Accepted: 7 April 1999

L. Gesualdo ()) ´ G. Grandaliano ´ G. Pertosa ´ F. P. SchenaDivision of Nephrology,Department of Emergency Medicine and Transplantation,University of Bari Policlinico,Piazza Giulio Cesare 11, I-70124 Bari, Italye-mail: l.gesualdo@nephro.uniba.itFax: + 39±080±5 575710

L. MasciaDivision of Anesthesia and Intensive Care,Department of Emergency Medicine and Transplantation,University of Bari Policlinico,Piazza Giulio Cesare 11, I-70124 Bari, Italy

Introduction

Acute renal failure (ARF) is a frequent complication ofcritically ill patients in the intensive care unit (ICU). Itmay be part of a multiorgan dysfunction syndrome(MODS) or may develop as an isolated complication.Numerous studies over the last two decades have clearlydemonstrated that a decrease in glomerular capillarypermeability, back-leak of glomerular filtrate, tubularobstruction and hemodynamic abnormalities are themost important factors in the initiation and continuanceof ARF. Isolated ARF is often induced by pharmacolog-ic agents frequently used in the management of criticallyill patients, such as aminoglycoside and mannitol.

Due to its multifactorial pathogenesis, ARF requiresa multidisciplinary approach in which the nephrologistand the intensive care physician should work side byside as a team. It is essential for the intensive care neph-rology team to define and to understand the etiopatho-genesis of ARF in order to choose the appropriate inter-ventions so as to prevent or ameliorate the severity ofARF. The prevention and management of ARF in criti-

cally ill patients in the ICU is therefore a challengingtask for clinicians. The following is a brief review of re-cent studies that have addressed the issues of ARF epi-demiology and treatment in critically ill patients in theICU.

F. Li�no, E. Junco, J. Pascual, R. Madero, E. Verde andthe Madrid Acute Renal Failure Study Group (1998)The spectrum of acute renal failure in the intensivecare unit compared with that seen in other settings. Kid-ney Int 53: S16±S24

This study was conducted to compare (1) ARF cases ob-served in ICU settings with those treated outside theICU and (2) the outcome of isolated ARF with the out-come of ARF as a part of MODS in both settings. Theanalysis was performed by reviewing the data of the pro-spective epidemiologic ARF Madrid study.

The incidence of ARF was 95 per million population(pmp)/year in ICU, and 143 pmp/year in non-ICU, de-partments. Sixty one percent of ICU patients devel-oped ARF after hospital admission. Acute tubular ne-crosis was the most frequent cause of ARF in thisgroup of patients. ARF occurred predominantly as apart of a MODS in the ICU setting, whereas isolatedARF was the usual presentation in non-ICU patients.Moreover, the study demonstrates that isolated ARFalso appears among ICU patients and ARF as a partof MODS may develop in patients treated in other hos-pital areas. Finally, the study shows that (1) the mortal-ity and severity of isolated ARF is similar in ICU andnon-ICU patients and (2) in both populations mortalityincreases proportionally to the number of organ systemfailures (OSF).

S.C. Franklin, M. Moulton, G. Sicard, M. R. Hammer-mann, S. B. Miller (1997) Insulin-like growth factor-Ipreserves renal function postoperatively. Am J Physiol272: F257±F259

L.GesualdoG. GrandalianoL.MasciaG. PertosaF.P. Schena

Acute renal failure in critically ill patients

Intensive Care Med (1999) 25: 1188±1190Ó Springer-Verlag 1999 CURRENT TOPICS

In animal models of ARF, administration of epidermalgrowth factor (EGF), hepatocyte growth factor (HGF)or insulin-like growth factor-I (IGF-I) accelerates therestoration of renal function and the recovery of histo-logic lesions, and reduces mortality. The rationale forthe use of these growth factors as therapeutic agents inARF is that (1) EGF, HGF and IGF-I bind to specificreceptors on proximal tubular cells and regulate meta-bolic and transport processes at this site, (2) EGF andHGF are mitogens for proximal tubular cells in vitroand (3) expression of IGF-I, HGF and the EGF, HGFand IGF-I receptors in the kidney are increased follow-ing ARF in rats.

On the basis of these findings, in this study the au-thors enrolled 58 patients in a randomized, double-blind, placebo-controlled trial of IGF-I as a therapeuticagent to prevent the decline in renal function that wasexpected to occur postoperatively. There were no signif-icant differences in the side effects between the placebogroup and the IGF-I treated patients. IGF-I was report-ed to reduce the incidence of renal dysfunction after sur-gery significantly, by 33%. The conclusions of this studyemphasized the feasibility and potential utility of ad-ministering growth factors to prevent postoperative re-nal dysfunction in high risk patients.

