Hyperglycaemia and renal ischaemia–reperfusion injury

Jan Melin, Olof Hellberg and Bengt Fellström

Department of Medical Sciences, Uppsala University, University Hospital, Uppsala, Sweden

Keywords: acute renal failure; diabetic nephropathy; hyperglycaemia; ischaemia–reperfusion injury; radiocontrast media; renal ischaemia

Introduction

Hyperglycaemia is most probably a contributing factor in the development of ischaemic acute renal failure (ARF) in many patients. Both clinical and experimental data suggest that hyperglycaemia increases the risk of ARF [13]. Hyperglycaemia also worsens the outcome in renal transplantation [4,5]. Conversely, ischaemia–reperfusion (I/R) combined with hyperglycaemia could also be important in the development of diabetic nephropathy. Studies in our laboratory show that a brief renal ischaemia results in a progressive injury leading to end-stage renal failure in diabetic animals [6,7]. The mechanisms behind this increased sensitivity to renal I/R during hyperglycaemia are still poorly understood.

Experimental findings

An increased susceptibility to renal I/R injury in diabetic rats has been shown in several studies [1,3,69]. Furthermore, non-diabetic rats and dogs are more vulnerable to I/R injury, when the blood glucose is elevated by intraperitoneal glucose injection or dextrose infusion [10,11]. We found that a unilateral renal ischaemia of 30 min caused a progressive, irreversible injury in the kidneys of diabetic rats, whereas kidneys in non-diabetic rats recovered almost completely [6]. The injury was characterized by tubular atrophy and dilatation of the remaining tubules, infiltration of inflammatory cells, and fibrosis. The inflammatory cells were mostly T-lymphocytes, macrophages and monocytes. An increased accumulation of hyaluronan in the renal cortex and outer medulla has also been observed (unpublished observations). Insulin treatment before, but not after, renal ischaemia almost abolished the increased susceptibility to I/R in the kidneys of diabetic animals [7].

Clinical observations

Critically ill patients
Strict metabolic control by continuous insulin infusion improves the prognosis for surgical intensive-care patients [2]. Intensive insulin therapy keeping the blood glucose between 4.4 and 6.1 mmol/l using a continuous insulin infusion was compared with conventional therapy where the blood glucose was kept between 10.0 and 11.1 mmol/l and insulin only given if the blood glucose was above 11.9 mmol/l. The overall mortality and the rate of ARF were reduced by ~40% with the intensive insulin treatment [2]. The same protocol was followed whether or not the patient had a history of diabetes in this study. As pointed out by the authors, the study was performed in a setting of mostly surgical patients, whereas patients with medical diseases may respond differently [2]. One possible confounding factor in this study is the high proportion of patients who had undergone cardiac surgery. It has been proposed that infusion of insulin, glucose and potassium have a positive effect on heart function after cardiac surgery [12]. It could not be excluded that the infusion of glucose and insulin protected the kidneys by improved renal perfusion from better cardiac function.

Kidney transplantation
In kidney transplantation, hyperglycaemia is associated with an increased number of complications [4,5]. Diabetic patients with good glycaemic control in the peri-operative period had fewer episodes of acute rejection and infection than patients with good metabolic control [4]. Also, non-diabetic patients with moderate hyperglycaemia, that is a blood glucose above 8 mmol/l, had more acute rejections than patients with lower blood glucose levels [5].

Hyperglycaemia and radiocontrast media
Decreased renal function is the main risk factor for ARF induced by radiocontrast media (RCM) [13], and earlier claims that diabetic patients with normal renal function also had an increased risk of ARF due to RCM [14], have not been confirmed [13]. To our knowledge, no clinical study specifically addressing the issue of hyperglycaemia and nephrotoxicity of RCM has been performed. Hyperglycaemia has, however, been reported to be a risk factor for contrast-media-induced renal failure in rats in one study [15], but not in another [16]. During percutaneous renal-artery angioplasty, radiocontrast nephrotoxicity is combined with temporarily impaired renal circulation, i.e. I/R, and in this setting, blood glucose could be of special importance.

Pathophysiology

Several mechanisms have been suggested to explain why hyperglycaemia and/or diabetes increase I/R injury. Intracellular oxidative stress, due to an increased production of superoxide by the electron-transport chain in the mitochondria, has been proposed as a unifying explanation for most metabolic alterations in diabetes [17]. I/R is also a state where oxidative stress has been implied [18]. It could be speculated that the combined oxidative stress from these two sources could be particularly harmful. The increased inflammatory response after I/R in diabetes may play a role [19], and disturbances in production and response to NO have also been suggested to contribute to the increased sensitivity to I/R in diabetes [3]. Wald et al. [1] explored whether dehydration was involved in the increased sensitivity to renal I/R seen in diabetic rats by infusing saline during ischaemia. They found that this treatment did not have any protective effect.

Hyperglycaemia is probably not harmful in all types of ARF; on the contrary, hyperglycaemia actually protects against the nephrotoxicity of some substances such as gentamicin and mercuric chloride in rats [1,20,21]. Interestingly, this protective effect was abolished by insulin treatment [22].

