Role of insulin resistance in uric acid nephrolithiasis

Table 1 Insulin resistance and kidney stone formation

Ref.	Type	Year	n	Study population	Relevant variables	Conclusion
Taylor et al[8]	Prospective	2005	241623	Health professionals from 3 different study cohorts starting as early as 1980	Patient reported BMI, waist circumference, and incidence of nephrolithiasis	Obesity, weight gain, and waist circumference are positively associated with renal stone disease
Taylor et al[7]	Cross-sectional	2005	220478	Health professionals	Patient reported incidence of diabetes and kidney stones	Patients with DM have higher relative risk of having stones. Patients with kidney stones were more likely to develop DM
Rendina et al[27]	Cross-Sectional, single institution	2009	2132	Consecutive Caucasian inpatients in a single Italian hospital	AHA/NHLBI criteria for MetS diagnosis, kidney stones diagnosed on US	MetS, specifically HTN and obesity (in females) is significantly associated with US evidence of kidney stones
Chang et al[28]	Prospective, single institution	2011	3872	South Korean workers participating in comprehensive health exam from 2002-2009	National Cholesterol Education Program’s Third Adult Treatment Panel criteria for MetS diagnosis, kidney stone diagnosed on US	MetS is significantly associated with acidified urine and increased risk of kidney stones MetS over time as well as each additional MetS trait predicted development of kidney stones
Kabeya et al[9]	Cross-Sectional, single institution	2012	2717	Japanese patients undergoing MetS screening	Fasting serum insulin, FPG, HbA1c, US for diagnosis of kidney stone	Glycemic control may be an independent risk factor for kidney stones. The number of MetS traits is positively associated with kidney stone risk; specifically, patients with all 5 traits are at a 2.7 x increased risk of kidney stones compared to those with 2 traits
Kohjimoto et al[29]	Cross-Sectional	2013	11555	Japanese survey	MetS traits, incident kidney stones – multiple and recurrent	Increasing number of MetS traits increased stone burden

IR: Insulin resistance; AHA/NHLBI: American Heart Association/National Heart, Lung, and Blood Institute; FPG: Fasting plasma glucose; MetS: Metabolic syndrome; DM: Diabetes mellitus; UA: Uric acid.

Table 2 Insulin resistance and uric acid stone formation

Ref.	Type	Year	n	Study population	Relevant variables	Conclusion
Lieske et al[30]	Retrospective, Case Control, single county in Minnesota	2006	7122	Known stone former vs Control	Stone analysis, metabolic evaluation	DM, obesity, and HTN are associated with the development of kidney stones. DM is significantly associated with UA stone formation
Daudon et al[10]	Cross-sectional	2006	2464	DM vs Non-DM stone formers	Stone analysis, BMI, clinical and lab data in a subset of stone formers	DM is associated with a higher overall frequency of kidney stones, specifically, UA. UA stone formation can reflect IR and patients should be evaluated for MetS and/or DM if UA stones are diagnosed.
Akman et al[11]	Retrospective, single institution	2012	146	MetS vs Non-MetS undergoing PCNL	Kidney stone analysis, imaging for initial/recurrent kidney stone diagnosis, baseline blood chemistry and urinalysis	Patients with MetS have a higher frequency of UA stones (21.9% vs 4.1%) and a higher rate of all stone recurrence following PCNL
Cho et al[12]	Retrospective, three institutions	2012	712	MetS vs Non-MetS undergoing endourologic intervention for stones	Stone analysis, metabolic data, International Diabetes Federation definition for MetS	MetS, specifically the traits of impaired fasting glucose and hypertriglyceridemia, is significantly associated with UA stone formation, but calcium based stones remain most common in this group
Kadlec et al[31]	Retrospective, single institution	2012	590	All stone formers undergoing endourologic intervention	Stone analysis, MetS factors (presence of obesity, DM, HTN, and HL)	DM and HTN, components of MetS, are significantly associated with UA containing stones
Stansbridge et al[32]	Retrospective, single institution	2013	1504	UA stone formers vs Non-UA	24H urine, stone analysis, relevant underlying diagnoses, including DM	UA containing stones are increased in DM, but calcium containing stones are still the most common in DM
Inci et al[33]	Case-control, single institution	2012	99	Control vs Stone formers (sub-stratified by stone type)	Stone analysis, metabolic evaluation	BMI and Hyperlipidemia, two major traits of IR/MetS, are significantly associated with calcium and UA stone formation
Zhou et al[34]	Retrospective, single institution	2013	269	UA stone formers vs Non-UA stone formers undergoing PCNL	CT for visceral fat area measurement, stone analysis, metabolic evaluation	HTN and visceral fat area, two traits highly associated with IR/MetS, are independent risk factors associated with UA stone formation

