Safety of Eplerenone for Kidney-Transplant Recipients with Impaired Renal Function and Receiving Cyclosporine A.

BACKGROUND: Animal studies have highlighted the role of vascular mineralocorticoid receptor during Cyclosporine A-induced nephrotoxicity. Mineralocorticoid receptor antagonists could improve kidney survival but are not commonly used during renal impairment and in association with several immunosuppressive drugs due to a supposed higher risk of adverse events. We tested the tolerance of eplerenone according to its expected adverse events: hyperkalemia, metabolic acidosis, hypotension, acute kidney failure, or any other adverse event. METHODS: We conducted a single-center, prospective, open-label study in 31 kidney-transplant recipients with impaired renal function (30 and 50 mL/min/1.73 m2) and receiving cyclosporine A. All patients received eplerenone 25 mg/d for 8 weeks. Serum potassium, renal function and expected adverse events were closely monitored. RESULTS: Eight patients experienced mild hyperkalemia (>5 mmol/L), one moderate hyperkalemia (>5.5 mmol/L) and had to receive potassium-exchange resin. No severe hyperkalemia (>6 mmol/L) occurred. One acute kidney failure was observed, secondary to diarrhea. Basal serum potassium and bicarbonate were independently associated with a higher risk of developing mild hyperkalemia (>5 mmol/L) under treatment (OR 6.5, p = 0.003 and 0.7, p = 0.007, respectively). A cut-off value of 4.35 mmol/L for basal serum potassium was the best factor to predict the risk of developing mild hyperkalemia (>5 mmol/L). CONCLUSIONS: Until eGFR falls to 30 mL/min/1.73 m2, eplerenone could be safely given to kidney-transplant recipients receiving cyclosporine A, if kalemia is closely monitored. When renal function is impaired and if basal kalemia is >4.35 mmol/L, then clinicians should properly balance risk and benefit of eplerenone use and offer dietary advice. An adequately powered prospective randomized study is now needed to test its efficiency (and safety) in this population. TRIAL REGISTRATION: ClinicalTrials.gov NCT01834768.

Microbiological diagnosis of severe diarrhea in kidney transplant recipients by use of multiplex PCR assays.

Diarrhea is a frequent complication after kidney transplantation, ascribed to adverse effects of the immunosuppressive therapy in case of negative microbiological examination of the stools. The aim of this study was to improve the microbiological diagnosis by implementing molecular tests. Fifty-four severe diarrhea events that occurred in 49 adult kidney transplant recipients from September 2010 to November 2011 were investigated. One or several enteric pathogens were detected in 13 (23%) stool samples using classical microbiological methods versus 39 (72%) for the seven commercially available multiplex PCR assays used retrospectively (P = 0.006). Interestingly, molecular diagnosis identified 15 multiple infections compared to none using classical techniques. The primary pathogens detected were enteropathogenic Escherichia coli (EPEC) (n = 15; 38%), Campylobacter spp. (n = 15; 38%), and Norovirus (n = 14; 36%). Specificities for Campylobacter and Norovirus infection diagnosis were 75 and 100%, respectively, by comparison to reference methods. Based on molecular findings, a cyclosporine-mycophenolate mofetil combination was identified as a risk factor for developing Norovirus-induced diarrhea. Norovirus infections were also responsible for higher weight loss than all the other causes of diarrhea. In samples from asymptomatic immunocompromised and immunocompetent patients, EPEC but not Norovirus and Campylobacter infections were detected at a frequency similar to that observed in symptomatic kidney transplant recipients. In conclusion, molecular tools significantly improved the detection of single and multiple enteric infections by comparison to classical techniques and could quickly become the key element in the management of severe acute diarrhea in transplant recipients.

Frequent occurrence of parvovirus B19 DNAemia in the first year after kidney transplantation.

