Rapid Responses to:

RESEARCH: Marcello Tonelli, Powell Jose, Gary Curhan, Frank Sacks, Eugene Braunwald, Marc Pfeffer Cholesterol and Recurrent Events (CARE) Trial Investigators Proteinuria, impaired kidney function, and adverse outcomes in people with coronary disease: analysis of a previously conducted randomised trial BMJ 2006; 332: 1426 [Abstract] [Full text]

Rapid Responses: Submit a response to this article

Rapid Responses published:

Some reservations

GH Hall   (19 June 2006)

Dipstick protein is inadequate for assessing dose effect

Emeka , Anthony Nwankwo   (22 June 2006)

Statins and Renal Function

Vassilios G Athyros, Stella S. Daskalopoulou, Moses Elisaf , Dimitri P. Mikhailidis   (30 June 2006)

Some reservations 19 June 2006
GH Hall, Retired physician EX1 2HW Send response to journal: Re: Some reservations	The authors have provided valuable data for those interested in the interpretation of multiple test results. Where one may beg to differ, however, is on the question of the evaluations of interaction and risk “additivity.” It seems hard to believe that the interaction between the tests is of only ”modest importance” when the odds of death are altered threefold for renal impairment and twofold for proteinuria (by the presence or absence of the other factor.) Admittedly, these are from unadjusted figures, but this situation is what the clinician will face as it is unlikely that all the values for the adjustment factors will be available. If only some are, the full regression equation would not be appropriate. Even with the adjusted figures, the difference in odds of death still amounts to some 16%. It would be helpful to know whether the interaction term for the two tests only is significant or not. Secondly, it is claimed in “What this study adds” that the risk estimates from the two tests are additive. Certainly, the positive likelihood ratios (LR+) for the separate tests ( 2.1 for proteinuria and 1.57 for renal impairment) sum to 3.67, almost the LR+ for the combined result (3.73). This result is likely to be an accident of the figures as risk combination is usually achieved by multiplication- of LR’s for Bayesian analysis or odds ratios for logistic regression (statistical independence assumed or imposed.) The product of the LR+’s is 3.3, an underestimate. The reason for this discrepancy is that the association between renal failure and proteinuria is more marked in the affected (dead) group (odds ratio 2.6) than the living (odds ratio 1.6.) Care is needed before single test results are combined. My own view is that there can be no substitute for empirical checking of the results of test combinations, which happily are available here. Regression models inevitably refer to an imaginary population with a different composition from the actual population. Competing interests: None declared
Dipstick protein is inadequate for assessing dose effect 22 June 2006
Emeka , Anthony Nwankwo, Senior Lecturer University of Maiduguri Send response to journal: Re: Dipstick protein is inadequate for assessing dose effect	Editor, Tonielli et al reported an association between proteinuria, impaired renal function and adverse outcomes in individuals who had suffered myocardial infarction (1). Their article is somewhat similar to the report by Madison et al from Hawai who noted that dipstick proteinuria could predict long term risk of coronary heart disease and stroke in individuals without history of CHD or stroke (2). Both studies lend support to the Steno hypothesis which postulates that proteinuria and atherosclerosis are the manifestations of generalized endothelial dysfunction in the kidneys and the arteries respectively (3). Certain issues however arise from the methodology of the research and the inferences drawn on the quantity of proteinuria estimated solely from one spot dipstick test. The NKF/K –DOQI guidelines recommend that the estimation of the protein excretion rate should be carried out by the use of the albumin: creatinine ratio of a time urine collection which can subsist for the 24 hour urine collection regarded as the gold standard for protein excretion measurements (4). One spot dipstick urine test is indeed a cheap affordable and effective screening test for detecting the presence of protein in urine but it is of limited value used alone in quantifying proteinuria as was applied by Tonielli et al. Assuming the typical dipstick measure of none, trace, 1+, 2+, 3+ correspond to < 0.1, 0.1 – 03, 0.31 – 1.0, 1.01 – 3.0, and greater than 3.0 g/ l makes it appear that we can prefer to define nephrotic syndrome as 3+ proteinuria. In practice that is not so because several factors including hydration status can greatly affect the reading of a given urine sample as to whether it turns out as 1+, 2+ or even 3+ proteinuria. Infections, contamination with menstrual blood posture and exercise are causes of transient proteinuria or spurious which were not taken into consideration by the authors. Differences in outcomes have been reported between the individuals with either transient or persistent proteinuria (2). Moreover dipstick test is not specific in detecting albuminuria as the alkaline urine can yield a