ArticleLiterature Review

Urinary citrate and renal stone disease: The preventive role of alkali citrate treatment

Authors:
  • Fondazione Ettore Sansavini per la Ricerca Scientifica ONLUS
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Abstract

Hypocitraturia or low urinary citrate excretion is a common feature in patients with nephrolithiasis, particularly in those with calcium stone disease. Citrate is a weak acid that is synthesized inside Krebs' cycle. It can also enter the body through dietary intake. Differences in intestinal handling, serum concentration as well as filtered load of citrate were not found between kidney stone formers and normal subjects. On the contrary, several metabolic abnormalities, such as metabolic acidosis, hypokalemia and starving, seem to influence the renal handling of citrate by inducing a decrease in the urinary citrate excretion. Hypocitraturia is defined as urinary citrate excretion lower than 320 mg/day. Literature data show a large prevalence of hypocitraturia in patients with nephrolithiasis, ranging from 8% up to 68.3%. The protective role of citrate is linked to several mechanisms; in fact citrate reduces urinary supersaturation of calcium salts by forming soluble complexes with calcium ions and by inhibiting crystal growth and aggregation. Furthermore, citrate increases the activity of some macromolecules in the urine (eg. Tamm-Horsfall protein) that inhibit calcium oxalate aggregation. Citrate seems able to reduce the expression of urinary osteopontin. A role of citrate in pathogenesis of metabolic bone diseases has been recently suggested and citrate measurement in urine has been proposed as a predictor of both bone mass loss and fracture risk. Idiopathic calcium stone disease, with or without hypocitraturia, can be treated with alkaline citrate, as well as other forms of nephrolithiasis and different pathological conditions. The therapy with potassium citrate, or magnesium potassium citrate, is commonly prescribed in clinical practice in order to increase urinary citrate and to reduce stone formation rates. Our data as well as those of the literature confirm that alkali citrate induces both an increase of protective urinay analytes (eg. citrate, potassium and pH) and a decrease of calcium oxalate supersaturation. Moreover, alkali treatment reduces the rate of stone recurrence and increases the clearance rates and dissolution of stone fragments. Last but not the least, an increasing number of papers pointed out the protective role of alkali citrate in preserving bone mass in stone formers as well as in healthy subjects with bone loss. Nevertheless, the evaluation of urinary citrate in patients with kidney stones and the treatment of these patients with alkali salts namely with potassium citrate are still scarce.

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... Existing literature shows significant prevalence of hypocitraturia in some KSD patients [14]. Use of alkali citrates such as potassium citrate has been shown to increase protective urinary compounds such as potassium, citrate, and pH [21]. Such alkali treatments are suggested to improve rates of KSD recurrence and increase rates of stone clearance [21]. ...
... Use of alkali citrates such as potassium citrate has been shown to increase protective urinary compounds such as potassium, citrate, and pH [21]. Such alkali treatments are suggested to improve rates of KSD recurrence and increase rates of stone clearance [21]. European Association of Urology (EAU) guidelines suggest that patients deemed high risk in the first instance increase their fluid intake aiming for a urine output over 2.5 l [31]. ...
Article
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Purpose of Review The association of kidney stone disease (KSD) and gastrointestinal (GI) surgery has been well established. With a rising obesity crisis, we wanted to see the correlation of urinary composition in patients undergoing bariatric surgery and their risk of KSD. The objective of this paper is to perform a systematic review and meta-analysis of literature to evaluate the changes in urinary composition and risk of KSD following bariatric surgery. Recent Findings A total of seven studies (2498 patients) underwent bariatric surgery with a mean age of 46.7 years and a male:female ratio of 1:3. The most popular bariatric surgery was the Roux-en-Y procedure. Meta-analysis of the studies showed that significant decrease in urinary calcium, citrate, and urate, and increase in urinary oxalate. There was also a nonsignificant volume reduction in the post-operative cohort. The decrease in urinary citrate and increase in urinary oxalate are both predisposing factors of stone formation. Summary There is strong evidence that bariatric surgery results in significant changes in urine composition in keeping with the increased risk of developing KSD. This identifies useful therapeutic targets in the prophylactic management of patients who have undergone bariatric surgery.
... The applicability of potassium nitrate to reduce urolithiasis recurrence has been investigated in several studies, and virtually all of them have emphasized a significant reduction in renal stones through this approach (11)(12)(13). Moreover, high clearance rates of stones can be expected using potassium citrate through several mechanisms, including modulating the concentrations of urine electrolytes and saturation of calcium oxalate (14). Encrustation and resultant urine stones are common following stent insertion. ...
... The mechanisms behind the decrease in odds of stone recurrence have been virtually illustrated. The strong binding between calcium ions and citrate leads to soluble complexes, thereby decreasing the supersaturation of calcium salts in urine (14,15). Moreover, it is essential to note that urinary secretion or citrate reabsorption depends on the body's acid-base status. ...
Article
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Introduction: This research was conducted to assess whether prophylactic citrate potassium can reduce double-J stent encrustation in patients with urolithiasis. Methods: In the present study, 70 patients with urolithiasis were randomly assigned to two groups of control [22 men; mean age 43 (33-55)] and intervention [25 men; mean age, 41 (37-56)] after meeting inclusion criteria. Potassium citrate (10 mEq Alithoral tablet) was administered three times a day from double-J stent insertion until removal in the intervention group. For the control group, no treatment was given. It was examined after removing the stent, and laboratory tests were performed in encrustation. Moreover, blood and urine were collected for assessing creatinine, crystalluria, and pyuria. Information concerning the duration of double-J stent placement, the composition of urinary stone (calcium oxalate or other), number of attack episodes, type of double-J stent (one way or other), and smoking habit were collected. Results: Three control group participants were excluded from the study due to missing follow-up. Patients of the two groups were matched for age, sex, duration of the double-J stent placement, and the number of attack episodes. There were significant differences regarding crystalluria and creatinine dosage between the two groups. Furthermore, double-J stent encrustation occurred in 3 (8.8%) and 11 (34.4%) patients of the intervention and control group, respectively, which showed a significant difference (P-value=0.012). Comparison between intervention and control group revealed an odds ratio of 18% (P-value=0.017) and 15% (P-value=0.023) in the crude and adjusted model, respectively. Conclusion: Potassium citrate can significantly reduce double-J stent encrustation in patients with urolithiasis. Therefore, it is recommended that urologists consider citrate potassium as a preventive treatment for encrustation.
... Most kidney stones are comprised of either uric acid, cystine, struvite, calcium oxalate or calcium phosphate and knowing stone composition may speak to the metabolic or genetic abnormality that led to its development as well as to the therapy that would most likely reduce stone recurrence in a particular patient [4,5]. Given that nutritional factors, such as low intake of calcium, fruits and vegetables and/or high intake of sodium, calcium and animal proteins, have been shown to be associated with stone occurrence, specific nutritional therapy, informed by both diet assessment and metabolic testing, has been shown to be more effective than generalized dietary measures in preventing stone formation [4][5][6][7]. In addition to dietary treatments, therapeutics such as potassium citrate, thiazide diuretics, allopurinol, α-mercaptopropionylglycine (tiopronin) and acetohydroxamic acid have been used to reduce the recurrence of stones of specific content [4,7,8]. ...
... Given that nutritional factors, such as low intake of calcium, fruits and vegetables and/or high intake of sodium, calcium and animal proteins, have been shown to be associated with stone occurrence, specific nutritional therapy, informed by both diet assessment and metabolic testing, has been shown to be more effective than generalized dietary measures in preventing stone formation [4][5][6][7]. In addition to dietary treatments, therapeutics such as potassium citrate, thiazide diuretics, allopurinol, α-mercaptopropionylglycine (tiopronin) and acetohydroxamic acid have been used to reduce the recurrence of stones of specific content [4,7,8]. Therefore, serum and urine tests for metabolic abnormalities as well as tests to determine stone composition are important for treatment decision making purposes. ...
Article
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Urine citrate is often used to identify patients at risk of recurrent nephrolithiasis or kidney stones. A high-throughput assay was developed to measure urine citrate and creatinine on the Vantera® Clinical Analyzer, a nuclear magnetic resonance (NMR) instrument designed for the clinical laboratory. Assay performance was evaluated and comparisons between the NMR and chemistry results were conducted. Linearity was demonstrated over a wide range of concentrations for citrate (6 and 2040 mg/L) and creatinine (2.8 and 1308 mg/dL). Intra-and inter-assay precision (%CV) ranged from 0.9 to 3.7% for citrate and 0.4 to 2.1% for creatinine. The correlation coefficients for the comparison between NMR and chemistry results were 0.98 (Y = 1.00X + 5.0) for citrate and 0.96 (Y = 0.968X + 0.97) for creatinine. The reference intervals for both analytes were confirmed. Ten endogenous and exogenous substances were tested and none were found to interfere with the assay results. In conclusion, the newly developed high-throughput NMR assay exhibited robust performance and generated results comparable to the currently utilized chemistry tests, thereby providing an alternative means to simultaneously quantify urine citrate and creatinine for clinical and research use. Furthermore, the NMR assay does not exhibit the same interference limitations as the chemistry tests and it enables multiplexing with other urine metabolite assays which saves time and costs.
... 144,145 Caudarela & Vescini suggested a protective role of alkali citrate in preserving bone mass in stone formers as well as in healthy subjects with bone loss. 146 The proposed mechanisms for this preservation were the induction of hypocalciuria, a sustained stimulation of osteoblast activity, and attenuating the skeletal effect of acid load provided by a high protein diet. 146 In 2006, Penido et al evaluated 88 children and adolescentes with idiopathic hypercalciuria. ...
