Lower Urinary Citrate Excretion Research Articles

HydroZitLa inhibits calcium oxalate stone formation in nephrolithic rats and promotes longevity in nematode Caenorhabditis elegans

Low fluid intake, low urinary citrate excretion, and high oxidative stress are main causative factors of calcium oxalate (CaOx) nephrolithiasis. HydroZitLa contains citrate and natural antioxidants and is developed to correct these three factors simultaneously. Antioxidants theoretically can prolong the lifespan of organisms. In this study, we preclinically investigated the antilithogenic, lifespan-extending and anti-aging effects of HydroZitLa in HK-2 cells, male Wistar rats, and Caenorhabditis elegans. HydroZitLa significantly inhibited CaOx crystal aggregation in vitro and reduced oxidative stress in HK-2 cells challenged with lithogenic factors. For experimental nephrolithiasis, rats were divided into four groups: ethylene glycol (EG), EG + HydroZitLa, EG + Uralyt-U, and untreated control. CaOx deposits in kidneys of EG + HydroZitLa and EG + Uralyt-U rats were significantly lower than those of EG rats. Intrarenal expression of 4-hydroxynonenal in EG + HydroZitLa rats was significantly lower than that of EG rats. The urinary oxalate levels of EG + HydroZitLa and EG + Uralyt-U rats were significantly lower than those of EG rats. The urinary citrate levels of EG + HydroZitLa and EG + Uralyt-U rats were restored to the level in normal control rats. In C. elegans, HydroZitLa supplementation significantly extended the median lifespan of nematodes up to 34% without altering feeding ability. Lipofuscin accumulation in HydroZitLa-supplemented nematodes was significantly lower than that of non-supplemented control. Additionally, HydroZitLa inhibited telomere shortening, p16 upregulation, and premature senescence in HK-2 cells exposed to lithogenic stressors. Conclusions, HydroZitLa inhibited oxidative stress and CaOx formation both in vitro and in vivo. HydroZitLa extended the lifespan and delayed the onset of aging in C. elegans and human kidney cells. This preclinical evidence suggests that HydroZitLa is beneficial for inhibiting CaOx stone formation, promoting longevity, and slowing down aging.

Monitoring acid base status in CKD patients: can urinary citrate help?

Metabolic acidosis is an early and deleterious complication of chronic kidney disease. Because it is frequently eubicarbonatemic, diagnosis may be difficult. In this issue, Gianella etal. suggest that lower urinary citrate excretion, considered as an homeostatic response to metabolic acidosis, may be helpful for early diagnosis and monitoring of alkali treatment. This study should be an incentive for further assessment of the tubular handling of urinary citrate in CKD patients and determination of the performance of urinary citrate for the diagnosis of eubicarbonatemic metabolic acidosis and monitoring of alkali therapy.

P0077A NEW MUTATION OF DNAJB11 AS A CAUSE OF CYSTIC KYDNEY DISEASE: THE FOURTH GENE OF ADPKD

Abstract Background and Aims Monogenic inherited diseases are an underestimated but important cause of chronic kidney disease (CKD). Despite the increasing knowledge about their inheritance, they are identified in fewer than 10% of CKD patients. Among monogenic causes of CKD, polycystic kidney diseases (PKD) represent a group of disorders with a clinical and genetic heterogeneity and a variable phenotype (from early manifestations during pregnancy or childhood to the absence of clinical manifestations until adulthood). We here present a PKD family with 5 members displaying the disease (Figure 1). Method We revised patients clinical history, laboratory data and imaging exams. An accurate family history was recovered. Blood samples were collected from living patients to perform an exome analysis using next generation sequencing to analyze all possible genes involved in PKD. Results Each patient presented a clinical history of nephrolithiasis, a variable degree of CKD (from normal kidney function to renal transplant), urinary and blood parameters compatible with distal renal tubular acidosis (hypercalciuria, low urinary citrate excretion and hypokalemia). Imaging exams showed several renal cysts in the medulla or at the cortico-medullary junction with intracystic calcifications (Figure 2). Some patients displayed also large cortical renal cysts and also hepatic and pancreatic cysts. The genetic analysis performed using next generation sequencing in four patients showed a new mutation on the gene DNAJB11; the mutation introduced a stop codon and was identified as pathogenic by prediction programs. It was present in heterozygosity in all subjects and had an autosomal dominant pattern of inheritance. Conclusion DNAJB11 mutations were reported as a cause of PKD for the first time in 2018 by Cornec-Le-Gall and colleagues. The nephropathy derived from these mutations need to be differentiated from ADPKD (autosomal dominant polycystic kidney disease), from ADTKD (autosomal dominant tubulointerstitial kidney disease) and from medullary sponge kidney. DNAJB11 encodes a co-chaperone of the endoplasmic reticulum (ER) also called ERdj3. It is part of the HSP40 protein family and plays a central role in both intracellular and extracellular proteomic homeostasis (proteostasis). In the intracellular compartment it acts as a co-chaperone in the pathway of the unfolded protein response (UPR) in which it binds misfolded proteins which have to be secreted and activates BiP an HSP70 of ER whose function is to correct the misfolding. In the kidney it is mainly expressed in the thick ascending limb of Henle’s loop, in the distal tubule and in the collecting duct justifying the clinical presentation of nephropathy and differentiating the disease from ADPKD (Figure 3).

