1.28 to 2.20; P<0.001), and diabetes (OR, 2.11; 95% CI, 1.32 to 3.35; P=0.002) were independently related to AS≥3. After a median follow-up of 35 months (interquartile range=17-36), there were 70 deaths (10%). After multivariate adjustment for age, smoking, diabetes, comorbidity, renal function, and level of phosphorous, AS≥3 but not KS>6 was independently associated with all-cause (hazard ratio [HR], 2.07; 95% CI, 1.07 to 4.01; P=0.03) and cardiovascular (HR, 3.46; 95% CI, 1.27 to 9.45; P=0.02) mortality as well as a shorter hospitalization event-free period (HR, 1.14; 95% CI, 1.06 to 1.22; P<0.001). VC did not predict renal progression. CONCLUSIONS: VC is highly prevalent in patients with CKD. VC assessment using AS independently predicts death and time to hospitalization. Therefore, it could be a useful index to identify patients with CKD at high risk of death and morbidity as previously reported in patients on dialysis.

Quality of life and stressors in patients with chronic kidney disease depending on treatment

This study evaluated health-related quality of life (HRQOL) in a Spanish sample of chronic kidney disease patients (n = 90) undergoing different renal replacement therapies, considering the influence of treatment stressors, mood, anxiety and quality of sleep. While all patients had worse physical functioning than controls (p < .01), only those undergoing haemodialysis (HD) showed worse physical well-being, occupational functioning, spiritual fulfillment and more health interference with work (p < .05). They also obtained higher depression scores than renal transplant patients (TX) (p = .005). Those TX receiving the immunosuppressor sirolimus exhibited more cardiac/renal, cognitive and physical limitations than the rest (p < .05). Dialysis vintage correlated positively with sleep disturbances and depression scores and negatively with total Quality of Life (QLI) (p < .05). HD patients experienced more psychological distress than peritoneal dialysis patients (PD) (p = .036). Regression models including sleep, anxiety and depression were estimated for subscales of HRQOL. In TX patients, low depressive scores related to an optimal QLI in almost all subscales, while in HD patients they explained part of the variability in psychological well-being, interpersonal functioning and personal fulfillment. HD condition results in a QLI more distant to the standards of controls (AU)

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The effect of cholecalciferol for lowering albuminuria in chronic kidney disease: a prospective controlled study.

BACKGROUND: Growing evidence indicates that vitamin D receptor activation may have antiproteinuric effects. We aimed to evaluate whether vitamin D supplementation with daily cholecalciferol could reduce albuminuria in proteinuric chronic kidney disease (CKD) patients. METHODS: This 6-month prospective, controlled, intervention study enrolled 101 non-dialysis CKD patients with albuminuria. Patients with low 25(OH) vitamin D [25(OH)D] and high parathyroid hormone (PTH) levels (n = 50; 49%) received oral cholecalciferol (666 IU/day), whereas those without hyperparathyroidism (n = 51; 51%), independent of their vitamin D status, did not receive any cholecalciferol, and were considered as the control group. RESULTS: Cholecalciferol administration led to a rise in mean 25(OH)D levels by 53.0 ± 41.6% (P < 0.001). Urinary albumin-to-creatinine ratio (uACR) decreased from (geometric mean with 95% confidence interval) 284 (189-425) to 167 mg/g (105-266) at 6 months (P < 0.001) in the cholecalciferol group, and there was no change in the control group. Reduction in a uACR was observed in the absence of significant changes in other factors, which could affect proteinuria, like weight, blood pressure (BP) levels or antihypertensive treatment. Six-month changes in 25(OH)D levels were significantly and inversely associated with that in the uACR (Pearson's R = -0.519; P = 0.036), after adjustment by age, sex, body mass index, BP, glomerular filtration rate and antiproteinuric treatment. The mean PTH decreased by -13.8 ± 20.3% (P = 0.039) only in treated patients, with a mild rise in phosphate and calcium-phosphate product [7.0 ± 14.7% (P = 0.002) and 7.2 ± 15.2% (P = 0.003), respectively]. CONCLUSIONS: In addition to improving hyperparathyroidism, vitamin D supplementation with daily cholecalciferol had a beneficial effect in decreasing albuminuria with potential effects on delaying the progression of CKD.

