Uric Acid Stone Formation Research Articles

Update on Uric Acid and the Kidney.

In this review, we report on new findings regarding associations of uric acid with kidney health. We discuss kidney stones, effects of uric acid in chronic kidney disease (CKD), and management of gout in CKD. Recent studies on neuroprotective effects of raising uric acid provide interesting data regarding nephrolithiasis. Elevated urate levels have been implicated in the progression of chronic kidney disease (CKD), but the results from PERL and CKD-FIX studies did not demonstrate that allopurinol slowed CKD progression. The SURE-PD3 sought to determine if increasing uric acid would slow the progression of Parkinson's disease. Results ultimately did not support this hypothesis, but high urinary uric acid levels caused uric acid stones, not calcium stones. Low urinary pH remains the key to the formation of uric acid stones. Thiazolidinediones improve insulin resistance, which is associated with an increase in urine pH. The most recent research has not supported the hypothesis that lowering serum uric acid levels will slow the progression of CKD or provide neuroprotection in Parkinson's disease. It is still unclear as to why uric acid stone formers have a high net acid excretion. The STOP-GOUT trial demonstrates that there was a lack of significant adverse events with higher urate-lowering dosages of allopurinol and febuxostat, despite patients' kidney function. This may push other studies to administer higher dosages per ACR guidelines. Future studies could then demonstrate decreased progression of CKD.

Optimization of urolithiasis treatment and diagnosis in the Turkestan region

The article aims to identify the main problems in treating urological pathologies by analyzing scientific literature from this field and developing recommendations. The quantitative excretion of uric acid, urine volume, and pH are essential in the formation of uric acid stones. The most important risk factor for uric acid nephrolithiasis is the acidic reaction of urine, which is a prerequisite for the formation of urinary stones. When urine is alkalized, the pH should be 6–6.5. Drugs alkalize urine, and one should titrate using urine pH indicator paper until the level is stable. This study found that the spread of genitourinary diseases is increasing. This situation can be improved by monitoring and assessing epidemiological processes, preventing urological pathology, and optimizing medical care organization in the context of health care reform.

Type Two Diabetes Mellitus and the Risk of Uric Acid Stone Formation

Type Two Diabetes Mellitus and the Risk of Uric Acid Stone Formation

The new patterns of nephrolithiasis: What has been changing in the last millennium?

Nephrolithiasis has been increasing over the last millennium. Although early epidemiologic studies have shown that kidney stones were two to three times more frequent in males than in females, recent reports have suggested that this rate is decreasing. In parallel a dramatic increase of nephrolithiasis has also been observed among children and adolescents. Furthermore, epidemiologic studies have shown a strong association between metabolic syndrome (Mets) traits and kidney stone disease. Patients with hypertension have a higher risk of stone formation and stone formers are predisposed to develop hypertension compared to the general population. An incidence of nephrolithiasis greater than 75% has been shown in overweight and obese patients compared to those of normal weight. It has also been reported that a previous diagnosis of diabetes mellitus increases the risk of future nephrolithiasis. Additionally, an association between metabolic syndrome and uric acid stone formation has been clearly recognized. Furthermore, 24-h urinary metabolic abnormalities have been decreasing among patients with nephrolithiasis over the last decades. Finally, nephrolithiasis could cause chronic kidney disease (CKD) and end stage renal disease (ESRD), especially in women and overweight patients. According to these observations, a better understanding of these new features among stone former patients may be required. Hence, the recognition and the correction of metabolic disorders could help not only to reduce the primary disease, but also stone recurrence.

MO119COMPUTER-DERIVED SOFTWARE IN CLINICAL PRACTICE: RESULTS FROM A SHORT-TERM FOLLOW-UP ACCORDING TO KIDNEY STONE COMPOSITION IN KIDNEY STONE FORMERS