Described for the first time in 1986, Parvovirus B19 (B19V) infection in kidney transplant recipients remains little-known and probably underestimated. The aims of this study were to establish B19V infection frequency during the first year after kidney transplant and to determine predisposing factors and manifestations of the infection in renal transplant recipients. Sixty consecutive adult patients, transplanted less than a year before, were included in this study. B19V and other opportunistic viral infections were detected retrospectively in plasma samples collected every 15 days during the first 3 months and every month from 3 months to 1 year following the kidney transplant. Demographic characteristics, immunosuppressive treatment and biological findings were recorded on each sampling date. Six patients (10%) presented B19V viremia, while eight CMV (13.3%), seven EBV (11.7%), five HHV-6 (8.3%), five BKV (8.3%), and two adenovirus (3.3%) infections were detected. The mean value of B19V viral load was 149 UI/ml. B19V infections were either reactivation or reinfection due to genotype two in five cases, while one case of primary infection with genotype 1 was observed. Neither risk factors nor biological consequences of B19V infection have been identified. These results rank B19V third among opportunistic viral infections occurring during the first year after a kidney transplant. With regard to this high incidence, and even if the risk factors and biological consequences of the infection should be assessed in larger studies, the question of systematic screening and follow-up of B19V infection in kidney transplant recipients is relevant.

[Digital arterial embolization from a previously thrombosed arteriovenous access: a rare and misdiagnosed complication]. / Ischémie digitale par embolie à partir d'un abord d'hémodialyse thrombosé: une complication rare à ne pas méconnaître.

Surgical removal of a hemodialysis access after thrombosis is generally not performed as it remains clinically well tolerated. However, it may be the source of distal embolization. We report the case of a 43-year-old patient, kidney recipient, who presented with digital ischemia of the right hand. He had a forearm arteriovenous fistula at the right wrist which thrombosed 5 years ago. Digital ischemia was due to thrombus formation at the anastomotic site and migration into the downstream arterial bed. Heparine was initiated together with antiplatelet treatment. The ischemia resolved after a few days, no recidive was observed. Surgical ligation of the arteriovenous fistula was rapidly performed and antiplatelet treatment was maintained after surgery. After a follow-up of 6 months, the patient remained asymptomatic without new embolization. This observation underlines the necessity of clinical monitoring after access thrombosis and preventive surgical ligation might be discussed when the risk of distal embolization is high.

Evaluation of sample bias for measuring plasma iohexol clearance in kidney transplantation.

BACKGROUND: Plasma clearance of iohexol (PCI) is becoming a commonly used standard tool in many clinical trials to evaluate the glomerular filtration rate (GFR). However, most studies performing PCI use only early plasma samples (2, 3, and 4 hr). This study aims to evaluate the role of early and late plasma sampling in the precision of PCI calculation in transplant recipients. METHODS: We evaluated 342 renal transplant recipients for both renal clearance (RC) and plasma clearance, using iohexol and six blood samples (2, 3, 4, 5, 6, and 24 hr). Patients were divided into three subgroups according to RC: <30, 30 to 60, and >60 mL/min/1.75 m(2). RESULTS: A simplified technique using early plasma samples overestimated GFR with a mean difference between plasma clearance and RC of 53.3%, 25.7%, and 12.5% for the three subgroups, respectively. This difference decreased to 8.8%, 6.3%, and 5.5%, respectively, when the 24-hr sample was included in plasma clearance calculation. CONCLUSION: These results demonstrate that GFR evaluation by PCI in renal transplant recipients requires a late plasma sample.

[Why and how correct calcidiol deficiency in haemodialysis patients?]. / Pourquoi et comment corriger le déficit en calcidiol chez les patients hémodialysés ?

