Metabolic and Environmental Profiling and Imaging for Kidney Stone Risk

Number: 0392

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses metabolic and environmental profiling and imaging for kidney stone risk.

Experimental and Investigational

The following interventions are considered experimental and investigational because the effectiveness of these approaches has not been established:

1. Metabolic and environmental profiling for assessing kidney stone risk because these studies have not been demonstrated in the peer-reviewed medical literature to improve health outcomes of individuals with kidney stones;
2. The use of computed tomography (CT) or magnetic resonance imaging (MRI) for urolithiasis screening of asymptomatic persons because there is a lack of clinical evidence regarding their use for this indication;
3. The use of calcifying nanoparticles for assessing kidney stone risk; 
4. The use of genetic/molecular analysis for assessing kidney stone risk.

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
Metabolic and environmental profiling for assessment of kidney stone risk:
No specific code
CPT codes not covered for indications listed in the CPB:
72192	Computed tomography, pelvis; without contrast material
72193	with contrast material(s)
72194	without contrast material(s) followed by contrast material(s) and further sections
72195	Magnetic resonance (e.g., proton) imaging, pelvis; without contrast material(s)
72196	with contrast material(s)
72197	without contrast material(s), followed by contrast material(s) and further sequences
Other CPT codes related to this CPB:
82340	Calcium; urine quantitative, timed specimen
82507	Citrate
82570	Creatinine; other source
82615	Cystine and homocystine, urine, qualitative
83945	Oxalate
83986	pH, body fluid, except blood
84105	Phosphorus inorganic (phosphate); urine
84540	Urea nitrogen, urine
84545	Urea nitrogen, clearance
84560	Uric acid; other source
ICD-10 codes coverd if selection criteria are met :
R82.991 - R82.998	Other abnormal findings in urine
ICD-10 codes not covered for indications listed in the CPB:
N20.0	Calculus of kidney
Z87.442	Personal history of urinary calculi

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Background

Nephrolithiasis (also known as urolithiasis, renal calculi, or kidney stones) is exceeded in frequency as a urinary tract disorder only by infections and prostatic disease.  Calcium salts, uric acid, cystine, and struvite are the basic components of most kidney stones in the Western Hemisphere.  Calcium stones constitute more than 70 % of all kidney stones.  It has been suggested that there are metabolic as well as environmental risk factors that render urine more conducive to crystallization, thus resulting in an increase risk of stone formation.  Metabolic and environmental profiling involves studies used to ascertain these risk factors of nephrolithiasis.  These clinical and laboratory tests usually entail measurements of a number of blood and urine parameters, including estimates of urine state of saturation with calcium and uric acid salts, net gastro-intestinal alkali absorption, renal threshold of phosphate and other renal clearances, as well as net acid and total nitrogen excretions.

Although there are published studies on metabolic and environmental profiling, the value of these tests in the management of patients with kidney stones is still questionable.  Additionally, there are factors other than urine composition that may play a role in stone formation.  Furthermore, there is a lack of data to show that metabolic and environmental profiling improves the health outcomes of patients with kidney stones.  Although guidelines on urolithiasis from the European Association of Urology (Tiselius et al, 2006) include metabolic profiling, they state that there is "no absolute consensus that a selective treatment is better than a non-selective treatment for recurrence prevention in idiopathic calcium stone disease", and note that an analysis of data from the literature has suggested only a slight difference in favor of treatment directed towards individual biochemical abnormalities.

Guidelines from the American College of Physicians (2014) on prevention of kidney stones recommends monotherapy with thiazide diuretics, potassium citrate and allopurinol in patients with active disease in which increased fluid intake fails to reduce the formation of stones. The evidence for this recommendation came primarily from calcium stone formers. According to ACP, although biochemistry and some observational data on stone recurrence suggest that the choice of treatment could be based on the type of metabolic abnormality, evidence from randomized, controlled trials is lacking to correlate the drug of choice and stone type to the prevention of stone recurrence. Most patients have calcium stones, notes ACP, and evidence showed that thiazide diuretics, citrates, and allopurinol all effectively reduced recurrence of this stone type.