Abstract Background and Aims Urinary supersaturation (SS) contributes to stone formation, and its assessment in stone formers may be helpful in clinical practice. Several computer programs are available for SS calculation, including EQUIL2, JESS and Lithorisk1. The aim of this study was to evaluate changes in SS in 24-hour urine in patients with known stone composition before and after about three months of regular treatment. Method Patients who submitted their stone/s for composition analysis and had provided an adequate 24-hour urine collection (creatinine 15-20 mg/kg/24-hour) before and around 90 days under regular treatment were included. Stone composition was defined using morphoconstitutional and infrared spectroscopy. The treatment was initiated in accordance with specific guidelines, and included dietary advices and medications2. SS for calcium oxalate (CaOx), calcium phosphate (CaP) and uric acid (UA) using EQUIL2, JESS and Lithorisk were calculated at baseline and after about 90 days on treatment. Continuous variables were reported as means (SD) while categorical variables were reported as frequencies and percentages. Baseline and follow-up SS urine values were compared using the Wilcoxon signed-rank test. 3D graphs were plotted using mean SS values of CaOx, CaP and UA obtained from each program before and after treatment, dividing the stones into 4 groups1: calcium oxalate monohydrate (COM), calcium oxalate dihydrate (COD), calcium phosphate (CaP), and uric acid (UA). Ethical Committee approval was obtained. Results 105 patients (61 men, 58%) were followed and provided 24h urine collection. Of these, 101 (96%) were recurrent patients. The mean (SD) follow-up was 94 (14) days. 48 (46%) of all calculi were made of CaOx, either COM or COD, 36 (34%) of UA, and 21 (20%) of CaP. A significant reduction in SS values during treatment was observed in patients with COM (p<0.05) , COD (p<0.001), and UA stones (p<0.001) with all programs. The reduction in SS values over time in patients with CaP stones was not significant (Table 1). Figure 1 shows 3D plots with SS before and after treatment into 4 groups of stone formers. Conclusion EQUIL2, JESS and Lithorisk are suitable software currently used for clinical and research purposes. SS values calculated by EQUIL2, JESS and Lithorisk during follow-up showed a significant reduction among COM, COD and UA stone formers. CaP stone formers did not show significant changes in SS over time.

Diabetes Mellitus Might Not Be Associated with Any Stone Component in a Local District

Background: Type II diabetes mellitus (DM) is a risk factor for urinary stones, but the pathogenesis remains unclear. The aim of our study was to present the distribution of stone components between DM and no DM group from a local stone center in China and to help the prevention department in decision-making. Methods: We reviewed the records of patients with upper urinary stones attending our hospital from January 2015 to September 2018. The patients with complete information were divided into 2 groups: type II DM group (DM group) and without DM group (no DM group). The distribution of stone components was analyzed. Results: Two hundred twenty-two patients were complicated with DM, whereas 1,894 (89%) were not. Significant difference was found in the distribution of hypertension and BMI (p = 0, p = 0, respectively). Distribution of sex, age, and stone components did not differ between the 2 groups. By the binary logistic analysis, increasing age and sex seemed to be the main risk factors influencing the stone components. Only the calcium stone seemed to be free of the ­impact from age and sex. Occurrence of hypertension is a single risk factor for calcium stone from our analysis. Presence of diabetes and increasing BMI was not found to be significantly associated with the risk for any stone component. Conclusions: In a local district, DM might not be the main factor associated with an increased risk for uric acid stone formation or any stone component. We should also consider the local characteristics of the stone distribution.

Uric acid stone disease: lessons from recent human physiologic studies.

An overly acidic urine resulting in supersaturation of urine with respect to uric acid is the major mechanism responsible for uric acid nephrolithiasis. The present review summarizes findings from recent human physiologic studies examining the pathophysiology and reversibility of low urine pH in uric acid stone formers. Epidemiologic and metabolic studies have confirmed an increase in the prevalence of uric acid nephrolithiasis and reported its association with several features of the metabolic syndrome including dyslipidemia, hyperglycemia, hepatic steatosis, and greater visceral adiposity. Physiologic studies in uric acid stone formers have identified diet-independent excessive net acid excretion and concomitant reduction in urinary buffering from impaired renal ammoniagenesis as the two causes underlying the greater aciduria. Administration of the insulin sensitizer pioglitazone to uric acid stone formers reduced the acid load presented to the kidney and enhanced ammoniagenesis and ammonium excretion, resulting in significantly higher urine pH. Recent human physiologic studies have identified greater acid excretion and reduced urinary buffering by ammonia as two culprits of aciduria in uric acid nephrolithiasis that can be reversed by pioglitazone, raising new questions regarding the origin of the aciduria and opening the door to pathophysiology-based treatment of uric acid stones.

