Metabolic evaluation in first time and recurrent urinary stone formers: Study from a tertiary care center of India

Abstract

BACKGROUND

Kidney stone disease is a common and often debilitating disorder with significant recurrence rate. It is a matter of debate whether the metabolic factors responsible for renal stone formation are similar or variable in different populations around the globe.

AIM

To evaluate the metabolic abnormalities via 24 hours urine profiles in first-time and recurrent renal stone formers.

METHODS

This retrospective study was conducted at a tertiary care center between 2022 and 2024 and included 70 patients with urolithiasis, comprising 30 first-time stone formers and 40 recurrent stone formers (RSF). All patients underwent biochemical evaluation, including serum calcium, phosphorus, uric acid, creatinine, and intact parathyroid hormone levels. A 24-hour urine analysis was performed to assess urinary volume and the excretion of calcium, oxalate, citrate, uric acid, and phosphate. Metabolic abnormalities were defined according to standard criteria. Statistical analysis was performed using the independent t-test for continuous variables and the χ² test for categorical variables, with a P value < 0.05 considered statistically significant.

RESULTS

Fifty-nine patients (84.2%) had at least one identifiable metabolic risk factor, with 37 patients (52.8%) having two or more metabolic abnormalities. The most common abnormalities detected were hypercalciuria 27 (38.5%) and hyper-oxaluria 19 (27.1%). Low urine volume, hypocitraturia and hyperuricemia was seen in 14 (20%), 16 (22.8%) and 4 (5.7%) patients respectively. Primary hyperparathyroidism was seen in a total of 8 (11.4%) patients. Metabolic abnormalities were seen more commonly in RSF but there was no statistically significant difference (P value > 0.05) in abnormalities between first time and RSF.

CONCLUSION

Metabolic evaluation reveals they were prevalent in > 70% of both groups, supporting routine evaluation even in first-time formers in high-risk regions. Hypocitraturia, hyperoxaluria, hyperphosphatemia and hyperparathyroidism are present in a significant proportion of Indian stone former patients.

Key Words: Urolithiasis; Metabolic evaluation; Hypercalciuria; Hyperoxaluria; First-time stone formers; Recurrent stone formers; Calcium phosphate stones

Core Tip: Renal stone disease shows high metabolic abnormality rates even at first presentation. In this prospective Indian tertiary-center study of 70 patients, 84.2% had at least one metabolic risk factor and 52.8% had multiple abnormalities. Hypercalciuria and hyperoxaluria were most frequent, with notable prevalence of primary hyperparathyroidism. Importantly, no significant metabolic differences were observed between first-time stone formers and recurrent stone formers. These findings support comprehensive metabolic evaluation after the first episode to enable targeted prevention and reduce recurrence.

INTRODUCTION

Urolithiasis is a multifactorial disorder influenced by metabolic, dietary, and environmental factors and represents a significant global health problem with a lifetime prevalence of 5%-15%[1]. In India, the burden of stone disease is substantial with marked regional variation[1]. The disease is associated with high recurrence rates, estimated at approximately 50% at 5 years and up to 80%-90% at 10 years[1,2]. Metabolic evaluation plays a crucial role in identifying modifiable risk factors and preventing recurrence; however, it remains underutilized, particularly in first-time stone formers (FTSF)[3].

Studies in Western populations have demonstrated a high prevalence of metabolic abnormalities among stone formers, with hypercalciuria and hyperoxaluria being the most common abnormalities[4]. However, regional dietary patterns and environmental factors may influence metabolic profiles, and data from Indian populations remain limited[5].

Recurrent stone formers (RSF) were defined as patients with ≥ 2 documented stone episodes (based on patient history and medical records), with at least one prior episode occurring more than 6 months before the current presentation, in accordance with established guidelines[6,7]. FTSF were defined as patients presenting with a single documented episode. This study aims to identify etiological metabolic factors in FTSF and RSF, assess their prevalence, and evaluate the feasibility of metabolic evaluation in FTSF.

MATERIALS AND METHODS

Study design and population

This retrospective study was conducted at tertiary care centre in India from 2022-2024. Seventy patients with confirmed urolithiasis (30 FTSF and 40 RSF) were enrolled. No formal sample size calculation was performed, and all eligible patients presenting during the study period were included in the analysis. Inclusion criteria included age > 18 years, normal renal function (serum creatinine < 1.5 mg/dL), and confirmed urinary stones via computed tomography of the kidney, ureter, and bladder. Exclusion criteria included pregnancy, urinary tract infections, anatomical abnormalities, or systemic diseases affecting stone formation (e.g., inflammatory bowel disease, primary hyperparathyroidism, renal tubular acidosis).