The significance of urolithiasis screening is controversial.  In a review on the clinical and cost effectiveness of CT and MRI for selected clinical disorders, the Canadian Agency for Drugs and Technologies in Health (CADTH) reported that no clinical or economic evidence was found on the use of CT and MRI for screening urolithiasis.  CADTH concluded that the use of CT or MRI for this indication should be considered investigational (Murtagh et al, 2006).

Dhar and Denstedt (2009) stated that imaging has an essential role in the diagnosis, management, and follow-up of patients with stone disease.  A variety of imaging modalities are available to urologists, including conventional radiography (KUB), intravenous urography (IVU), ultrasound (US), magnetic resonance urography, and CT scans, each with its advantages and limitations.  Traditionally, IVU was considered the gold standard for diagnosing renal calculi, but this modality has largely been replaced by un-enhanced spiral CT scans at most centers.  Renal US is recommended as the initial imaging modality for suspected renal colic in pregnant women and children, but recent literature suggests that a low-dose CT scan may be safe in pregnancy.  Intra-operative imaging by fluoroscopy or US plays a large part in assisting urologists with the surgical intervention chosen for the individual stone patient.  Post-treatment imaging of stone patients is recommended to ensure complete fragmentation and stone clearance.  Plain radiography is suggested for the follow-up of radiopaque stones, with US and limited IVU reserved for the follow-up of radiolucent stones to minimize cumulative radiation exposure from repeated CT scans.  Patients with asymptomatic calyceal stones who prefer an observational approach should have a yearly KUB to monitor progression of stone burden.

Shiekh and associates (2009) noted that although much has been learned regarding the pathogenesis of kidney stones, the reason(s) why some individuals form stones while others do not remains unclear.  Nanoparticles, which have been observed in geological samples, have also been isolated from biological specimens, including kidney stones.  These nanoparticles have certain properties that are consistent with a novel life form, including in vitro self-replication, and contain lipids, DNA and proteins.  Thus, it has been hypothesized that nanoparticles may represent a type of infective agent that initiates stone formation in some patients.  Despite a large body of suggestive evidence, the true biological nature of these entities has been elusive, and controversy remains as to whether these nano-sized particles are analogous to other recently described unusual and novel microorganisms, or a transmissible, yet inert nanoparticle.  Although unique DNA or RNA has yet to be identified, a proteomic biosignature is beginning to emerge that may allow more definitive clinical investigation.  The authors stated that there is need for additional research to further elucidate the role, if any, of calcifying nanoparticles in the formation of kidney stones.

Sayer (2011) stated that nephrolithiasis may be the manifestation of rare single gene disorders or part of more common idiopathic renal stone-forming diseases.  Molecular genetics has allowed significant progress to be made in the understanding of certain stone-forming conditions.  The molecular defect underlying single gene disorders often contributes to a significant metabolic risk factor for stone formation.  In contrast, idiopathic renal stone formation relates to the interplay of environmental, dietary and genetic factors, with hypercalciuria being the most commonly found metabolic risk factor.  Candidate genes for idiopathic stone formers have been identified using numerous approaches, some of which are outlined here.  Despite this, the genetic basis underlying familial hypercalciuria and calcium stone formation remains elusive.  The molecular basis of other metabolic risk factors such as hyperuricosuria, hyperoxaluria and hypocitraturia is being unraveled and is allowing new insights into renal stone pathogenesis.  The author concluded that the discovery of both rare and common molecular defects leading to renal stones will hopefully increase the understanding of the disease pathogenesis.  Such knowledge will allow screening for genetic defects and the use of specific drug therapies in order to prevent renal stone formation.