Cuantificación del riesgo de formación de cálculos cálcicos en la orina correspondiente a 2 momentos del día en un grupo de niños estudiados para descartar prelitiasis

BackgroundVarious genetic and environmental factors are involved in urolithiasis. The 2 most common metabolic abnormalities are the increase in urinary calcium and low urinary citrate excretion. The ratio calculated between the concentrations of both substances is a good risk marker for the formation of calcium stones. ObjectivesTo determine whether the risk of urinary calcium stone formation changes throughout the day in the same patient. MethodsWe studied 56 children (23V, 33M) to check if they had prelithiasis. Calcium, citrate, and creatinine concentrations were determined in two urine samples collected one before dinner and the other in the morning. It was collected if they had ultrasound stones and if there was a history of urolithiasis in first and/or second degree relatives. ResultsIn 25 patients (44.6%), renal ultrasound was positive for lithiasis (stones [n=9] and microlithiasis [n=16]). Forty of the 56 families (71.4%) had a history of urolithiasis. The percentage of abnormal urinary calcium (28.6%) concentrations and an abnormal calcium/citrate ratio (69.6%) was higher in the first urine of the day. The calcium/citrate ratio was the only studied parameter that was related to a family history of urolithiasis. There were no differences in urinary parameters between patients with and without ultrasound-confirmed kidney stones. ConclusionsUrinary concentrations of calcium and the calcium/citrate ratio vary throughout the day. Urine produced at night has a higher risk of urinary calcium stone formation.

Quantification of the risk of urinary calcium stone formation in the urine collected at 2 times of the day in a group of children studied to rule out prelithiasis

BackgroundVarious genetic and environmental factors are involved in urolithiasis. The 2 most common metabolic abnormalities are the increase in urinary calcium and low urinary citrate excretion. The ratio calculated between the concentrations of both substances is a good risk marker for the formation of calcium stones. ObjectivesTo determine whether the risk of urinary calcium stone formation changes throughout the day in the same patient. MethodsWe studied 56 children (23 V, 33 M) to check if they had prelithiasis. Calcium, citrate, and creatinine concentrations were determined in two urine samples collected one before dinner and the other in the morning. It was collected if they had ultrasound stones and if there was a history of urolithiasis in first and/or second degree relatives. ResultsIn 25 patients (44.6%), renal ultrasound was positive for lithiasis (stones [n=9] and microlithiasis [n=16]). Forty of the 56 families (71.4%) had a history of urolithiasis. The percentage of abnormal urinary calcium (28.6%) concentrations and an abnormal calcium/citrate ratio (69.6%) was higher in the first urine of the day. The calcium/citrate ratio was the only studied parameter that was related to a family history of urolithiasis. There were no differences in urinary parameters between patients with and without ultrasound-confirmed kidney stones. ConclusionsUrinary concentrations of calcium and the calcium/citrate ratio vary throughout the day. Urine produced at night has a higher risk of urinary calcium stone formation.

