Adherence to therapy: burden, complexity, and perception

peer reviewe

Interleukin-10 Promoter Polymorphisms and Susceptibility to Skin Squamous Cell Carcinoma After Renal Transplantation

After organ transplantation, susceptibility to cancer is multifactorial, especially for skin carcinomas. Risk factors may include genetic susceptibilities, such as the control of cytokine production. Interleukin-10 is a cytokine that is implicated in tumorigenesis, and it has been shown that polymorphisms in its gene promoter correlate with differential amounts of production. The aim of this study was to investigate a possible association between interleukin-10 gene promoter polymorphisms and the occurrence of skin carcinomas after renal transplantation. Seventy kidney transplant recipients who developed a squamous cell carcinoma or a basal cell carcinoma were examined for polymorphisms in the interleukin-10 gene promoter using polymerase chain reaction based methods. Single base pair mutations were studied at positions –1082, –819, and –592. These patients were compared to 70 healthy controls and to 70 matched renal transplant recipients without cancer. The interleukin-10 secretion capability was tested in a subgroup of 40 of these patients by in vitro stimulation of peripheral mononuclear cells. Interleukin-10 genotypes and haplotypes were differently distributed in kidney transplant recipients who developed a skin carcinoma, but especially a squamous cell carcinoma, with an increased frequency of the GCC haplotype and a decreased frequency of the ATA haplotype. Subsequently, we found a shift in the predicted phenotypes from the low production phenotype to the high production phenotype. Secretion of interleukin-10 was strongly correlated to the production predicted phenotype, and tended to be higher in patients who developed a squamous cell carcinoma than in the others. These results indicate that interleukin-10 gene polymorphisms and interleukin-10 production capability may contribute to the development of skin squamous cell carcinomas after renal transplantation

NGAL, biomarker of acute kidney injury

peer reviewedLe diagnostic precoce de l’insufissance renale aigue (IRA) est necessaire et devrait se faire au stade de lesion renale avant meme la degradation du debit de filtration glomerulaire. Plusieurs biomarqueurs d’atteinte renale aigue sont actuellement a l’etude. Parmi ceux-ci, le Neutrophil Gelatinase Associated Lipocalin (NGAL) semble l’un des plus prometteurs et fait l’objet de nombreuses publications. La performance diagnostique de NGAL, dose dans le plasma ou les urines, pour le depistage de l’IRA depend de nombreux facteurs. Bien que les donnees experimentales recentes soient en faveur de l’utilisation preferentielle du dosage urinaire de NGAL, les donnees cliniques issues de nombreuses etudes ne permettent pas de trancher formellement sur la superiorite du dosage urinaire par rapport au dosage plasmatique pour le depistage des atteintes renales aigues. Il n’en reste pas moins que sur le plan analytique, les techniques de dosage du NGAL urinaire sont actuellement plus fiables que celles du dosage plasmatique. La performance diagnostique de NGAL dans un contexte d’IRA est maximale en chirurgie cardiaque pediatrique. Les resultats, chez l’adulte en postoperatoire de chirurgie cardiaque et dans d’autres situations (reanimation, urgences, transplantation), sont moins convaincants. Par ailleurs, il n’est actuellement pas possible d’extrapoler des etudes cliniques une valeur seuil discriminante unique de NGAL, aussi bien dans les urines que dans le plasma. D’autres etudes sont necessaires pour valider definitivement NGAL comme biomarqueur de l’atteinte renale aigue et en preciser les conditions d’utilisation en pratique clinique

Performance de la nouvelle équation CKD-EPI (sans la variable ethnique) en transplantation rénale.

peer reviewe

Estimating GFR in Renal Transplanted Patients With Equations Based on Creatinine (With or Without Race Variable) and/or Cystatin C

peer reviewedAbstract BACKGROUND AND AIMS Current Glomerular filtration rate (GFR) estimating equations based on serum creatinine are facing increased criticism due to the inclusion of a race correction in black Americans with the CKD-EPI equation (CKD-EPIASR, A = Age, S = Sex, R = Race). New equations without race (CKD-EPIAS) has been proposed with creatinine and/or cystatin C. These equations were developed mainly from US cohorts with few renal transplanted patients. In the current analysis, we compared these new equations, notably with the new European Kidney Function Consortium (EKFC) equation. METHOD In this retrospective analysis, 489 transplanted patients from the University Hospital of Saint-Etienne were included. All subjects were white. GFR was measured with inulin or iohexol clearances. IDMS creatinine and standardized cystatin C results were available. Median bias (eGFR—mGFR), imprecision (interquartile range: IQR), and P30 accuracy (percentage of eGFR-values within ± 30% of mGFR) were calculated. RESULTS Among creatinine-based equations, the bias were 2.3, 5.5 and 2.2 mL/min/1.73 m² for the CKD-EPIASR, CKD-EPIAS and EKFC, respectively. IQRs were 16.1, 16.2 and 15.3 mL/min/1.73 m², respectively. P30 were 74.2, 68.3 and 75.3%, respectively. Among cystatin C-based equations, the bias were −3.1 and 0.8 mL/min/1.73 m² for the CKD-EPICC and the EKFCCC, respectively. IQRs were 13.7 and 13.4 mL/min/1.73 m², respectively. P30 were 78.5 and 81.4%, respectively. Among equations combining creatinine and CC, the bias were −1.3, 0.5 and 1.6 mL/min/1.73 m² for the CKD-EPIASR-CC, CKD-EPIAS-CC and EKFCcreatCC, respectively. IQRs were 12.7, 12.4 and 12.1 mL/min/1.73 m², respectively. P30 were 84.5, 82.6 and 80.6%, respectively. CONCLUSION In our cohort of European transplanted patients, both the EKFCcreat and CKD-EPIASR equations performed better than the new CKD_EPIAS. Compared with creatinine-based equations, the new EKFCCC equation and all combined equations performed better. Cystatin C-based equations have the advantage to be accurate without any race variable