IR: Insulin resistance; MetS: Metabolic syndrome; DM: Diabetes Mellitus; UA: Uric acid; HTN: Hypertension; PCNL: Percutaneous nephrolithotomy.

Table 3 Pathophysiologic relationship between insulin resistance and uric acid stone formation

Ref.	Study Type	Year	n	Study population	Outcomes	Conclusion
Facchini et al[13]	Cross-sectional, single institution	1991	36	Healthy volunteers with varying degrees of IR	24H urine (pH, UA), UA clearance, steady-state plasma glucose, metabolic evaluation	As IR increases serum UA increases and urinary UA clearance decreases. Thus, increased serum UA concentration may be considered an additional trait of MetS
Cappuccio et al[14]	Cross-sectional, single institution	1993	568	Factory volunteers	Fasting spot urine (UA), fractional excretion of Na+, fasting blood analysis	The higher the serum UA level, the greater the amount of renal Na+ reabsorption. This phenomenon is consistent with hyperinsulinemia, and possibly IR, as insulin is known to increase renal sodium reabsorption
Pak et al[15]	Retrospective, single institution	2001	56	UA stone formers vs matched control with diet control	24H urine	UA stone formers have increased serum UA, decreased fractional excretion of urinary UA, and decreased urinary pH
Sakhaee et al[16]	Prospective, single institution	2002	70	Healthy vs stone formers (UA vs Calcium vs Mixed) with diet control	24H urine (pH, NH4+), fasting glucose	UA stone formers are more likely to have IR/DM. UA stone formation occurs due to impaired NH4+ excretion and urine acidification. Acid loading further decreases urinary pH in these patients as compared to non-UA stone formers/Controls
Abate et al[17]	Prospective, single institution	2004	68	Stone free patients vs UA stone formers with diet control	24H urine (pH, NH4+), glucose disposal rate	Acute hyperinsulinemia leads to elevated urinary pH and NH4+ excretion in normal insulin-sensitive subjects. Alternatively, IR is associated with low urinary pH and impaired NH4+ excretion and could be renal manifestations of IR causing UA stone formation
Maalouf et al[23]	Cross-sectional, single institution	2007	148	MetS vs No MetS (all stone free)	24H urine (pH, NH4+), Homeostasis model for IR, metabolic evaluation	Acidic urine is a feature of MetS and is associated with the degree of IR. As MetS traits increase, urine pH decreases
Bobulescu et al[24]	Prospective, single institution	2013	35	Matched patients with and without UA stones, matched non-stone forming diabetic controls	24H urine, urinary ammonium excretion	Both uric acid non-diabetic patients as well as DM non-stone forming patients had lower urinary pH as compared to matched non-stone forming non-diabetic controls
Cameron et al[25]	Prospective, single institution	2011	19	UA stone formers vs normal controls with diet control	24H urine, diurnal urinary pH	UA stone formers had decreased urinary pH with increased undissociated UA secretion compared to normal controls

IR: Insulin resistance; DM: Diabetes mellitus; UA: Uric acid; MetS: Metabolic syndrome.