Минералогический состав камней, факторы риска и метаболические нарушения у пациентов с кальций-оксалатным уролитиазом

To identify the most likely metabolic disturbances and risk factors for stone formation in a group of patients with calcium oxalate urolithiasis, and to establish the relationship between the mineralogical composition of calculi and impaired excretion of inhibitors and promoters of stone formation. Fifty patients with calcium oxalate urolithiasis were tested using a complex of physicochemical methods. Patients assessment included evaluation of quantitative mineralogical composition of calculi, daily urine pH profile and daily urinary excretion of urates, calcium, magnesium, oxalate, phosphate and citrate ions. The main mineralogical phase of the stones in over 80% of patients was calcium oxalate monohydrate; none of the patients had pure dihydrate stones. The most frequent metabolic disorders were hypocitraturia, hypercalciuria and hyperuricosuria. Predominant risk factors were excessive body weight and insufficient fluid intake. Only one patient had an idiopathic stone formation. It was established for the first time that patients with calcium oxalate stones, containing 10 or more mass percent of apatites had statistically significantly lower daily urinary calcium and oxalate excretion and simultaneously increased phosphate excretion. The study findings showed that patients with calculi based on calcium oxalate dihydrate should undergo testing for daily urinary excretion of calcium and citrate while pa-tients with calcium oxalate stones containing 10 or more mass percent of apatites should also be tested for daily phosphate excretion and urine pH-profile. Daily urinary citrate excretion was reduced in all study patients, and urate excretion was significantly increased, apparently due to an imbalanced diet and excessive intake of animal protein. Menopausal and postmenopausal women are at a particular risk due to low urinary citrate excretion and high urinary calcium excretion regardless of stone composition.

Dyslipidaemia in overweight children and adolescents is associated with an increased risk of kidney stones.

There is conflicting evidence about the role of obesity in paediatric nephrolithiasis. This Polish study explored the influence of nutritional status and lipid disturbances on urinary lithogenic factors and the risk of kidney stone formation in children and adolescents from three to 18years of age. We carried out serum lipid profile evaluations and 24-h urine chemistry analyses on 493 overweight/obese paediatric participants (mean age 13years) without nephrolithiasis and 492 healthy normal weight sex and age-matched controls. A third (33%) of the study group had blood lipid disturbances, with more acidic urine, lower urinary citrate excretion and a higher fraction of ionised calcium and higher Bonn Risk Index than the controls. The participants' body mass index standard deviation score (BMI Z-score) was positively correlated with urinary oxalate and uric acid and negatively correlated with citrate excretion. Total cholesterol, low-density lipoprotein cholesterol and triglycerides correlated negatively with citraturia, while high-density lipoprotein cholesterol correlated positively. The main factor that predisposed overweight and obese children to kidney stones was hypocitraturia. Urinary citrate excretion was related to both BMI Z-scores and all lipid fraction abnormalities. However, hypercholesterolaemia and particularly low-density lipoprotein hypercholesterolaemia seemed to play a major role.

Comparison of 24-hour urinary citrate excretion in stone formers and healthy volunteers.

Low urinary citrate excretion is a risk factor in stone formers (SF). This study aimed to measure the urinary citrate excretion in SF and healthy volunteers at our center from 12 June 2008 to 20 August 2009. There were 28 SF patients (18 males and ten females) and 27 (18 males and nine females) age-matched healthy adult volunteers who participated in this study. Both groups had a similar living environment, extrinsic factors, diet and genetic descent. After collecting 24-h urine, citrate was measured using an enzymatic kit. Routine urinalysis and 24-h creatinine and uric acid were also performed. There was a significant difference in urinary citrate excretion level among SF (mean 310, SD 260 mg/L) and normal volunteer subjects (mean 800, SD 300 mg/L). By applying the previously defined normal values (320 mg/24 h) of urinary citrate in the local population, 43% of the SF in our study group was hypocitric, and none among the controls. We conclude that prevalence of hypocitraturia in stone formers was higher than that in healthy volunteers in our population.

Urinary Metabolic Evaluation of Stone Formers—A Malaysian Perspective

To investigate the urinary metabolic excretion pattern among local stone formers given the great differences in the intrinsic and extrinsic risk factors as well as the urinary metabolic excretions compared with other populations. Thirty urinary stone formers out of an initial 62 recruited provided a complete 24-hour urine sample for metabolic evaluation. Student's t-test and Pearson correlation test were used for the statistical analysis. Urinary volume (1719 ± 712 vs 1215 ± 575, P < .05) and oxalate excretion (0.386 ± 0.111 vs 0.306 ± 0.104, P < .05) were significantly higher among stone formers than controls. Other commonly studied urinary parameters and urinary melamine did not differ significantly between the 2 groups. Similarly, the calcium/citrate ratio was unable to discriminate the stone formers from their controls. Hypocitraturia was the most prevalent urinary abnormality found in stone formers and low urinary citrate excretion was a general phenomenon in both stone formers and controls. Comparing within the stone formers cohort, the recurrent stone formers had a significantly higher urinary saturation and calcium excretion than their first-time stone former counterparts. Elevated urinary oxalate level was the most important urinary risk factor among the local stone formers. A low urinary citrate excretion appeared to be a general phenomenon among the studied cohorts.