20-year longitudinal follow-up of measured and estimated glomerular filtration rate in kidney transplant patients

peer reviewe

Assessing renal graft function in clinical trials: Can tests predicting glomerular filtration rate substitute for a reference method?

Assessing renal graft function in clinical trials: Can tests predicting glomerular filtration rate substitute for a reference method?BackgroundIn clinical trials, comparison of renal graft function needs a rigorous determination of glomerular filtration rate (GFR). Since reference methods to measure GFR cannot be easily implemented, a number of tests predicting GFR are usually used. However, little is known about their validity in renal transplant patients. We aimed to compare the performances of six GFR tests with inulin clearance in this population.MethodsFive hundred consecutive inulin clearances performed in 294 renal transplant recipients with stable renal function were retrospectively selected. For each of them, we computed six estimates: the 24-hour creatinine clearance, the Cockcroft-Gault, Walser, Jelliffe, Nankivell, and Levey formulas. Their respective performance was assessed by correlation (simple linear regression), accuracy (dispersion of true error), and agreement (Bland and Altman method).ResultsEach GFR test closely correlated with inulin clearance (P < 0.0001). Comparisons between pairs of GFR tests did not show any significant difference in accuracy between the Levey, Jelliffe, and Walser formulas. Conversely, each of these formulas demonstrated a significant lower dispersion (P < 0.005) than the others. Nevertheless, all GFR tests displayed considerable lack of agreement with limits of agreement over 40mL/min/1.73m2 apart. The proportion of predicted GFR differing from inulin clearance by ± 10mL/min/1.73m2, ranged from 34% for the Jelliffe formula to 53% for the Nankivell's one.ConclusionNone of these formulas seems to be able to safely substitute for inulin clearance. In clinical trials, renal graft function should be preferably assessed using a reference method of GFR measurement

Continuous infusion of ceftazidime in critically ill patients undergoing continuous venovenous haemodiafiltration: pharmacokinetic evaluation and dose recommendation

INTRODUCTION: In seriously infected patients with acute renal failure and who require continuous renal replacement therapy, data on continuous infusion of ceftazidime are lacking. Here we analyzed the pharmacokinetics of ceftazidime administered by continuous infusion in critically ill patients during continuous venovenous haemodiafiltration (CVVHDF) in order to identify the optimal dosage in this setting. METHOD: Seven critically ill patients were prospectively enrolled in the study. CVVHDF was performed using a 0.6 m(2 )AN69 high-flux membrane and with blood, dialysate and ultrafiltration flow rates of 150 ml/min, 1 l/hour and 1.5 l/hour, respectively. Based on a predicted haemodiafiltration clearance of 32.5 ml/min, all patients received a 2 g loading dose of ceftazidime, followed by a 3 g/day continuous infusion for 72 hours. Serum samples were collected at 0, 3, 15 and 30 minutes and at 1, 2, 4, 6, 8, 12, 24, 36, 48 and 72 hours; dialysate/ultrafiltrate samples were taken at 2, 8, 12, 24, 36 and 48 hours. Ceftazidime concentrations in serum and dialysate/ultrafiltrate were measured using high-performance liquid chromatography. RESULTS: The mean (± standard deviation) elimination half-life, volume of distribution, area under the concentration-time curve from time 0 to 72 hours, and total clearance of ceftazidime were 4 ± 1 hours, 19 ± 6 l, 2514 ± 212 mg/h per l, and 62 ± 5 ml/min, respectively. The mean serum ceftazidime steady-state concentration was 33.5 mg/l (range 28.8–36.3 mg/l). CVVHDF effectively removed continuously infused ceftazidime, with a sieving coefficient and haemodiafiltration clearance of 0.81 ± 0.11 and 33.6 ± 4 mg/l, respectively. CONCLUSION: We conclude that a dosing regimen of 3 g/day ceftazidime, by continuous infusion, following a 2 g loading dose, results in serum concentrations more than four times the minimum inhibitory concentration for all susceptible pathogens, and we recommend this regimen in critically ill patients undergoing CVVHDF

ROXADUSTAT FOR THE TREATMENT OF ANEMIA IN CHRONIC KIDNEY DISEASE PATIENTS NOT ON DIALYSIS: A PHASE 3 RANDOMIZED OPEN-LABEL ACTIVE-CONTROLLED STUDY (DOLOMITES)