UNLABELLED: The plasma concentration of 25(OH) D - calcidiol - is low in most of stage 5 renal patients. Due to the lack of renal 1alpha-hydroxylase, no supplementation is recommended. However, calcidiol also displays many extraosseous beneficial antiproliferative effects. It may be useful to correct its deficiency in dialysis patients. The efficacy of an oral supplementation for 6 months with ergocalciferol, (Sterogyl), was evaluated in a monocentric cohort of 107 prevalent hemodialysis patients. Plasma levels of 25(OH) D, parathormone, total and ionized calcium, phosphates, were measured at month 0, 3 and 6 in all patients and plasma levels of 1-25(OH) D at month 0 and 6 in 38 patients with the lowest 25(OH) D levels at baseline. Patients were divided into four groups according to their initial 25(OH) D plasma levels and received ergocalciferol supplementation in accordance to the KDOQI Guidelines for stage 3 and 4 renal patients. RESULTS: 101/107 patients display low levels of 25(OH) D at baseline: mean 11.8+/-11.6 microg/l (normal> 30 microg/l). At the end of the initial three months correction period, the plasma levels of 25(OH) D rose significantly. However, only 60% of patients reach a normal plasma concentration of calcidiol with the highest - 600,000UI - ergocalciferol cumulative dosage. At the end of the three months maintenance period, plasma 25(OH) D concentrations fell in all patients. No significant change was observed in parathormone, calcium, phosphates and 1-25(OH) D plasma levels. There was no hypercalcemic episode. CONCLUSION: KDOQI ergocalciferol recommended doses for stages 3 and 4 renal patients did not correct calcidiol deficiency in hemodialysis patients. New prospective studies are required for defining the modalities of an efficient vitamin D supplementation with ergocalciferol or cholecalciferol.

The clinical evaluation of low-dose heparin in haemodialysis: a prospective study using the heparin-coated AN69 ST membrane.

BACKGROUND: The AN69 ST haemodialysis membrane, a new membrane resulting from coating polyethyleneimine upon the polyacrylonitrile surface, binds heparin. In patients at risk of bleeding, a pilot study has demonstrated the efficient anticoagulant effect of this heparin-coated membrane. Study design. In chronic haemodialyzed patients, we evaluated whether this anticoagulant effect can be validated in a controlled, prospective, open study. Pragmatically, we tested the hypothesis of no difference of the massive clotting rate in two groups of patients haemodialyzed either with 50% reduced standard doses of nonfractionated heparin using the heparin-coated AN69 ST or with a full dose of heparin (100%) using another type of dialysis membrane that does not bind heparin. Secondary objectives included evaluation of partial clotting, changes in haemoglobin levels, erythropoietin consumption and dialyzer performances. RESULTS: One hundred and eighty-four patients were elected and 170 finally included in an 18-month follow-up study. They were allocated to one of the two arms of the study. In the heparin-reduced group (n = 85, mean age: 73 +/- 11 years), 12 472 sessions were performed after priming the AN69 ST dialyzer with 2 L of heparinized saline (5000 IU/L heparin) and using 50% reduced doses of previously administered heparin. In the control group with standard heparin (n = 85, mean age: 74 +/- 13 years), 14 154 sessions were analysed (NS), and mean heparin doses were 2718 +/- 1388 and 4800 +/- 1564 IU per session, respectively (P < 0.001). In the heparin-reduced group, massive clotting occurred in 1.4 per 1000 sessions, whereas it occurred in 1.6 per 1000 sessions in the standard heparin group (P < 0.05). Mild to moderate partial clotting in the venous drip chamber and in the dialyzer was evaluated in a subset of patients, on a visual scale. It was more frequent in the experimental group than in the control group (P < 0.001). Platelets, haemoglobin levels, erythropoietin needs and dialyzer performances remained unchanged in both groups. The global mean death rate was 16.8% per year and did not differ significantly between groups. CONCLUSION: The use of the heparin-coated AN69 ST membrane allows a 50% reduction of standard doses of nonfractionated heparin administration for routine haemo- dialysis without increasing the risk of massive clotting of the extracorporeal circuit. This result needs confirmation since massive clotting questions clinical practice and is team dependent.

Assessment of the heparin-binding AN69 ST hemodialysis membrane: II. Clinical studies without heparin administration.