J.D. Kopple, R. Hirschberg, H. P. Guber, M. Pike andthe Chiron Study Group (1996) Lack of effect of recom-binant human insulin-like growth factor-I (IGF-I) in pa-tients with acute renal failure (ARF). J Am Soc Nephrol7: 1375

This is a multicenter placebo-controlled clinical studyevaluating the effect of rhIGF-I on 72 patients affectedby ARF. The study was interrupted due to the lack ofdifferences between treated and untreated patients. Inconclusion, this study taken together with the reportfrom Franklin et al. suggests that IGF-I may be benefi-cial in patients with mild renal injury who do not requirerenal replacement therapy, whereas administration ofthis growth factor in patients with severe renal damageseems to be devoid of any therapeutic effect.

R.L. Allgren, T. C. Marbury, S. N. Rahman, L. S. Wein-berg, A. Z. Fenves, R. A. Lafayette, R. M. Sweet, F. C.Genter, B. R. Kurnik, J. D. Conger, M. N. Sayegh(1997) Anaritide in acute tubular necrosis. AuriculinAnaritide Acute Renal Failure Study Group. NewEngl J Med 336: 828±834

Atrial natriuretic factor (ANF) inhibits sodium and wa-ter readsorption in the collecting ducts, vasodilates theafferent arterioles and vasoconstricts the efferent arteri-oles. The final effect is a net increase in the glomerularfiltration rate without affecting renal blood flow. Thisrandomized study was carried out in 504 patients with

ARF. The synthetic ANF derivative (Anaritide) wasable to reduce significantly the need for dialysis andthe mortality rate in a subgroup of oliguric patients. Incontrast, Anaritide worsened dialysis-free survival innon-oliguric ARF patients. Fifty percent of these pati-ents presented with hypotension, a hypothetical causeof treatment failure. On the basis of these results, morecarefully designed studies on the use of this drug arewarranted.

Discussion

ARF, defined as the abrupt decline in glomerular filtra-tion rate, occurs frequently as a part of MODS in criti-cally ill patients, although cases of isolated ARF arealso observed. Several studies report a prevalence ofARF among ICU patients, ranging from 3 to 30%[Wilkins et al. (1983) Anaesthesia 38: 628±634; Krameret al. (1979) Crit Care Med 7: 263±266; Menashe et al.(1979) Crit Care Med 16: 1106±1109; Groenevald et al.(1991) Nephron 59: 602±610].

Recent evidence [reviewed by Nissenson (1998) Kid-ney Int 66: S7±10] suggests that there are four major fac-tors in the initiation and continuance of ARF.

1. Decreased glomerular capillary permeability, mostlikely caused by endothelial cell swelling.

2. Back-leak of glomerular filtrate due to renal hemo-dynamic derangements present in experimental andhuman ARF [Myers et al. (1984) J Clin Invest 73:329±341]

3. Tubular obstruction that is the direct consequence oftubular cell damage induced by toxins or ischemia.Sublethal and lethal epithelial cell injury may occurin ARF. Sublethal injury causes cellular dysfunctionand altered gene expression, while lethal injury mayresult in necrosis or apoptosis. The latter event ismainly due to a loss of survival factors, includingEGF, IGF-I and HGF, caused by toxic or ischemic in-sults. The release of apoptotic bodies or necrotic cellsinto the tubular lumen mixed with proteins results incast formation and tubular obstruction [Lieberthal(1997) Kidney Int 52: 1102±1115]

4. Hemodynamic abnormalities, demonstrated by amarked reduction in renal blood flow, particularly,within the outer medulla. Under normal conditionsthis part of the kidney is constantly hypoxic for thecountercurrent diffusion of oxygen from the de-scending to the ascending portions of vasa recta. Anischemic or toxic insult may result in a further reduc-tion of oxygen tension, thus contributing to the de-velopment of ARF. The worsening of the hypoxicstate may be responsible for later endothelial cell in-jury and the release of potent vasoconstrictor factors,such as endothelin-1 (ET-1) that, if not balanced by

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vasodilators (i. e. EDRF), may exacerbate the preex-isting ischemia. This hypothesis may explain theworsening effect observed in the Anaritide study, inwhich the subgroup of patients with non-oliguricARF presented a high percentage of hypotensionwith the ANF derivative.

In conclusion, ARF is one of the most frequent and seri-ous complications in critically ill patients. A better un-derstanding of its pathogenesis will certainly increasethe possibility of developing new therapeutic approach-es able to prevent, reverse or, at least, ameliorate the se-

verity of ARF. The role of growth factors in the mainte-nance of tubular trophism and the balance betweenvasodilators and vasoconstrictors (i. e. ET-1/EDRF) arereceiving considerable attention as major factors in thepathogenesis of ARF. Thus, therapeutic approachesaiming to restore the physiologic balance of these sub-stances may improve cellular trophism and renal hemo-dynamics and may, therefore, represent a bonus for phy-sicians dealing with ARF in critically ill patients. Thedevelopment of critical care teams comprising nephrol-ogists and intensive care physicians will certainly helpin pursuing this difficult task.

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