... 146 The proposed mechanisms for this preservation were the induction of hypocalciuria, a sustained stimulation of osteoblast activity, and attenuating the skeletal effect of acid load provided by a high protein diet. 146 In 2006, Penido et al evaluated 88 children and adolescentes with idiopathic hypercalciuria. They divided them into groups: G1 patients with hypercalciuria combined with hypocitraturia, G2 those without hypocitraturia and G3 controls. ...
Article
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There is evidence that over the past few decades pediatric urolithiasis has become more common. It affects children of all ages and is the end product of a multifactorial process. In industrialized countries 80-90% of the stones are composed of calcium oxalate, calcium phosphate or a mixture of both. The increased incidence and prevalence of urolithiasis are associated with considerable morbidity and high recurrence rates. The reasons for the increased prevalence and incidence of urolithiasis are not completely clear, and have been attributed to climate changes, lifestyle changes, nutritional habits, and possibly other environmental factors.This review addresses an update on current management and future directions of primary urolithiasis in childhood and adolescence. For the purpose of this review primary urolithiasis is defined as stone formation due an abnormality in urine biochemistry resulting from genetic, acquired or yet unknown etiology.
... 6) Distention of bladder, accumulation of high urine that exceeds the ability of bladder will cause maximal vasodilation of the bladder. Therefore, a dam will be felt (distention) when the Vesica region is palpated [5,6,7]. ...
... Some areas show a higher incidence of nephrolithiasis than other areas. 6) Work Jobs that require work in a high temperature environment and limited or limited fluid intake can stimulate a lot of fluid loss and are the greatest risk in the stone formation process due to a decrease in the volume of urine. 7) Fluid intake is said to be insufficient if <1 liter / day, this lack of fluid intake is the main cause of nephrolithiasis, especially nephrolithiasis because this can lead to reduced urine flow / urine volume [17]. ...
Article
Introduction: Nephrolithiasis is a urinary tract stone disease that can be found in the kidneys, ureters, bladder, and urethra. This disease is the three most common diseases in the field of urology besides urinary tract infections and benign prostate enlargement. Kidney stones are the most common, with an estimated lifetime prevalence as high as 15%. Bladder stones have significant morbidity but occur much less frequently than kidney stones. Many factors cause reduced urine flow and cause obstruction, one of which is urine static and decreased urine volume due to dehydration and inadequate fluid intake, this can increase the risk of nephrolithiasis. Low urine flow is a common abnormal symptom. In addition, various conditions that trigger nephrolithiasis such as the composition of various stones are the main factors in identifying the cause of nephrolithiasis. Aims of this article is to review risk factors and pathophysiology of nephrolithiasis. Discussion: Symptoms associated with urinary tract stones depend on the location of the stone, the size of the stone, and any complications that have occurred. Usually, stones in the kidney calyx are asymptomatic. When the stone falls off and descends into the narrow ureter, it becomes symptomatic. Stones generally get stuck in the narrowest part of the ureter, such as the uretero-pelvic junction, when the ureter crosses the iliac vasa, and the uretero-vesical junction. The main symptom of ureteric stones is often an acute onset of pain in the back. This pain can be colicky or not. Colic pain occurs because the peristaltic activity of the smooth muscle of the calical system or ureter increases in an attempt to remove stones from the urinary tract. The increase in peristalsis causes the intraluminal pressure to increase so that there is stretching of the nerve terminals that provide a sensation of pain. The pain can radiate from the pelvis and to the ipsilateral groin. Other symptoms include nausea, vomiting and hematuria. Hematuria can occur macros or microscopy from urinalysis. Hematuria occurs as a result of trauma to the urinary tract mucosa caused by stones. Conclusion: Nephrolithiasis is rock-forming salt reaches a urine concentration that exceeds the equilibrium point between the dissolved component and crystallization occurs. There are several risk factors that nephrolithiasis occurs due to various causes. Therapy and lifestyle changes are interventions that can change risk factors, but there are also risk factors that cannot be changed.
... In addition, it also inhibits crystal growth and aggregation by forming soluble complexes with Ca ++ ions, thus decreasing the urinary supersaturation of Ca ++ salts. Moreover, it also increases urolithiasis inhibitors like Tamm-Horsfall protein (THP) and helps to reduce the expression of urinary promoters like osteopontin [59]. Thus, hypocitraturia can elevate the crystallization potential of urine and induce CaOx stone formation. ...
... Similarly, studies on rats, fed with hyperoxaluric agents like ethylene glycol or hydroxyl l-proline, and tissue cultures provided convincing evidence for an association between CaOx crystal deposition and OPN expression. However, clinical studies do not have conclusive evidence about the relationship between OPN and urolithiasis, as some studies have reported a decrease in urinary OPN concentration of stone formers compared to non-stone formers (59), while some studies are unable to provide such relationship (60). Thus, it is concluded that OPN may have an important role in preventing kidney stone; however, in clinical trials the cause-and-effect relationship between OPN and human kidney stone formation still needs to be confirmed. ...
Article
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The formation of urinary stone, urolithiasis, is one the oldest known disease affecting human throughout different civilizations and times. The exact pathophysiological mechanism of urolithiasis is not yet clear, as these calculi are of various types and too complex for simple understanding. A single theory cannot explain its formation; therefore, different theories are presented in various times for its explanation like free particle, fixed particle, Randall's plaque theory. In addition, various factors and components are identified that play an important role in the formation of these urinary calculi. In this review, composition of kidney stones, its prevalence/incidence, explanation of pathophysiological mechanisms and role of various factors; urinary pH, uric acid, parathyroid hormone, citrate, oxalate, calcium and macromolecules; osteopontin, matrix Gla protein, kidney injury molecules, urinary prothrombin fragment-1, Tamm-Horsfall protein, inter-α-inhibitors, have been discussed in detail.
... For renal stones prevention oral hydration is recommended at a rate that produces approximately 2.5 liters of urine per day. Consumption of citrate helps to prevent stone formation as it inhibits crystal aggregation by forming complexes with calcium salts within the urine [15][16]. Previous studies have shown that metabolic diseases including obesity, hyperlipidemia, and type 2 diabetes mellitus (T2DM) have a strong predilection for calcium oxalate and uric acid stones formation [17][18]. ...
... The non-stented group included 235 procedures done for 210 different patients and they were assigned to four subgroups: B1-66, B2-43, B3-49 and B4-77. The median time elapsed from DJ stenting to URS was 13 (9-17) days; the median time elapsed from initial admission to the elective URS was 15 (12)(13)(14)(15)(16)(17)(18) days. The patient's characteristics are included in Table 1. ...
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Objective: We aimed to investigate the role of upstream Double J-stent insertion on surgical outcomes of retrograde semi-rigid ureteroscopy in patients with upper ureter stones. Materials and methods: In this retrospective study, we analyzed 290 patients who underwent retrograde semi-rigid ureteroscopy (URS) for upper ureter stones between April 2018 and September 2019. Patients were divided into two groups: delayed primary URS, and upstream, preoperative DJ stent placement URS group (using DJ stent). Operation time, postoperative hospital stay, complications, stone-free rate and risk for repeat operation and requisites for postoperative DJ stent were measured for each patient after ureteroscopy. Results: The median age in the DJ stented and non-stented groups was 49.1±14.3 and 46.4±13 years, respectively (p=0.11). Stone laterality, the proportion of male patients, and urinary tract infection prevalence were comparable between the groups. The median operation time was 15.5±7 min vs. 16±8.7 min (p=0.89), and stone-clearance rate was 95% vs. 88.8 % (p=0.12). Impressively, the need for "rescue" DJ stenting at the end of initial ureteroscopy (27.7% and 54%, respectively, P<0.001), the duration of postoperative indwelling DJ stenting (11.7 vs. 16.4 days, P<0.001, respectively), and the need for redo ureteroscopy (3.75% vs. 11.9%, P<0.03) were all significantly lower in the upstream DJ group. Conclusion: facilitated semi-rigid ureteroscopy with upstream DJ stenting for small and medium size ureteral stones has favorable periprocedural outcomes compared with primary ureteroscopy. Therefore, it seems prudent to preoperatively insert DJ stent whenever ureteroscopy is considered for ureteral stones.
... This explains why one of the most common metabolic disorders associated with calcium nephrolithiasis is the hypocitraturia. Hypocitraturic patients have been described between 19 and 63% of stone formers in different statistics [48]. The measurement of citrate in the urine has been introduced into the metabolic routine of stone formers and its deficiency is correctable with an oral support of alkali in the majority of patients [48], even if one part of them does not normalize the excretion of citrate with the oral load of alkalis or citrate. ...
... Hypocitraturic patients have been described between 19 and 63% of stone formers in different statistics [48]. The measurement of citrate in the urine has been introduced into the metabolic routine of stone formers and its deficiency is correctable with an oral support of alkali in the majority of patients [48], even if one part of them does not normalize the excretion of citrate with the oral load of alkalis or citrate. The main cause for hypocitraturia is metabolic acidosis , in its various forms. ...
Article
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Idiopathic calcium nephrolithiasis is a multifactorial disease with a complex pathogenesis due to genetic and environmental factors. The importance of social and health effects of nephrolithiasis is further highlighted by the strong tendency to relapse of the disease. Long-term prospective studies show a peak of disease recurrence within 2–3 years since onset, 40-50% of patients have a recurrence after 5 years and more than 50-60% after 10 years. International nutritional studies demonstrated that nutritional habits are relevant in therapy and prevention approaches of nephrolithiasis. Water, right intake of calcium, low intake of sodium, high levels of urinary citrate are certainly important for the primary and secondary prevention of nephrolithiasis. In this review is discussed how the correction of nutritional mistakes can reduce the incidence of recurrent nephrolithiasis.