Discrepancy Between Stone and Tissue Mineral Type in Patients with Idiopathic Uric Acid Stones.

Objectives: To describe the papillary pathology found in uric acid (UA) stone formers, and to investigate the mineral form of tissue deposits. Materials and Methods: We studied eight UA stone formers treated with percutaneous nephrolithotomy. Papillae were imaged intraoperatively using digital endoscopy, and cortical and papillary biopsies were taken. Biopsies were analyzed by light microscopy, micro-CT, and microinfrared spectroscopy. Results: As expected, urine pH was generally low. UA supersaturation exceeded one in all but one case, compatible with the stone material. By intraoperative imaging, the renal papillae displayed a heterogeneous mixture of plaque and plugging, ranging from normal to severe. All patients had mineral in ducts of Bellini and inner medullary collecting ducts, mainly apatite with lesser amounts of urate and/or calcium oxalate in some specimens. Papillary and cortical interstitial tissue injury was modest despite the tubule plugging. No instance was found of a stone growing attached to either plaque or plugs. Conclusions: UA stone formers resemble those with ileostomy in having rather low urine pH while forming tubule plugs that contain crystals that can only form at pH values above those of their bulk urine. This discrepancy between tissue mineral deposits and stone type suggests that local tubular pH exceeds that of the bulk urine, perhaps because of localized tubule injury. The manner in which UA stones form and the discordance between tubule crystals and stone type remain open research questions.

Patients treated for uric acid stones reoccur more often and within a shorter interval compared to patients treated for calcium stones.

We aimed to investigate the association between stone composition and recurrence rate in a well-characterized group of patients. From our prospectively assembled database of 1328 patients undergoing ureteroscopy and percutaneous nephrolithotomy (PCNL) between 2010 and 2015, we identified 457 patients who met the inclusion criteria: a minimum of two years' followup, stone-free status following surgery, normal anatomy, and Fourier transform infrared (FT-IR) stone analysis results. Stone recurrence was identified by kidney-ureter-bladder (KUB) or an ultrasound (US). All symptomatic events were recorded. Kaplan-Meier and Cox proportional hazard regression methods were used to assess the differences in recurrence rates and associated risk factors. Calcium oxalate (CaOx), uric acid (UA), and struvite stones were found in 298 (65.2%), 99 (21.7%), and 28 (6.1%) patients, respectively. During a median followup of 38 months (interquartile range [IQR] 31-48), stone recurred in 111 (24%) patients. One-year stone-free rates (SFRs) stratified by composition were: CaOx 98%, UA 91.9%, calcium phosphate 90%, struvite 88%, and, cystine 83%; the two-year SFRs were 92.6%, 82.7%, 80%, 73%, and 75%, respectively. On multivariate Cox regression analysis, UA composition, the absence of medical preventive therapy, and preoperative stone burden were associated with a shorter time to recurrence. Secondary intervention for recurrent, symptomatic stones was required in 11 (11.1%) and 22 (7.4%) of patients with UA and CaOx stones, respectively (p=0.02). UA stone-formers are more likely to have a recurrence and to undergo surgical intervention in comparison to CaOx stone-formers, regardless of medical preventive treatment. These differences are more prominent during the first year of followup and should be incorporated into the patient's followup protocol.

Re: Increased Production and Reduced Urinary Buffering of Acid in Uric Acid Stone Formers is Ameliorated by Pioglitazone

Re: Increased Production and Reduced Urinary Buffering of Acid in Uric Acid Stone Formers is Ameliorated by Pioglitazone

Targeted renal knockdown of Na+/H+ exchanger regulatory factor Sip1 produces uric acid nephrolithiasis in Drosophila.

