COVID-19 Infection in Kidney Transplant Recipients: Disease Incidence and Clinical Outcomes.

BACKGROUND: COVID-19 has been associated with high morbidity and mortality in kidney transplant recipients. However, risk factors for COVID-19 disease in patients with kidney transplants remain poorly defined. METHODS: We enrolled patients who underwent kidney transplantation and were actively followed up in two hospitals in Paris on March 1st, 2020. Patients were screened for baseline and transplant characteristics, functional parameters, comorbidities, and immunosuppressive therapies. COVID-19 disease was assessed. Patients were followed up during the pandemic until April 30th, 2020 by the COVID-19 SLS KT survey program, including teleconsulting, at-home monitoring for patients with COVID-19, and a dedicated phone hotline platform. RESULTS: Among 1216 patients with kidney transplants enrolled, 66 (5%) patients were identified with COVID-19 disease, which is higher than the incidence observed in the general population in France (0.3%). Their mean age was 56.4±12.5 years, and 37 (56%) patients were men. The following factors were independently associated with COVID-19 disease: non-White ethnicity (adjusted odds ratio [OR], 2.17; 95% confidence interval [95% CI], 1.23 to 3.78; P=0.007), obesity (OR, 2.19; 95% CI, 1.19 to 4.05; P=0.01), asthma and chronic pulmonary disease (OR, 3.09; 95% CI, 1.49 to 6.41; P=0.002), and diabetes (OR, 3.33; 95% CI, 1.92 to 5.77; P<0.001). The mortality rate related to COVID-19 disease was 1% in the overall study population and 24% in COVID-19-positive patients. CONCLUSIONS: Patients with kidney transplants display a high risk of mortality. Non-White ethnicity and comorbidities such as obesity, diabetes, asthma, and chronic pulmonary disease were associated with higher risk of developing COVID-19 disease. It is imperative that policy makers urgently ensure the integration of such risk factors on response operations against COVID-19.

Evaluation of outcomes in renal transplantation with hypothermic machine perfusion for the preservation of kidneys from expanded criteria donors.

In 2012, an expert working group from the French Transplant Health Authority recommended the use of hypothermic machine perfusion (HMP) to improve kidney preservation and transplant outcomes from expanded criteria donors, deceased after brain death. This study compares HMP and cold storage (CS) effects on delayed graft function (DGF) and transplant outcomes. We identified 4,316 kidney transplants from expanded criteria donors (2011-2014) in France through the French Transplant Registry. DGF occurrence was analyzed with a logistic regression, excluding preemptive transplants. One-year graft failure was analyzed with a Cox regression. A subpopulation of 66 paired kidneys was identified: one preserved by HMP and the other by CS from the same donor. Kidneys preserved by HMP (801) vs CS (3515) were associated with more frequent recipient comorbidities and older donors and recipients. HMP had a protective effect against DGF (24% in HMP group and 38% in CS group, OR = 0.49 [0.40-0.60]). Results were similar in the paired kidneys (OR = 0.23 [0.04-0.57]). HMP use decreased risk for 1-year graft failure (HR = 0.77 [0.60-0.99]). Initial hospital stays were shorter in the HMP group (P < 0.001). Our results confirm the reduction in DGF occurrence among expanded criteria donors kidneys preserved by HMP.

Candiduria in kidney transplant recipients: Is antifungal therapy useful?

A French single-centre retrospective study between 2010 and 2014 was undertaken to assess candiduria's incidence in kidney transplant recipients (KTR), and the use and impact of antifungal treatment on outcome. Candiduria was defined as a urine culture with ≥103  cfu/mL of Candida species. Candiduria clearance, severe complications and death rates were estimated by Kaplan-Meier methods and the effect of treatment by Cox models. 52/1223 (4.3%) KTR had ≥1 episode of candiduria, 42 (81%) were females, 18 (35%) had diabetes, with an incidence of 2.3/100 person-year of follow-up. Candiduria was asymptomatic in 51 (98%) patients. Candida glabrata was the most frequent pathogen identified. Overall fungal clearance rate was 89%. Antifungal therapy was initiated in only 14 episodes (12%), according to guidelines. Three patients (6%) developed severe complications in the first 2 weeks after transplantation, and 8 (15%) died. Antifungal treatment had no impact on candiduria clearance (HR, 0.6; 95% CI, 0.3-1.1; P = .10), on recurrence rate (HR, 0.5; 95% CI, 0.1-2.3; P = .41) and on the risk of severe complications or death (HR, 1.1; 95% CI, 0.3-4.8; P = .89). Candiduria is rare and usually asymptomatic among KTR. Candiduria management in the immediate post-transplant period deserves careful attention.