... 46 Hypocitraturia is one of the principal factors promoting stone formation in idiopathic stone disease, with a prevalence ranging from 8% up to 68.3%. 47 Hypocitraturia was found in 15 children, and was associated with high protein intake in only eight children. A low citrate output in stone formers may also be linked to renal defects (impairment of the sodium citrate cotransport or alteration of intracellular citrate regulation), inappropriate intestinal citrate or alkali absorption 47 or low magnesium or potassium levels. ...
Article
Full-text available
We evaluated the metabolic and the nutritional aspects of 134 urolithiasis children in order to outline the characteristics of idiopathic urolithiasis in children. This prospective study group of 134 children (56 females, 78 males) with renal calculi was evaluated. The age range of the patients was six months to 16 years. A dietary survey was performed on every child. All patients were investigated with respect to stone localization and serum and urine risk factors. Statistical analysis of data was carried out using software SPSS 11.0 for Windows. Hypercalciuria was the most common risk factor detected in this group (28.3%). A decrease of water intake was noted in all age groups, especially in the rural area (549.6 mL/day vs. 1150.6 mL/day), and there was an increase in animal protein intake in 17 cases (mean: 1.9 g/kg). In addition, increased intake of starchy foods and food with high oxalate content (sorgum) were detected in the ten to 16 years age group (51%) of our study. Calcium oxalate monohydrate represents the principal component of idiopathic stone (58.2%), which is more frequent in children (68%) than in infants (51.7%) (P <0.02). The major etiology of idiopathic urolithiasis highlights the influence of dietary habit in stone formers in our country. The increased occurrence of calcium oxalate stones in school age children confirms the change in the etiology of urolithiasis according to age.
... [4,5] Intervention with potassium citrate has been used for many years to reduce the risk of lithiasic recurrence in an individual who has overcome an acute episode; and its efficacy has been evaluated in various observational studies. [6][7][8][9][10] However, apart from the accrued observational data, the efficacy of this intervention has also been evaluated through a randomized, placebo-controlled clinical trial, [11] which represents a design of greater epidemiologic hierarchy to establish a better causality ratio with regard to the efficacy of potassium citrate. ...
Article
Objectives To determine whether the potassium citrate therapy is more cost-effective than diet alone. Methods Effectiveness was rated in terms of ‘avoided recurrences’ for both interventions. Costs were calculated on the basis of the patient's perspective. The time horizon for this analysis was 3 years, considering the follow-up period for patients included in this clinical trial. Key findings Those patients who did not show evidence of de novo stone images avoided six recurrence episodes by using potassium citrate and a change in diet. In those patients who showed evidence of de novo stone images with either of the two interventions, we assumed that recurrence would not be avoided (0 avoided recurrences). The cost per individual treated with potassium citrate who showed de novo lithiasis was US$2086 while that for untreated individuals who showed de novo lithiasis was US$1096 under the assumption that recurrence would not be avoided in any case with de novo lithiasis. We calculated a cost-effectiveness (C-E) ratio of US$360 for the intervention with potassium citrate and a C-E ratio of US$3795 for the dietary intervention alone. The incremental C-E ratio indicated that it is necessary to pay US$193 for every additional recurrence avoided with potassium citrate. Conclusions Intervention with potassium citrate proved to be more cost-effective than changes to diet alone. Two sensitivity tests proved the robustness of these results.
... Many large epidemiologic studies have demonstrated that hypercalciuria is the most common metabolic abnormality in children with urolithiasis [31,32]. Other studies have indicated that approximately 2-36 % of patients with pediatric urolithiasis have hyperoxaluria [33][34][35] and that there is a large prevalence of hypocitraturia in patients with urolithiasis, ranging from 8 to 68.3 % [36]. It is interesting to note that in our study we were able to demonstrate that serum cholesterol level in the urolithiasis group was significantly higher than that in the reference group. ...
Article
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Background There are indications that obesity and hyperuricemia may influence the formation and composition of urinary stones. The aim of our study was to determine the effect of obesity and hyperuricemia on the urinary lithogenic risk profile in a large cohort of pediatric patients. Methods The study population comprised 478 children with urolithiasis and 517 healthy children (reference group). We studied the effects of obesity on the lithogenic profile by dividing the patients with urolithiasis into two groups based on body mass index Z-score (patients who were overweight/obese vs. those with normal weight for age) and comparing the two groups. To study the effect of hyperuricemia on the lithogenic profile, we divided the patients with urolithiasis into two groups based on the presence or not of hyperuricemia (110 patients with urolithiasis accompanied by hyperuricemia vs. 368 patients with urolithiasis and normal serum uric acid levels) and compared the groups. Results Among the children and adolescents with urolithiasis and hyperuricemia, there was a significantly lower excretion of crystallization inhibitors (citrates, magnesium). We also found significantly negative correlations between serum uric acid levels and the urine citrate/creatinine ratio (citrate/cr.; r = −0.30, p
... Hypocitraturia can be isolated or associated with other metabolic conditions such as hypercalciuria or hyperoxaluria [30]. It can also be associated with distal tubular acidosis, hypokalemia or a high protein diet. ...
Article
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Nephrolithiasis is a rare disease in children. For many years children with kidney stones have been managed like “small adults”, but there are significant differences between the pediatric and the adult age in clinical presentation, etiology and treatment. Management of this condition in children has some peculiarities with respect to the adult, as it is often the sign of an underlying metabolic abnormality. Some of these metabolic alterations can lead to serious consequences, such as chronic renal failure, if not adequately diagnosed and treated. Moreover, stones in children with a metabolic abnormality can recur throughout their life, with the need for repeated surgical procedures over the years. So a systematic approach to every child with nephrolithiasis is mandatory to diagnose metabolic defects and establish a personalized therapy. Even the surgical approach in the child has changed significantly over the last two decades: open surgery has now been almost completely replaced by minimally invasive surgery due to the miniaturization of endoscopic instruments and technical advancements in optical and lithotripters systems. The goal is to obtain a stone-free status with the lowest number of minimally invasive procedures and with no complications. Many breakthroughs in our understanding of the physiopathology of renal stones and in surgical technology have been made over the last decades, but the best approach to use in a child with nephrolithiasis remains a true challenge for pediatric nephrologists and urologists.
... En caso de hipocitraturia, el objetivo terapéutico es aumentar su excreción urinaria. Esto se pude lograr al alcalinizar el plasma mediante citrato de potasio o bicarbonato de potasio y medidas dietéticas (27). Es importante señalar que el cloruro de potasio no tiene un efecto similar. ...
Article
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Los pacientes con litiasis renal requieren de investigaciones para identificar las condiciones médicas subyacentes y otras anomalías metabólicas predisponentes. Los resultados de estas investigaciones se utilizan para guiar el tratamiento preventivo. La profundidad del estudio necesario depende de varios factores, incluyendo la edad, la historia clínica de la persona y el número y la frecuencia de los cálculos. Una variedad de factores dietéticos y metabólicos pueden contribuir o causar la formación de litiasis renal. Los factores dietéticos incluyen una alta ingesta de proteínas animales, oxalato y sodio, y una baja ingesta de líquidos y de productos cítricos que contienen potasio. Las alteraciones metabólicas más frecuentemente asociadas a litiasis son la hipercalciuria, la hipocitraturia, la gota, la hiperoxaluria y la hiperuricosuria. Las modificaciones en la dieta deben aplicarse en todos los pacientes con litiasis renal, y consisten en una elevada ingesta de líquidos, la restricción de oxalato y sodio, una dieta balanceada en proteínas animales y complementadas por una ingesta adecuada de frutas y verduras. Cuando las modificaciones en la dieta no son suficientes en prevenir la formación de litiasis o en la presencia de alteraciones metabólicas importantes, es necesaria una intervención farmacológica especifica.
... Idiopathic hypocitraturia has been linked to intrinsic renal disease including impairment of the sodium-citrate transport in the proximal tubule. 18 Detection of LMW proteins in urine has been shown to indicate tubular dysfunction in various diseases, including diabetic and inherited nephropathies. 19 RET4 is a carrier for lipophilic vitamin A (retinol) in the blood. ...
Article
Objective: To investigate whether inflammation, oxidation and tubular injury is present in children with stones (RS) compared to healthy controls (HC) by measuring urinary proteins involved in these processes. Methods: Quantitative proteomic comparison of pooled urine from RS (N=30, 24 females, mean age 12.95±4.03 years) versus age- and gender-matched HC (N=30), using liquid chromatography-mass spectrometry. Relative protein abundance was estimated using spectral counting. Proteins of interest were selected using the following criteria: 1) ≥5 spectral counts; 2) ≥2-fold difference in spectral counts; and 3) ≤0.05 p-value for the Fisher's Exact Test. Results: Of the 1813 proteins identified, 230 met the above criteria, with 163 proteins up-regulated in the RS group and 67 up-regulated in HC. Functional analysis revealed 19 inflammatory proteins, 5 proteins involved in oxidative stress, and 5 involved in tubular injury. Of those, NADPH-oxidase, a major source of reactive oxygen species, was only found in the RS group, while glutathione S-transferase A2, an important antioxidant enzyme, was more abundant in controls. ELISA analysis confirmed statistically significant differences in the urinary excretion of retinol-binding protein 4, a marker of proximal tubular dysfunction, between stone patients with hypercalciuria and controls. Conclusion: We provide proteomic evidence of oxidative stress, inflammation, and tubular injury in children with renal stones. We speculate that inflammation and changes in the oxidant-antioxidant balance may cause tubular damage in these patients. Targeting these proteins may have therapeutic benefits.
... Citrate was significantly reduced in urinary milieu since it will be reabsorbed to prevent excess acidification of proximal tubular region [44]. On the other hand, no clear evidence has been reported regarding decrease in the urinary magnesium level but supplementation of exogenous Mg have resulted in reduction in crystal formation, because it competes with calcium during crystallization process and forms more soluble form of oxalate [45]. ...
