Blog entry by Meguid El Nahas

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by Meguid El Nahas - Thursday, 1 November 2012, 5:04 PM
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Chronic Kidney Disease—A Challenge for All Ages .

Ian H. de Boer, MD, MS. JAMA. Published online October 30, 2012. doi:10.1001/jama.2012.30761

Context:  Chronic kidney disease (CKD) is prevalent in older individuals, but the risk implications of low estimated glomerular filtration rate (eGFR) and high albuminuria across the full age range are controversial.

Objective:  To evaluate possible effect modification (interaction) by age of the association of eGFR and albuminuria with clinical risk, examining both relative and absolute risks.

Design, Setting, and Participants:  Individual-level meta-analysis including 2 051 244 participants from 33 general population or high-risk (of vascular disease) cohorts and 13 CKD cohorts from Asia, Australasia, Europe, and North/South America, conducted in 1972-2011 with a mean follow-up time of 5.8 years (range, 0-31 years).

Main Outcome Measures:  Hazard ratios (HRs) of mortality and end-stage renal disease (ESRD) according to eGFR and albuminuria were meta-analyzed across age categories after adjusting for sex, race, cardiovascular disease, diabetes, systolic blood pressure, cholesterol, body mass index, and smoking. Absolute risks were estimated using HRs and average incidence rates.

Results:  Mortality (112 325 deaths) and ESRD (8411 events) risks were higher at lower eGFR and higher albuminuria in every age category. In general and high-risk cohorts, relative mortality risk for reduced eGFR decreased with increasing age; eg, adjusted HRs at an eGFR of 45 mL/min/1.73 m2 vs 80 mL/min/1.73 m2were 3.50 (95% CI, 2.55-4.81), 2.21 (95% CI, 2.02-2.41), 1.59 (95% CI, 1.42-1.77), and 1.35 (95% CI, 1.23-1.48) in age categories 18-54, 55-64, 65-74, and ≥75 years, respectively (P <.05 for age interaction). Absolute risk differences for the same comparisons were higher at older age (9.0 [95% CI, 6.0-12.8], 12.2 [95% CI, 10.3-14.3], 13.3 [95% CI, 9.0-18.6], and 27.2 [95% CI, 13.5-45.5] excess deaths per 1000 person-years, respectively). For increased albuminuria, reduction of relative risk with increasing age was less evident, while differences in absolute risk were higher in older age categories (7.5 [95% CI, 4.3-11.9], 12.2 [95% CI, 7.9-17.6], 22.7 [95% CI, 15.3-31.6], and 34.3 [95% CI, 19.5-52.4] excess deaths per 1000 person-years, respectively by age category, at an albumin-creatinine ratio of 300 mg/g vs 10 mg/g). In CKD cohorts, adjusted relative hazards of mortality did not decrease with age. In all cohorts, ESRD relative risks and absolute risk differences at lower eGFR or higher albuminuria were comparable across age categories.

Conclusions:  Both low eGFR and high albuminuria were independently associated with mortality and ESRD regardless of age across a wide range of populations. Mortality showed lower relative risk but higher absolute risk differences at older age.

MY COMMENTS:

The reported increased risk of mortality associated with low eGFR (<60ml/min) and albuminuria in all age group including the elderly is not surprising.

This is because older patients with low eGFR (<60ml/min) also have underlying CVD, clinically detectable or subclinically, as shown by Park and colleagues recently: http://www.ncbi.nlm.nih.gov/pubmed/22935481

Otherwise, why on earth would an older patient have declining GFR without proteinuria?! The Baltimore Aging Longitudinal Study (BALS) study implied that those whose kidney function decline with age have co-morbidities most often hypertension. Lindeman et al. http://www.ncbi.nlm.nih.gov/pubmed/3989190

The problem with the above study is that underlying CVD, and in particular hypertension, are not factored in these analyses of hazard risk in relation to low eGFR and mortality. Hypertension, for example, is neither adequately diagnosed, treated or controlled worldwide; to take the US example, only around 60% of hypertensive individuals are treated....and 35% are controlled....as shown by Chobanian: 

http://www.ncbi.nlm.nih.gov/pubmed/19710486

Furthermore, in most of the studies quoted in the above analysis, BP is seldom measured and when it is, it is not measured adequately. It is measured at the office and casually, measurements known to be of little correlation with CV outcomes and mortality. Night time, home and 24h ambulatory BP measurements are nowadays thought to be more predictive of CVD outcomes when compared to office BP monitoring.

http://www.ncbi.nlm.nih.gov/pubmed?term=Drawz%2C%20abdalla 

So it is not surprising that older individuals with poorly treated and uncontrolled hypertension have a higher prevalence of target organ damage including CKD. It is also not surprising that they have a higher risk of CVD and related death.

So my take on this paper is that those older people who are at higher risk of death because of low eGFR, are at higher risk because low GFR is a MARKER of underlying CVD NOT a maker of risk....I would also argue that underlying CVD is not properly, if at all, assessed in these individuals.

When CVD risk is properly assessed the NIR (added predictive risk) of renal markers (eGFR and albuminuria) to the standard CVD risk markers is NIL... http://www.ncbi.nlm.nih.gov/pubmed?term=Chang%2C%20Kramer%2C%20Nephron

As to low level albuminuria, it is probably a reflection of underlying hypertension or diffuse vascular damage!

So once more, the authors do not seem to discern the fact that CKD most likely reflects underlying age-related atherosclerosis/CVD and hypertension (clinical or subclinical-diagnosed or undiagnosed) and therefore it is not surprising that older people with these abnormal markers have a higher mortality....!!!!! 

 

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