[Renal transplantation from ABO incompatible donors]. / TRANSPLANTATION RÉNALE ABO INCOMPATIBLE.

ABC-incompatible (ABOi) living donor renal transplantation is being developed since the 80s, and may provide a significant source of organs. Blood group A and B antigens are expressed not only on red blood cells but also on renal vascular endothelial and renal epithelial membranes. Each individual has preformed natural antibodies against his/ her absent A and/or B antigens. These antibodies may directly damage the ABOi allograft and cause its diffuse thrombosis and primary non-function. ABOi allogratf recipients are conditioned with one dose of rituximab (as a "pharmacological splenectomy") and oral immunosuppressive treatment is introduced several days pre-operatively. Anti A/B titers are lowered by plasmapheresis or specific immunoadsorption. Close follow-up is mandatory in the first two weeks after transplantation, due to higher acute humoral rejection risk, until reaching an "accommodation" state. Thereafter, graft and patient survivals are the same as those of ABO compatible renal transplantations.

Kidney allograft fibrosis after transplantation from uncontrolled circulatory death donors.

BACKGROUND: Existing data suggest that increased interstitial fibrosis may occur abnormally in renal transplants from donations after uncontrolled circulatory death (uDCD). METHODS: To evaluate the factors that are associated with the progression of fibrosis and its functional impact on renal grafts, we compared 76 uDCD recipients with 86 recipients of kidney donations after brain death at 1-year after transplantation. Groups were matched for donor age, rank of transplantation, and absence of human leukocyte antigen sensitization. Histology was performed on sequential biopsies in uDCD recipients. Associations between variables were analyzed using linear mixed models and univariate analyses. RESULTS: In the uDCD group, increased fibrosis was detected 3 months after transplantation compared to before implantation. After 1 year, interstitial fibrosis and tubular atrophy score was significantly greater (1.5±0.7 vs. 1.0±0.9; P=0.003) and estimated glomerular filtration rate (49.5±17.4 vs. 60.6±19.1 mL/min/1.73 m2; P=0.0003) was significantly lower in the uDCD group than in the donations after brain death group. No flow duration and donor age were significantly associated with accelerated fibrosis. Interstitial fibrosis and tubular atrophy score, interstitial inflammation score, and estimated glomerular filtration rate were significantly worse in uDCD patients with no flow longer than 10 min. CONCLUSION: Donations after uncontrolled circulatory death grafts show more fibrosis after transplantation. No flow duration is associated with accelerated fibrosis and should be considered during uDCD graft allocation.

[Renal complications after hematopoietic stem cell transplantation]. / Complications rénales au décours de la greffe de cellules souches hématopoïétiques.

Hematopoietic stem cell transplantation is a widely used therapeutic modality for many, mainly malignant, diseases. Toxicities of this procedure include acute and chronic renal dysfunction. Acute renal failure, generally reversible is due to acute tubular necrosis (tumor lysis syndrome, marrow-infusion toxicity, sepsis, nephrotoxins), hepatic veno-occlusive disease or acute graft-versus-host disease. Chronic renal failure is often multifactorial, caused by conditioning-associated endothelial cell toxicity (bone marrow transplant nephropathy) and calcineurin inhibitors toxicity. Renal pathologic findings are somewhat similar to thrombotic microangiopathy, with sometimes systemic disease. Rare cases of nephrotic syndrome have been described after hematopoietic stem cell transplantation, mainly membranous nephropathy, associated with graft-versus-host disease. Therapeutic options for renal dysfunction after hematopoietic stem cell transplantation are limited but kidney transplantation is possible in case of end-stage renal disease.

Kidney graft dysfunction in simultaneous pancreas-kidney recipients after pancreas failure: analysis of early and late protocol biopsies.