Nephrolithiasis is one of the most common kidney diseases, with poorly understood pathophysiology, but experimental study has been hindered by lack of experimentally tractable models. Drosophila melanogaster is a useful model organism for renal diseases because of genetic and functional similarities of Malpighian (renal) tubules with the human kidney. Here, we demonstrated function of the sex-determining region Y protein-interacting protein-1 (Sip1) gene, an ortholog of human Na+/H+ exchanger regulatory factor (NHERF1), in Drosophila Malpighian tubules and its impact on nephrolithiasis. Abundant birefringent calculi were observed in Sip1 mutant flies, and the phenotype was also observed in renal stellate cell-specific RNA interference Sip1 knockdown in otherwise normal flies, confirming a renal etiology. This phenotype was abolished in rosy mutant flies (which model human xanthinuria) and by the xanthine oxidase inhibitor allopurinol, suggesting that the calculi were of uric acid. This was confirmed by direct biochemical assay for urate. Stones rapidly dissolved when the tubule was bathed in alkaline media, suggesting that Sip1 knockdown was acidifying the tubule. SIP1 was shown to collocate with Na+/H+ exchanger isoform 2 (NHE2) and with moesin in stellate cells. Knockdown of NHE2 specifically to the stellate cells also increased renal uric acid stone formation, and so a model was developed in which SIP1 normally regulates NHE2 activity and luminal pH, ultimately leading to uric acid stone formation. Drosophila renal tubules may thus offer a useful model for urate nephrolithiasis.

Re: Increased Production and Reduced Urinary Buffering of Acid in Uric Acid Stone Formers is Ameliorated by Pioglitazone

Re: Increased Production and Reduced Urinary Buffering of Acid in Uric Acid Stone Formers is Ameliorated by Pioglitazone

Association of Adherence to The Mediterranean Diet with Urinary Factors Favoring Renal Lithiasis: Cross-Sectional Study of Overweight Individuals with Metabolic Syndrome.

Our purpose was to study the relationship of adherence to the Mediterranean diet (MedDiet) with urinary factors that favor the formation of renal calcium and uric acid stones in overweight and obese participants who had metabolic syndrome. This cross-sectional study examined 267 participants. A well-known MedDiet score (range 0–9) was calculated for each patient, and patients were then categorized has having low (≤3), medium (4–5), or high (≥6) adherence to the MedDiet. Baseline characteristics and urinary parameters were also analyzed. High calcium salt urinary crystallization risk (CaUCR) and high uric acid urinary crystallization risk (UrUCR) were calculated from urinary parameters using pre-defined criteria. More than half of patients with MedDiet scores ≤3 had high UrUCR (55.4%) and high CaUCR (53.8%). In contrast, fewer patients with high adherence (≥6) to the MedDiet had high UrUCR (41.2%) and high CaUCR (29.4%). Relative to those with low adherence, individuals with high adherence had a prevalence ratio (PR) of 0.77 for a high UrUCR (95% CI: 0.46–1.12; p for trend: 0.069) and a PR of 0.51 for a high CaUCR (95% CI: 0.26–0.87; p for trend: 0.012) after adjusting for age, sex, body mass index, type 2 diabetes, and total energy intake. Our findings indicate that greater adherence to the MedDiet was associated with a reduced CaUCR and a reduced UrUCR. This suggests that adequate dietary management using the MedDiet patterns may prevent or reduce the incidence and recurrence of calcium salt and uric acid renal stones.

Long-term Recurrence Rates in Uric Acid Stone Formers With or Without Medical Management

To determine if medical therapy affects long-term clinical outcomes in uric acid stone formers (UASF). We identified 53 UASF who had complete stone clearance following stone procedure by computed tomography (CT) and had ≥1 postoperative 24-hour urine collection and a clinical follow-up ≥6 months with a surveillance CT scan. Patients were divided into "adherent to medical therapy" (compliance with potassium citrate ± allopurinol verified by computerized pharmacy data) or nonadherent groups. Primary outcomes were CT stone recurrence rate and need for surgical stone intervention. We found 28 of 53 (53%) adherent and 25 of 53 (47%) nonadherent individuals (14 declined medication, 11 intolerant). With median follow-up of 24 months, no significant differences were noted between groups in regards to stone recurrence (32%; P = .99) or in 24-hour urine pH compared to baseline or follow-up (range 5.46-5.62; P = 0.06). Adherent patients, however, had smaller CT stone recurrence sizes (6.3 ± 3.8 vs 11.8 ± 6.2 mm, P = .02), were 28% less likely to require stone surgery compared to those without therapy (P <.01), and trended toward longer time intervals without recurrence (23.1 ± 18.8 vs 10.5 ± 7.5 months, P = .10) compared to nonadherents. Study confounders included a variety of medication dosages and adherences, limited nonadherent follow-up, and small study number. UASF adherent to medical therapy had smaller recurrence sizes and fewer surgical interventions vs nonadherent, highlighting the protective role of potassium citrate in UA stone disease. The comparable urine pH and stone recurrence rates between groups, however, underscore areas for improvement in future UA stone prevention strategies.

