Insulin resistance and low urinary citrate excretion in calcium stone formers

Abstract

Epidemiological data suggest an association between kidney stones and some features of metabolic syndrome such as an overweight condition, arterial hypertension or glucose intolerance. However, mechanisms remain to be elucidated. This study aimed to evaluate insulin resistance, as assessed by homeostasis model assessment (HOMA-IR), and urine composition analysis in patients affected by calcium nephrolithiasis. A cohort of 61 (38 male, 29-57 years of age) non-diabetic calcium stone formers was studied. Data about body mass index, arterial blood pressure, serum biochemistry including parathyroid hormone and calcitriol were recorded in all the patients; fasting glucose and insulin were determined to calculate HOMA-IR value and accordingly the patients were grouped into tertiles. Urine pH and urinary excretion of calcium, citrate, phosphate, oxalate, uric acid, urea and creatinine were measured on 24h urine samples. Patients of the highest HOMA-IR tertile showed lower urine citrate levels than patients of the lowest HOMA-IR tertile (475+/-243 vs. 630+/-187 mg/24h, p<0.05), whereas no difference was detected as far as urinary oxalate, calcium, uric acid, phosphate, and urine pH and urine volume output were concerned. HOMA-IR values were positively related to uric acid serum levels (r=0.31, p<0.05) and negatively to urinary citrate excretion (r=-0.26, p<0.05). Hypocitraturic patients showed higher levels of HOMA-IR than normocitraturic ones (3.03+/-0.92 vs. 2.25+/-1.19, p<0.05). This study shows that a higher level of insulin resistance is associated with lower urinary citrate excretion, and that hypocitraturic patients show a greater insulin resistance than normocitraturic calcium stone formers. This may be related to changes in citrate, Na(+)-K(+) and H(+) renal tubule transports, which have been described in insulin resistance. In conclusion, insulin resistance may contribute to an increased risk of calcium stone formation by lowering urinary citrate excretion. This finding suggests the need for a careful metabolic assessment in patients known to form calcium stones in order to ensure stone recurrence prevention and cardiovascular protection.

Dietary and Lifestyle Factors and Medical Conditions Associated with Urinary Citrate Excretion

“…Several studies have shown an association between metabolic acidosis and diabetes mellitus. In a study of 61 young calcium SFs, Cupisti et al (4) showed an association between insulin resistance and lower urinary citrate excretion. However, our study included an older population of both SFs and NSFs and considered prevalent diabetes rather than measures of insulin resistance.…”

“…Lower urinary citrate excretion is a known modifiable risk factor for calcium oxalate nephrolithiasis (1,2) and associated with both prevalent hypertension (3) and greater insulin resistance (4). However, the independent associations of several dietary and lifestyle factors and medical conditions with urinary citrate excretion are unclear.…”

“…However, these associations have yet to be explored on the population level. Furthermore, numerous other dietary and lifestyle factors and medical conditions are known to be associated with low urine pH, including obesity (12), diabetes mellitus (4,(13)(14)(15), and gout (16,17). However, the independent associations between these factors and urinary citrate excretion have not yet been reported.…”

Plasma bicarbonate and risk of type 2 diabetes mellitus

“…Diet exposures and physical activity were calculated as updated cumulative average levels as of the baseline (1990) questionnaire. We also summarized intake of cereal fibre and trans fats, glycemic load and the ratio of polyunsaturated to saturated fats (with each component categorized in quintiles and scored 1-5, where 5 was assigned to the healthiest intake) in a diabetes diet score (ranging from [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20], with a high diet score associated with a reduced risk of type 2 diabetes mellitus in the Nurses' Health Study. 16 The reproducibility and validity of the food-frequency questionnaires have been described.…”

“…8 In addition, higher levels of serum lactate, a small component of the anion gap, were associated with higher odds of prevalent type 2 diabetes mellitus in the Atherosclerosis Risk in Communities study 9 and with higher odds of incident type 2 diabetes mellitus in a retrospective cohort study of the risk factors for diabetes in Swedish men. 10 Other biomarkers associated with metabolic acidosis, including higher levels of serum ketones, 11 lower urinary citrate excretion 12 and low urine pH, 13 have been associated in crosssectional studies with either insulin resistance or the prevalence of type 2 diabetes mellitus. However, it is unclear whether these associations are a cause or consequence.…”