Data collection

Patients underwent a detailed history, including dietary habits, fluid intake, and family history of urolithiasis. Clinical features, stone characteristics (location, size, and number), and body mass index (BMI) were recorded. Biochemical evaluation included: Serum: Creatinine, calcium, phosphorus, uric acid, and intact parathyroid hormone. 24-hour urine: Volume, pH, calcium, oxalate, citrate, uric acid, and phosphate. Stone analysis: Performed in 29 patients using qualitative chemical analysis.

Hypercalciuria was defined as > 4 mg/kg/day, hyperoxaluria as > 40 mg/day, hypocitraturia as < 320 mg/day, and hyperuricosuria as > 600 mg/day[8]. Primary hyperparathyroidism was diagnosed based on elevated intact parathyroid hormone and hypercalcemia.

A single 24-hour urine sample was collected from each patient for metabolic evaluation. Patients were instructed regarding proper urine collection technique, including complete collection over 24 hours. Metabolic testing (24-hour urine) was performed at least 4 weeks after stone passage or intervention, when patients were stone-free and on a self-selected diet. Follow-up for recurrence was not part of this study design. Patients were advised to continue their usual diet and fluid intake prior to sample collection, and no standardized dietary restrictions were imposed, in order to reflect habitual metabolic conditions.

Statistical analysis

Data were analyzed using SPSS version 22. Continuous variables were reported as mean ± SD, and categorical variables as n (%). Differences between FTSF and RSF were assessed using the χ² test for categorical variables and the t-test for continuous variables. A P value < 0.05 was considered statistically significant.

RESULTS

Demographic and clinical characteristics

The study included 70 patients (41 males, 29 females) with a mean age of 38.2 ± 14.3 years (Table 1). The male-to-female ratio was 2.15:1. Farmers (32.8%) and laborers (24.2%) were the most common occupations. Most patients (80%) had a normal BMI (≤ 25 kg/m²), and only 2.8% had BMI > 35 kg/m². Pain was the predominant symptom (88.5%), followed by lower urinary tract symptoms and fever (Table 2). Comorbidities (e.g., diabetes, hypertension) were more frequent in RSF (22.5%) than FTSF (13.3%).

Table 1 Demographic characteristics, n (%).

Characteristic	FTSF (n = 30)	RSF (n = 40)	P value
Age (years, mean ± SD)	36.5 ± 13.8	39.4 ± 14.7	0.42
Sex (male/female)	18/12	23/17	0.84
Occupation			0.93
Farmers	10 (33.3)	13 (32.5)
Laborers	7 (23.3)	10 (25.0)
Housewives	6 (20.0)	7 (17.5)
BMI category			0.55
≤ 25	25 (83.3)	31 (77.5)
25-35	4 (13.3)	8 (20.0)
> 35	1 (3.3)	1 (2.5)

FTSF: First time stone formers; RSF: Recurrent stone formers; BMI: Body mass index.

Table 2 Clinical features, n (%).

Symptom	FTSF	RSF	P value
Pain	26 (86.7)	36 (90.0)	0.66
LUTS	10 (33.3)	15 (37.5)	0.72
Fever	8 (26.7)	13 (32.5)	0.60
Hematuria	6 (20.0)	9 (22.5)	0.80
Dysuria	2 (6.7)	3 (7.5)	0.90
Vomiting	2 (6.7)	3 (7.5)	0.90

FTSF: First time stone formers; RSF: Recurrent stone formers; LUTS: Lower urinary tract symptoms.

Dietary and environmental factors

A mixed diet (vegetarian and non-vegetarian) was reported by 80% of patients, with 20% being strictly vegetarian. Low fluid intake (< 2 L/day) was prevalent in 47.1% of patients, contributing to low urine volume in 22.8% (Table 3). Most participants were from Jaisalmer (33%) or Barmer (21%), areas known for high urolithiasis incidence.

Table 3 Dietary and fluid intake, n (%).