Binding polyanionic unfractionated heparin over the modified AN69 polyacrylonitrile membrane, the surface electronegativity of which has been neutralized by polyethyleneimine (AN69-ST), renders the membrane more hemocompatible. This property was tested in two groups of long-term hemodialysis patients. Results were rated as massive or partial clotting of a dialyzer at the end of the session. Group I patients were included in a prospective, cross-over study comparing standard dialysis with hemodialysis without systemic administration of unfractionated heparin (n = 12, 123 sessions). In all instances, priming was made with 2 I saline containing 5,000 IU/l heparin. Only patchy or partial clotting was observed in 11% and 39% of the sessions with standard and heparin-free administration, respectively. Group II patients were included in an open, observational pilot study testing the effects of the heparin-coated membrane, without systemic administration of heparin, in patients at high risk of bleeding (n = 68, 331 sessions). Massive clotting was observed in six sessions only (less than 2%) and normal or slightly patchy dialyzers were found in 88% of the sessions. It is concluded that the dialysis AN69 ST membrane, after adequate priming at bedside, can be used without systemic administration of heparin for hemodialysis in patients at high risk of bleeding.

Assessment of heparin binding to the AN69 ST hemodialysis membrane: I. Preclinical studies.

The AN69 ST membrane was designed to render the surface of the native polyacrylonitrile polymer less cationic. This was achieved by layering the membrane with the polycationic biopolymer polyethyleneimine. This new membrane is able to bind heparin to its surface, through electrical interactions, without altering the reactivity of the sulfonate groups of the membrane, regularly distributed in the membrane bulk. The kinetics of unfractionated or low-molecular-weight heparins were studied in vitro and in vivo in sheep. Encouraging results were obtained indicating that heparin-coated hemodialyzers are potent anticoagulants. Priming the AN69 ST membrane-equipped hemodialyzer with heparin, as in regular hemodialysis, could allow drastic reduction of heparin consumption in hemodialysis.

Icodextrin-induced peritonitis: study of five cases and comparison with bacterial peritonitis.

BACKGROUND: An epidemic of aseptic peritonitis related to the presence of peptidoglycan contaminant in some batches of icodextrin solution (Extraneal, Baxter Healthcare Corporation) occurred in Europe in the first six months of 2002. METHODS: By case-control study we examined the clinical and biologic features of 5 patients with icodextrin-induced peritonitis (group AP) and compared them with 7 patients with bacterial peritonitis (group BP) recruited in our clinical center between January and June 2002. RESULTS: Diagnosis of icodextrin-induced peritonitis was confirmed in all cases by a positive reintroduction test with contaminated batches of icodextrin. No recurrence was observed on re-exposure to icodextrin free of peptidoglycan. Skin tests were positive with contaminated icodextrin in 2 of 5 patients, while they were negative with icodextrin solution free of peptidoglycan (<0.6 ng/mL). During peritonitis, serum level of C-reactive protein (CRP) was lower in group AP (42.4 +/- 34 mg/L) than in group BP (135 +/- 59 mg/L) (P= 0.01). Leukocyte number in peritoneal dialysis effluent was lower in group AP (284 +/- 101/mm3), with a lower neutrophil/monocyte ratio (N/M = 0.67) than in group BP (1410 +/- 973/mm3; N/M = 4) (P < 0.05). A low number of peritoneal fluid eosinophilia (11 +/- 8%) was detected in group AP. CONCLUSION: Icodextrin-induced peritonitis was associated with a burst of intraperitoneal cytokines. The phenotype of peritoneal neutrophils was different between aseptic and bacterial peritonitis, indicating that inflammatory stimuli that activate neutrophils in both types of peritonitis are clearly distinct. Finally, peritoneal injury measured by weight gain, peritoneal permeability, and CA125 concentration seemed to be less severe during icodextrin-induced peritonitis than during bacterial peritonitis.

Optimal anticoagulation strategy in haemodialysis with heparin-coated polyacrylonitrile membrane.