Biochemical risk factors for stone formation in a Scottish paediatric hospital population

Renal stones in children, although rare, may be associated with morbidity and renal damage. Scottish children have a different ethnic composition and diet compared with paediatric populations previously studied. Urinary stone promoters include calcium, oxalate and urate. Postulated inhibitors include citrate and glycosaminoglycans (GAGs). We tested the hypothesis that Scottish paediatric stone-formers have higher excretion of urinary stone promoters (calcium/oxalate/urate) and/or lower excretion of stone inhibitors (citrate/GAGs) than children with isolated haematuria and controls. In this case-controlled study, we measured creatinine, calcium, oxalate, urate, citrate and GAGs in random urine samples from 24 stone-formers (excluding inherited metabolic disorders), median age 10.2 (range 1.0-17.2) y; 25 patients with isolated haematuria, 6.3 (0.6-13.7) y; and 32 controls, 7.5 (0.8-14.7) y. Excretion of urinary promoters and inhibitors differed among stone-formers, haematuria and control groups for (median (range)): calcium (0.82 (0.02-2.19), 0.43 (0.08-2.65), 0.31 (0.04-2.12) mmol/mmol creatinine, respectively, P = 0.005), citrate (0.42 (0.13-0.72), 0.33 (0.05-0.84), 0.61 (0.11-1.75) mmol/mmol creatinine, P = 0.001), calcium:citrate ratio (1.68 (0.19-4.81), 1.30 (0.19-9.57), 0.54 (0.10-2.27) mmol/mmol, P < 0.0001) and the promoter:inhibitor ratio (calcium x oxalate)/(citrate x GAGs) (8.3 (1.0-82.5), 4.3 (1.2-69.5), 2.8 (0.3-13.2) mmol/g, P < 0.0001). Scottish paediatric stone-formers had lower urinary citrate excretion and higher urinary calcium excretion, calcium:citrate ratio and promoter:inhibitor ratio compared with controls. Urinary calcium excretion and promoter:inhibitor ratio was also higher than children with isolated haematuria. Nevertheless, marked overlap between the stone-former and haematuria groups for promoter:inhibitor and calcium:citrate ratios suggests that some patients with isolated haematuria may be at future risk of urolithiasis.

Insulin resistance and low urinary citrate excretion in calcium stone formers

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 24 h 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/24 h, 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.

Biochemical and Stone-Risk Profiles With Topiramate Treatment

Topiramate is a novel neuromodulatory agent commonly prescribed for the treatment of seizure disorders and for migraine headache prophylaxis. Calcium phosphate kidney stones have been observed with topiramate treatment, but a comprehensive elucidation of stone-risk profile was not reported previously. This study explores the relationship between topiramate treatment and propensity for kidney stone formation. Thirty-two topiramate-treated subjects and 50 healthy volunteers participated in a cross-sectional study in which serum chemistry test and 24-hour urine collection results were evaluated for stone risk. Furthermore, a short-term longitudinal study was conducted in 7 patients to assess stone risk before and 3 months after topiramate treatment. Serum bicarbonate levels were lower with topiramate treatment. Urinary pH, urinary bicarbonate excretion, and fractional excretion of bicarbonate increased, whereas urinary citrate excretion was significantly lower (737 +/- 329 versus 278 +/- 226 mg/d; P < 0.001). Net acid excretion did not change. The relative saturation ratio for brushite increased with topiramate treatment (3.14 +/- 1.69 versus 1.27 +/- 1.26; P < 0.001) because of urinary alkalinization and decreased urinary citrate levels. Urinary saturation of undissociated uric acid decreased (41 +/- 52 versus 76 +/- 60 mg/d; P < 0.001). Treatment with topiramate causes systemic metabolic acidosis, markedly lower urinary citrate excretion, and increased urinary pH. These changes increase the propensity to form calcium phosphate stones.