Variable	FTSF (n = 30)	RSF (n = 40)	P value
Diet (mixed/vegetarian)	24/6	32/8	1.00
Fluid intake			0.95
< 2 L/day	14 (46.7)	19 (47.5)
2-3 L/day	12 (40.0)	17 (42.5)
> 3 L/day	4 (13.3)	4 (10.0)

FTSF: First time stone formers; RSF: Recurrent stone formers.

Stone characteristics

Renal calculi were present in 42% of patients, and ureteric calculi in 54%. Most stones (51.5%) were 10-20 mm in size. Bilateral and multiple calculi were more common in RSF (27.1% and 32.8%, respectively) than FTSF (Table 4). Stone analysis in 29 patients revealed calcium phosphate (37.9%), mixed stones (31.0%), calcium oxalate (20.6%), and uric acid (6.8%) (Table 5).

Table 4 Stone characteristics, n (%).

Characteristic	FTSF	RSF	P value
Renal stone	13 (43.3)	16 (40.0)	0.78
Ureteric stone	16 (53.3)	22 (55.0)	0.89
Stone < 10 mm	10 (33.3)	10 (25.0)	0.45
Stone 10-20 mm	15 (50.0)	21 (52.5)	0.83
Stone > 20 mm	5 (16.7)	9 (22.5)	0.55
Bilateral	6 (20.0)	13 (32.5)	0.25
Multiple stones	7 (23.3)	14 (35.0)	0.30

FTSF: First time stone formers; RSF: Recurrent stone formers.

Table 5 Stone composition (n = 29).

Composition	n (%)
Calcium phosphate	11 (37.9)
Mixed	9 (31.0)
Calcium oxalate	6 (20.6)
Uric acid	2 (6.8)
Other	1 (3.4)

Biochemical and metabolic findings

Mean serum creatinine was 0.92 ± 0.6 mg/dL in FTSF and 1.01 ± 0.4 mg/dL in RSF, indicating normal renal function. Urine pH < 5.5 was observed in 43.3% of FTSF and 37.5% of RSF, while pH > 5.5 was more common (56.6% FTSF, 62.5% RSF). Metabolic abnormalities were detected in 84.2% of patients, with 52.8% having two or more abnormalities (Table 6). Hypercalciuria (38.5%) was the most frequent, followed by hyperoxaluria (30%), hypocitraturia (22.8%), and hyperuricosuria (14.2%). Primary hyperparathyroidism was identified in 11.4% of patients, with 3 cases confirmed as parathyroid adenoma. No significant differences in metabolic abnormalities were found between FTSF and RSF (P > 0.05).

Table 6 Metabolic abnormalities, n (%).

Abnormality	Total (n = 70)	FTSF (n = 30)	RSF (n = 40)	OR	95%CI	P value
Hypercalciuria	27 (38.5)	11 (36.6)	16 (40.0)	1.15	0.45-2.94	0.78
Hyperoxaluria	21 (30.0)	9 (30.0)	12 (30.0)	1.00	0.36-2.77	1.00
Hypocitraturia	16 (22.8)	7 (23.3)	9 (22.5)	0.96	0.31-2.98	0.94
Low urine volume	16 (22.8)	7 (23.3)	9 (22.5)	0.96	0.31-2.98	0.94
Hyperuricosuria	10 (14.2)	4 (13.3)	6 (15.0)	1.15	0.29-4.45	0.84
Hyperphosphatemia	11 (15.7)	5 (16.7)	6 (15.0)	0.88	0.26-2.96	0.85
Primary hyperparathyroidism	8 (11.4)	3 (10.0)	5 (12.5)	1.29	0.27-6.13	0.74
No abnormality	11 (15.7)	7 (23.3)	4 (10.0)	0.36	0.10-1.24	0.12

FTSF: First time stone formers; RSF: Recurrent stone formers; OR: Odds ratio; CI: Confidence interval.

Odds ratios (ORs) were calculated to assess the association between recurrent stone formation and metabolic abnormalities. Most abnormalities, including hypercalciuria (OR 1.15), hyperoxaluria (OR 1.00), hypocitraturia (OR 0.96), and low urine volume (OR 0.96), demonstrated no meaningful difference between groups. Although the absence of any metabolic abnormality showed lower odds among RSF (OR 0.36), this finding was not statistically significant. Overall, these results indicate a comparable distribution of metabolic abnormalities between first-time and RSF.