Tang et al (2012) stated that the role of vitamin D in kidney stone disease is controversial.  Current evidence is inconsistent and existing studies were limited by small sample populations.  These investigators used the 3rd National Health and Nutrition Examination Survey (NHANES III), a large US population-based cross-sectional study, to determine the independent association between serum 25-hydroxyvitamin D [25(OH)D] concentration and prevalent kidney stone disease in a sample of 16,286 men and women aged 18 years or older.  A prevalent kidney stone was defined as self-report of any previous episode of kidney stones.  Among 16,286 adult participants, 759 subjects reported a history of previous kidney stones.  Concentrations of serum 25(OH)D were not different between stone formers and non-stone formers (mean of 29.28 versus 29.55 ng/ml, p = 0.57).  Higher 25(OH)D concentration was not associated with increased odds ratio (OR) for previous kidney stones [OR = 0.99; 95 % confidence interval (CI): 0.99 to 1.01] after adjustment for age, sex, race, history of hypertension, diabetes, body mass index, diuretic use and serum calcium.  Furthermore, after these researchers divided 25(OH)D concentrations into quartiles, or into groups using clinically significant cut-offs (e.g., 40 and 50 ng/ml), still no significant differences were found in stone formation in group comparisons.  The authors concluded that high serum 25(OH)D concentrations were not associated with prevalent kidney stone disease in NHANES III participants.  They stated that prospective studies are needed to clarify the relationship between vitamin D and kidney stone formation, and whether nutritional vitamin D supplementation will increase risk of stone recurrence.

Nguyen et al (2014) noted that increasing 25(OH)D serum levels can prevent a wide range of diseases.  There is a concern about increasing kidney stone risk with vitamin D supplementation.  These investigators used GrassrootsHealth data to examine the relationship between vitamin D status and kidney stone incidence.  The study included 2,012 participants followed prospectively for a median of 19 months; 13 individuals self-reported kidney stones during the study period.  Multi-variate logistic regression was applied to assess the association between vitamin D status and kidney stones.  These researchers found no statistically significant association between serum 25(OH)D and kidney stones (p = 0.42).  Body mass index was significantly associated with kidney stone risk (OR = 3.5; 95 % CI: 1.1 to 11.3).  The authors concluded that a serum 25(OH)D level of 20 to 100 ng/ml has no significant association with kidney stone incidence.

Dasgupta and colleagues (2014) stated that compound heterozygous and homozygous (comp/hom) mutations in solute carrier family 34, member 3 (SLC34A3), the gene encoding the sodium (Na(+))-dependent phosphate co-transporter 2c (NPT2c), cause hereditary hypophosphatemic rickets with hypercalciuria (HHRH), a disorder characterized by renal phosphate wasting resulting in hypophosphatemia, correspondingly elevated 1,25(OH)2 vitamin D levels, hypercalciuria, and rickets/osteomalacia.  Similar, albeit less severe, biochemical changes are observed in heterozygous (het) carriers and indistinguishable from those changes encountered in idiopathic hypercalciuria (IH).  These investigators reported a review of clinical and laboratory records of 133 individuals from 27 kindreds, including 5 previously unreported HHRH kindreds and 2 cases with IH, in which known and novel SLC34A3 mutations (c.1357delTTC [p.F453del]; c.G1369A [p.G457S]; c.367delC) were identified.  Individuals with mutations affecting both SLC34A3 alleles had a significantly increased risk of kidney stone formation or medullary nephrocalcinosis, namely 46 % compared with 6 % observed in healthy family members carrying only the wild-type SLC34A3 allele (p = 0.005) or 5.64 % in the general population (p < 0.001).  Renal calcifications were also more frequent in het carriers (16 %; p = 0.003 compared with the general population) and were more likely to occur in comp/hom and het individuals with decreased serum phosphate (OR, 0.75, 95 % CI: 0.59 to 0.96; p = 0.02), decreased tubular reabsorption of phosphate (OR, 0.41; 95 % CI: 0.23 to 0.72; p = 0.002), and increased serum 1,25(OH)2 vitamin D (OR, 1.22; 95 % CI: 1.05 to 1.41; p = 0.008).  The authors concluded that additional studies are needed to examine if these biochemical parameters are independent of genotype and can guide therapy to prevent nephrocalcinosis, nephrolithiasis, and potentially, chronic kidney disease.

