Kidney function and risk of cardiovascular disease and mortality in women: a prospective cohort study

The risk of cardiovascular (CV) events and death increases as serum creatinine increases¹ or glomerular filtration rate (GFR) declines² but this relationship is exponential as GFR declines <_45 ml="ml" min="min" _1.73="_1.73" msup="msup"/>2. Patients with chronic kidney disease (CKD) and cardiovascular disease (CVD) often have common cardiovascular (CV) risk factors during early stages of CKD (stages 1, 2 & 3_a) and the CV risk is similar unless proteinuria is present³. The non-traditional risk factors – such as, inflammation, anemia and calcium phosphate metabolism, contribute to CVD especially at advanced stages of CKD (stage 3_b, 4 & 5), especially when the glomerular filtration rate (GFR) is <_45 ml="ml" min="min" _1.73msup="_1.73msup"/>2.

In the Women’s Health Study⁴, off the 27,939 women, 4.7% (1315) women had a GFR of <_60 ml="ml" min="min" _1.73msup="_1.73msup"/>2. Of these 84 women had any CV event and 60 women died with 21 from CVD and 39 from non-CVD. Although total number of women with GFR of <_40 ml="ml" min="min" _1.73msup="_1.73msup"/>2 is not given but 67 of the 84 women with CV events had a GFR of <_40 ml="ml" min="min" _1.73msup="_1.73msup"/>2 and authors claim that the small number of women in this category limited the interpretation. However, it appears that most of the CV events occurred in women with GFR of <_40 ml="ml" min="min" _1.73msup="_1.73msup"/>2, than what authors claim to be in patients with GFR of <_60 ml="ml" min="min" _1.73msup="_1.73msup"/>2. I am not clear why authors selected a GFR of <_40 ml="ml" min="min" _1.73msup="_1.73msup"/>2 and NOT GFR of <_45 ml="ml" min="min" _1.73msup="_1.73msup"/>2, that has recently been categorized to be a separate category⁵ because of a small proportion of patients with CKD with increased risk of CKD progression, complications and risk of CVD, compared to stage 3_a CKD (GFR 46-60 ml/min/1.73m²) that is more prevalent⁶ than stages 3_b, 4 and 5 combined and majority of this stage patients are NOT at increased risk of CVD compared to general population³, so that limited resources be used effectively in real high-risk patients.

However, Kurth et al⁴, combined stage 3_a (apples) and stage 3_b, 4 &5 (oranges) in their analyses and no doubt accordingly concluded that “GFR of <_60 ml="ml" min="min" _1.73msup="_1.73msup"/>2 in this cohort of women was associated with increased risk of CVD death” or simply that the “apples are sour!”

There are large numbers of patients in stage 3_a CKD compared to stages 3_b, 4 and 5 combined and these two groups are different and the later group is at increased risk for CV disease and events and
It is important to differentiate these two groups of CKD patients to effectively utilize limited resources.

References:

1. Shulman NB, Ford CE, Hall WD, Blaufox MD, Simon D, Langford HG, Schneider KA. Prognostic value of serum creatinine and effect of treatment of hypertension on renal function. Results from the hypertension detection and follow-up program. The Hypertension Detection and Follow-up Program Cooperative Group. Hypertension. 1989 May;13(5 Suppl):I80-93.

2. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004 Sep 23; 351(13):1296-305.

3. Brantsma AH, Bakker SJL, Hillege HL, de Zeeuw D, de Jong PE, Gansvoort RT for the PREVEND study. Cardiovascular and renal outcomes in subjects with K/DOQI stage 1-3 chronic kidney disease: the importance of urinary albumin excretion. Nephrol Dial Transplant 2008; 23:3851-58.

4. Kurth T, de jong PE, Cook NR, Buring JE, Ridker PM. Kidney function and risk of cardiovascular disease and mortality in women: a prospective cohort study. BMJ 2009;338:b2392

5. Crowe E, Halpin D, Stevens P, on behalf of the guideline development group. Early identification and management of chronic kidney disease: summary of NICE guidance. BMJ 2008; 337:a1530

6. Imai E, Horio M, Yamagata K, Eseki K, Hara S, Ura N, Kiyohara Y, Makino H, Hishida A, Matsuo S. Slower decline of glomerular filtration rate in the Japanese General Population: A longitudinal 10-year Follow-up study. Hypertn Res 2008; 31(3):433-41.

Competing interests:
None declared

We read the interesting article and editorial on kidney function and
risk of cardiovascular disease 1, 2 with great interest. We would like to
suggest a U shaped rather than J shaped curve actually exists related to
mortality and renal function.

We agree that as well as predicting end stage renal disease, there is
growing evidence that worsening chronic kidney disease carries an
increasing risk of cardiovascular death3, 4 as well as all cause5 and non-
cardiovascular mortality6. However we have previously shown, in a study
examining the 6 year survival of over 33, 00 patients (~18,600 female and
~14700 male) aged 50 years over the full range of eGFR values, that as a
marker of mortality, both low and high eGFRs are equally predictive of
increased mortality7. In this study we also found that death due to
cardiovascular disease increased as eGFR declined in both men and women.
In addition to showing the increased mortality at low eGFR, our study has
shown that the risk of death increases as eGFR increases. Indeed the ‘J’
shaped relationships between eGFR and all-cause mortality reported by
others 5 actually elongates to a ‘U’ shape 7. While cardiovascular
disease predominated in patients with low eGFR, respiratory and neoplastic
causes appeared to account for most of the deaths in the high eGFR groups.
It seems likely, therefore, that a cachexia-associated reduction in lean
muscle mass is at least part of the reason for lower creatinine
concentrations, especially in those patients who subsequently died from
cancer. Therefore we would agree that the high eGFR maybe in part simply a
limitation of the MDRD formula to predict GFR accurately in this group of
patients. However as a marker of mortality, a high eGFR can be as
predictive of death as low values.

References

1.Weiner DE. Kidney function and the risk of cardiovascular disease.
BMJ 2009: 339; 2.

2.Kurth T, de Jong PE, Cook NR, Buring JE, Ridker PM, Kidney function
and the risk of cardiovascular disease and mortality in women: a
prospective cohort study. BMJ 2009: 338; b2392.

3.Levey AS, Eckardt KU, Tsukamoto Y, Levin A, Coresh J, Rossert J, et
al. Definition and classification of chronic kidney disease: a position
statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney
Int 2005: 67; 2089-100.

4.Levey AS, Stevens LA, Hostetter T. Automatic Reporting of Estimated
Glomerular Filtration Rate-Just What the Doctor Ordered. Clinical
Chemistry 2006: 52; 2188.

5.Go AS, Chertow GM, Fan DJ, McCulloch CE, Hsu CY. Chronic kidney
disease and the risks of death, cardiovascular events, and
hospitalization. N Engl J Med 2004: 351;1296-305.

6.Fried LF, Katz R, Sarnak MJ, Shlipak MG, Chaves PHM, Jenny NS, et
al. Kidney Function as a Predictor of Noncardiovascular Mortality. J Am
Soc Nephrol 2005:16; 3728-35.

7.Cox HJ, Bhandari S, Rigby AS, Kilpatrick ES. Mortality at low and
high estimated GFR values. A U- shaped curve. Nephron Clinical Practice
2008: 110; 67-72.

Competing interests:
Received funding support to attend National conferences from Amgen, Novartis and Roche and received honrarium from BMS, Pfizer. Has been on the advisory boear for Roche and Astellas.