BMJ  2006;332:1402-1403 (17 June), doi:10.1136/bmj.332.7555.1402

Editorial

Proteinuria, renal impairment, and death

If reducing proteinuria improves cardiovascular outcomes, urine dipstick testing will become crucial in hypertension

It has been known for many years that patients with chronic kidney disease have a significantly increased risk of cardiovascular morbidity and mortality. Many studies have shown that, in renal failure, increasing proteinuria and worse renal function are associated with more rapid progression and a higher incidence of cardiovascular events. Does the same hold true for patients with relatively minor degrees of renal impairment and low levels of proteinuria, even microalbuminuria? Is the combination especially important? And does this affect the management of patients?

First some technicalities. Proteinuria usually refers to protein that is detectable in urine with conventional urine dipsticks, and the amount of protein can vary from 300 mg to several grams a day. Proteinuria can be quantified reliably and easily by using spot urine protein: creatinine ratios, where normal is said to be < 20 mg/mmol (but see below). Just to confuse the issue, diabetologists have for many years measured albumin (rather than total protein) excretion in urine as an excretion rate (mg/day or µg/minute) and more recently as albumin:creatinine ratios. In patients with low levels of proteinuria the two results may be quite different since much of the urinary protein in this setting may not be albumin. Microalbuminuria refers to very low excretion rates of albumin (> 2.5 (men) or > 3.5 (women) to 30 mg/mmol), not detectable by conventional urine dipsticks. Defining a normal cutoff is proving increasingly difficult as it becomes clear that even within the normal range higher levels of protein excretion are associated with poorer vascular and renal outcomes.

A large body of data indicates that in patients with relatively normal renal function a lower glomerular filtration rate is associated with increased risk for poor cardiovascular outcomes. Most recently the rates of cardiovascular outcomes in the ALLHAT study (high risk hypertensive patients treated first line with either chlorthalidone, amlodipine or lisinopril) were re-analysed to look for the effect of renal function.¹ A low glomerular filtration rate (GFR; present in > 5500 patients (13%)) independently predicted increased risk for coronary heart disease, and patients with a baseline GFR < 53 ml/min/1.73 m² had a 32% higher risk of heart disease than those with GFR > 104 ml/min/1.73 m². Many elderly patients in particular will have a GFR within this lower range and are not at high risk for developing progressive renal failure. In this study none of the anti-hypertensive agents were better at protecting patients with reduced GFR from fatal coronary heart disease or non-fatal myocardial infarction. Similarly, in the cardiovascular health study of 4893 low risk subjects with a predicted GFR of 15-130 ml/min/1.73 m², each 10 ml/min lower GFR throughout the range was associated with a 5% increased risk for cardiovascular disease.²

Proteinuria has been known to be a marker for cardiovascular disease for some time, both in diabetic and non-diabetic patients. Various hypertension studies have demonstrated the risk posed by proteinuria—for example, in the INSIGHT study (nifedipine and diuretics for treatment of hypertension) proteinuria was as important a risk factor for cardiovascular events as abnormal serum creatinine, and equal to a previous myocardial infarction.³ The LIFE study (losartan intervention for end points in hypertension) showed a similar finding, increasing albuminuria being associated with increased risk of cardiovascular end points, fatal and non-fatal stroke, and cardiovascular mortality, as a continuous effect, with no threshold. Left ventricular hypertrophy, coronary artery calcification, and carotid artery stenosis are all more common in apparently normal individuals with increasing proteinuria, even within the normal range. Microalbuminuria is also associated with a failure of nocturnal dipping in blood pressure, insulin resistance, and abnormal vascular responses to various stimuli. Finally, in the Copenhagen heart study the risk for coronary heart disease or death doubled once microalbuminuria exceeded 5 µg/min, a very low threshold previously considered well within "normal."⁴