The pathophysiology of contrast-media-induced ARF remains to be established. Several theories have been proposed. Contrast-media infusion may result in vasoconstriction of renal vessels, thereby causing hypoxia, and direct toxic effects on tubular cells have also been suggested [13]. Considering the possibility that hyperglycaemia could increase ischaemic ARF, but protect against toxic ARF, it is not surprising that clinical studies concerning ARF due to RCM have yielded conflicting results.

The increased sensitivity to I/R in kidneys during hyperglycaemia corresponds to similar findings in other organs. Hyperglycaemia increases the damage to the brain after stroke, regardless of whether the patient had diabetes or not [23]. The blood glucose concentration on hospital admission is a predictor of the outcome after myocardial infarction [24].

Diabetic nephropathy

The finding that hyperglycaemia increases renal I/R injury may have implications for the understanding of diabetic nephropathy as well. Ischaemia has been suggested in the development of diabetic nephropathy [25]. Besides the glomerular changes, interstitial fibrosis and infiltration of inflammatory cells are important features of diabetic nephropathy [26]. In fact the degree of tubulointerstitial injury is as closely related to the decline in function as are the glomerular alterations [27]. The tubulointerstitial fibrosis and infiltration of inflammatory cells observed in diabetic rats after renal I/R share similarities with what is seen in diabetic nephropathy [6]. Repeated minor ischaemic events, caused for instance by smoking or sympathetic activation due to stress, could clearly participate in the development of diabetic nephropathy.

Prevention

Clinical studies concerning hyperglycaemia and acute renal failure are few, so far. The available data are also from specific clinical settings such as surgical intensive care and renal transplantation, making it difficult to extrapolate the results to other situations. However, these studies call for an increased awareness of hyperglycaemia when renal circulation could be jeopardized, for example during intensive care, intravenous injection of RCM, or sepsis. Obviously an extremely strict metabolic control is associated with an increased risk of hypoglycaemia, but this can be avoided, especially in an ICU setting, were blood glucose can be monitored on a regular basis.

However, there could be additional beneficial effects of insulin per se, besides lowering the blood glucose. For instance, anti-apoptotic effects of insulin have been shown in vitro [28,29]. Insulin treatment reduces apoptosis in the tubular cells in the renal medulla after renal I/R injury in diabetic rats, if given prior to the injury [7]. This may explain in part why insulin protects renal function and morphology after renal I/R in diabetic rats. However, none of the studies published so far is able to distinguish between a direct protective effect of insulin, an effect on glycaemic control, or a combination of both.

Conclusion

Data are accumulating to indicate that hyperglycaemia is a contributing factor in the development of ischaemic ARF. We believe that hyperglycaemia, in situations where the kidney is subjected to poor perfusion or ischaemia, represents an underestimated clinical problem. Further research is needed to define in which settings an improved glycaemic control is beneficial, and to establish the mechanisms behind the increased sensitivity to I/R during hyperglycaemia. Also, the question whether glycaemic control is important during radiocontrast infusion is not definitively solved.

Notes

Correspondence and offprint requests to: Jan Melin, Department of Medical Sciences, Uppsala University, University Hospital, S-751 85 Uppsala, Sweden. Email: jan.melin{at}medsci.uu.se Back

