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Renal function significantly affects this balance. Degradation of insulin
by liver and skeletal muscle is reduced in patients with CKD. At the
13
same time, renal insulin handling is altered. Approximately 25% of the
insulin secreted by beta cells is removed by healthy kidneys, equating
to 6-8 units per day. 13, 14 The kidneys, due to bypassing of the portal
circulation and first-pass clearance by the liver, clear a much larger
proportion of injected insulin - over half in some studies. 13, 14 As a pep-
tide of ~6 kDA in size, insulin is freely filtered at the glomerulus. Some
insulin is also extracted from peri-tubular capillaries and secreted into
the urine, possibly via insulin receptor-dependent transport. In the
15
healthy kidney, >98% of filtered/secreted insulin is then reabsorbed and
degraded. While peri-tubular insulin uptake increases as renal func-
16
tion declines to maintain renal insulin clearance, tubular injury in the
diabetic kidney combined with a falling estimated glomerular filtration
rate (eGFR) ultimately means that intact insulin is often found in the
urine and, ultimately, the urinary insulin clearance approaches that of
the (low) glomerular filtration rate. As a consequence, the circulating
half-life of insulin is significantly modified in patients with CKD, especially
when eGFR falls to below 30 ml/min/1.73m . Indeed, the insulin half-
2 13
life has been proposed as a valid test of kidney function. 17
This prolonged insulin half-life significantly increases the risk of hypo-
glycaemia in patients with CKD as the glucose lowering effects of insulin
and secretogogues carryover beyond the immediate post-prandial
period. The effect of renal impairment on insulin kinetics appears similar
for both short- and long-acting insulin, as well as agents that stimulate
endogenous insulin production. As a result, some authors have recom-
mended avoiding long-acting insulin preparations in patients with ad-
vanced renal failure to reduce the risk of hypoglycaemia. However,
18
other studies support the use of long-acting insulin in this setting. The
13
most important thing appears to be close monitoring and individuali-
sation of diabetes care and glucose control targets in patients with
CKD. This always involves reduced insulin doses. In general, those with an
eGFR 30-45 ml/min/1.73m need 10% less insulin, those 15-30 ml/min/1.73m
2
2
need 25% less insulin, and those with <15 ml/min/1.73m need about
2
half their requirement when they have an eGFR >60 ml/min/1.73m .
2
Although insulin sensitisers such as metformin and the glitazones are
not traditionally associated with hypoglycaemia, because of the pro-
longed actions of insulin in CKD, the incidence and severity of hypo-
glycaemia can also be increased by these drugs in this setting.

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