Management

Conservative management was successful in 7.1% of patients, with 4.2% passing stones spontaneously. Surgical intervention was required in 89% of cases, with ureteroscopic stone removal (47%) and percutaneous nephrolithotomy (32%) being the most common procedures (Table 7). All patients received tailored medical therapy based on metabolic findings, including thiazides for hypercalciuria, potassium citrate for hypocitraturia, and dietary modifications.

Table 7 Management patterns, n (%).

Management	Total (n = 70)	FTSF (n = 30)	RSF (n = 40)
Conservative	5 (7.1)	3 (10.0)	2 (5.0)
Spontaneous passage	3 (4.2)	2 (6.7)	1 (2.5)
Surgical	62 (88.6)	25 (83.3)	37 (92.5)
URSL	29 (41.4)	12 (40.0)	17 (42.5)
PCNL	20 (28.6)	8 (26.7)	12 (30.0)
Other	13 (18.6)	5 (16.7)	8 (20.0)

FTSF: First time stone formers; RSF: Recurrent stone formers; URSL: Ureteroscopic lithoripsy; PCNL: Percutaneous nephrolithotomy.

Overall, metabolic abnormalities were identified in the majority of patients with urolithiasis. A total of 59 patients (84.2%) had at least one metabolic abnormality, while 52.8% of patients exhibited two or more metabolic derangements. Hypercalciuria (38.5%) was the most frequent abnormality, followed by hyperoxaluria (30.0%), hypocitraturia (22.8%), and low urine volume (22.8%). Less common abnormalities included hyperuricosuria (14.2%), hyperphosphatemia (15.7%), and primary hyperparathyroidism (11.4%). Although metabolic abnormalities were slightly more frequent among RSF, no statistically significant differences were observed between first-time and RSF (P > 0.05). These findings highlight that metabolic risk factors are prevalent even in patients presenting with their first episode of stone disease. Logistic regression analysis did not identify any independent predictors of stone recurrence, as none of the variables showed statistically significant association.

DISCUSSION

Urolithiasis is a multifactorial disease influenced by metabolic, dietary, genetic, and environmental factors. The present study evaluated the metabolic profile of urinary stone formers in a tertiary care population from North-Western India and demonstrated a high prevalence of metabolic abnormalities (84.2%) among patients with urolithiasis. More than half of the patients (52.8%) exhibited two or more metabolic abnormalities, highlighting the multifactorial nature of stone formation. Similar high prevalence rates have been reported in previous studies evaluating metabolic profiles of stone formers. Yagisawa et al[9] and Eisner et al[10] demonstrated that a large proportion of both first-time and RSF exhibit identifiable metabolic risk factors on comprehensive metabolic evaluation.

The demographic characteristics of our cohort were consistent with the well-recognized epidemiological patterns of urolithiasis. The mean age of patients in the present study was 38.2 ± 14.3 years, with the majority of cases occurring in the 20-40-year age group, representing the most economically productive period of life. Similar age distributions have been reported in several epidemiological studies. Sorokin et al[1] reported that the peak incidence of stone disease occurs between the third and fifth decades of life, reflecting the combined influence of metabolic activity, dietary habits, and environmental exposures during these years. Curhan[2] similarly demonstrated that the incidence of nephrolithiasis is highest among adults aged 30-50 years, supporting our observations.

A male predominance was observed in the present study, with 41 males (58.5%) and 29 females (41.5%), yielding a male-to-female ratio of approximately 2.15:1. This finding is consistent with global epidemiological trends that demonstrate a higher prevalence of stone disease among men. Several studies have reported male-to-female ratios ranging from 2:1 to 3:1, although the gender gap has narrowed in recent decades due to lifestyle and dietary changes[3]. Hormonal influences, including the protective effect of estrogen in females and higher urinary calcium and oxalate excretion in males, have been proposed to explain this difference[4].

The occupational distribution of patients in our cohort also deserves attention. A considerable proportion of patients were farmers (32.8%) and laborers (24.2%), occupations commonly associated with prolonged outdoor work and exposure to high temperatures. Chronic dehydration resulting from inadequate fluid intake may contribute to low urinary volume and increased urinary supersaturation of lithogenic salts. This observation is particularly relevant in arid regions such as Rajasthan, where environmental conditions may significantly contribute to the high burden of stone disease.

