FURTHER READING

FURTHER READING

section 21  Disorders of the kidney and urinary tract 4986 be made with some confidence, although the evidence base for bene- ficial intervention at lower levels of albuminuria is not secure. Current recommendations from national diabetes associations advise at least annual screening, based on the diagnostic flowchart shown in Fig. 21.10.1.3. Extrapolating the known effects of ACE inhibitors on a re- duction of UAER to a possible prevention of severe albuminuria and thus endstage renal disease has led several authors to propose a poten- tial cost benefit from the early use of these agents. However, there are no consistent data showing a benefit of these drugs in terms of pre- vention of moderately increased albuminuria in normoalbuminuric patients with normal or well-​controlled blood pressures. Can glycaemic control reverse established
nephropathy? The DCCT was inconclusive, but data from clinic populations and following pancreas transplantation suggest benefit, at least in type 1 diabetes. The situation in type 2 is much less certain. Why does intensive glycaemic control fail to completely prevent development of moderately increased albuminuria? Glycaemia is one of many factors leading to nephropathy, so correc- tion of this alone may not be enough. Moreover, even in the DCCT complete glycaemic normalization was not achieved. It is possible that newer insulins and delivery systems with continuous glucose monitoring may make sustained normoglycaemia more easily achievable and enable us to test its effectiveness. Do drugs that block the renin–​angiotensin system prevent or only delay the development of nephropathy? Can they reverse established nephropathy? The data are not conclusive, partly because of the relatively short duration of many trials, but most studies show a benefit in terms of reduction of UAER. For those with severely elevated albuminuria and CKD stage 3 and beyond, there is no doubt that renin–​angiotensin system blocking drugs delay endstage renal disease. For moderately increased albu- minuria, there are no studies of sufficient power to confirm benefit on hard clinical endpoints such as mortality or endstage renal dis- ease. Primary prevention of moderately increased albuminuria using renin–​angiotensin system blockade has only been shown in hypertensive type 2 patients or those at high cardiovascular risk. Likely developments in the near future Hyperglycaemia is thought to lead to nephropathy through sev- eral pathways, as outlined in Box 21.10.1.1. There are develop- ments in most of these fields, with the following being studied in trials: pyridoxamine and other inhibitors of glycation; atrasentan and other endothelin inhibitors; allopurinol; antifibrotic agents; al- dosterone antagonists; and inhibitors of inflammatory pathways. FURTHER READING ACCORD Study Group (2008). Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med, 358, 2545–​59. ACCORD Study Group (2010). Effects of intensive blood-​pressure control in type 2 diabetes mellitus. N Engl J Med, 362, 1575–​85. Adler AI, et al. (2003). Development and progression of nephropathy in type 2 diabetes: the United Kingdom Prospective Study (UKPDS 64). Kidney Int, 63, 225–​32. American Diabetes Association. (2015). Executive summary: stand- ards of medical care in diabetes—​2015. Diabetes Care, 38 Suppl 1, S4. Bilous R (2008). Microvascular disease: what does the UKPDS tell us about diabetic nephropathy? Diabetic Med, 25 Suppl 2, 25–​9. Bilous R, et al. (2009). Effect of candesartan on microalbuminuria and albumin excretion rate in diabetes: 3 randomised trials. Ann Intern Med, 151, 11–​20. DCCT/​EDIC Research Group (2003). Sustained effect of intensive treatment of type 1 diabetes mellitus on development and progres- sion of diabetic nephropathy. JAMA, 290, 2159–​67. 0.1% (0.0% to 0.1%) 0.1% (0.1% to 0.2%) 2.0% (1.9% to 2.2%) 1.4% (1.3% to 1.5%) 3.0% (2.6% to 3.4%) 4.6% (3.6% to 5.7%) D E A T H 19.2% (14.0% to 24.4%) 2.8% (2.5% to 3.2%) 2.3% (1.5% to 3.0%) No nephropathy Microalbuminuria Macroalbuminuria Elevated plasma creatinine or renal replacement therapy 0.3% (0.1% to 0.4%) Fig. 21.10.1.4  Annual transition rates and 95% confidence interval through stages of nephropathy in 5097 newly diagnosed type 2 diabetic patients in the UKPDS.

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