Effect of thiazolidinedione therapy on the risk of uric acid stones

The most important variable leading to uric acid stones is low urine pH. Major causal conditions associated with low urine pH are metabolic syndrome and diabetes. In the study by Maalouf etal., treatment of uric acid stone formers with pioglitazone led to small but significant increases in urine pH. Pioglitazone will not supplant alkali administration to prevent uric acid stones, but the study helps confirm that insulin resistance is an important cause of low urine pH that causes uric acid stones.

Роль фруктозы в генезе нефролитиаза

Obesity is one of the actual problems of modern medicine. The comorbid conditions in patients with obesity and metabolic syndrome have no less important value, attracting the attention of scientists and clinicians. Renal stone disease is one these diseases. We are interested in its development, which is directly related to the effect of excess amounts of such a monosaccharide, as fructose. For quite a long time, this carbohydrate was considered to have only positive properties, including its role in carbohydrate metabolism in general, and, in particular, in diabetes mellitus. Over the years, a pathological effect of excess fructose was detected. Since fructose was used to replace glucose, and accordingly, its amount in food, and especially in diabetic foods, was growing. In addition, the industrial production of corn-based fructose has become much less expensive than the production of sucrose, which has also contributed to the increased use of this monosaccharide in the food industry. In this article, the mechanisms leading to the development of pathologies which are associated with the excessive use of fructose, increase in the level of uric acid with subsequent formation of uric acid stones, are reviewed. Thus, the study of the effect of fructose on the pathogenesis of renal stone disease is interesting and extremely relevant, since for many specialists, it is animal protein that is associated with the development of kidney stone disease and the role of fructose is not only unobvious, but is also a revelation.

Increased production and reduced urinary buffering of acid in uric acid stone formers is ameliorated by pioglitazone

Idiopathic uric acid nephrolithiasis is characterized by an overly acidic urine pH caused by the combination of increased acid production and inadequate buffering of urinary protons by ammonia. A large proportion of uric acid stone formers exhibit features of the metabolic syndrome. We previously demonstrated that thiazolidinediones improved the urinary biochemical profile in an animal model of the metabolic syndrome. In this proof-of-concept study, we examined whether the thiazolidinedione pioglitazone can also ameliorate the overly acidic urine in uric acid stone formers. Thirty-six adults with idiopathic uric acid nephrolithiasis were randomized to pioglitazone 30 mg/day or matching placebo for 24 weeks. At baseline and study end, participants underwent collection of blood and 24-hour urine in an inpatient research unit while consuming a fixed metabolic diet, followed by assessment of the ammoniagenic response to an acute oral acid load. Twenty-eight participants completed the study. Pioglitazone treatment improved features of the metabolic syndrome. Pioglitazone also reduced net acid excretion and increased urine pH (5.37 to 5.59), the proportion of net acid excreted as ammonium, and ammonium excretion in response to an acute acid load, whereas these parameters were unchanged with placebo. Treatment of patients with idiopathic uric acid nephrolithiasis with pioglitazone for 24 weeks led to a reduction in the acid load presented to the kidney and a more robust ammoniagenesis and ammonium excretion, resulting in significantly higher urine pH. Future studies should consider the impact of this targeted therapy on uric acid stone formation.