Avances en la inmunosupresión para el trasplante renal. Nuevas estrategias para preservar la función renal y reducir el riesgo cardiovascular / Advances in immunosuppression for kidney transplantation: new strategies for preserving kidney function and reducing cardiovascular risk

El interés principal en el desarrollo de nuevos inmunosupresores para el trasplante renal no sólo radica en la mejora de los resultados a corto plazo, sino también en un mejor perfil de seguridad, una menor nefrotoxicidad y un mejor perfil cardiovascular y metabólico. Belatacept es una proteína de fusión que bloquea la coestimulación de los linfocitos al unirse a los antígenos CD80 y CD86. En los estudios clínicos, especialmente BENEFIT y BENEFIT-EXE, se ha demostrado que belatacept preserva la función y la estructura del injerto renal y que sus efectos se mantienen a largo plazo. En comparación con los inhibidores de la calcineurina, belatacept se asocia a una menor incidencia de nefropatía crónica del injerto y ofrece un perfil cardiovascular y metabólico más favorable. Su eficacia y seguridad se mantienen en trasplantes renales de donantes con criterios ampliados (AU)

The development of new immunosuppressants for renal transplantation is aimed not only at improving short-term outcomes, but also at achieving better safety, cardiovascular, and metabolic profiles and at decreasing nephrotoxicity. Belatacept is a fusion protein that inhibits T cell activation by binding to CD80 and CD86 antigens. Clinical trials, particularly the BENEFIT and BENEFIT-EXT studies, have shown that belatacept preserves function and structure in renal grafts. The effects of belatacept provide long-term, sustained results, and the safety and efficacy of this drug have been demonstrated in cases of renal transplantation from expanded criteria donors. Compared to calcineurin inhibitors, belatacept is associated with a lower incidence of chronic allograft nephropathy and a more favourable cardiovascular and metabolic profile (AU)

Advances in immunosuppression for kidney transplantation: new strategies for preserving kidney function and reducing cardiovascular risk.

The development of new immunosuppressants for renal transplantation is aimed not only at improving short-term outcomes, but also at achieving better safety, cardiovascular, and metabolic profiles and at decreasing nephrotoxicity. Belatacept is a fusion protein that inhibits T cell activation by binding to CD80 and CD86 antigens. Clinical trials, particularly the BENEFIT and BENEFIT-EXT studies, have shown that belatacept preserves function and structure in renal grafts. The effects of belatacept provide long-term, sustained results, and the safety and efficacy of this drug have been demonstrated in cases of renal transplantation from expanded criteria donors. Compared to calcineurin inhibitors, belatacept is associated with a lower incidence of chronic allograft nephropathy and a more favourable cardiovascular and metabolic profile.

Effects of immunosuppressive drugs on the cognitive functioning of renal transplant recipients: a pilot study.

Some renal transplant patients show cognitive, emotional, and behavioral changes as part of possible neurotoxic effects associated with immunosuppressive medication, especially tacrolimus. This study evaluated effects of immunosuppressive drugs on some cognitive tasks. Patients treated with sirolimus and cyclosporine reported some of the noncognitive side effects related to immunosuppressive treatment. We observed attention and working memory impairment in patients treated with sirolimus or tacrolimus. Performance of cyclosporine-treated subjects was similar to that of healthy volunteer controls. Since the mood, anxiety, and sleep patterns measured were unaffected, it could be concluded that the cognitive deficit found was partly related to treatment.

Fluvastatin in the prevention of renal transplant vasculopathy: results of a prospective, randomized, double-blind, placebo-controlled trial.