... It is mainly administered to patients with kidney stones (cystine, uric acid, and calcium stones), which require alkalinization. [16][17][18] Na/K citrate with standard hydration was evaluated for reduction of CIN earlier and was stated to be efficient. 19 Taking into consideration that alkalinization of urine can be used to prevent CIN, we aimed to determine the efficacy of Na/K citrate in reducing the frequency of contrast nephropathy in comparison to sodium bicarbonate in patients after coronary angiography (CAG). ...
Article
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Contrast-induced nephropathy (CIN) is one of the important complications of radiographic procedures, especially in patients with chronic kidney disease. It is also one of the common causes of acute kidney injury. The pathogenesis is postulated to be the effect of oxygen- free radicals and hyperosmolar stress on the renal medulla. It is reported that the production of superoxide is most active at acid environment. K/Na citrate is well known as a urine alkalini- zation medium, and this has been evaluated earlier with standard hydration for reduction of CIN and was stated to be efficient. We aimed to determine the efficacy of Na/K citrate in reducing the frequency of CIN in comparison to sodium bicarbonate in patients after coronary angiography. Two hundred and ten patients with renal dysfunction [estimated glomerular filtration rate (eGFR), 60 mL/min/1.73 m2or less] who underwent elective or emergency coronary angiography (CAG) with/without percutaneous coronary intervention (PCI) at our institution were enrolled into the study. The patients were randomized into two groups, Group 1-Taking Na/K citrate and Group 2-Taking sodium bicarbonate. Radiographic contrast agent iohexol was used. Change in creatinine, percent change in creatinine, percent change in eGFR, change in serum potassium, and urine pH were all compared between the two groups. There was no significant difference for prevention of CIN when comparing the Na/K citrate with sodium bicarbonate solution in patients exposed to CAG with or without PCI. Mean absolute change in eGFR after 48 h after administration of contrast between sodium bicarbonate group and Na/K citrate group was −0.60 ± 1.58 versus −0.71 ± 1.38. Serum potassium decreased postprocedure in the sodium bicarbonate group than in the citrate group (3.90 ± 0.33 vs. 4.14 ± 0.39). Both agents are equally effective in reducing the incidence of CIN, but the citrate would possibly be a safer option for patients at risk of hypokalemia.
... Moreover, using TCC as the supplement may also reduce the risk of renal stones, due mainly to citrate complexation of calcium and to the enhanced citrate excretion which augments the inhibitory activity against calcium oxalate crystallization ( Table 4) [119]. ...
... Ethylene glycol is a commonly utilized agent in animal experimentation to induce nephropathy. Ethylene glycol administration may lead to intrarenal accumulation of CaOx and acute renal injury (8). ...
Article
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Antioxidative and nephroprotective effects of royal jelly against ethylene glycol induced renal injury were examined in this study. Five groups of rats were used. Rats in Group 1 served as control. Rats in Group 2 received ethylene glycol (1%) in drinking water, while those in Group 3 received 100 mg/kg of royal jelly through oral gavage. Group 4 served as protective group and received ethylene glycol 1% in drinking water and 100 mg/kg of royal jelly administered. Group 5 served as treatment group and received ethylene glycol 1% in the drinking water for the initial 15 days, followed by 100 mg/kg of royal jelly administered last 15 days. Oxidative stress was induced by ethylene glycol. Royal jelly was found to reduce renal damage with measured BUN and CREA (creatinine) levels. It was considered that royal jelly has positive effects on antioxidant system and decreased effects on lipid peroxidation. Royal jelly may have positive nephroprotective effects on the injury induced by ethylene glycol exposure. Particularly, the effects observed in the treatment group were remarkable. © 2017, Chartered Inst. of Building Services Engineers. All rights reserved.
... Ethylene glycol is a commonly utilized agent in animal experimentation to induce nephropathy. Ethylene glycol administration may lead to intrarenal accumulation of CaOx and acute renal injury (8). ...
... This continuous precipitation-dissolution process made the crystallites blunt ( Figure 6C and D). 4. The increase in pH can strengthen the inhibitory activity of some components in urine, such as TH protein and pyrophosphate. 28,29 TH protein plays dual roles in CaOx crystallite aggregation. TH protein promotes crystallite aggregation at lower pH but inhibits aggregation at higher pH. ...
Article
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The property changes of urinary nanocrystallites in 13 patients with calcium oxalate (CaOx) stones were studied before and after ingestion of potassium citrate (Kcit), a therapeutic drug for stones. The analytical techniques included nanoparticle size analysis, transmission electron microscopy, X-ray diffraction, and Fourier-transform infrared spectroscopy. The studied properties included the components, morphologies, zeta potentials, particle size distributions, light intensity autocorrelation curves, and polydispersity indices (PDIs) of the nanocrystallites. The main components of the urinary nanocrystallites before Kcit intake included uric acid, β-calcium phosphate, and calcium oxalate monohydrate. After Kcit intake, the quantities, species, and percentages of aggregated crystals decreased, whereas the percentages of monosodium urate and calcium oxalate dehydrate increased, and some crystallites became blunt. Moreover, the urinary pH increased from 5.96 ± 0.43 to 6.46 ± 0.50, the crystallite size decreased from 524 ± 320 nm to 354 ± 173 nm, and the zeta potential decreased from -4.85 ± 2.87 mV to -8.77 ± 3.03 mV. The autocorrelation curves became smooth, the decay time decreased from 11.4 ± 3.2 ms to 4.3 ± 1.7 ms, and the PDI decreased from 0.67 ± 0.14 to 0.53 ± 0.19. These changes helped inhibit CaOx calculus formation.
... Tamm-Horsfall protein) that inhibit CaOx aggregation and seems to be able to reduce the expression of urinary osteopontin. 47 In addition, findings suggest that oral antioxidant therapy prior to lithotripsy may reduce the severity of long-term renal injury caused by the shock waves. 48 Despite the decrease in MDA level, treatment with antioxidant nutrients after EG consumption led to significant decrease in the androgen levels, as well. ...
Article
Administration of natural antioxidants has been used to protect against nephrolithiasis. Urolithiasis was induced by ethylene glycol (EG) in Wistar rats. For 4 weeks, group 1 (control) was fed with a standard commercial diet. Group 2 received the same diet with 0.75% of EG. Group 3 received EG plus the diet and water added with antioxidant nutrients and lime juice as the dietary source of citrate (EG + AX). Group 4 same as group 3 with no EG in water. For 8 weeks, group 5 was fed the standard diet with EG in water for the first 28 days, followed by no EG. Group 6 received the diet with EG for the first 28 days, followed by discontinuation of EG and addition of antioxidant nutrients. Group 7 were provided the diet with antioxidant nutrients for 8 weeks. Group 8 received the diet with antioxidant nutrients for 4 weeks, followed by antioxidant nutrients with EG for the next 4 weeks. Blood samples were collected and kidneys were removed. The size and the mean number of crystal deposits in EG-treated groups was significantly higher than the EG-treated groups, added with antioxidant nutrients and lime juice. After 4 weeks, the mean concentration of malondialdehyde in group 2 was higher than the group 3, and significantly lower in group 4; and in groups 7 after 8 weeks, as well. After 8 weeks, supplementation developed less mean number of deposits in group 6 as compared to group 5; and in group 8, the crystal deposits was substantially less than either group 2 or group 5 (EG-treated rats). Elevated concentration of androgens (as promoters of the formation of renal calculi) as a result of EG consumption decreased following antioxidant supplementations. Results showed a beneficial effect of antioxidant and provided superior renal protection on treating and preventing stone deposition in the rat kidney.
... Citrate is known as a potent inhibitor of the formation and development of calcium oxalate stones [13,16]. Because citrate only slightly changes the supersaturation of AHU with respect to calcium oxalate, its inhibitory mechanism is connected with the adsorption of citrate ions onto the surface of calcium oxalate crystal thereby preventing further crystal development. ...
Article
Thermodynamic equilibria in urine at 37 °C showed that the inorganic urinary constituents, citrate and oxalate are present as 76 different species. Complexes formed by uric acid and various organic compounds, such as creatinine, proteins, hormones and metabolites, for which the relevant thermodynamic data are not available in the library of the computer program MINTEQA2 Version 3 were not considered. The actual thermodynamic supersaturation of urine with respect to calcium oxalate monohydrate and dihydrate was calculated. The effects of varying composition of urine at the same pH and the violation of the condition of electroneutrality on the calculated supersaturation were shown. The supersaturation of urine should never be computed from incomplete data of urine composition. Incomplete urine composition should always be supplemented with data for the other urinary components. Guidelines for extension of urine composition were suggested. A requisite condition for formation of solid calcium oxalate in urine is the presence of active heterogeneous nuclei. Supersaturation of urine with respect to calcium oxalates per se cannot be regarded as a diagnostic measure of the risk of calcium oxalate stone formation. Graphical abstract Open image in new window COM formation through heterogenous nucleation on hydroxyapatite
... Este tratamiento no solo previene la aparición de nuevas litiasis, sino que puede disolver las ya preexistentes. Es importante señalar que las sales de sodio (bicarbonato de sodio o citrato de sodio), no tienen un efecto similar, ya que puede incrementar la calciuria y el riesgo de litiasis (30). El uso crónico de Alopurinol, que reduce la producción de ácido úrico, se reserva para pacientes que excretan más de 1000 mg de acido úrico al día y que no responden a la hidratación y terapia alcalinizante. ...