Causes of Hypocitraturia in Recurrent Calcium Stone Formers: Focusing on Urinary Potassium Excretion

Multiple factors associated with hypocitraturia have been identified. However, limited studies addressing the causal relationship to hypocitraturia are available. We therefore conducted this study to determine factors associated with hypocitraturia and show their causal relationship in recurrent calcium stone formers. Dietary review and 24-hour urine samples were obtained from all recurrent calcium stone formers referred for metabolic workup in the stone clinic. One month of oral potassium chloride supplementation was prescribed to stone formers to determine the causal relationship between urinary potassium and citrate levels. Eighty-three subjects, 44 men and 39 women, were recruited to participate in this study. Hypocitraturia (citrate < 300 mg/d [<1.43 mmol/d]) was found in 50.6% of subjects. Four independent urinary variables associated with hypocitraturia were identified, including potassium level, net gastrointestinal alkaline absorption, calcium level, and titratable acid. Urinary potassium level was the strongest predictor of urinary citrate level. Hypocitraturic subjects also had lower fruit intake compared with subjects with high urinary citrate levels. Potassium chloride supplementation to a subgroup of this population (n = 58) resulted in a significant increase in urinary citrate excretion (350.73 +/- 27.25 versus 304.15 +/- 30.00 mg/d [1.67 +/- 0.13 versus 1.45 +/- 0.14 mmol/d]; P < 0.02), but no alteration in fractional excretion of citrate (19.7% +/- 2.7% versus 23.1% +/- 2.4%; P > 0.05). Hypocitraturia was found to be a common risk factor associated with recurrent calcium stone formation and low urinary potassium level, low alkaline absorption, low urinary calcium level, and high titratable acid excretion. Hypocitraturia is predominantly of dietary origin. Estimation of fruit intake should be included in the metabolic evaluation for recurrent calcium stone formation.

Association of Prevalent Hypertension With 24-Hour Urinary Excretion of Calcium, Citrate, and Other Factors

The relation between hypertension and the urinary excretion of calcium, citrate, and other factors is unclear. It has been proposed that increased urinary calcium excretion is a central feature of essential hypertension. Metabolic acidosis also may be associated with hypertension and decreases urinary citrate levels. To compare the urine composition of individuals with and without hypertension, we studied 24-hour urinary excretion of calcium, citrate, oxalate, uric acid, sodium, magnesium, potassium, phosphorus, and creatinine and pH in a subset of participants with and without nephrolithiasis in the Nurses' Health Study I (older women; N = 1,284), Nurses' Health Study II (younger women; N = 952), and the Health Professionals Follow-up Study (men; N = 788). Logistic regression models adjusted for age, weight, dietary intake, and urinary factors. In participants with and without nephrolithiasis, citrate was the only urinary factor consistently related to hypertension. Compared with those in the lowest quartile of urinary citrate excretion, multivariate odds ratios of prevalent hypertension in the highest quartile were 0.37 (95% confidence interval [CI], 0.24 to 0.55; P trend < 0.001) for older women, 0.54 (95% CI, 0.32 to 0.92; P trend = 0.03) for younger women, and 0.27 (95% CI, 0.16 to 0.45; P trend < 0.001) for men. Urinary calcium levels were not related consistently to hypertension. Excluding participants with single 24-hour urine collections and those administered thiazide diuretics or angiotensin-converting enzyme inhibitors did not change the results. Lower urinary citrate excretion is associated independently with prevalent hypertension. Factors that regulate urinary citrate excretion may play a role in hypertension.

The increased risk of urinary stone disease in betel quid chewers

The chewing of betel quid is a common practice in many countries of the world, particularly in Southeast Asia. The quid consists of a preparation of areca nut, betel leaf and calcium hydroxide "lime" paste ("chuna"). For the first time, we present a study that links its use to urinary stone disease. Eight patients (seven male and one female) who presented to our Stone Unit with recurrent urinary stones were included in the study. All were from the Indian subcontinent and were found to regularly chew betel. The patients underwent metabolic screening including blood, random urine and 24-h urine tests, quantitative chemical analysis of their calculi (where possible) and each completed a 7-day Diet Diary on his/her free, home diet. The study demonstrated a high incidence of hypercalciuria, a tendency to pass an alkaline urine and low urinary citrate excretion among the patients. Together these urinary risk factors increase the probability of developing both calcium phosphate-containing and calcium oxalate-containing stones. In support of this hypothesis, the patients were found to form stones consisting mainly of calcium phosphate but mixed with calcium oxalate. It is concluded that the use of calcium hydroxide "chuna" in the betel quid is the major contributor to the cause of urinary stones in its users. Moreover, the development of urinary lithiasis in such patients may be a precursor to milk-alkali syndrome in those individuals whose chewing habit is more extensive than in the patients in this study and who do not seek to decrease their habit over the long term.