BACKGROUND: Statins prevent the progression of transplant vasculopathy in heart transplants, but its beneficial effect on the transplanted kidney is controversial. METHODS: The aim is to evaluate the utility of fluvastatin 80 mg/day to reduce the progression of 6-month renal transplant vasculopathy in a multicenter, prospective, randomized, placebo-controlled trial stratified according to donor age. All patients received cyclosporine, mycophenolate mofetil, and prednisone. The progression of transplant vasculopathy was evaluated in paired donor and 6-month protocol biopsies. The primary efficacy variable was the progression of mean arterial intimal volume fraction (deltaVvintima/artery) evaluated with histomorphometry. The minimum sample size to detect a 50% reduction in the progression of deltaVvintima/artery was 62 patients per group. The secondary efficacy variable included the incidence of transplant vasculopathy evaluated according to Banff criteria. RESULTS: A total of 89 patients were included, 74 completed the 6-month study and 57 have paired biopsies with sufficient tissue for histological evaluation. The deltaVvintima/artery was not different between treatment and placebo groups (6.9+/-8.2% vs. 6.9+/-7.4%, P=ns), whereas the incidence of transplant vasculopathy was lower in the fluvastatin group (7% vs. 33%; P=0.02). Because there was a discrepancy between the primary and secondary efficacy variables, post hoc analysis was performed to evaluate the reproducibility of both variables in a subset of 50 biopsies. The reproducibility of transplant vasculopathy was higher than the reproducibility of Vvintima/artery (kappa 0.86 vs. 0.33). CONCLUSIONS: In summary, there were no differences in deltaVvintima/artery between groups, but fluvastatin treatment was associated with a reduced incidence of transplant vasculopathy.

Assessment of phosphorus and calcium metabolism and its clinical management in hemodialysis patients in the community of Valencia.

AIM: The objective of the study was to determine the situation concerning mineral metabolism and bone disease in hemodialysis (HD) patients living in the community of Valencia (Spain), as well as the clinical practices for bone disease control in relation to the laboratory targets recommended in the National Kidney Foundation Dialysis Outcomes Quality Initiative (K/DOQI) guidelines. METHODS: In December 2003, a cross-sectional study was performed including 2392 patients (1485 males and 907 females) from 43 different centers in the council of Valencia (the entire HD population). Mean age was 65.8 +/- 14 yrs. Cut-off levels for the study of calcium, phosphorus, calcium-phosphorus product (Ca x P) and parathyroid hormone (PTH) were performed following the recommendations of the K/DOQI guidelines. RESULTS: The mean values for calcium were 9.57 +/- 0.7 mg/dL, phosphorus 4.97 +/- 1.5 mg/dL, intact PTH (iPTH) 297 +/- 353 pg/mL, Ca x P 47.5 +/- 15 mg2/dL2. Hypocalcemia (<8.4 mg/dL) was present in 5% of patients, whereas 17.8% of patients presented hypercalcemia (>10.2 mg/dL), 60.3% of whom received vitamin D. Hypophosphoremia (<3.5 mg/dL) was present in 16% of patients, and 29% of patients presented hyperphosphoremia (>5.5 mg/dL). Ca x P was <55 mg2/dL2 in 73% of patients. Thirty one percent of patients presented secondary hyperparathyroidism (HPTH >300 pg/mL), being severe in 12% (>600 pg/mL); 43% of patients presented iPTH <150 pg/mL. Only 7.3% of patients achieved the four recommendations provided in the K/DOQI guidelines. Vitamin D treatment was administered in 48% of patients. CONCLUSIONS: The population undergoing dialysis in the community of Valencia achieved targets based on the clinical recommendations of the K/DOQI guidelines as follows: 45% of patients achieved targets for calcium, 55% for phosphorus, 73% for Ca x P and 26% for iPTH levels. Surprisingly, only 7.3% of patients achieved all four targets.

Use of Neoral C monitoring: a European consensus.

Large-scale clinical trials using C(2) monitoring of cyclosporine (CsA) microemulsion (Neoral) in renal transplant recipients have demonstrated low acute rejection rates and good tolerability with a low adverse event profile in a variety of settings: with or without routine induction therapy; in combination with mycophenolate mofetil; with standard-exposure or low-exposure Neoral; and in patients with immediate or delayed graft function. In liver transplantation, C(2) monitoring significantly reduces the severity and incidence of acute rejection compared with C(0) monitoring, without adverse consequences in terms of renal function or tolerability. Different C(2) targets are appropriate depending on adjunctive immune suppression, level of immunologic risk, CsA tolerability, risk of renal toxicity and time since transplantation. CsA absorption may increase substantially in most patients during the first 1-2 weeks post-transplant, and this should be taken into account to avoid overshooting C(2) target range. A patient with a low C(2) value may be either a low or a delayed absorber of CsA, or be a normal absorber who is receiving too low a dose of Neoral. C(2) monitoring alone is insufficient to differentiate between these types of patients, and measurement of additional timepoints is recommended. Adopting C(2) monitoring in maintenance transplant patients identifies those who are overexposed to CsA. In summary, randomized, prospective, multicenter studies and single-center trials have evaluated Neoral C(2) monitoring within a range of regimens in different organ types, providing a robust evidence base for the benefits of this sensitive monitoring technique.