Rai et al (2014) examined the fate of indeterminate lesions incidentally found on non-contrast computed tomography (NCCT) for suspected urolithiasis.  These investigators performed a retrospective review of 404 consecutive cases of suspected urolithiasis between May 2010 and April 2011.  Data were collected for patient demographics, presence of calculus disease, and additional urologic or non-urologic pathologies and their clinical relevance.  The indeterminate or suspicious lesions were followed-up and the data were reviewed in September 2012.  In total, 404 patients underwent NCCT for renal colic (mean age of 50 years [range of 13 to 91 years]; 165 females).  Minimum follow-up period was 15 months; 58 patients (14 %) had ureteric, 85 (21 %) had renal, and 39 patients (10 %) had combined ureteric and renal stones.  Non-calculus pathologies were found in 107 patients (26 %).  Sixty patients (15 %) had indeterminate lesions.  Of these patients, 6 required operative intervention, 35 had a benign diagnosis after further imaging and multi-disciplinary team meeting, and 13 remained under surveillance after 1 year.  Indeterminate pulmonary lesions (8 of 16) were the commonest lesions to remain under surveillance.  The authors concluded that NCCT is vital for the diagnosis of urolithiasis with a pick up rate of 45 % and remains the standard of care.  However, with incidental detection of potential malignant lesions, a significant minority will need close monitoring, intervention, or both.  In this study, approximately 1/3 of these lesions either remained under surveillance or had intervention.

An UpToDate review on “Diagnosis and acute management of suspected nephrolithiasis in adults” (Curhan et al, 2015) states that “The diagnosis of nephrolithiasis is initially suspected by the clinical presentation.  Helical non-contrast computerized tomography (CT) or ultrasonography can be used initially to visualize and confirm the presence of a stone …. Radiological tests that are less frequently used include plain X-ray, intravenous pyelography, and magnetic resonance imaging.  Some of these tests are used in the initial diagnosis of nephrolithiasis only if CT is unavailable …. Magnetic resonance imaging is rarely used during the management of stone disease, except in the evaluation of pregnant patients, because this modality is not optimal for identifying stones.  Thus, this modality can be utilized if there is a specific indication to reduce radiation exposure”.

Wang and colleagues (2016) stated that many epidemiological studies have been conducted to evaluate the association between serum vitamin D levels and the risk of kidney stone.  These investigators summarized the evidence from epidemiological studies.  Pertinent studies were identified by a search of PubMed, Embase, the Cochrane Library, China National Knowledge Infrastructure (CNKI) and China Biology Medical literature up to July 2015.  Standardized mean difference (SMD) was conducted to combine the results.  Random-effect model was used.  Publication bias was estimated using Egger's regression asymmetry test.  A total of 7 articles involving 451 kidney stone cases and 482 controls were included in this meta-analysis.  The pooled results suggested that kidney stone patients had a significantly higher serum vitamin D level compared with controls [summary SMD = 0.65, 95 % CI: 0.51 to 0.79, I(2) = 97.0 %].  The associations were also significant both in Europe [SMD = 0.35, 95 % CI: 0.17 to 0.53] and in Asia [SMD = 1.00, 95 % CI: 0.76 to 1.25].  No publication bias was found.  The authors concluded that the findings of this analysis indicated that serum vitamin D level in kidney stone patients was significantly higher than that in non-kidney stone controls, both in Europe and Asia populations.