Urinary citrate excretion in patients with renal stone: roles of leucocyte ATP citrate lyase activity and potassium salts therapy

Background: Hypocitraturia is a major metabolic abnormality in rural Northeast Thais with renal stones. These people also have low serum and urinary potassium and consume a high carbohydrate and low fat diet, which together might influence the intracellular metabolism and urinary excretion of citrate. Methods: In Study A, we measured plasma and urinary chemistries and assayed leucocyte ATP citrate lyase (ACL) activity in 30 normal urban control subjects (Group A1) and 30 rural renal stone patients (Group A2) in Northeast Thailand. Some of the subjects from both groups were also used to evaluate the intake of carbohydrate, protein and fat. In Study B, we examined the effects of potassium salts therapy with another group of 30 rural renal stone patients: Group B1 ( n=15) treated with potassium chloride and Group B2 ( n=15) with potassium-sodium citrate (with an aim to achieve 42 mEq potassium, 21 mEq sodium and 62 mEq citrate per day for 1 month). Results: In Study A, the leucocyte ACL activity of Group A1 was much lower than that of Group A2 (3.2±0.7 vs. 9.3±3.8 μmol acetylhydroxamate/mg protein/30 min, p<0.0001). The plasma potassium, urinary excretions of potassium and citrate in Group A1 were higher than in Group A2. When data of the two groups were combined, urinary citrate excretion was inversely correlated with leucocyte ACL activity ( r=0.6783, p<0.001). While the dietary protein intake did not differ between Groups A1 and A2, the carbohydrate intake by Group A1 was significantly lower (65.2±7.9% vs. 83.1±2.9%, p<0.01) and fat higher (21.0±6.4% vs. 6.2±4.1%, p<0.002) than Group A2. After treatment with potassium chloride (Group B1), only the potassium was increased ( p<0.001), while those treated with potassium-sodium citrate (Group B2) experienced a significant increase in urinary pH ( p<0.002), potassium ( p<0.001) and citrate ( p<0.001), and a decrease in leucocyte ACL activity ( p<0.001). Conclusions: Compared to normal subjects, renal stone patients have low urinary citrate excretion with high leucocyte ACL activity. In Northeast Thailand, low potassium status and a high carbohydrate and low fat diet may cause the increased ACL activity. However, hypokaliuria, hypocitraturia and high leucocyte ACL activity can be corrected by potassium-sodium citrate salt therapy.

Risk factors for urolithiasis in children on the ketogenic diet.

Kidney stones have been associated with use of the ketogenic diet in children with refractory seizure disorders. We performed a case-control study examining risk factors for the development of stones on the ketogenic diet, and prospectively followed children initiating the ketogenic diet to evaluate the incidence of urolithiasis. Clinical characteristics of 18 children presenting with stones (8 uric acid stones, 6 mixed calcium/uric acid stones, 1 calcium oxalate/phosphate stone, 3 stones not evaluated) were compared with characteristics of non-stone-forming children initiating the ketogenic diet at Johns Hopkins since July 1996. Since July 1996, 112 children initiating the ketogenic diet have been followed for development of stones. Follow-up times on the diet range from 2 months to 2.5 years. Of 112 children, 6 have developed stones (3 uric acid, 3 mixed calcium/uric acid stones) (0.8 children developing stones/ 100 patient-months at risk). Comparisons of children presenting with stones on the ketogenic diet with characteristics of the entire cohort initiating the ketogenic diet suggest younger age at diet initiation and hypercalciuria are risk factors for the development of stones. Prospective evaluation of children initiating the ketogenic diet revealed that almost 40% of patients had elevated fasting urine calcium: creatinine ratios at baseline; this increased to 75% after 6 months on the diet. Median urine pH was 5.5 at diet initiation, and remained at 6.0 thereafter. In a subset of patients tested, urinary citrate excretion fell from a mean of 252 mg/24 h pre diet initiation to 52 mg/24 h while on the diet. Uric acid excretion remained normal. Patients maintained on the ketogenic diet often have evidence of hypercalciuria, acid urine, and low urinary citrate excretion. In conjunction with low fluid intake, these patients are at high risk for both uric acid and calcium stone formation.

