Journal reference: Di Angelantonio E, Chowdhury R, Sarwar N, et al. Chronic kidney disease and risk of major cardiovascular disease and no-vascular mortality: prospective population based cohort study. BMJ. 2010;341:c4986 ^[1]

Link: http://dx.doi.org/10.1136/bmj.c4986

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Even the earliest stages of chronic kidney disease (CKD) seem to be independently associated with an increased risk of subsequent coronary heart disease. Stage 1 CKD: ↑ 55% Stage 2 CKD: ↑ 72% When serum creatinine and urine tests for proteinuria have been performed, effort should be made to exclude or confirm the diagnosis of chronic kidney disease. Note: this dataset has some limitations.  Read below for more details.

More details:

Article details

Study design:

prospective population based cohort study

Study aim:

quantify associations of chronic kidney disease (CKD) stages with major cardiovascular disease and non-vascular mortality in adults

Methods summary:

Data from the Reykjavik study

• 9134 male and 9769 participants (72% response rate of all eligible participants)
• Serum creatinine; eGFR calculated with the four variable modification of diet in renal disease (MDRD) prediction equation
• Presence of proteinuria was assessed at baseline with a urinary dipstick; considered positive if 1+ or greater
• Monitored by central registries for occurrence of non-fatal myocardial infarction until the end of 2005
• Cause specific mortality according to death certificate with international classification of diseases (ICD) codes until end of 2007 (ICD-9 up to December 1996 and ICD-10 subsequently)
• Loss of follow-up about 0.6% to date

Statistical analysis:

• Principal analyses excluded participants with:
  • Cardiovascular disease at entry
  • Or known to be receiving renal replacement treatment
• Subsidiary analyses also excluded participants with:
  • Self reported diabetes mellitus
  • Fasting blood sugar level (BSL) ≥ 7 mmol/L at entry
• Chronic kidney disease definition:
  • Presence of proteinuria or eGFR < 60 mL/min/1.73 m²
  • the CKD staging system (Stages 1-5) used
• Those without CKD were subdivided into three groups:
  • eGFR: 60-74
  • eGFR: 75-89
  • eGRF: ≥ 90 mL/min/1.73 m²

Outcome measure:

• principal outcome was coronary heart disease, either:
  • non-fatal myocardial infarction, or
  • fatal myocardial infarction, or
  • coronary revascularisation
• participants only contributed their first principal outcome in the analysis
• median follow up of 24 years

Results summary:

Comparing people with and without CKD:

• hazard ratio (HR) for coronary heart disease after adjustment for age, sex, smoking status, diabetes, systolic BP, BMI, total cholesterol and triglycerides: 1.45 (95% CI 1.29-1.62)
• CKD was not associated with an increased risk of stroke but 95% confidence intervals were too wide for meaningful interpretation

Comparing people with and without proteinuria after the aforementioned adjustments:

• HR for coronary heart disease: 1.72 (95% CI 1.40-2.11)

Hazard ratios for coronary heart disease by CKD stage after adjustment:

• Stage 1 (eGFR ≥90 + proteinuria): HR 1.55 (95% CI 1.02-2.35)
• Stage 2 (eGFR 60-89 + proteinuria): HR 1.72 (95% CI 1.30-2.24)
• Stage 3a (eGFR 45-59): HR 1.39 (95% CI 1.22-1.58)
• Stage 3b (eGFR 30-44): HR 1.90 (95% CI 1.22-2.96)
• Stage 4 (eGFR 15-29): HR 4.29 (95% CI 1.78-10.3)

Other results:

• Participants with reduced eGFR but without CKD were not associated with increased risk of coronary heart disease:
  • eGFR 60-74 mL/min/1.73 m²: HR 1.04 (95% CI 0.00-1.10)
• Participants with CKD stages 1-3a not associated with increased non-vascular mortality
• CKD stages 3b and 4 were associated with increased non-vascular mortality after adjustment:
  • Stage 3b (eGRF 30-44): HR 1.82 (95% CI 1.24-2.68)
  • Stage 4 (eGFR 15-29): HR 5.97 (95% CI 2.24-15.9)

Study conclusion:

In people without manifest vascular disease, even the earliest stages of chronic kidney disease are associated with excess risk of subsequent coronary heart disease. Assessment of chronic kidney disease in addition to conventional risk factors modestly improves prediction of risk for coronary heart disease in this population. Further studies are needed to investigate associations between chronic kidney disease and nonvascular mortality from causes other than cancer.

Participants:

Reykjavik study:

• All men born between 1907 and 1934 and all women born between 1908 and 1935
• Were residents of Reykjavik, Iceland and its adjacent communities on 1 December 1966 as identified in the national population register
• Five stages of recruitment from between 1967 and 1991
• Total of 9134 males and 9769 females with a 72% response rate
• Loss to follow-up only 0.6%

Demographics:

• Mean age: 52.5 years, SD = 8.6
• Men: 48.6%
• Current smokers: 47.3%
• Mean systolic BP = 138 mmHg, SD = 22
• Mean diastolic BP = 87, SD = 12
• Mean BMI = 25.4, SD 3.9

Methodological weaknesses

• Participants are very racially homogenous (Icelandic, Northern European descent); the results may not apply to other populations.
• Urinary dipsticks are not as sensitive as quantitative methods of determining proteinuria; this may have exaggerated hazard ratios.
• Disease registers may preferentially give patients with known CKD cardiovascular diagnoses; again, this may have exaggerated hazard ratios.

Methodological strengths

• Large cohort of participants who are likely representative of the general population.
• Robust follow up with very few participants lost to follow up.
• Very long follow up (median 24 years)

Biases and conflicts of interests

Nil declared and nil seem obvious.

Clinical relevance to primary health care

This study demonstrates that even the earliest stages of chronic kidney disease are associated with a higher subsequent risk of coronary heart disease.  The participants with stage 1 and stage 2 CKD were at 55% and 72% greater risk respectively of developing coronary heart disease compared to those without CKD.  Much of the risk in early CKD seems to be related to the presence of proteinuria rather than the absolute eGFR level.  A curious finding is that the participants with stage 1 and 2 CKD (which require the presence of proteinuria or other signs of kidney disease) were associated with a higher risk than the participants at stage 3 CKD, where the diagnosis is commonly made on the eGFR alone.

It is unclear whether serum creatinine measurement and urinary tests for proteinuria should be routinely performed for cardiovascular risk screening.  From a practical standpoint, however, this is of lesser relevance as serum creatinine and tests for proteinuria (both bedside dipstick tests and laboratory assessment) are frequently performed for other diagnostic reasons.  Where these tests have been performed, clinicians should avoid missing the diagnosis of early chronic kidney disease.  The diagnosis with the staging should be noted in the patient’s medical history as its presence is an independent risk factor for future cardiovascular disease.

Caution needs to be made when generalising the results from this study.  The participants were almost entirely of Northern European descent (Icelandic) and may not be valid for other populations.

References

1. Di Angelantonio E, Chowdhury R, Sarwar N, et al. Chronic kidney disease and risk of major cardiovascular disease and no-vascular mortality: prospective population based cohort study. BMJ. 2010;341:c4986