This study had several drawbacks:

1. 6 of 7 studies were of case-control design and only 1 study was of randomized controlled trial design,
2. as a meta-analysis of epidemiologic studies, the authors could not rule out that individual studies may have failed to control for potential confounders, which may introduce bias in an unpredictable direction,
3. for the subgroups of geographic locations, the associations were significant both in Europe and in Asia between serum vitamin D levels and kidney stone risk. Only 1 study was conducted from United States. Thus, these researchers did not combine the results for other populations.  Due to this limitation, the results are applicable to Europe and Asia, but cannot be extended to other populations. More studies originating in other countries are needed to investigate the association between serum vitamin D levels and kidney stone risk, and
4. between-study heterogeneity was high in the pooled analysis, but the heterogeneity was not successfully explained by the subgroup analysis and meta-regression.

However, other environment variables, as well as their possible interaction may be potential contributors to this disease-effect unconformity.

Ticinesi and colleagues (2018) stated that the involvement of the gut microbiota in the pathogenesis of calcium (Ca) nephrolithiasis has been hypothesized since the discovery of the oxalate-degrading activity of oxalobacter formigenes, but never comprehensively studied with metagenomics.  In a case-control study, these researchers compared the fecal microbiota composition and functionality between recurrent idiopathic Ca stone formers (SFs) and controls.  Fecal samples were collected from 52 SFs and 48 controls (mean age of 48 ± 11 years).  The microbiota composition was analyzed via 16S rRNA microbial profiling approach; 10 samples (5 SFs, 5 controls) were also analyzed with deep shotgun metagenomics sequencing, with focus on oxalate-degrading microbial metabolic pathways.  Dietary habits, assessed via a food-frequency questionnaire, and 24-hour urinary excretion of pro-lithogenic and anti-lithogenic factors, including Ca and oxalate, were compared between SFs and controls, and considered as co-variates in the comparison of microbiota profiles.  SFs exhibited lower fecal microbial diversity than controls (Chao1 index 1,460 ± 363 versus 1,658 ± 297, fully adjusted p = 0.02 with step-wise backward regression analysis). At multi-variate analyses, 3 taxa (fecalibacterium, enterobacter, dorea) were significantly less represented in fecal samples of SFs.  The oxalobacter abundance was not different between groups.  Fecal samples from SFs exhibited a significantly lower bacterial representation of genes involved in oxalate degradation, with inverse correlation with 24-hour oxalate excretion (r = -0.87, p = 0.002).  The oxalate-degrading genes were represented in several bacterial species, whose cumulative abundance was inversely correlated with oxaluria (r = -0.85, p = 0.02).  The authors concluded that idiopathic Ca SFs exhibited altered gut microbiota composition and functionality that could contribute to nephrolithiasis physiopathology.

Agudelo et al (2022) examined the role of the urinary metabolome in the genesis of urinary stone disease (USD).  Untargeted metabolomics was used in comparative analyses of calcium-based stones (CBS) and spot urine samples from patients with a history of USD with or without urinary stone activity based on radiologic imaging.  Stone and urine metabolomes were stratified by composition and radiographic stone-activity, respectively.  Furthermore, these researchers quantified highly abundant metabolites that were present in either calcium oxalate (CaOx) or calcium phosphate (CaPhos) stones and also significantly enriched in the urine of active stone formers (SF) compared to non-active SF.  These data were used to delineate either a direct involvement of urinary metabolites in lithogenesis or the passive uptake of biomolecules within the stone matrix.  Urinary metabolomes were distinct based on radiographic stone-activity and the 2 types of CBS.  Stratification by radiologic stone activity was driven by the enrichment of 14 metabolites in the urine of active SF that were also highly abundant in both CaOx and CaPhos stones, indicative of a potential involvement of these metabolites in lithogenesis.  By means of the combination of these 14 metabolites in total, these investigators generated a model that correctly classified patients as active versus non-active SF in a prospectively recruited cohort with 73 % success.  The authors concluded that these findings suggested specific urinary metabolites directly contribute to the formation of urinary stones and that active SF may excrete higher levels of lithogenic metabolites than non-active patients.  Moreover, these researchers stated that future studies are needed to confirm these findings and establish the causative mechanisms associated with these metabolites.