References

  1. Wald H, Markowitz H, Zevin S, Popovtzer MM. Opposite effects of diabetes on nephrotoxic and ischemic acute tubular necrosis. Proc Soc Exp Biol Med1990; 195:51–56[Abstract]
  2. van den Berghe G, Wouters P, Weekers F et al. Intensive insulin therapy in the surgical intensive care unit. N Engl J Med2001; 345:1359–1367[Abstract/Free Full Text]
  3. Goor Y, Peer G, Iaina A et al. Nitric oxide in ischaemic acute renal failure of streptozotocin diabetic rats. Diabetologia1996; 39:1036–1040[CrossRef][ISI][Medline]
  4. Thomas MC, Mathew TH, Russ GR, Rao MM, Moran J. Early peri-operative glycaemic control and allograft rejection in patients with diabetes mellitus. a pilot study. Transplantation2001; 72:1321–1324[CrossRef][ISI][Medline]
  5. Thomas MC, Moran J, Mathew TH, Russ GR, Mohan Rao M. Early peri-operative hyperglycaemia and renal allograft rejection in patients without diabetes. BMC Nephrol2000; 1:1.[CrossRef][Medline]
  6. Melin J, Hellberg O, Aküyrek M, Källskog Ö, Larsson E, Fellström B. Ischemia causes rapidly progressive nephropathy in the diabetic rat. Kidney Int1997; 52:985–991[ISI][Medline]
  7. Melin J, Hellberg O, Larsson E, Zezina L, Fellstrom BC. Protective effect of insulin on ischemic renal injury in diabetes mellitus. Kidney Int2002; 61:1383–1392[CrossRef][ISI][Medline]
  8. Kuramochi G, Homma S. Postischemic recovery process of renal oxygen consumption in normal and streptozotocin diabetic rats. Ren Fail1993; 15:587–594[ISI][Medline]
  9. Kuramochi G, Homma S. Effects of furosemide on renal oxygen consumption after ischemia in normal and streptozotocin diabetic rats. Nephron1993; 64:436–442[ISI][Medline]
  10. Moursi M, Rising CL, Zelenock GB, D'Alecy LG. Dextrose administration exacerbates acute renal ischemic damage in anesthetized dogs. Arch Surg1987; 122:790–794[Abstract]
  11. Podrazik RM, Natale JE, Zelenock GB, D'Alecy LG. Hyperglycemia exacerbates and insulin fails to protect in acute renal ischemia in the rat. J Surg Res1989; 46:572–578[CrossRef][ISI][Medline]
  12. Taegtmeyer H, Goodwin GW, Doenst T, Frazier OH. Substrate metabolism as a determinant for postischemic functional recovery of the heart. Am J Cardiol1997; 80:3–10A
  13. Mueller C, Buerkle G, Buettner HJ et al. Prevention of contrast media-associated nephropathy. Randomized comparison of 2 hydration regimens in 1620 patients undergoing coronary angioplasty. Arch Intern Med2002; 162:329–336[Abstract/Free Full Text]
  14. Lautin EM, Freeman NJ, Schoenfeld AH et al. Radiocontrast-associated renal dysfunction. Incidence and risk factors. AJR Am J Roentgenol1991; 157:49–58[Abstract]
  15. Shyh TP, Friedman EA. Uninephrectomy does not potentiate contrast media nephrotoxicity in the streptozotocin-induced diabetic rat. Nephron1990; 55:170–175[ISI][Medline]
  16. Vaamonde CA, Bier RT, Papendick R et al. Acute and chronic renal effects of radiocontrast in diabetic rats. Role of anesthesia and risk factors. Invest Radiol1989; 24:206–218[ISI][Medline]
  17. Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature2001; 414:813–820[CrossRef][ISI][Medline]
  18. Chien CT, Lee PH, Chen CF, Ma MC, Lai MK, Hsu SM. De novo demonstration and co-localization of free-radical production and apoptosis formation in rat kidney subjected to ischemia/reperfusion. J Am Soc Nephrol2001; 2:973–982
  19. Panés J, Kurose I, Rodriguez-Vaca D et al. Diabetes exacerbates inflammatory responses to ischemia-reperfusion. Circulation1996; 93:161–167[Abstract/Free Full Text]
  20. Teixeira RB, Kelley J, Alpert H, Pardo V, Vaamonde CA. Complete protection from gentamicin-induced acute renal failure in the diabetes mellitus rat. Kidney Int1982; 21:600–612[ISI][Medline]
  21. Elliott WC, Houghton DC, Gilbert DN, Baines HJ, Bennett WM. Experimental gentamicin nephrotoxicity: effect of streptozotocin-induced diabetes. J Pharmacol Exp Ther1985; 233:264–270[Abstract]
  22. Gouvea W, Roth D, Alpert H, Kelley J, Pardo V, Vaamonde CA. Insulin reverses the protection given by diabetes against gentamicin nephrotoxicity in the rat. Proc Soc Exp Biol Med1994; 206:445–453[Abstract]
  23. Pulsinelli WA, Levy DE, Sigsbee B, Scherer P, Plum F. Increased damage after ischemic stroke in patients with hyperglycemia with or without established diabetes mellitus. Am J Med1983; 74:540–544[ISI][Medline]
  24. Malmberg K, Norhammar A, Wedel H, Ryden L. Glycometabolic state at admission: important risk marker of mortality in conventionally treated patients with diabetes mellitus and acute myocardial infarction: long-term results from the Diabetes and Insulin–Glucose Infusion in Acute Myocardial Infarction (DIGAMI) study. Circulation1999; 99:2626–2632[Abstract/Free Full Text]
  25. Ziyadeh FN. Significance of tubulointerstitial changes in diabetic renal disease. Kidney Int1996; 49:10–13
  26. Bohle A, Wehrmann M, Bogenschutz O, Batz C, Müller CA, Müller GA. The pathogenesis of chronic renal failure in diabetic nephropathy. Investigation of 488 cases of diabetic glomerulosclerosis. Pathol Res Pract1991; 187:251–259[ISI][Medline]
  27. Bader R, Bader H, Grund KE, Mackensen HS, Christ H, Bohle A. Structure and function of the kidney in diabetic glomerulosclerosis. Correlations between morphological and functional parameters. Pathol Res Pract1980; 167:204–216[ISI][Medline]
  28. Jonassen AK, Brar BK, Mjøs OD, Sack MN, Latchman DS, Yellon DM. Insulin administered at reoxygenation exerts a cardioprotective effect in myocytes by a possible anti-apoptotic mechanism. J Mol Cell Cardiol2000; 32:757–764[CrossRef][ISI][Medline]
  29. Farrelly N, Lee YJ, Oliver J, Dive C, Streuli CH. Extracellular matrix regulates apoptosis in mammary epithelium through a control on insulin signaling. J Cell Biol1999; 144:1337–1347[Abstract/Free Full Text]




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