Chronic kidney disease prevalence and secular trends in a UK population: the impact of MDRD and CKD-EPI formulae.

INTRODUCTION: Most UK laboratories use the MDRD4 formula to estimate glomerular filtration rate (eGFR), but this may exaggerate chronic kidney disease (CKD) prevalence. In a large adult population, we examined the impact of the more accurate CKD-EPI formulae on prevalence estimates, and on secular trends in prevalence. METHODS: We extracted all serum creatinine (SCr) results for adults, processed in our laboratory during two 1-year periods (2004, 2009-10). To minimize the effect of acute illness, a patient's lowest SCr was used for each period. eGFR (traceable to isotope dilution mass spectrometry value) was calculated using the MDRD4 and CKD-EPI formulae. Prevalence estimates were compared, with sub-group analysis by age and sex. RESULTS: In 2004, 102 322 patients had SCr tested (35.4% of the adult population), rising to 123 121 (42.3%) in 2009-10. The proportion tested rose with age to 86% of 85- to 89-year olds. The prevalence of CKD stages 3-5 was lower with the CKD-EPI formulae than the MDRD4 formula. The CKD-EPI formulae reclassified 17 014 patients (5.8%) to milder stages of CKD, most commonly from eGFR 60-89 ml/min/1.73m(2) and CKD stage 3A, in women, and in those <70 years old. 5172 patients (1.8%), mostly elderly women, were reclassified to more severe stages of CKD. Between the two time periods, the prevalence of CKD stages 3-5 rose from 5.44% to 5.63% of the population using MDRD4, but was static at 4.94% with CKD-EPI. CONCLUSION: The CKD-EPI formulae, which are more accurate than the MDRD4 formula at higher GFR, reduced the estimated prevalence of CKD stages 3-5 by 0.5% in 2004 and 0.7% in 2009-10. The greatest reclassification was seen in CKD 3A, particularly amongst middle-aged females. The minor rise in CKD prevalence between 2004 and 2009-10 seen with the MDRD4 formula was not confirmed with the CKD-EPI formulae. The CKD-EPI formulae may reduce overdiagnosis of CKD, but further assessment in the elderly is required before widespread implementation.

Chronic kidney disease: evolving strategies for detection and management of impaired renal function.

Nephrologists have long been concerned about late referral of patients with severe kidney disease, and resultant poor outcomes on dialysis. But there is an increasing realisation that mild to moderate chronic kidney disease is far more common than previously appreciated. Furthermore, the main consequence of chronic kidney disease is not progression to dialysis, but increased risk of cardiovascular disease. Chronic kidney disease is at least as common and important a risk factor for cardiovascular disease as diabetes mellitus. The MDRD formula is a well-validated formula to estimate glomerular filtration rate, which is now being widely implemented by clinical chemistry laboratories, and should increase the recognition of chronic kidney disease. The K/DOQI classification of chronic kidney disease has gained international acceptance and provides the structure to guide referral and management. This classification, and associated guidelines, also focus attention on areas where evidence is lacking, and which urgently require research. These current developments will substantially change and improve how chronic kidney disease is identified and managed.

Development of indices for determining extracellular fluid sodium and water status in acute diabetic ketoacidosis: possible tools for clinical audit.

The limitation of plasma sodium concentration as an indicator of extracellular hydration status in cases of acute diabetes is well recognized and could lead to individually inappropriate fluid therapy. However, in view of the small analytical and biological variations exhibited by plasma concentrations of protein, water, and sodium in health, we have developed simple laboratory indices that may better describe the extracellular environment. Preliminary data presented here for 20 patients with acute diabetic ketoacidosis admitted as emergencies to Crosshouse Hospital suggest that the type of approach we describe has the potential to supply meaningful therapeutic data to the managing physician and, therefore, merits further study in a clinical setting.

Effects of 1,2-cyclohexanedione modification on the metabolism of very low density lipoprotein apolipoprotein B: potential role of receptors in intermediate density lipoprotein catabolism.

The conversion of very low density (VLDL) to low density lipoproteins (LDL) is a two-step process. The first step is mediated by lipoprotein lipase, but the mechanism responsible for the second is obscure. In this study we examined the possible involvement of receptors at this stage. Apolipoprotein B (apoB)-containing lipoproteins were separated into three fractions, VLDL (Sf 100-400), an intermediate fraction IDL (Sf 12-100), and LDL (Sf 0-12). Autologous 125I-labeled VLDL and 131I-labeled 1,2-cyclohexanedione-modified VLDL were injected into the plasma of four normal subjects and the rate of transfer of apoB radioactivity was followed through IDL to LDL. Modification did not affect VLDL to IDL conversion. Thereafter, however, the catabolism of modified apoB in IDL was retarded and its appearance in LDL was delayed. Hence, functional arginine residues (and by implication, receptors) are required in this process. Confirmation of this was obtained by injecting 125I-labeled IDL and 131I-labeled cyclohexanedione-treated IDL into two additional subjects. Again, IDL metabolism was delayed by approximately 50% as a result of the modification. These data are consistent with the view that receptors are involved in the metabolism of intermediate density lipoprotein.