BACKGROUND: Binding of polycationic unfractionated heparin onto the modified AN69 polyacrylonitrile membrane, whose surface electronegativity has been neutralized by layering polyethyleneimine (AN69ST), produces stable coating. We investigated whether the heparin-coated membrane was suitable for regular haemodialysis with low heparin doses. METHODS: Sheep were instrumented for extracorporeal circulation perfusing a dialyser equipped with either the AN69ST or the original AN69 membrane. Dialysis sessions were performed after priming the dialyser with heparinized saline. The session was conducted without systemic administration of heparin. In chronic haemodialysis patients, the AN69ST membrane was tested for safety, clotting and thrombin generation according to protocols of 4-h haemodialysis sessions with tapered heparin doses. The goal was to define optimal heparin requirements with the heparin-coated membrane in the setting of continuous or intermittent administration of heparin. Both unfractionated and low molecular weight heparin (LMWH) (enoxaparin) were tested. RESULTS: In sheep, systemic heparin-free haemodialysis was conducted for 6 h without clotting using the heparin-coated dialyser. In the same conditions, massive clotting was observed within 90 min of dialysis with the native AN69 membrane. In man, through kinetic measurements of activated partial thromboplastin time (APTT), heparin anti-Xa concentration and thrombin-anti-thrombin complexes levels (TAT), significant dialyser clotting was avoided when APTT and anti-Xa concentration at 180 min of dialysis, were maintained at >40 s and >0.2 IU/ml, respectively. With the AN69ST heparin-coated membrane, thrombin generation was reduced then suppressed, as compared with the original AN69, primed in the same conditions. Safety of haemodialysis conducted with the AN69ST heparin-coated membrane and low doses of unfractionated heparin (50% reduction of the reference dose) was validated by a survey of 2590 sessions in 32 patients. Doses of LMWH were also safely reduced by 50%. In addition, haemodialysis without systemic administration of heparin was possible with minor risk of clotting. CONCLUSION: During the rinsing phase, the ionic interactions between the new AN69ST polyacrylonitrile membrane and unfractionated heparin induce stable heparin coating. This allows a significant reduction of systemic anticoagulant requirements without increasing the risk of clotting, both in the experimental setting and in the chronic haemodialysis patients. Further studies are required to assess this advantage in patients with acute renal failure and at risk of bleeding and to reduce the metabolic consequences of long-term treatment with heparin.

Amlodipine reduces cyclosporin-induced hyperuricaemia in hypertensive renal transplant recipients.

BACKGROUND: Hypertension and hyperuricaemia are common side-effects of cyclosporin A (CsA) treatment in renal transplant recipients. While it is well established that the calcium channel blocker amlodipine can control CsA-induced hypertension effectively in this patient population, recent evidence suggests amlodipine might also reduce hyperuricaemia. The present study was designed to compare the effects of the calcium channel blocker amlodipine (5-10 mg/day) and the beta-adrenoceptor antagonist tertatolol (5-10 mg/day) on CsA-induced hyperuricaemia in post-renal transplant recipients with hypertension. METHODS: Forty-eight hypertensive renal transplant recipients on a stable dose of CsA were randomized in a double-blind, parallel-group manner to receive either amlodipine (n = 24) or tertatolol (n = 24) for 60 days. The primary outcome measure was the change from baseline in serum uric acid concentration. Secondary analyses of efficacy were based on changes in renal function and blood pressure. RESULTS: Amlodipine significantly decreased serum uric acid levels from 483 +/- 99 to 431 +/- 110 microM/l (P < 0.001), while tertatolol significantly increased uric acid from 450 +/- 98 to 476 +/-84 microM/l (P = 0.006). Amlodipine also significantly increased glomerular filtration rate (P = 0.0048) and the clearance rate of uric acid (P = 0.023) and it reduced the fractional proximal tubular reabsorption of sodium (P < 0.001), compared with tertatolol. Renal plasma flow and filtered fraction were unaffected by both treatments, as was trough CsA blood concentration. Amlodipine lowered systolic blood pressure to a significantly greater extent than did tertatolol (P = 0.007). The time-dependent profile of diastolic blood pressure did not differ significantly between treatment groups. Both drugs were well tolerated. CONCLUSIONS: Amlodipine could be more appropriate than tertatolol for CsA-induced hypertension and hyperuricaemia in renal transplant recipients.