Efficacy and safety outcomes among de novo renal transplant recipients managed by C2 monitoring of cyclosporine a microemulsion: results of a 12-month, randomized, multicenter study.

BACKGROUND: The clinical benefits of C2 monitoring of cyclosporine microemulsion have been demonstrated, but C2 targets in renal transplant recipients during the first year require validation. METHODS: MO2ART was a prospective, multicenter study of renal transplant recipients managed by C2 monitoring of cyclosporine microemulsion with steroids and mycophenolate mofetil or azathioprine. Patients were randomized on day 3 to two groups, which were managed from month 3 with higher or lower C2 target ranges (months 4-6, 1,000-1,200 ng/mL vs. 800-1,000 ng/mL; months 7-12, 800-1,000 ng/mL vs. 600-800 ng/mL, respectively). The primary endpoint was the glomerular filtration rate (GFR) at month 12. RESULTS: A total of 296 patients were recruited, of whom 250 remained in the study at 3 months (higher-C2, n=131; lower-C2, n=119). GFR at 12 months did not differ between the higher- and lower-C2 groups (65+/-17 mL/min vs. 66+/-14 mL/min). When patients were regrouped according to C2 achieved by months 8 to 12, those with the lowest C2 (<700 ng/mL) showed the lowest GFR at month 3 and the most pronounced increase in GFR between month 3 and month 12 (P=0.04). Five episodes of biopsy-proven acute rejection occurred after month 3 (higher-C2 group, n=2; lower-C2 group, n=3). The overall 12-month Kaplan-Meier incidence of biopsy-proven acute rejection was 13.7%. Patient and graft survival were 93% and 89%, respectively, at 12 months. CONCLUSION: Both C2 target ranges investigated showed excellent and nearly equivalent outcomes at 12 months. The decision to target the higher or lower end of these C2 ranges should be made on an individual basis, taking into account patient and graft characteristics, and co-medication.

Clinical outcomes during the first three months posttransplant in renal allograft recipients managed by C2 monitoring of cyclosporine microemulsion.

BACKGROUND: MO2ART (monitoring of 2-hr absorption in renal transplantation) is the first prospective, multicenter trial of cyclosporine (CsA) blood level 2 hr postdose (C2) monitoring in de novo kidney recipients receiving CsA microemulsion (ME) (Neoral; Novartis, Basel, Switzerland). Efficacy and safety results from the first 3 months are presented here. METHODS: MO2ART is a 12-month, open-label, randomized study involving 296 patients. In all patients, the dose of CsA-ME was adjusted to achieve protocol-defined C2 targets of 1.6 to 2.0 microg/mL for the first month, with subsequent tapering. Randomization into two target groups occurred at 3 months. All patients received steroids and mycophenolate mofetil (89%) or azathioprine. For patients with delayed graft function, the protocol permitted reduced C2 targets and prophylactic administration of antibodies. RESULTS: At 3 months, overall incidence of biopsy-proven acute rejection was 11.5%. Median serum creatinine was 132 micromol/L. Patient and graft survival were 96.6% and 91.2%, respectively. C2 levels greater than 1.6 microg/mL were achieved within 5 days by 60.6% of patients with immediate graft function and 19.5% of patients with delayed graft function. Prophylactic antibodies were used in 15% of the total population. Twenty-four patients (8.1%) experienced serious adverse events with a suspected relation to CsA, and 26 patients (8.8%) discontinued the study because of adverse events (n=15) or after a switch in immunosuppression after rejection episodes (n=11). CONCLUSIONS: Patient management by C2 monitoring resulted in a low incidence of biopsy-proven acute rejection in standard risk de novo kidney recipients, 85% of whom did not receive prophylactic antibodies. CsA-ME with C2 monitoring provides excellent short-term efficacy and safety among de novo renal transplant patients.