Menopause Live (08 November, 2010) from IMS

In a post hoc analysis, an increased risk of nephrolithiasis (renal stones) has been reported amongst users of hormone replacement therapy (HRT) in the Women’s Health Initiative (WHI) randomized, controlled trial [1]. A total of 10,739 postmenopausal women were included in the estrogen-alone vs. placebo trial (average follow-up 7.1 years), whereas 16,608 women composed the estrogen + progestin vs. placebo trial (average follow-up 5.6 years). The overall relative risk was 1.21 (95% confidence interval 1.03–1.44) which, in absolute terms, amounted to five extra cases of renal stones per 10,000 women per year (39 cases in the active treatment arms vs. 34 cases in the placebo arms). The increased nephrolithiasis risk was independent of progestin co-administration.

Comment
By age 70 years, 11% of American males and 5.5% of females will have experienced a symptomatic kidney stone; 80% of these stones are calcium oxalate, the balance being calcium phosphate, uric acid or struvite [2].

Risk factors for renal stones include anatomical variants, hypercalcemia and high oxalate levels which may themselves be influenced by dehydration (chronic diarrhea, small bowel surgery, malabsorption), primary hyperparathyroidism, hyperthyroidism, myeloma, calcium supplements, use of alkalis, high vitamin D and excess dietary salt. Incidence also increases with obesity, age and immobilization [2]. The gender difference in favor of women may be due to the effect of estrogen on calcium oxalate crystallization in urine [3]. 

Heller and colleagues [4] found lower levels of mean 24-h calcium, mean 2-h fasting urine calcium and mean calcium oxalate saturation amongst postmenopausal estrogen users than non-users with a personal history of renal stones, suggesting estrogen use may reduce the risk of recurrence. 

In the only other study to examine the effect of HRT on renal stones, the Nurses’ Health Study [5] found no association overall between menopausal status and risk of kidney stones, nor between postmenopausal hormone use and the risk of kidney stones. The present study [1] therefore stands alone in finding that HRT increases the risk of renal stones. 

There are obvious limitations to this study. First, it is a post hoc analysis of an endpoint never included in the original primary or secondary endpoints. Second, it depends for its data on a self-reported questionnaire which was not verified. The validity of this methodology is bought into question by the finding of an incidence of renal stones in the WHI population of 35 per 10,000 person-years, compared to 20.5 per 10,000 woman-years in the Nurses’ Health Study, suggesting possible reporting error. Third, the authors are unable to explain a mechanism whereby this effect may have occurred, whilst others have provided possible mechanisms for an opposite effect.

The data show an overall increase in relative risk for renal stones; however, taken individually, neither the group receiving conjugated estrogen group (CEE) nor the group receiving CEE/medroxyprogesterone acetate showed any statistically significant change. When examined for HRT use, no statistically significant effect was seen for past or current users (only never-users), nor for women between the ages of 50 and 59 years or within 5 years of their menopause.

Renal stones cause severe pain and may contribute to renal disease and to hypertension and should not be disregarded. Men and women should be warned of avoidable risk factors, notably obesity.

This latest WHI study [1] is, however, more a case of data dredging than good science, and the finding of an increased incidence of five more renal stones per 10,000 women per year that is not applicable to younger, recently postmenopausal women currently using HRT should not discourage such women from using HRT appropriately for the short-term relief of menopausal symptoms. Therefore, the conclusion of the WHI investigators that, ‘These findings should be considered in decision-making regarding postmenopausal estrogen use’, seems inappropriate.

Rodney J. Baber
Associate Professor of Obstetrics and Gynaecology at The University of Sydney, Head, Menopause Unit, The Royal North Shore Hospital of Sydney, New South Wales, Australia

References
1. Maalouf NM, Sato AH, Welch BJ, et al. Postmenopausal hormone use and the risk of nephrolithiasis. Arch Intern Med 2010;170:1678-85.
http://www.ncbi.nlm.nih.gov/pubmed/20937929
2. Worcester EM, Coe FL. Calcium kidney stones. N Engl J Med 2010;363:954-63.
http://www.ncbi.nlm.nih.gov/pubmed/20818905
3. Fan J, Chandhoke P, Grampsas S. Role of sex hormones in experimental calcium oxalate nephrolithiasis. J Sam Soc Nephrol 1999;10:S376-80.
http://www.ncbi.nlm.nih.gov/pubmed/10541267
4. Heller HJ, Sakhaee K, Moe OW, Pak CY. Etiological role of estrogen status in renal stone formation. J Urol 2002;168:1923-7.
http://www.ncbi.nlm.nih.gov/pubmed/12394677
5. Mattix Kramer HJ, Grodstein F, Stampfer MJ, Curhan GC. Menopause and post menopausal hormone use and risk of incident kidney stones. J Am Soc Nephrol 2003;14:1272-7.
http://www.ncbi.nlm.nih.gov/pubmed/12707395