Hypercalciuria was the most frequent metabolic abnormality detected in our study, present in 38.5% of patients, including 36.6% of FTSF and 40.0% of RSF. Hypercalciuria is a well-established risk factor for calcium stone formation due to increased urinary supersaturation of calcium salts. Previous studies have consistently identified hypercalciuria as one of the most important metabolic abnormalities among calcium stone formers. Çakıroğlu et al[5] reported similar findings in patients with calcium oxalate stones, emphasizing the importance of urinary calcium excretion in stone pathogenesis. Coe et al[8] further demonstrated that idiopathic hypercalciuria plays a critical role in the development of calcium-based renal stones.

Hyperoxaluria was the second most common metabolic abnormality in our cohort, detected in 30% of patients, with similar prevalence in both first-time and RSF. Oxalate is an important determinant of calcium oxalate supersaturation, and even modest increases in urinary oxalate significantly increase the risk of stone formation. Previous studies have demonstrated that hyperoxaluria is an important metabolic contributor to stone disease, particularly in populations with high dietary oxalate intake[11].

Hypocitraturia was identified in 22.8% of patients, including 23.3% of FTSF and 22.5% of RSF. Citrate acts as a natural inhibitor of stone formation by binding to calcium ions and preventing crystal aggregation. Reduced citrate excretion therefore predisposes individuals to calcium stone formation. Similar findings have been reported in earlier studies evaluating urinary metabolic abnormalities in stone formers[10].

Low urine volume was documented in 22.8% of patients, while nearly half of the participants (47.1%) reported fluid intake of less than 2 L/day. Reduced urinary volume increases the concentration of lithogenic solutes and promotes crystal formation. Randomized studies have shown that increasing daily fluid intake significantly reduces the recurrence of kidney stones by lowering urinary supersaturation of stone-forming salts[12]. These findings are particularly important in regions with high ambient temperatures such as Rajasthan.

An important observation in our study was the presence of primary hyperparathyroidism in 11.4% of patients, including 10% of FTSF and 12.5% of RSF, with three patients diagnosed with parathyroid adenoma. Primary hyperparathyroidism is a recognized cause of hypercalcemia and hypercalciuria and should always be considered in patients presenting with recurrent or unexplained stone disease. Previous studies have emphasized the importance of screening for parathyroid disorders in stone formers to enable early diagnosis and curative surgical treatment[13].

Stone composition analysis in our study revealed a predominance of calcium phosphate stones (37.9%), followed by mixed stones (31.0%) and calcium oxalate stones (20.6%). This distribution differs from several Indian studies where calcium oxalate stones predominate[14,15]. Differences in dietary habits, urinary pH, and environmental conditions may explain these variations.

Recent Indian data further support the importance of metabolic evaluation in FTSF. Ranjan et al[16] conducted a prospective study evaluating metabolic abnormalities in first-time uncomplicated renal stone formers and reported that 76.7% of patients had at least one metabolic abnormality, with low urine volume and hypocitraturia being the most common findings. The demographic profile in their study, including a mean age of 35.6 years and male predominance, was comparable to the present study, further supporting the generalizability of our findings.

A large proportion of patients in our study required surgical intervention (88.6%), reflecting the relatively large stone burden and complexity of disease at presentation. Advances in minimally invasive techniques such as ureteroscopy and percutaneous nephrolithotomy have significantly improved outcomes in stone management. Nevertheless, the high surgical burden highlights the importance of preventive strategies. Targeted medical therapy based on metabolic evaluation, including thiazide diuretics for hypercalciuria and potassium citrate supplementation for hypocitraturia, has been shown to significantly reduce recurrence rates[17].

The study has certain limitations, including the relatively small sample size and the absence of a prior sample size calculation, which may limit the statistical power to detect small differences between first-time and RSF. Also this study has limited availability of stone composition analysis. Furthermore, advanced metabolic testing to classify subtypes of hypercalciuria was not performed. Future studies with larger populations and longer follow-up may provide deeper insights into the metabolic determinants of stone recurrence in this region. The absence of significant predictors on regression analysis may be due to the relatively small sample size and suggests that recurrence is likely multifactorial.

CONCLUSION

Overall, the findings of the present study demonstrate that metabolic abnormalities are highly prevalent among urinary stone formers in North-Western India and occur with comparable frequency in both first-time and RSF. These observations support the growing consensus that comprehensive metabolic evaluation should be considered even at the first presentation of stone disease in order to identify modifiable risk factors and implement preventive strategies.