The best data on the interaction of proteinuria and renal impairment on cardiovascular outcomes come from a large study recently reported from Japan. This was a huge population survey including a total of 96 739 normal individuals aged 40-79 who were followed for 10 years. At outset 3% of the men and 2% of the women had proteinuria (assessed simply by dipstick analysis), and 3% had a GFR < 60 ml/min/1.73 m². Compared to those without proteinuria, those with proteinuria had 1.8 to 2.9 times the (age adjusted) risk of death from coronary heart disease, cardiovascular disease, and all other causes. The age adjusted risk of death was 1.3 to 2.1 times higher for stroke, cardiovascular disease, and all other causes among people with the lowest GFR category (< 60 ml/min/1.73 m²) than those with the highest GFR category (> 100 ml/min/1.73 m²). Men with both proteinuria and raised creatinine had 2.7 to 2.8 times the age adjusted risks of death from cardiovascular disease and all other causes, while women had 4.8 to 7.0 times the risk. The combination of proteinuria with reduced GFR was therefore associated with a substantial increase in risk of death for both men and women.⁵ The paper by Tonelli et al in this week's BMJ (p 1426) provides similar results,⁶ and the American JNC7 guidelines for hypertension recommend both a GFR < 60 ml/min/1.73 m² and microalbuminuria as major cardiovascular risk factors.

Proteinuria is therefore undoubtedly associated with poorer outcomes from vascular disease, and as such is a risk factor, but is it modifiable, since impaired renal function is often not? One recent study in 3500 hypertensive people without diabetes showed that microalbuminuria was an important risk factor for cardiovascular end points, and that patients in whom proteinuria decreased (in this case through using ramipril) had a reduced incidence of cardiovascular events.⁷ Further studies are in progress to confirm this finding, since it is clear various anti-hypertensive agents can reduce proteinuria (angiotensin converting enzyme inhibitors, angiotensin receptor blockers, indapamide, verapamil, etc), but data on clinical outcomes are mostly lacking. Data showing that reduction in proteinuria or microalbuminuria was associated with a better outcome could change the choice of first line anti-hypertensive agent and make dipstick testing of urine a crucial assessment in all hypertensive patients.

West London Renal and Transplant Centre, Hammersmith Hospital, London W12 0HS
(j.levy{at}imperial.ac.uk)

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Research p 1426

Competing interests: None declared.

References

1. Rahman M, Pressel S, Davis B, Nwachuku C, Jackson T, Whelton P, et al. Cardiovascular outcomes in high risk hypertensive patients stratified by baseline glomerular filtration rate. Ann Intern Med 2006;144: 172-80.[Abstract/Free Full Text]
2. Manjunath G, Tighiouart H, Coresh J, Macleod B, Salem D, Griffith J, et al. Level of kidney function as a risk factor for cardiovascular outcomes in the elderly. Kid Internat 2003;63: 1121-9.
3. Segura J, Campo C, Ruilope L. Effect of proteinuria and glomerular filtration rate on cardiovascular risk in essential hypertension. Kid Internat 2004;66(suppl 92): S45-9.[CrossRef]
4. Klausen K, Scharling H, Jensen G, Jensen J. New definition of microalbuminuria in hypertensive subjects. Hypertension 2005;46: 33-7.[Abstract/Free Full Text]
5. Irie F, Iso H, Sairenchi T, Fukasawa N, Yamagishi K, Ikehara S, et al. The relationships of proteinuria, serum creatinine, glomerular filtration rate with cardiovascular disease mortality in Japanese general population. Kid Internat 2006;69: 1264-71.[CrossRef][ISI][Medline]
6. Tonelli M, Jose P, Curhan G, Sacks F, Braunwald E, Pfeffer M, et al. Proteinuria, impaired kidney function, and adverse outcomes in people with coronary disease: analysis of a previously conducted randomised trial. BMJ 2006;332: 1426-9.[Abstract/Free Full Text]
7. Schrader J, Luders S, Kulschewski A, Hammersen F, Zucher C, Venneklaas U, et al. Microalbuminuria and tubular proteinuria as risk predictors of cardiovascular morbidity and mortality in essential hypertension. J Hypertension 2006;24: 541-8.[ISI][Medline]

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Relevant Article

Proteinuria, impaired kidney function, and adverse outcomes in people with coronary disease: analysis of a previously conducted randomised trial

Marcello Tonelli, Powell Jose, Gary Curhan, Frank Sacks, Eugene Braunwald, Marc Pfeffer Cholesterol and Recurrent Events (CARE) Trial Investigators
BMJ 2006 332: 1426. [Abstract] [Full Text] [PDF]