Clinical benefits of tight glycaemic control: effect on the kidney

Acute kidney injury is a frequent and life-threatening complication of critical illness. Prevention of this condition is crucial. Two randomized single center trials in critically ill patients have shown a decrease in acute kidney injury by tight glycaemic control, an effect that appears most pronounced in surgical patients. Subsequent randomized trials did not confirm this renoprotective effect. This apparent contradiction is likely explained by methodological differences between studies, including different patient populations, insufficient patient numbers, comparison with a different control group, use of inaccurate blood glucose analyzers, and differences in the degree of reaching the target blood glucose level. The optimal glycaemic target for renoprotection in critical illness remains to be defined. Possible mechanisms underlying the renoprotective effect of tight glycaemic control are prevention of glucose overload and toxicity and the associated mitochondrial damage, an anti-inflammatory or anti-apoptotic effect, prevention of endothelial dysfunction, and an improvement of the lipid profile.

Introduction

Acute kidney injury (AKI) is a common complication of critical illness and its presence is an independent risk factor for mortality.1, 2, 3 Because of the variability in how AKI is defined and the differences in subpopulations studied, the reported incidence in intensive care patients varies between 1% and 25%. In order to streamline the research in the field of AKI the ADQI (Acute Dialysis Quality Initiative) group proposed the RIFLE (Risk-Injury- Failure- Loss of kidney function-End stage renal disease) criteria for classification of AKI.¹ At present, this multilevel scoring system, based on changes in serum creatinine and/or in urine output, has been validated in multiple clinical studies. Compared to patients without AKI, there is a stepwise increase in the risk of death, going from RIFLE-Risk to RIFLE-Injury to RIFLE-Failure.⁴ As treatment of AKI is largely supportive, prevention is crucial. At present, no pharmacological intervention has demonstrated a protective effect on kidney function in critically ill patients and maintaining adequate hydration and haemodynamics and avoiding nephrotoxic substances remain the mainstay in prevention of AKI.5, 6

About one third of patients with diabetes mellitus develop kidney disease and diabetes is the leading cause of end-stage renal disease in developed countries. The mechanism of diabetic nephropathy is incompletely elucidated. As well hemodynamic, metabolic and genetic factors are thought to be involved.7, 8, 9, 10, 11 The role of strict glycaemic control in the management of diabetes has recently been questioned after three large randomized trials found no effect on macrovascular disease in patients with risk factors.12, 13, 14 One of these trials was even prematurely stopped because of an increased mortality.¹² However, previous randomized trials have clearly shown a protective effect of strict glycaemic control on the development and progression of diabetic microangiopathy including nephropathy15, 16, 17, 18, 19 and also one of the recent studies focusing on macrovascular complications, established a reduction in the incidence of nephropathy with more strict glucose control.¹³

Patients in the ICU commonly develop hyperglycaemia, the so-called stress-induced hyperglycaemia, which is directly associated with adverse outcomes,20, 21, 22 including kidney dysfunction. Indeed, several observational studies found an association between pre- or intraoperative hyperglycaemia and postoperative AKI after cardiac surgery,23, 24 between hyperglycaemia at cardiac catheterization and contrast nephropathy,²⁵ between hyperglycaemia during total parenteral nutrition and the development of AKI26, 27 and between hyperglycaemia and glomerular filtration rate (GFR) in brain dead organ donors.²⁸ The induction of diabetes or acute hyperglycaemia in animals also increases the susceptibility to renal ischemia-reperfusion injury.29, 30, 31

In the past, stress-induced hyperglycaemia was interpreted as a beneficial metabolic adaptation and was not treated unless excessive (>200 mg/dl [11.1 mmol/l]).²⁰ This dogma was challenged by two single center randomized trials (the Leuven studies) showing a beneficial effect of tight glycaemic control (TGC) with intensive insulin therapy (IIT) on morbidity and/or mortality of critically ill patients.*32, *33 After these positive studies, many centers worldwide adopted IIT as part of their usual care, and this treatment was implemented in several guidelines.34, 35, 36, 37 Subsequent trials, assessing the external validity of the results obtained in Leuven, showed conflicting results,38, 39, 40, 41, 42, *43 resulting in a lively debate.44, 45, 46, 47, 48

This chapter aims to give an overview of the studies evaluating the effect of glycaemic control on kidney function in critical illness, as well as a discussion of potential underlying mechanisms.