Comparison of Metabolic Risk Factors in Patients with Recurrent Urolithiasis Stratified according to Age and Gender

Objective: Little is known regarding the metabolic features associated with aging and gender in urolithiais patients. We compared the metabolic characteristics among 3 generations (young, middle–aged and old) with recurrent calcium–containing urinary stones.Methods: One hundred and eighty–one patients with recurrent calcium–containing stones, including 71 patients aged ≤45 years (group 1), 71 patients aged 46–60 years (group 2) and 39 patients aged ≥61 years (group 3), were investigated by metabolic evaluation. The frequencies of metabolic abnormalities, the value of each urinary constituent and the supersaturation index (AP(CaOx) index) were compared among subgroups of the 3 generations, containing both males and females.Results: The number of metabolic abnormalities was the greatest in group 1, followed by group 2 and group 3. Hyperoxaluria was the most common abnormality in each group. Group 1 females showed a lower frequency of hypocitraturia than group 3 females. This was the only characteristic that showed a significant difference between the groups. Urinary calcium excretion was significantly greater in group 1 than in group 3. Urinary citrate excretion and the AP(CaOx) index were significantly higher in group 1 than in group 3 in females. Male patients had a significantly higher number of metabolic abnormalities than female patients, especially in group 1.Conclusion: Multiple metabolic abnormalities, particularly a high calcium excretion appear to be crucial factors in the development and recurrence of urolithiasis in young patients. Low urinary citrate excretion could play an important role in the occurrence of urolithiasis in elderly females.

Risk factors for low urinary citrate in calcium nephrolithiasis: low vegetable fibre intake and low urine volume to be added to the list.

Risk factors for low urinary citrate excretion were assessed in 34 consecutive male recurrent idiopathic calcium stone formers (RCSF) who collected two 24-h urines while on free-choice diet. Overt hypocitraturia (hypo-cit) was defined as UCit x V < 1.70 mmol/day, and 'low' citraturia (low-cit) as UCit x V between 1.70 and 2.11 mmol/day. Twenty-three RCSF had normocitraturia (normo-cit), six low-cit and five hypo-cit. UCit x V positively correlated with urine volume (VOLUME, r = 0.44, P = 0.009), vegetable fibre intake (fibers, r = 0.46, P = 0.009) and GI-alkali absorption (alkali, r = 0.47, P = 0.006), and volume, fibres and alkali tended to be lower among RCSF with low-/hypo-cit. A 3-day NH4Cl loading test (0.95 mEq/kg BW daily in 3 doses) was performed in RCSF as well as in 14 age-matched healthy male controls (C). On a plot of urine pH versus serum bicarbonate, 10 of 11 RCSF with low-/hypo-cit, but only six of 23 with normo-cit (P = 0.0004) fell off the normal range, indicating incomplete RTA. Two or more risk factors simultaneously occurred in only four of 23 RCSF with normo-cit, but in eight of 11 with low-/hypo-cit (P = 0.002). In conclusion, incomplete RTA is the most prevalent risk factor for low-/hypo-cit in RCSF, and decreases in vegetable fibres and urine volume emerge as two new risk factors for low urinary CIT.

Clinical significance of hypocitraturia in kidney stone patients.

Although a low concentration of urinary citrate is cited as one of the risk factors promoting stone formation or recurrence among patients with urinary stones, its clinical significance remains obscure. We studied 62 kidney stone patients with a low urinary citrate excretion (hypocitraturia) of less than 320 mg/day, without any apparent cause. The incidence of hypocitraturia in 722 kidney stone patients followed up at our stone clinic was 14.6%. Among the 62 patients, 37 had an uncomplicated hypocitraturia as the sole abnormality, while 25 had other associated stone risk factors, including hypercalciuria in 11% (7/62), hyperuricosuria in 24% (15/62), hyperoxaluria in 5% (3/62) and hypomagnesuria in 24% (15/62). The rate of urinary stone recurrence was 38% (14/37) in uncomplicated hypocitraturia, and 52% (13/25) in complicated hypocitraturia, but no statistical difference was observed. Regarding the outcome of stones, more stones were managed with lithotripsy and more passed spontaneously in the hypocitraturic patients than in the control patients with normal urinary citrate excretion. The diagnosis of hypocitraturia complicated with additional stone risks urged us to treat patients more vigorously with lithotripsy and medication, resulting in a prompt cure.