BACKGROUND: Kidney graft survival in simultaneous pancreas-kidney (SPK) recipients is known to decrease after pancreas graft failure. METHODS: Sixty-three consecutive SPK recipients were retrospectively reviewed. Kidney graft function and proteinuria were evaluated at three months after the transplantation and at last follow-up. Histopathologic findings of protocol biopsies performed three months and one yr after transplantation were analyzed. RESULTS: Twelve patients lost the pancreas graft. Donors' characteristics were similar in patients with or without pancreas failure. After a median follow-up of 36 months, mean eGFR with a functional pancreas was 69.5 mL/min/1.73 m² vs. 56.3 mL/min/1.73 m² (p = 0.01) after pancreas loss. Patients who lost pancreas had a median proteinuria of 0.28 g vs. 0.13 g per 24 h (p = 0.02). Analysis of three-month protocol biopsies revealed more frequent isolated glomerulitis after pancreas failure (p = 0.0001), without peritubular capillaritis or C4d deposition. No donor-specific anti-HLA antibodies were detectable in these patients. Chronic tubulointerstitial changes were more frequent in patients with pancreas loss. There was no evidence of diabetic nephropathy recurrence. CONCLUSION: SPK recipients develop an early kidney graft dysfunction after pancreas failure. Histopathologic findings revealed frequent glomerulitis without antibody-mediated rejection and early chronic changes.

Chronic kidney diseases in long-term survivors after allogeneic hematopoietic stem cell transplantation: monitoring and management guidelines.

Chronic kidney disease (CKD) occurs commonly (prevalence of approximately 20% in a large series) after allogeneic hematopoietic stem cell transplantation (HSCT). There are three distinct clinical entities that occur after HSCT: thrombotic microangiopathy (TMA), nephrotic syndrome (NS), and idiopathic or graft-versus-host disease (GVHD)-related CKD. Acute renal function decline occurs in the majority of patients in the first months after transplantation. This acute kidney injury can persist and is a risk factor for the later development of CKD. However, the potentially independent role of GVHD, chronic inflammation, and chronic exposure to calcineurin inhibitors in the development and progression of CKD warrants further investigation. Careful monitoring of blood pressure, renal function, and proteinuria is mandatory in patients undergoing HSCT, especially older patients with pre-existent renal impairment. Renal function should be evaluated before HSCT and monitoring should occur at least every 6 to 12 months in these patients. Renal biopsies are indicated in patients with proteinuria and persistent or progressive rises in serum creatinine to determine etiology and prevent progression to end-stage renal disease (ESRD).

Preliminary results of transplantation with kidneys donated after cardiocirculatory determination of death: a French single-centre experience.

BACKGROUND: Donation after circulatory determination of death (DCDD), formerly non-heart-beating donation and donation after cardiac death, has been re-introduced into clinical practice in France since June 2006 as a potential solution to organ shortage, but this kidney transplantation programme is not popular yet, mainly because of logistical concerns and uncertainty about the long-term warm ischaemia impact on transplanted kidneys. METHODS: Our institution started the DCDD programme in January 2007, following the national 'BioMedicine Agency' protocol. We only considered uncontrolled donors with an initial no-flow period (i.e. delay between collapse and external cardiac massage start) <30 min. A 5-min stand-off period was observed before declaring the death and performing in situ cold perfusion, and since January 2010, normothermic subdiaphragmatic extracorporeal membrane oxygenation. All kidneys were machine-perfused using the hypothermic pulsatile preservation system before transplantation. Morphologic assessment and perfusion indexes were used to assess the suitability for transplantation. RESULTS: From January 2007 to December 2010, our team performed 58 kidney transplantations from uncontrolled Maastricht Category I and II donors. Mean recipient age was 47 ± 9 years. Male/female ratio was 45/13. Mean waiting time on transplantation registry was 30 months (4-180). Mean cold ischaemia time was 13 h 40 min (7-18) and pulsatile perfusion time 8 h (1-16). We had three cases (5%) of primary non-function (PNF) and 95% of delayed graft function. There was no increase in biopsy-proven acute rejection incidence (12.7%). Patient and graft survivals were 98 and 91.4%, respectively, at 1 year and 98 and 88%, respectively, at last follow-up. Estimated glomerular filtration rate ( Modification of Diet in Renal Disease formula) was 48 ± 16 mL/min/1.73 m(2) at 1 year and 48 ± 15 mL/min/1.73 m(2) at the last follow-up. CONCLUSIONS: DCDD kidneys are a valuable additional source of organs for transplantation. Our results show encouraging outcomes, which give rise to further interest in this donor pool. Respecting the national protocol is crucial to prevent PNF and deleterious warm ischaemia effect on transplanted kidney.

Plasma neutrophil gelatinase-associated lipocalin in kidney transplantation and early renal function prediction.