Article
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Resumen La litiasis urinaria representa una patología importante en la práctica urológica y requiere de un abordaje multidisciplinario. Su incidencia es del 10%, afecta a un grupo etario extenso, con factores que pueden influir en su aumento en determinados lugares. Su diagnóstico aparece como hallazgo en controles rutinarios de salud o a través del sindrome de cólico renal, cuadro característico y de consulta frecuente en los servicios de urgencia. Su etiología no está del todo definida, siendo las hipótesis más aceptadas, las alteraciones excretoras del riñón sumada a factores ambientales y hábitos. El estudio incluye exámenes de laboratorio para descartar complicaciones como infecciones e insuficiencia renal. Las imágenes determinan el volumen de la litiasis, su ubicación y densidad, para decidir de qué manera resolver el caso, ya sea de manera espontánea o activa mediante distintos tipos de intervenciones quirúrgicas. La tomografía computarizada sin contraste se considera como el estándar de oro para el diagnóstico por imágenes de la litiasis urinaria. Los tratamientos se plantean según las distintas situaciones clínicas: manejo médico del cólico renal y terapia expulsiva para resolución espontánea del cuadro; manejo quirúrgico, cuyas técnicas más frecuentes son la nefrolitectomía o ureterolitectomía endoscópica rígida o flexible, litotripcia extracorpórea (LEC), nefrolitectomía percutánea (NLP), y finalmente el estudio etiológico de la litiasis urinaria y medidas de prevención. En niños, la incidencia de litiasis urinaria es menor que en adultos, sin embargo, las consecuencias de esta enfermedad pueden ser desastrosas. La etiología es fuertemente asociada a factores genéticos. Actualmente los tratamientos quirúrgicos son similares a los practicados en pacientes adultos.
... The evaluation of urinary citrate excretion has widely been used in the diagnostic and therapeutic management of renal stone disease. Citrate salts are widely used in the treatment of nephrolithiasis, since potassium-citrate and potassium-magnesium-citrate have shown an inhibitory effect on kidney stone formation and recurrence [24,71,72]. Although potassium-citrate and potassium-magnesiumcitrate are clearly indicated in all calcium-oxalate stone formers with hypocitraturia, the beneficial effects are also evident in normocitraturic patients, in so far as a higher is urinary citrate concentration is associated with a stronger inhibition of stone formation [24]. ...
Article
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Adequate daily calcium intake should normally be achieved by dietary sources. Since low calcium diets are quite common in subjects that do not reach the recommended intake and particularly those at risk of fractures, calcium supplements may become necessary. Different forms of calcium salts are available, but products containing calcium citrate and calcium carbonate complexes are the most frequently used. Although only limited evidence on the efficacy and long-term safety of calcium citrate is available, these supplements may represent a valuable product for the management of different chronic pathological conditions. The aim of this review was to evaluate the current and potential clinical applications of calcium citrate. In particular, we focused on the use of calcium citrate supplementation in subjects with osteoporosis or in bariatric patients. Other pathological conditions that could benefit calcium citrate supplementation may include achloridria, chronic hypoparathyroidism and hypocitraturic subjects with moderate/high risk of nephrolithiasis. Indeed, citrate salts are widely used in the treatment of nephrolithiasis, since they have shown an inhibitory effect on kidney stone formation and recurrence.
... It emerges as a result of a reduction in citrate levels in urine, which forms a complex with calcium to produce a freely soluble complex known as calcium citrate. In the absence of citrate, calcium forms complexes with phosphate and oxalate, yielding calcium phosphate and calcium oxalate, both of which are extremely insoluble in nature [16] [17]. ...
Article
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Urolithiasis is one of the third most common disease of calculi formation in any part of urinary tract includes kidney, ureter and urinary bladder. Urolithiasis is a multifactorial disease; therefore, this review compiles the factors responsible in emergence of different types of calculi and the pathophysiology of calculi formation. The medical management of urolithiasis has witnessed a great change with wide range of treatment options comprises of medical expulsion therapy, surgical techniques, synthetic drugs and herbal medication. The options include medical expulsion therapy, surgical techniques and synthetic drugs treatment results lack of success rate, increase in rate of retreatment, recurrence and results in several complications. In present scenario the handling of urolithiasis is not only restricted with stone removal but also protect against from its complications and recurrence. Therefore now a day's herbal medication is attracting the attention due to its merits in curing the urolithiasis condition by minimizing all the draw backs accompanied with other treatment possibilities. A final outlook explains the eminence and effectiveness of herbal medication and beneficial to upcoming researchers to shift their attentiveness to traditional medicine in order to cure or prevent urolithiasis effectively.
... Citrate also inhibits crystal growth and aggregation, and prevents adhesion of calcium oxalate to renal epithelial cell. 39,40 Although it did not reach statistical significance, proline betaine, which is a known biomarker of citrus fruit consumption, was also higher in controls. 41 Thus, consumption of citrate-rich fruits and vegetables could be protective against kidney stone disease by multiple mechanisms. ...
Article
Background: The urine metabolites and chemistries that contribute to kidney stone formation are not fully understood. This study examined differences between the urine metabolic and chemistries profiles of first-time stone formers and controls. Methods: High resolution ¹ H-nuclear magnetic resonance (NMR) spectroscopy-based metabolomic analysis was performed in 24-hour urines from a prospective cohort of 418 first-time symptomatic kidney stone formers and 440 controls. Forty-eight NMR-quantified metabolites in addition to 12 standard urine chemistries were assayed. Analysis of covariance was used to determine the association of stone former status with urine metabolites or chemistries after adjusting for age and sex and correcting for false discovery rate. Gradient boosted machine methods with nested cross-validation were applied to predict stone former status. Results: Among the standard urine chemistries, stone formers had lower urine oxalate and potassium and higher urine calcium, phosphate, and creatinine. Among NMR urine metabolites, stone formers 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 0.760 (95% CI: 0.728 to 0.792). A cross-validated model using urine chemistries, NMR-quantified metabolites, age, and sex did not meaningfully improve the discrimination (mean AUC:0.776 (95% CI: 0.745 to 0.807). In this combined model, among the top 10 discriminating features 4 were urine chemistries and 6 NMR-quantified metabolites. Conclusion: Although NMR-quantified metabolites did not improve discrimination, several urine metabolic profiles were identified that may improve understanding of kidney stone pathogenesis.
... Цитрат снижает абсорбцию кальция в кишечнике из-за связывания кальция с ионами цитрата. В результате образуется комплексное соединение с кальцием, что ограничивает связывание кальция с оксалатом и фосфатом, снижает экскрецию кальция в связи с увеличением его канальцевой реабсорбции, ингибирует спонтанное осаждение и агломерацию кристаллов CaOx и СаР, повышает рН мочи, обладает антиоксидантным эффектом [61]. Цитратные добавки используют для растворения камней из мочевой кислоты (целевой показатель рН мочи -7,0-7,2) и предупреждения формирования камней из цистина (целевой уровень рН мочи -от 7,0 до 7,5) [62]. ...
Article
Kidney stone disease (KSD) is a disease caused by the formation of calculi in kidneys and other parts of the urinary tract. The rate of hospitalization of children with KSD worldwide is increasing. The adequate method of calculus extraction and further therapy according to calculus composition and metabolic disorders are crucial for effective treatment of patients with KSD and recurrence risk reduction. This review covers surgical (extracorporeal lithotripsy, percutaneous nephrolithotripsy, retrograde intrarenal surgery, ureterolithotripsy, laparoscopy, open surgery) and non-surgical (lithokinetic and litholytic) therapy. Special attention is paid to metaphylaxis, or recurrence prevention, and calculi formation. It is noted that medication of children with KSD can be aggravated by various adverse reactions, complexity in drugs dosages in children of first years of life. Moreover, all surgical methods are characterized by high risk of postoperative complications development. The relevance of KSD genetic nature in children, the role of lifestyle changes in disease development, the implementation of new drugs for metabolic disorders correction are presented in the article.
... [20] Citrate exhibits inhibitory action against the urinary stone and especially against the CaOx crystal formation. [21] It interacts with calcium and forms its complex, thus reduces the levels of CaOx, and thus prevents the formation of CaOx agglomerates. [5] Furthermore, GAGs exhibit the inhibitory potential against CaOx nucleation, growth, and aggregation as well as the prevention of crystals adherence to the renal surface. ...
... Also, the formation of calcium oxalate stones seems more unlikely with the use of calcium citrate. This for mulation, in fact, favors the sequestration of calcium ions and the inhibition of crystal accretion; at the same time, it augments the urinary excretion of macromole cules, such as TammHorsfall protein, finally preventing the development of calciumoxalate stones [55]. ...
Article
The aim of this review is to describe the metabolism of calcium in ankylosing spondylitis compared to physiologic conditions, and to present the current evidence on the benefits and disadvantages of calcium supplementation in these patients. A narrative review of the literature was conducted using the PubMed database and a total of 65 articles were selected. Calcium is involved in many physiopatholo­gical processes, including inflammation, bone loss and bone formation, all of which occur in ankylosing spondylitis. Many ankylosing spondylitis patients suffer from concomitant osteopenia or osteoporosis, which represent indications for calcium supplementation. Conversely, there are still concerns about the use of calcium salts for the prevention of bone fragility in non-osteoporotic or non-osteopenic patients. In these cases, biologic agents may indirectly normalize calcium dysmetabolism by rebalancing the cyto­kine milieu, in turn associated with bone remodeling. Calcium supplements may be disadvantageous for entheseal calcifications, but so far there are no clear data confirming that such an association exists.
... The reference values for urinary citrate levels range from 320 to 1260 mg/24 h, with an average in males of 550 mg/24 h and in females of 680 mg/24 h [18,19]. The higher excretion of citrate in females is in relation to the estrogenic [20] and explains the lower incidence of nephrolithiasis in premenopausal women, considering that citrate-calcium binding is one of the main mechanisms for inhibiting stone formation [21]. Based on the reference values for lithogenic risk, the threshold for the diagnosis of hypocitraturia is usually fixed as less than 320 mg per day. ...