false positive dipstick proteinuria. Secondly it appears simplistic to dichotomize the whole spectrum of CKD into GFR greater or less than 60 ml/min and yet infer a dose effect for proteinuria and kidney function. Though present in the early stages of kidney disease the risk of cardiovascular disease is markedly elevated in End stage Renal Disease by as much as 10 -20 fold compared to the general public(5). Studies investigating the dose effect of proteinuria will be better appreciated if protein in urine is quantified by use of the more specific methods than dipstick estimates. Reference: 1. Tonielli M, Jose P, Curham G, Sacks F, Braunwald E, Pfeffer M, for Cholesterol and Recurrent Events (CARE) Trial investigators. BMJ 2006 332: 1426 - 9 2. Madison JR, Spies C, Schartz IJ, Masaki K, Chen R, Yano K, Curb JD. Proteinuria and risk for stroke and Coronary Heart Disease during 27 years of follow up. The Honolulu Heart Program. Arch Intern Med 2006; 166: 884 – 889 3. Deckert T, Feldt – Rasmussen B, Borsh – Johnson K, Jensen T, Kofoed – Enevoldsen A: Albuminuria reflects widespread vascular damage. The Steno hypothesis. Diabetologia 1989 32: 219 - 26 4. National Kidney Foundation: K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation Classification and Stratification: Am J Kidney Dis 2002 39 S1 -S266 (suppl 1) 5. Parfrey PS, Foley RN. The clinical epidemiology of cardiac disease in chronic renal failure. J Am Soc Nephrol 1999 10:1606 -15 Competing interests: None declared
Statins and Renal Function 30 June 2006
Vassilios G Athyros, Director Atherosclerosis Unit, Aristotelian Univsersity 15 Marmara St, Thessaloniki, 55132, Greece, Stella S. Daskalopoulou, Moses Elisaf , Dimitri P. Mikhailidis Send response to journal: Re: Statins and Renal Function	EDITOR-Tonelli et al.1 considered the link between estimated glomerular filtration rate (eGFR) and the risk of vascular events. There is evidence that statins improve/protect renal function. For example, in HPS2 simvastatin 40 mg (compared with placebo) was associated with less deterioration in eGFR in patients at high-risk for vascular events. In the GREACE trial3 (titrated dose of atorvastatin to achieve an LDL-C level of 2.6 mmol/l versus ‘usual care’) there was a significant increase in eGFR in the aggressive treatment arm, especially at higher doses of atorvastatin and higher baseline serum creatinine levels. Creatinine clearance was an independent predictor of vascular events. More recently, the TNT study4 (atorvastatin 10 versus 80 mg/day) reported similar findings. Serum urate levels are influenced by eGFR, but there may also be a drug- related component.5 Some statins can reduce urate levels.5 In GREACE,5 serum urate was an independent predictor of risk. It is relevant to identify whether better “nephroprotection” is driven by specific drug (e.g. anti-hypertensive or statin) effects and/or by aggressive risk factor (blood pressure or lipids) control. Whether drug combinations are more “nephroprotective” than monotherapy remains to be established. Future trials should address these important issues. Stella S. Daskalopoulou, postdoctoral fellow, Department of Medicine, Division of Clinical Epidemiology, Royal Victoria Hospital, McGill University, Montreal, Canada Vassilios G. Athyros, consultant physician, Atherosclerosis Unit, 2nd Propedeutic Department of Internal Medicine, Aristotelian University, Hippocration Hospital, Thessaloniki, 55132, Greece Moses Elisaf, professor of medicine, Department of Internal Medicine, Medical School, University of Ioannina, Greece Dimitri P. Mikhailidis, reader and honorary consultant, Department of Clinical Biochemistry (Vascular Disease Prevention Clinics), Royal Free Hospital, Royal Free and University College Medical School, London, UK MIKHAILIDIS@aol.com Declaration of interest Some of the authors have attended conferences, given lectures and participated in advisory boards or trials sponsored by various pharmaceutical companies. References 1. Tonelli M, Jose P, Curhan G, Sacks F, Braunwald E, Pfeffer M. Proteinuria, impaired kidney function, and adverse outcomes in people with coronary disease: analysis of a previously conducted randomised trial. BMJ 2006;332:1426-9. (17 June.) 2. Collins R, Armitage J, Parish S, Sleigh P, Peto R; Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol- lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet 2003;361:2005-16. 3. Athyros VG, Mikhailidis DP, Papageorgiou AA, et al. The effect of statins versus untreated dyslipidaemia on renal function in patients with coronary heart disease. A subgroup analysis of the Greek atorvastatin and coronary heart disease evaluation (GREACE) study. J Clin Pathol 2004;57:728-34. 4. LaRosa JC, Grundy SM, Waters DD, et al.; Treating to New Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005;352:1425-35. 5. Athyros VG, Elisaf M, Papageorgiou AA, et al.; GREACE Study Collaborative Group. Effect of statins versus untreated dyslipidemia on serum uric acid levels in patients with coronary heart disease: a subgroup analysis of the GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) study. Am J Kidney Dis 2004;43:589-99. Competing interests: None declared