BACKGROUND: This prospective observational study aimed to assess the relevance of serial postoperative plasma neutrophil gelatinase-associated lipocalin (NGAL) measurements on prediction of early renal transplant function. METHODS: Plasma NGAL (pNGAL) was measured (Triage NGAL Test; Biosite Inc., Inverness Medical) in 41 patients scheduled for kidney transplantation from deceased or living donors, immediately before and after surgery, and at 12 hr, day 1, day 3, and day 7. A delayed graft function (DGF) was defined as the need for dialysis during the first week. The results were expressed as median (Q1, Q3). RESULTS: Of the 41 consecutive patients enrolled, all had a high preoperative pNGAL level: 453 ng/mL (382, 595). Fifteen (36.6%) presented a DGF. In patients with DGF, pNGAL was significantly higher at 12 hr (571 [467, 634] vs. 242 [158, 299] ng/mL, P<0.0001) and at day 1 (466 [356, 627] vs. 165 [91, 248] ng/mL, P<0.0001). A pNGAL higher than 400 ng/mL 12 hr after transplantation predicted DGF with a sensitivity of 93.3%, a specificity of 88.5%, and an odds ratio of 63.2 (P=0.0004). This predictive performance was higher than for plasma creatinine. CONCLUSIONS: pNGAL level early and accurately predicted DGF after renal transplantation. pNGAL measurements allowed monitoring of the renal function in this striking situation of ischemia-reperfusion aggression. Early identification of patients at risk of DGF, before graft lesions are consolidated, opens the field of a precise monitoring of renal injury and the impact of future protective therapeutics.

Pulsatile perfusion preservation for expanded-criteria donors kidneys: Impact on delayed graft function rate.

PURPOSE: Expanded criteria donors (ECD) kidneys are a potential solution to organ shortage, but exhibit more delayed graft function (DGF). We conducted a prospective controlled study aiming to evaluate the impact of pulsatile perfusion preservation (PPP) on DGF rate. METHODS: Inclusion criteria were: 1) ECD definition (any brain-dead donor aged > 60 years or aged 50-60 years with at least 2 of the following: history of hypertension, terminal serum creatinin level = 1.5 mg/dL, death resulting from a cerebrovascular accident; 2) Donor prolonged circulatory arrest (> 20 mn); 3) previsible cold ischemia time longer than 24 hours. In each pair of kidneys, one organ was preserved with PPP and the other organ was preserved in static cold storage. RESULTS: From February 2007 to September 2009, a total of 22 donors (44 recipients) were included. Recipients were comparable in the two groups with respect to demographic and immunological data. The rate of DGF was significantly lower (9% vs. 31.8%, p = 0.021) in the PPP group. At 1, 3, and 12 months, renal function was comparable in the two groups. CONCLUSIONS: Pulsatile perfusion preservation significantly reduced DGF rate in ECD kidney transplantation.

Calcineurin inhibitor-free monotherapy in human leukocyte antigen­identical live donor renal transplantation.

BACKGROUND: Most recent trials in human leukocyte antigen (HLA)-identical living donor (LD) renal transplantation have used immunosuppressive regimens with no induction therapy, corticosteroid-free long-term treatment, and calcineurin inhibitor minimization. PATIENTS AND METHODS: Seven HLA-identical LD recipients were prospectively enrolled. Immunosuppression included induction therapy with antithymocyte globulins for 10 days and long-term monotherapy with mycophenolate mofetil (2 g/day) in six cases and sirolimus (target trough levels: 6-10 ng/mL) in the last case. A single preoperative steroid bolus was administered. RESULTS: After a median follow-up time of 26 months (range: 5-50 months), patient and graft survival was 100%. Only one patient experienced borderline lesions at 3 months and received steroids for a 5-month period. All patients had a protocol biopsy at 3 months, and four had a second at 12 months. Acute cellular rejection was not observed. Median serum creatinine at 3 months, 12 months, and last follow-up were 103.1, 107.1, and 106.1 [mu]mol/L, respectively. For four patients, measured glomerular filtration rate was evaluated at 3 months, and the mean value was 71.2 mL/min/1.73 m2. CONCLUSIONS: Induction therapy with antithymocyte globulins followed by mycophenolate mofetil or sirolimus monotherapy provides excellent patient and graft survival, excellent renal function, and no acute rejection episodes in HLA-identical LD renal transplant recipients.

Impact of morbidity and mortality conferences on analysis of mortality and critical events in intensive care practice.