Article
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Citrate is an intermediate in the “Tricarboxylic Acid Cycle” and is used by all aerobic organisms to produce usable chemical energy. It is a derivative of citric acid, a weak organic acid which can be introduced with diet since it naturally exists in a variety of fruits and vegetables, and can be consumed as a dietary supplement. The close association between this compound and bone was pointed out for the first time by Dickens in 1941, who showed that approximately 90% of the citrate bulk of the human body resides in mineralised tissues. Since then, the number of published articles has increased exponentially, and considerable progress in understanding how citrate is involved in bone metabolism has been made. This review summarises current knowledge regarding the role of citrate in the pathophysiology and medical management of bone disorders.
... Various citrate preparations (sodium potassium citrate, potassium citrate, potassium magnesium citrate, potassium bicarbonate, and sodium bicarbonate) were known to reduce the risk in stoneformer patients. Findings based on randomized studies show that potassium citrate has a greater potential for preventing recurrence than does sodium potassium citrate [20][21][22][23][24][25][26]. When oral intake of citrate preparations is unpleasant for the patient, lemon or orange juice could be a valuable option, the latter being a better alkalinising and citraturic agent [21][22][23]. ...
Article
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This review summarizes recent literature on advances regarding renal and ureteral calculi, with particular focus in areas of recent advances in the overall field of urolithiasis. Clinical management in everyday practice requires a complete understanding of the issues regarding metabolic evaluation and subgrouping of stone-forming patients, diagnostic procedures, effective treatment regime in acute stone colic, medical expulsive therapy, and active stone removal. In this review we focus on new perspectives in managing nephrolitihiasis and discuss recentadvances, including medical expulsive therapy, new technologies, and refinements of classical therapy such as shock wave lithotripsy, give a fundamental modification of nephrolithiasis management. Overall, this field appears to be the most promising, capable of new developments in ureterorenoscopy and percutaneous approaches. Further improvements are expected from robotic-assisted procedures, such as flexible robotics in ureterorenoscopy.
... 2 Hypocitraturia is a well-recognized risk factor for the development of kidney stones, 2 and it is identified as a metabolic abnormality in 20 to 60% of adult stone formers (SF). 2,3 In children, the demographics of nephrolithiasis have been changing 1 and hypocitraturia has now emerged as the most prevalent reason for nephrolithiasis in children. 4,5 Contributing to the development of hypocitraturia are distal renal tubular acidosis, hypokalemia, bowel dysfunction, and a high-protein and low-alkali diet. 2 The gold standard for the diagnosis of hypocitraturia is a 24-hour urine collection and it is defined as urinary citrate excretion < 320 mg (1.67 mmol) per 24 hours for adults. ...
Article
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The purpose of the study was to evaluate urinary citrate/creatinine (UCi/UCr) and urinary calcium/citrate (UCa/UCi) ratios for distinguishing stone formers (SF) from non-stone formers (NSF) in an at-risk population. This was a retrospective study that included all pediatric patients who underwent urinary citrate testing from April 2017 to March 2018. The urinary levels of citrate, calcium, sodium, potassium, creatinine, oxalate, urate, pH, and specific gravity (SG) were measured in our clinical laboratory. Diagnosis of kidney stones was obtained through chart review. A total of 97 patients were included (46 NSF and 51 SF). The UCi/UCr ratio was not significantly different between NSF and SF. Median UCa/UCr ratio was higher in SF (0.67) compared with NSF (0.21, p < 0.0001). The median ratio of UCa/UCi was also higher in SF (1.30) than in NSF (0.65, p = 0.001). Oxalate, urate, pH, SG, and urinary sodium/potassium ratio did not differentiate between the SF and NSF. Positive correlation was seen between UCa/UCr and urinary sodium/creatinine UNa/UCr (p < 0.0001), as well as between UCa/UCr and UCi/UCr (p < 0.0001). The study has demonstrated significantly higher UCa/UCi and UCa/UCr in SF compared with NSF, while the use of urinary oxalate, urate, pH, and SG did not differentiate between SF from NSF. We also confirmed a positive correlation between UNa/UCr and UCa/UCr. While the utility of UCa/UCr is well established, our data suggest that UCa/UCi rather than UCi/UCr may be more predictive in the clinical setting when evaluating for nephrolithiasis.
... 4 Expression levels of NaDC-1 mRNA in stone-adjacent renal tissues of CaOx NL patients compared among AA, AG and GG carriers. Patients with AA genotype had significantly higher level of intrarenal NaDC-1 mRNA than patients with AG and GG genotypes studies that used a cut-off of 320 mg/day to define hypocitraturia (Caudarella and Vescini 2009;Pak 1994). We did ROC analysis and selected an appropriate cut-off for Thai population at 200 mg/day. ...
Article
Hypocitraturia is a profound risk for kidney stone formation and recurrence. Sodium-dicarboxylate cotransporter-1 (NaDC-1) is a main transporter responsible for citrate reabsorption in renal proximal tubules. To investigate an association of sodium-dicarboxylate cotransporter-1 (NaDC-1) polymorphism with hypocitraturia in Thai patients with nephrolithiasis (NL). Exonic SNPs in NaDC-1 were screened in peripheral blood DNA of 13 NL patients. The rs11567842 (A/G) variant was found and further genotyped in 145 NL patients and 115 non-stone forming controls. NL patients had significantly lower level of urinary citrate than the controls. Based on logistic regression, hypocitraturia was significantly associated with urinary stone formation (adjusted OR 8.34, 95% CI 4.63–15.04). Significant association of urinary citrate level with rs11567842 genotype was found only in the NL group. NL patients with GG genotype had significantly higher urinary citrate than those with AA and AG genotypes. GG carrying patients had significantly reduced risk for hypocitraturia (adjusted OR 0.15; 95% CI 0.05–0.48, AA as reference). In selected 15 calcium oxalate stone patients, AA carriers had significantly higher intrarenal NaDC-1 mRNA than GG and AG carriers. Homozygous GG of rs11567842 SNP in NaDC-1 gene was a protective genotype for hypocitraturia in kidney stone patients. The findings suggested that patients with AA genotypes were more susceptible to hypocitraturia than those with GG, hence carrying a higher risk for kidney stone recurrence. © 2018 The Genetics Society of Korea and Springer Science+Business Media B.V., part of Springer Nature
... eventually results in calculus, normally some chelating agents are present in the urine which inhibits the growth nucleation and aggregation of the crystals that contains calcium, if these chelating agents are less in the urine they can also be a cause of the stone formation in the urinary tract. [9][10][11] Several studies have been published on the importance of positive family history in the development of renal stones. A cohort study was published in which 37,999 male patients were included in the study in which 4873 cases of stones were reported with familial history. ...
Article
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Background The purpose of the research is to know the sonographic evaluation of urolithiasis formation with positive family history in population of Lahore because urolithiasis is a major problem in Pakistan. According to a survey in 1985–1987 the incidence rate reaches to 8.3/100,000 individuals in the Punjab. In Pakistan, urolithiasis is the sixth major cause of surgery. The study was conducted to rule out the role of positive family history in people suffering from urolithiasis. Materials and Methods This was an observational cross-sectional study conducted at the Radiology department of the University of Lahore teaching hospital and Gilani Ultrasound center-Afro-Asian Institute, Lahore, Pakistan. A total of 125 patients were included in the study which were diagnosed with urolithiasis and individuals with any other abnormality were excluded from the study. The duration of the study was from January 2017 to April 2017. Data were tabulated and analyzed using SPSS version 24. The data were reported using descriptive and inferential statistics. The quantitative variable like age was assessed using mean standard deviation and standard errors. The qualitative variables like gender were reported using percentages and frequencies. Results Urolithiasis is commonly seen in the males (77 individuals out of 125) as compared to females (48 individuals out of 125) and mid pole of right kidney is the most common site of the renal stones deposition (13.6%), and the relationship of father is mostly seen as familial history (39.2%). Conclusion It is concluded that positive family history is the major predisposing factor in urolithiasis and one of the cause in the development of stones in the urinary tract or in other words people who have a history of urolithiasis in blood relations have more tendency of stone formation in any part of their lives. Its positive aspect is that we can do a screening in blood relations, especially whose parents or family members diagnosed with stones and can do preventive measures for that. Moreover, its negative aspect is that there are several causes of the stone formation in the urinary tract.
... It is also useful for performing various biological functions in human body such as to regulate the blood balance and acid-base balance in the blood and tissues [3]. KDC also exhihibits great importance in the medical field as a medical aid of urolithiasis [4][5][6][7]. ...
Chapter
Le alterazioni del metabolismo minerale e del tessuto osseo rappresentano una complicazione comune nella storia naturale di numerose nefropatie, e trovano la loro espressione più tipica nei pazienti con insufficienza renale cronica in fase uremica (IRC). La comparsa di osteopatie metaboliche nei pazienti nefropatici è la conseguenza del ruolo chiave svolto dal rene nella regolazione dell’omeostasi minerale; infatti esso modula l’equilibrio esterno di calcio, fosforo e magnesio, controlla la sintesi di 1,25(OH)2D3, degrada e rimuove dal circolo l’ormone paratiroideo (PTH), contribuisce alla regolazione dell’equilibrio acido—base ed è il principale responsabile dell’escrezione di alluminio.