The authors stated that this study had several drawbacks.  First, some clinical aspects not considered like degree of renal impairment, use of anti-microbials or other medications, could affect the urine chemistry.  There was a difference in imaging modality between the active and non-active stone formers.  However, biases between these modalities were minimized by adjusting the selection criteria based on stone size.  Second, active and non-active stone formers were recruited independent of stone composition, since chemical stone composition based just on radiology is unreliable.  Given this limitation, this study could only identify urinary metabolites that generally associate with stones/lithogenesis.  A targeted analysis, differentiating patients based on types of stones would identify metabolites associated with stone composition.  Third, while the results indicated that the 14 metabolites identified via untargeted metabolomics represented candidate lithogenic agents, the causal relationship of these metabolites for stone formation has not been established and warrants additional studies.

Thongprayoon et al (2022) noted that the urine metabolites and chemistries that contribute to kidney stone formation are not fully understood.  These researchers examined differences between the urine metabolic and chemistries profiles of 1st-time SFs and controls.  High-resolution 1H-nuclear magnetic resonance (NMR) spectroscopy-based metabolomic analysis was carried out in 24-hour urine samples from a prospective cohort of 418 1st-time symptomatic kidney SFs and 440 controls.  A total of 48 NMR-quantified metabolites in addition to 12 standard urine chemistries were assayed.  Analysis of co-variance was used to determine the association of SF status with urine metabolites or chemistries after adjusting for age and sex and correcting for the false discovery rate.  Gradient-boosted machine methods with nested cross-validation were used to predict SF status.  Among the standard urine chemistries, SFs had lower urine oxalate and potassium and higher urine calcium, phosphate, and creatinine.  Among NMR urine metabolites, SFs had lower hippuric acid, trigonelline, 2-furoylglycine, imidazole, and citrate and higher creatine and alanine.  A cross-validated model using urine chemistries, age, and sex yielded a mean AUC of 0.76 (95 % CI: 0.73 to 0.79).  A cross-validated model using urine chemistries, NMR-quantified metabolites, age, and sex did not meaningfully improve the discrimination (mean AUC, 0.78; 95 % CI: 0.75 to 0.81).  In this combined model, among the top 10 discriminating features, 4 were urine chemistries and 6 NMR-quantified metabolites.  The authors concluded that although NMR-quantified metabolites did not improve discrimination, several urine metabolic profiles were identified that may improve understanding of kidney stone pathogenesis.

Campschroer et al (2022) stated that Roux-en-Y gastric bypass (RYGB) is associated with an increased risk of kidney stone formation; however, this is not observed after sleeve gastrectomy (SG).  These researchers examined if pre-operative metabolic profiling would aid in selecting the most optimal bariatric procedure for patients with a kidney stone history.  Patients with a kidney stone history and in the run up to bariatric surgery were screened with non-contrast abdominal CT, serum profiling, and 24-hour urine analysis.  Those with stones on radiologic imaging and/or high pre-operative urinary oxalate were advised to undergo SG instead of RYGB.  Pre- and post-operative urine and serum profile differences between both groups were evaluated retrospectively.  Post-operatively, RYGB (n = 28, M:F = 8:20) was associated with a 23.5 % reduction in urinary volume, a 85 % increase in urinary oxalate excretion with a 230 % increase in calcium oxalate (CaOx) super-saturation and a 62 % decrease in urinary citrate.  Although SG (n = 30, M:F = 12:18) was also associated with a reduction in urinary volume, it had no adverse effects on urinary oxalate and citrate excretion, nor on calcium oxalate supersaturation (CaOx-SS).  Both RYGB and SG showed favorable effects on post-operative sodium, calcium, uric acid, and phosphate excretion.  The authors concluded that the findings of this study indicated that pre-operative metabolic profiling was important to select the optimal bariatric procedure in patients with an a priori increased risk of kidney stone development.  These patients should be strongly encouraged to undergo SG instead of RYGB to prevent progressive or recurrent kidney stone disease.  These preliminary findings need to be validated by well-designed studies.

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References