BACKGROUND: Morbidity and mortality conferences are a tool for evaluating care management, but they lack a precise format for practice in intensive care units. OBJECTIVES: To evaluate the feasibility and usefulness of regular morbidity and mortality conferences specific to intensive care units for improving quality of care and patient safety. METHODS: For 1 year, a prospective study was conducted in an 18-bed intensive care unit. Events analyzed included deaths in the unit and 4 adverse events (unexpected cardiac arrest, unplanned extubation, reintubation within 24-48 hours after planned extubation, and readmission to the unit within 48 hours after discharge) considered potentially preventable in optimal intensive care practice. During conferences, events were collectively analyzed with the help of an external auditor to determine their severity, causality, and preventability. RESULTS: During the study period, 260 deaths and 100 adverse events involving 300 patients were analyzed. The adverse events rate was 16.6 per 1000 patient-days. Adverse events occurred more often between noon and 4 pm (P = .001).The conference consensus was that 6.1% of deaths and 36% of adverse events were preventable. Preventable deaths were associated with iatrogenesis (P = .008), human errors (P < .001), and failure of unit management factors or communication (P = .003). Three major recommendations were made concerning standardization of care or prescription and organizational management, and no similar incidents have recurred. CONCLUSION: In addition to their educational value, regular morbidity and mortality conferences formatted for intensive care units are useful for assessing quality of care and patient safety.

A paraneoplastic membranoproliferative glomerulonephritis with isolated C3 deposits associated with hairy cell leukaemia.

We describe a 35-year-old woman who presented with proteinuria and microscopic haematuria. Blood tests revealed a low C3 complement level, with no evidence of cryoglobulin. Renal biopsy showed a Type 1 membranoproliferative glomerulonephritis (MPGN) with isolated C3 deposits on immunofluorescence study. Bone marrow aspirate, done for monocytopenia, was consistent with a diagnosis of hairy cell leukaemia (HCL). Both haematological and nephrological diseases completely responded to treatment with cladribine, strongly suggesting that the renal disease was a paraneoplastic syndrome. To our knowledge, this is the first report of a non-cryoglobulinaemic MPGN associated to HCL.

Kidney retrieval after sudden out of hospital refractory cardiac arrest: a cohort of uncontrolled non heart beating donors.

INTRODUCTION: To counter the shortage of kidney grafts in France, a non heart beating donor (NHBD) program has recently been implemented. The aim of this study was to describe this pilot program for kidney retrieval from "uncontrolled" NHBD meaning those for whom attempts of resuscitation after a witnessed out-of-hospital cardiac arrest (CA) have failed (Maastricht 1 and 2), in a centre previously trained for retrieval from brain dead donors. METHODS: A prospective, monocentric, descriptive study concerning NHBD referred to our institution from February 2007 to June 2008. The protocol includes medical transport of refractory CA under mechanical ventilation and external cardiac massage, kidney protection by insertion of an intraaortic double-balloon catheter (DBC) with perfusion of a hypothermic solution, kidney retrieval and kidney preservation in a hypothermic pulsatile perfusion machine. RESULTS: 122 potential NHBD were referred to our institution after a mean resuscitation attempt of 35 minutes (20-95). Regarding the contraindications, 63 were finally accepted and 56 had the DBC inserted. Organ retrieval was performed in 27 patients (43%) and 31 kidneys out of the 54 procured (57%) have been transplanted. Kidney transplantation exclusion was related to family refusal (n = 15), past medical history, time constraints, viral serology, high vascular ex vivo resistance of the graft and macroscopic abnormalities. The 31 kidneys exhibited an expected high delayed graft function rate (92%). Despite these initial results transplanted kidney had good creatinine clearance at six months (66 +/- 24 ml/min) with a 89% graft survival rate at six months. CONCLUSIONS: This study shows the feasibility and efficacy of an organ procurement program targeting NHBD allowing a 10% increase in the kidney transplantation rate over 17 months. With a six months follow-up period, the results of transplanted kidney function were excellent.

Chronic kidney dysfunction in patients alive without relapse 2 years after allogeneic hematopoietic stem cell transplantation.