Article
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There are 2 major categories of patients with seizures and chronic kidney disease (CKD): patients who develop acute symptomatic seizures in the setting of CKD and patients with epilepsy who at some point develop CKD. The incidence of uremic seizures with kidney failure is ∼10%. These seizures are often nonconvulsive and may mimic uremic encephalopathy. Recognition and management of such situations may be challenging for treating physicians who are non-neurologists. Furthermore, practitioners caring for patients with seizures with or without an established diagnosis of epilepsy in the setting of CKD frequently encounter challenges in the selection, loading, titration, and maintenance of antiepileptic drugs (AEDs) due to potentially altered pharmacokinetics of the AEDs. We review the pathophysiology of uremia, uremic seizures, and other neurologic complications of kidney failure; management approaches to the treatment of such complications; the relevant mechanisms of action and pharmacokinetics of AEDs with their use in CKD; and in particular, the management of AEDs in patients requiring hemodialysis therapy.
Chapter
Assessment of a patient’s habitual dietary pattern and intake of specific foods and beverages is important in identifying whether diet is contributory to stone formation. Registered dietitian nutritionists are experts at obtaining patients’ diet histories and generating assessments of their habitual intake.
Article
Introduction: Migraine is a very common medical disorder characterized by attacks of moderate-severe headache, nausea and disability. Topiramate is an effective, popular prophylactic migraine treatment, which is approved for use in adults and adolescents. Due to its multiple mechanisms of action, topiramate has multiple potential safety issues, including systemic and CNS adverse events, which may complicate therapy. Areas covered: This review evaluates common adverse events as seen in the pivotal trials of topiramate for migraine as well as those observed in postmarketing studies. These include weight loss, metabolic acidosis, renal calculi, acute angle closure glaucoma, visual distortions and cognitive slowing. Topiramate use during pregnancy is associated with an increased risk of cleft lip. This review highlights both common and unusual safety issues associated with topiramate use, including important drug interactions and a comparison with other migraine prophylactic agents. Expert opinion: Topiramate is highly effective in migraine prophylaxis but clinicians using the drug need to be aware of the potential for bothersome or serious adverse events. When treating with topiramate, use a slow titration to the goal dose of 100 mg or the lowest dose, which helps prevent migraine.
Article
Introduction: Urolithiasis is a common, highly recurrent disease with increasing prevalence worldwide. There are many dietary and pharmacological measures to prevent kidney stones. Areas covered: Herein, the authors explore medical expulsive therapy as well as pharmacological therapies to prevent/treat urolithiasis. Expert opinion: All stone formers should be advised to increase their fluid intake sufficiently to achieve a urine volume of at least 2.5 L/day. In the case of hypercalciuria, a thiazide diuretic should be prescribed while in cases of hypocitraturia, potassium citrate should be given. In the case of hyperoxaluria, the treatment depends on the type of hyperoxaluria. Pyridoxine or calcium supplements with a meal can be offered. For uric acid stone formers, alkali therapy is the standard of care whereas allopurinol can be beneficial in hyperuricosuric stone formers. For cystine stone formers, increased fluid intake, restriction of sodium and animal protein ingestion, and urinary alkalinization are the standard therapies used. Cystine binding thiol drugs such as tiopronin and D-penicillamine are reserved for patients where a conservative approach fails. For struvite stone formers, optimal management is the complete stone removal. Acetohydroxamic acid may be offered only after surgical options have been exhausted, for patients with residual stones but it has many side effects.
Article
The literature data suggest a positive effect of thiazide diuretic treatment on bone health both by increasing bone mineral density and by decreasing the risk of fracture. The protective effect of thiazides seems to be linked both to the dosage and to the duration of treatment; moreover, the protective effects of thiazides in preserving bone mass and in decreasing the risk of fractures does not last long after discontinuation of treatment. Thiazides influence bone health by means of different mechanisms. In fact, they increase renal calcium reabsorption by inhibiting the sodium chloride cotransporter in the distal tubule, thus increasing sodium urinary excretion and decreasing urinary calcium excretion. Still, thiazides contribute to maintaining calcium homeostasis by increasing calcium intestinal absorption. Moreover, thiazides have a direct effect on bone cells, especially on osteoblast differentiation and bone mineral formation. Finally, it was suggested that thiazides prevent bone loss as they decrease the acid production by means of inhibition of carbonic anhydrase activity in the osteoclasts. The dual action shown by thiazides on both osteoblasts and osteoclasts could explain the reduced bone remodeling observed in patients taking these drugs, in the absence of changes in plasma parathyroid hormone levels. In conclusion, thiazides might play an interesting role in osteoporosis management, particularly in those patients affected by both hypertension and osteoporosis, but efficacy in reducing fractures and the safety of this treatment must still be evaluated by means of further randomized controlled clinical trials which have the reduction in fractures as primary outcomes.
Article
Aim & Objective: To evaluate the 24 hour urinary citrate levels in chronic renal failure and healthy controls and to define the role of urinary citrates in the chronic renal failures. Materials and Methods: The 24 hours urinary citrates, Blood urea, Serum creatinine, Na+, K+were evaluated in 25 chronic renal failure patients and 25 healthy subjects taken as controls. In both groups participants were on their usual diet. In addition, none of the participant was taking any drugs that could interfere with the citrate excretion. Results: The mean 24 hour urinary citrate excretion in patients and healthy controls was 296.3 ± 8.543mg and 323.9 ± 4.304mg respectively. Using previously defined values of normal urinary citrates as more than 320 mg.The difference in 24 hour urinary citrate excretion in all patients and healthy control was statistically significant (<P =0.001). Conclusion: There is statistically significant difference in urinary citrate excretion in recurrent renal failures and healthy controls. Uniformly low citrate excretion in patients indicates that low citrate levels may be a feature seen in predisposing factor for renal failure.
Article
BACKGROUND AND OBJECTIVE: Diagnosis and treatment of renal stone are very important especially according to non-special symptoms and risk of complication in children. According to invasive surgical methods for treatment of these patients, this study was done to evaluate oral potassium citrate solution efficacy in children with urolithiasis. METHODS: This quasi experimental study was done on 150 children who referred to nephrology department or clinic with renal stone and without urinary obstruction (2002-2010). All children were treated with potassium citrate solution initially 1 ml/kg/day and then it was increased till urine PH reached to above 6.5-7. Urinary ultrasonography was done every 3 months and response to treatment was evaluated according to the stone size, age and duration of treatment. FINDINGS: The age of children was 25 days to 15 years (Mean 36.7±37.4 month). Eighty five cases (56.6%) were male and 65 (43.4%) were female. The rate of complete response to drug (absence of stone) was 78.7% during one year. Mean of follow up was 15.9± 14.6 months and the risk of relapse (recurrence of stone) was 12.4%. There weren't significant difference between response to treatment and stone size, age and children sex. CONCLUSION: Potassium citrate has been found to be significantly effective in treatment of renal stone, so we suggest using this drug for treatment of renal stone in all children without urinary obstruction.
Article
Leveraging the multifunctional nature of citrate in chemistry and inspired by its important role in biological tissues, a class of highly versatile and functional citrate-based materials (CBBs) has been developed via facile and cost-effective polycondensation. CBBs exhibiting tunable mechanical properties and degradation rates, together with excellent biocompatibility and processability, have been successfully applied in vitro and in vivo for applications ranging from soft to hard tissue regeneration, as well as for nanomedicine designs. We summarize in the review, chemistry considerations for CBBs design to tune polymer properties and to introduce functionality with a focus on the most recent advances, biological functions of citrate in native tissues with the new notion of degradation products as cell modulator highlighted, and the applications of CBBs in wound healing, nanomedicine, orthopedic, cardiovascular, nerve and bladder tissue engineering. Given the expansive evidence for citrate's potential in biology and biomaterial science outlined in this review, it is expected that citrate based materials will continue to play an important role in regenerative engineering.
Chapter
This chapter is an overview of the biochemical evaluation of patients with urinary tract stone disease. The aim is to give practical aspects on how the search for risk factors can be carried out when stone composition is known or unknown. The physical chemistry of stone formation is superficially touched. Aspects on the importance of the medical history, the radiographic evaluation, and the stone, blood, and urine analysis are discussed. The goal of every metabolic or biochemical evaluation is to provide a basis for a reasonable and effective recurrence prevention. The intention with this chapter is to give information in this regard.
Chapter
Hypercalciuria is the commonest metabolic alteration found in patients with idiopathic calcium disease, and the absorptive type is the most prevalent. Therapies for hypercalciuria include thiazides, thiazide-like drugs, alone or together with potassium citrate, and bisphosphonates. In the past, orthophosphates appeared to be highly indicated for absorptive hypercalciuria treatment since they reduce serum 1,25-dihydroxyvitamin D levels, urinary calcium excretion, and, perhaps, bone resorption. Inorganic phosphate salts include acid potassium phosphate, neutral mixtures of acid and alkaline potassium phosphate, and neutral mixtures of sodium and potassium phosphate. Moreover, neutral potassium orthophosphates include compounds characterized by fast or slow release. The effect is most pronounced for neutral orthophosphates, which not only reduce calcium and increase pyrophosphate excretion but also induce greater urinary citrate excretion; inhibitory power in urine against the crystallization process thus results as increased. The hypocalciuric response to the drug is probably the result of the combined effects of reduced intestinal calcium absorption, increased renal tubular calcium reabsorption, and diminished bone resorption. Positive effects of orthophosphate therapy have been described in several papers, although most of them consisted of open non-randomized studies. There are only two double-blind studies with orthophosphate treatment; in the first, no differences were observed between treated and untreated patients, whereas in the second, a reduced rate of stone formation was observed.