The relationship between visceral fat area and uric acid stone formation

Objective To investigate the relationship between uric acid stone formation and visceral fat area based on computed tomography. Methods As many as 247 patients admitted to our hospital were retrospectively reviewed from January 2017 to January 2018. There were 161 males (65.2%) and 86 females (34.8%). The average age was 51 (20-88 years). According to the results of stone analysis after surgery, the patients were divided into uric acid stone group and non-uric acid stone group. According to the abdominal CT scan, Image J software was used to measure the anthropometric measurements like waist circumference, total fat area (TFA), and visceral fat area (VFA), and subcutaneous fat area (SFA). The clinical characteristics of different stone components were compared. An univariate and multivariate logistic regression analysis was used to identify the independent factors associated with uric acid stone formation. Different anthropometric measurements were compared by using the area under receiver operating characteristic curve. Results The uric acid stones in high VFA group (28/110; 25.5%) were obviously more frequent than that in the low VFA group (7/137; 5.1%) (P<0.05). The results of the univariate logistic regression analysis showed that age, diabetes, hyperlipidemia, TFA, waist circumference, body mass index (BMI), VFA, uric acid, and urine pH were statistically significant (P<0.05). Multivariate logistic regression analysis revealed that diabetes (OR=3.408, 95%CI 1.123-10.340, P=0.030), VFA (OR=6.740, 95%CI 1.951-23.279, P=0.003), uric acid (OR=3.182, 95%CI 1.120-9.040, P=0.030) and urine pH (OR=4.052, 95%CI 1.095-14.989, P=0.036) were independent factors associated with uric acid stone formation. The area under the curve of TFA, waist circumference, BMI, VFA, and SFA were 0.659, 0.665, 0.632, 0.723 and 0.544, respectively. Conclusions Diabetes, VFA, uric acid and urine pH are independent factors influencing the formation of uric acid stones. Compared with other anthropometric measurements such as TFA, waist circumference, BMI, and SFA, VFA can better assess abdominal obesity and predict the formation of uric acid stones. Key words: Visceral fat area; Uric acid stone; Metabolic syndrome; Abdominal obesity

Pathophysiology and Treatment of Uric Acid Stones

Uric acid is the third most common stone composition and comprises 7 to 10% of all kidney stones sent for analysis. These stones are more common with increasing age and in men. Uric acid stone disease is associated with conditions such as the metabolic syndrome and type 2 diabetes mellitus. Uric acid is produced by the enzyme, xanthine oxidase and is the final product of purine metabolism in humans. Three main factors contribute to the formation of uric acid stones: low urine pH (the most important), hyperuricosuria (rare, includes conditions such as myeloproliferative disorders and Lesch-Nyhan syndrome), and low urine volume. Uric acid stones appear radiolucent on plain radiographs and are ultimately diagnosed via stone analysis. These stones may be treated with medical expulsive therapy, dissolution therapy, or surgical intervention depending on the size, location, and clinical presentation. Urine pH manipulation therapy with potassium citrate is the first-line treatment for the prevention of uric acid stones and attempts at dissolution. Allopurinol should not be offered as the first-line therapy for uric acid stones. This review contains 3 figures, 1 table and 38 references Key Words: ammonium, diabetes mellitus, epidemiology, management, metabolic syndrome, nephrolithiasis, pathophysiology, potassium citrate, uric acid, urine pH

Variation in Kidney Stone Composition Within the United States

Kidney stone incidence has been known to vary with temperature and climate. However, little is known about any variation in the composition of kidney stones across different regions of the United States. We attempted to evaluate whether stone composition changes depending on region. We were given access to de-identified data from LABCORPs database of kidney stone composition from August 1, 2016, to October 24, 2016, for states in seven representative areas of the country: Virginia, Minnesota, Florida, Arizona, Colorado, California, and Texas. We analyzed each component of kidney stones with optical microscopy supplemented with Fourier-transform infrared spectroscopy (FT-IR) spectrometry using both the percentage of the stone that was composed of that component as well as a binary variable coded none vs any. Univariate associations between component and state were examined using chi-square or Fisher's exact test for the binary indicator, and analysis of variance for the continuous percentage. The same set of analyses was used for decade of age vs each component. The association between age and state was examined using analysis of variance. Data were available for 4335 kidney stones, from patients in the 7 states mentioned. The most common components across all stones were calcium oxalate monohydrate and calcium phosphate (both present in 93% of stones), calcium oxalate dihydrate (in 57% of stones), and uric acid (in 12% of stones). Stone composition did not vary widely across regions, except for uric acid stones, which were more prevalent in Florida compared to other states, with an odds ratio of 1.43 (95% confidence interval 1.12, 1.83). Kidney stone composition does not vary widely by region within the United States. Although temperature and humidity play a role in stone incidence, there does not appear to be a large variation between different climates, with the exception of uric acid stone formation in Florida.