Apolipoprotein A and B (Sf 100-400) metabolism during bezafibrate therapy in hypertriglyceridemic subjects.

This study describes the effects of bezafibrate, an analogue of clofibrate, on the plasma lipid and lipoprotein profiles of 11 hypertriglyceridemic subjects and on their metabolism of apolipoproteins A-I, A-II, and B. The major action of the drug was to lower plasma triglyceride (by 58%; P less than 0.01). This was accompanied by a reduction in the level of very low density lipoprotein apoprotein B (Svedberg units of flotation [Sf] 60-400), whose mean residence time in the plasma fell threefold (from 3.4 to 1.0 h). Synthesis of the B protein in this fraction was not significantly altered, so the drug acts to accelerate the transit of very low density lipoprotein particles down the delipidation cascade. The metabolism of very low density lipoprotein remnant apoprotein B (Sf 12-100) changed little in response to treatment, although we detected a 30% increment (P less than 0.05) in the plasma concentration of this fraction. The mean residence time of these remnant particles in the plasma did not correlate with that of Sf 100-400 very low density lipoprotein apoprotein B, nor was this parameter altered by the drug. The most consistent and significant perturbation seen in the Sf 0-12 fraction (low density lipoprotein) was a reduction in the fractional catabolism of its apoprotein B moiety (26%; P less than 0.05). In those subjects who were grossly hypertriglyceridemic and who responded well to treatment, the level of this protein rose substantially owing to a combined increase in its synthesis and a reduction in its catabolism. In the group as a whole, high density lipoprotein cholesterol rose 13% (P less than 0.02), and detailed examination showed that this was associated with a small but significant increment in the plasma concentration of the high density lipoprotein subfraction 2. High density lipoprotein subfraction 3 also rose on the average, but this was not a consistent feature in all patients. The plasma concentrations and turnovers of the A proteins (A-I and A-II) were not significantly altered by bezafibrate therapy.

The hypolipidemic action of probucol: a study of its effects on high and low density lipoproteins.

This study examines the effects of probucol (1 g/day) on the plasma concentration, composition, and metabolism of low and high density lipoproteins (LDL and HDL) in eleven hyperlipidemic subjects, (seven Type II and four Type IV). The drug lowered plasma cholesterol in the Type II patients by 11% (P < 0.02) without affecting triglyceride. Both LDL and HDL cholesterol levels fell by 6% and 26%, respectively. The small reduction in the former was not associated with a change in the composition of the lipoprotein nor with a measurable alteration in the level of circulating apoLDL. Kinetic studies revealed that probucol had no consistent effect on either the synthesis or catabolism of apoLDL. However, probucol did exert a potent influence on HDL, lowering the level of this lipoprotein in both the Type II and Type IV patients despite the fact that total plasma cholesterol in the latter group was unchanged by treatment. The fall in HDL mass largely affected the HDL(3) subfraction; HDL(2), which was initially low in our subjects, did not show a consistent response to therapy. Not all of the constituents in HDL were equally affected by the drug. Specifically, the fall in total plasma apoA levels (which derived from significant reductions in the rates of synthesis of apoproteins A-I and A-II) was less than that of HDL cholesterol. Direct measurement of the composition of the lipoprotein confirmed that during therapy it carried less cholesterol per unit protein. The significance of these observations in relation to the prophylaxis of ischemic heart disease is not yet clear, but it seems prudent at present to use probucol selectively in subjects who show a substantial hypocholesterolemic response that derives primarily from a reduction in circulating LDL.-Atmeh, R. F., J. M. Stewart, D. E. Boag, C. J. Packard, A. R. Lorimer, and J. Shepherd. The hypolipidemic action of probucol: a study of its effects on high and low density lipoproteins.

Effects of bezafibrate on receptor-mediated and receptor-independent low density lipoprotein catabolism in type II hyperlipoproteinaemic subjects.

This study examines the effects of bezafibrate (200 mg t.i.d.) on LDL metabolism in 7 type II hyperlipoproteinaemic subjects. Eight weeks of treatment lowered plasma cholesterol and triglyceride by 10% and 30%, respectively (P less than 0.02). These reductions were associated with a fall in circulating VLDL (31%, P less than 0.02) and LDL (11%, P less than 0.05), while HDL cholesterol stayed the same. LDL metabolism changed during therapy. The plasma fractional clearance rate (FCR) of autologous [125I]LDL normalized from a low value of 0.256 +/- 0.048 (mean +/- SD) to 0.298 +/- 0.040 pools/day (P less than 0.001). This was attributable to a 65% increase (P less than 0.01) in receptor-mediated LDL catabolism since the clearance of simultaneously injected 1,2-cyclohexanedione-modified [131I]LDL, which measures the receptor-independent pathway, was unaltered (FCR of [131I]cyclohexanedione/LDL in control phase = 0.194 +/- 0.030 pools/day; during drug treatment = 0.194 +/- 0.024 pools/day). We conclude that bezafibrate lowers plasma LDL in type II hyperlipoproteinaemia by promoting its degradation via high affinity receptors.