Cilj rada: Ocjena oralnog inhibitora prolil-hidroksilaze hipoksijom induciranog faktora roksadustata za liječenje anemije povezane s kroničnom bubrežnom bolešću (KBB). Metode: U ovom su se randomiziranom, otvorenom, aktivnim lijekom kontroliranom ispitivanju faze 3 uspoređivali roksadustat i darbepoetin alfa (DA) u bolesnika s anemijom i KBB-om neovisnih o dijalizi tijekom razdoblja od ≤ 104 tjedna. Doze lijeka titrirale su se da bi se razina hemoglobina (Hb) korigirala i održala u rasponu od 10,0 do 12,0 g/dl. Primarna mjera ishoda bio je odgovor Hb-a u cjelovitom skupu podataka za analizu, koji se defi nirao kao Hb ≥ 11,0 g/dl i promjena početne vrijednosti Hb-a za ≥ 1,0 g/dl u bolesnika kojima je početni Hb iznosio > 8,0 g/dl odnosno promjena početne vrijednosti Hb-a za ≥ 2,0 g/dl u bolesnika kojima je početni Hb bio ≤ 8,0 g/dl tijekom prva 24 tjedna liječenja bez primjene dodatne terapije za postizanje zadovoljavajuće razine hemoglobina (rescue) (granica neinferiornosti: 15 %). Ključne sekundarne mjere ishoda uključivale su promjenu vrijednosti lipoproteina male gustoće (LDL), vrijeme do prve intravenske (i.v.) primjene željeza, promjenu srednjeg arterijskog tlaka i vrijeme do pojave hipertenzije. U ispitivanju su se ocjenjivale i nuspojave. Rezultati: Od 616 randomiziranih bolesnika (roksadustat: 323; DA: 293) 424 dovršilo je liječenje (roksadustat: 215; DA: 209). Odgovor Hb-a zabilježen uz roksadustat bio je neinferioran onome opaženome uz DA [roksadustat: 256/286 (89,5 %) u odnosu na DA: 213/273 (78,0 %); razlika: 11,51 %; interval pouzdanosti od 95 %: 5,66 - 17,36 %]. Roksadustat je održao vrijednosti Hb-a tijekom razdoblja do 2 godine. Roksadustat je bio neinferioran u odnosu na DA s obzirom na promjenu srednjeg arterijskog tlaka i vrijeme do nastupa hipertenzije, a superioran s obzirom na promjenu vrijednosti LDL-a i vrijeme do prve i.v. primjene željeza. Obje su skupine imale usporedive sigurnosne profi le. Rezultati pokazuju da nije bilo razlike između skupina s obzirom na kompozitne mjere ishoda, koje su uključivale velike kardiovaskularne štetne događaje (MACE) i MACE+ [MACE: 0,81 (0,52 - 1,25), P=0,339; MACE+: 0,90 (0,61 - 1,32), P=0,583]. Zaključak: Roksadustat je prihvatljiva opcija za liječenje anemije u bolesnika s KBB om neovisnih o dijalizi, koja omogućuje održane razine Hb-a tijekom razdoblja do 104 tjedna.Background: Roxadustat, an orally administered hypoxia-inducible factor prolyl hydroxylase inhibitor, is being evaluated for the treatment of anemia of chronic kidney disease (CKD). Methods: This randomized, open-label, active-controlled Phase 3 study compared roxadustat versus darbepoetin alfa (DA) in non-dialysis-dependent (NDD) CKD patients with anemia for ≤104 weeks. Doses were titrated to correct and maintain hemoglobin (Hb) within 10.0-12.0 g/dL. The primary endpoint was Hb response in the full analysis set, defi ned as Hb ≥11.0 g/dL and Hb change from baseline (BL; CFB) ≥1.0 g/dL in patients with BL Hb >8.0 g/dL or CFB ≥2.0 g/dL in patients with BL Hb ≤8.0 g/dL during the fi rst 24 weeks of treatment without rescue therapy (non-inferiority margin, -15%). The key secondary endpoints included change in low-density lipoprotein (LDL), time to fi rst intravenous (IV) iron use, change in mean arterial pressure (MAP), and time to hypertension occurrence. Adverse events were assessed. Results: Of 616 randomized patients (roxadustat, 323; DA, 293), 424 completed treatment (roxadustat, 215; DA, 209). Hb response with roxadustat was non-inferior to DA (roxadustat: 256/286, 89.5% versus DA: 213/273, 78.0%, difference 11.51%, 95% confi dence interval 5.66-17.36%). Roxadustat maintained Hb for up to 2 years. Roxadustat was non-inferior to DA for change in MAP and time to occurrence of hypertension, and superior for change in LDL and time to fi rst IV iron use. Safety profi les were comparable between the groups. Findings suggest that there was no difference between groups regarding the composite endpoints major adverse cardiovascular events (MACEs) and MACE+[MACE: 0.81 (0.52-1.25), p=0.339; MACE+: 0.90 (0.61-1.32), p=0.583]. Conclusions: Roxadustat is a viable option to treat anemia in NDD CKD patients maintaining Hb levels for up to 104 weeks