Allogeneic hematopoietic stem cell transplantation (HSCT) is the treatment of choice for a wide range of diseases, but is associated with a significant risk of chronic kidney disease (CKD), affecting up to 25% of survivors with a significant morbidity. The causes of CKD after HSCT vary between different studies. The present study evaluated CKD in patients undergoing allogeneic HSCT. We analyzed the clinical course of 148 patients who received allogeneic HSCT at the University Hospital of St. Louis in Paris between 1999 and 2002 and were alive after 2 years without relapse. CKD was defined as a glomerular filtration rate (GFR) <60 mL/min/1.73 m(2), using the abbreviated modification of diet in renal disease (MDRD) equation for adults and the Schwartz formula for children. Of the 148 relapse-free 2-year survivors, 11 (7%) patients had renal dysfunction. No chronic renal failure was noted in the younger age group (<15 years at transplantation). CKD was associated with total body irradiation (TBI) (odds ratio [OR] = 4.53; 95% confidence interval [CI] 1.15 to 17.9; P = .026) and chronic graft-versus-host disease (cGVHD) (OR = 4.58; 95% CI 1.16-18.1; P = .026). Only 1 additional patient developed CKD between 2 and 5 years of follow-up (cumulative incidence of 0.7% over the 3-year period). In the CKD group, renal function tended to stabilize over the 3-year period (estimated GFR 45 +/- 14 mL/min/1.73 m(2) at 2 years and 46 +/- 14 mL/min/1.73 m(2) at 5 years). A 7% prevalence of CKD was noted in the relapse-free 2-year survivor patients. Renal impairement was correlated with TBI and cGVHD. Minor incidence of CKD and a relative stability of renal function were noted between 2 and 5 years after HSCT.

Pharmacokinetics of epinephrine in patients with septic shock: modelization and interaction with endogenous neurohormonal status.

INTRODUCTION: In septic patients, an unpredictable response to epinephrine may be due to pharmacodynamic factors or to non-linear pharmacokinetics. The purpose of this study was to investigate the pharmacokinetics of epinephrine and its determinants in patients with septic shock. METHODS: Thirty-eight consecutive adult patients with septic shock were prospectively recruited immediately before epinephrine infusion. A baseline blood sample (C0) was taken to assess endogenous epinephrine, norepinephrine, renin, aldosterone, and plasma cortisol levels before epinephrine infusion. At a fixed cumulative epinephrine dose adjusted to body weight and under steady-state infusion, a second blood sample (C1) was taken to assess epinephrine and norepinephrine concentrations. Data were analyzed using the nonlinear mixed effect modeling software program NONMEM. RESULTS: Plasma epinephrine concentrations ranged from 4.4 to 540 nmol/L at steady-state infusion (range 0.1 to 7 mg/hr; 0.026 to 1.67 microg/kg/min). A one-compartment model adequately described the data. Only body weight (BW) and New Simplified Acute Physiologic Score (SAPSII) at intensive care unit admission significantly influenced epinephrine clearance: CL (L/hr) = 127 x (BW/70)0.60 x (SAPS II/50)-0.67. The corresponding half-life was 3.5 minutes. Endogenous norepinephrine plasma concentration significantly decreased during epinephrine infusion (median (range) 8.8 (1 - 56.7) at C0 vs. 4.5 (0.3 - 38.9) nmol/L at C1, P < 0.001). CONCLUSIONS: Epinephrine pharmacokinetics is linear in septic shock patients, without any saturation at high doses. Basal neurohormonal status does not influence epinephrine pharmacokinetics. Exogenous epinephrine may alter the endogenous norepinephrine metabolism in septic patients.

Impact of energy deficit calculated by a predictive method on outcome in medical patients requiring prolonged acute mechanical ventilation.

To assess energy balance in very sick medical patients requiring prolonged acute mechanical ventilation and its possible impact on outcome, we conducted an observational study of the first 14 d of intensive care unit (ICU) stay in thirty-eight consecutive adult patients intubated at least 7 d. Exclusive enteral nutrition (EN) was started within 24 h of ICU admission and progressively increased, in absence of gastrointestinal intolerance, to the recommended energy of 125.5 kJ/kg per d. Calculated energy balance was defined as energy delivered - resting energy expenditure estimated by a predictive method based on static and dynamic biometric parameters. Mean energy balance was - 5439 (sem 222) kJ per d. EN was interrupted 23 % of the time and situations limiting feeding administration reached 64 % of survey time. ICU mortality was 72 %. Non-survivors had higher mean energy deficit than ICU survivors (P = 0.004). Multivariate analysis identified mean energy deficit as independently associated with ICU death (P = 0.02). Higher ICU mortality was observed with higher energy deficit (P = 0.003 comparing quartiles). Using receiver operating characteristic curve analysis, the best deficit threshold for predicting ICU mortality was 5021 kJ per d. Kaplan-Meier analysis showed that patients with mean energy deficit > or =5021 kJ per d had a higher ICU mortality rate than patients with lower mean energy deficit after the 14th ICU day (P = 0.01). The study suggests that large negative energy balance seems to be an independent determinant of ICU mortality in a very sick medical population requiring prolonged acute mechanical ventilation, especially when energy deficit exceeds 5021 kJ per d.