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Purpose of Review With recent advances in sequencing technologies and increasing research into the gut microbiome (GMB), studies have revealed associations between the GMB and urinary stone disease (USD). We sought to determine whether the evidence pointed towards a few specific gut bacteria or the broader GMB network is seemingly responsible for this relationship. Recent Findings Initially, Oxalobacter formigenes (OF) was pursued as the main link between GMB and USD given its ability to degrade oxalate in the gut. However, the latest studies consistently suggest that the entire GMB is much more likely to be involved in handling oxalate absorption and other risk factors for urinary stone formation, rather than just a few microbiota. Summary The GMB has complex networks that are likely involved in the pathophysiology of USD, although the causal mechanisms remain unclear. With increasing interest and research, potential modalities that act on the GMB may help to prevent incidence of USD.
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The urinary citrate excretion was examined in patients with nephrolithiasis who were categorized on the basis of different physiologic or metabolic abnormalities. A wide prevalence of low citrate excretion (hypocitraturia) was observed, with over one half of our patients with stones exhibiting it. Hypocitraturia was found in all patient categories except primary hyperparathyroidism and hyperuricosuric calcium oxalate nephrolithiasis. As expected, hypocitraturia was present in renal tubular acidosis and in enteric hyperoxaluria. However, urinary citrate was also low in absorptive and renal hypercalciurias, and in patients in whom an acid-base disturbance was clearly excluded.
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The cDNA coding for a rabbit renal Na+/dicarboxylate cotransporter, designated NaDC-1, was isolated by functional expression in Xenopus oocytes. NaDC-1 cDNA is approximately 2.3 kilobases in length and codes for a protein of 593 amino acids. NaDC-1 protein contains eight putative transmembrane domains, and the sequence and secondary structure are related to the renal Na+/sulfate transporter, NaSi-1. Northern analysis shows that the NaDC-1 message is abundant in kidney and small intestine, and related transporters may be found in liver, lung, and adrenal. The transport of succinate by NaDC-1 was sodium-dependent, sensitive to inhibition by lithium, and inhibited by a range of di- and tricarboxylic acids. This transporter also carries citrate, but it does not transport lactate. In kinetic experiments, the Km for succinate was around 0.4 mM and the Vmax was 15 nmol/oocyte/h, while the Hill coefficient of Na+ activation of succinate transport was 1.9. The transport of succinate by NaDC-1 was insensitive to changes in pH, whereas the transport of citrate increased with decreasing pH, in parallel with the concentration of divalent citrate in the medium. The results of the functional characterization indicate that NaDC-1 likely corresponds to the renal brush-border Na+/dicarboxylate cotransporter.
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Chronic metabolic acidosis increases, while alkali feeding inhibits, proximal tubule citrate absorption. The activity of the apical membrane Na+/citrate cotransporter is increased in metabolic acidosis, but is not altered by alkali feeding. Renal cortical mRNA and brush border membrane protein abundances of sodium/dicarboxylate-1 (NaDC-1), the apical membrane Na+/citrate transporter, were measured. By immunohistochemistry, NaDC-1 was localized to the apical membrane of the proximal tubule. Chronic metabolic acidosis caused an increase in NaDC-1 protein abundance that was maximal in the S2 segment and that increased with time. Metabolic acidosis also increased NaDC-1 mRNA abundance, but this was first seen at three hours and correlated with the severity of the metabolic acidosis. Alkali feeding had no effect on NaDC-1 protein or mRNA abundance. Chronic metabolic acidosis increases renal cortical NaDC-1 mRNA abundance and apical membrane NaDC-1 protein abundance, while alkali feeding is without effect on NaDC-1.
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Citrate is a weak acid that is formed in the tricarboxylic acid cycle or that may be introduced with diet. In the present paper all the mechanisms involved in intestinal absorption, renal handling and modulation of citrate will be reviewed. The evaluation of plasma citric acid is scarcely used in the diagnosis of human diseases. On the contrary urinary citrate excretion is a common tool in the differential diagnosis of kidney stones, renal tubular acidosis and it plays also a role in bone diseases. Therefore the importance of hypocitraturia will be reviewed with regard to bone mass, urine crystallization and urolithiasis. Finally particular attention will be paid to the incidence of hypocitraturia and to the therapy with citrate salts, both in kidney stone disease and in osteopenia.
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Using the keywords "urolithiasis and citrate treatment", "nephrolithaisis and citrate treatment", "kidney stones and citrate treatment", a Medline search revealed 635 articles published between 1 January 1966 and 1 December 2004. For the present analysis, only studies meeting all of the following criteria were included: (1) publications in English or German, (2) studies on preventive alkali citrate treatment in patients with calcium oxalate, uric acid and infection stone disease, (3) clinical studies including at least ten subjects, and (4) treatment phases of at least 1 week duration. A total of 43 studies met the inclusion criteria and were further subclassified according to intermediate or ultimate endpoints as well as to study design. With stone recurrence as the ultimate endpoint, 21 uncontrolled studies in almost 1,000 patients demonstrated a reduction in stone forming rate by 47-100%. In four randomized controlled trials including 227 patients, 53.5% on alkali citrate vs 35% on placebo remained stone-free after at least 1 year of treatment (P<0.0005). Similar values (66% vs 27.5% for alkali citrate vs placebo, P<0.0005) were obtained in 104 patients from two randomized trials with dissolution/clearance of residual stones as endpoint. Unfortunately, up to 48% of alkali citrate treated patients left the studies prematurely, primarily due to adverse effects such as eructation, bloating, gaseousness or frank diarrhea.
Article
Previous studies have described the inhibitory effects of citrate on calcium oxalate crystallization in place of crystal growth, but the effects of citrate on matrix proteins of stones has not been studied in vivo. To examine the effect of citrate on the matrix, we investigated the effect of citrate on osteopontin (OPN) expression, which we had previously identified as an important stone matrix protein. Control rats were treated with saline while rats of the stone group were treated with ethylene glycol (EG) and vitamin D3, and the citrate groups (low-dose and high-dose groups) were treated with a citrate reagent compound of sodium citrate and potassium citrate, in addition to EG and vitamin D3. The rate of renal stone formation was lower in the citrate groups than in the stone group. This was associated with a low expression of OPN mRNA in citrate-treated rats relative to that in the stone group. Citrate was effective in preventing calcium oxalate stone formation and reduced OPN expression in rats. Our results suggest that citrate prevents renal stone formation by acting against not only the crystal aggregation and growth of calcium oxalate but also OPN expression.
Article
Gastrointestinal absorption of citrate was measured in stone patients with idiopathic hypocitraturia to determine if citrate malabsorption could account for low urinary citrate. Citrate absorption was measured directly from recovery of orally administered potassium citrate (40 mEq.) in the intestinal lavage fluid, using an intestinal washout technique. In 7 stone patients citrate absorption, serum citrate levels, peak citrate concentration in serum and area under the curve were not significantly different from those of 7 normal subjects. Citrate absorption was rapid and efficient in both groups, with 96 to 98% absorbed within 3 hours. The absorption of citrate was less efficient from a tablet preparation of potassium citrate than from a liquid preparation, probably due to a delayed release of citrate from wax matrix. However, citrate absorption from solid potassium citrate was still high at 91%, compared to 98% for a liquid preparation. Thus, hypocitraturia is unlikely to be due to an impaired gastrointestinal absorption of citrate in stone patients without overt bowel disease.
Article
Chronic K depletion (KD) causes hypocitraturia. In the present studies, the effect of KD, induced by a low-K diet for 14 days (serum [K] 4.1 +- 0.1, control vs. 2.2 +/- 0.1 meq/l, KD, P less than 0.01), on renal cortical brush-border membrane (BBM) Na-citrate cotransporter activity was examined. KD significantly decreased fractional citrate excretion (3.90 +/- 0.68 vs. 0.53 +/- 0.10%, P less than 0.01). This was paralleled by a significant increase in the initial linear rate of BBM Na-dependent citrate transport (81 +/- 4 vs. 141 +/- 6 pmol citrate.5 s-1.mg protein-1, P less than 0.01). Kinetic studies varying extravesicular citrate concentration demonstrated that KD increased the maximal activity (Vmax) (152 +/- 17 vs. 296 +/- 14 pmol citrate.5 s-1.mg protein-1, P less than 0.01) with no difference in citrate affinity (118 +/- 23, control vs. 135 +/- 22 microM citrate, KD). Similarly, when extravesicular Na concentration was varied, KD increased the Vmax (132 +/- 9 vs. 206 +/- 6 pmol citrate.5 s-1.mg protein-1, P less than 0.01) with no difference in Na affinity (29 +/- 3, control vs. 28 +/- 1 mM Na, KD). The effect of KD on Na-citrate cotransport was specific in that KD did not alter Na-glucose (84 +/- 12, control vs. 89 +/- 5 pmol glucose.5 s-1.mg protein-1, KD) or Na-proline (87 +/- 3, control vs. 84 +/- 5 pmol proline.5 s-1.mg protein-1, KD) cotransport. In conclusion, KD increases the Vmax of the proximal tubule apical membrane Na-citrate cotransporter.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
Mechanisms for the citraturic response to potassium citrate treatment were sought by assessing renal citrate clearance and acid-base status after oral administration of potassium citrate, potassium bicarbonate, and potassium chloride. After 2 weeks of treatment of eight patients with stones at a dose of 80 meq/day, urinary citrate rose significantly from 2.5 +/- 1.6 mmol/day (no drug) to 5.1 +/- 1.7 mmol/day with potassium citrate and to 4.5 +/- 1.5 mmol/day with potassium bicarbonate (P less than 0.05), but did not change significantly with potassium chloride. Citrate clearance increased from 8.0 to 27.4 mL/min with potassium citrate and 25.8 mL/min with potassium bicarbonate (P less than 0.05), but did not increase with potassium chloride. Both potassium citrate and potassium bicarbonate significantly raised urinary bicarbonate and decreased urinary ammonium, titratable acid, and net acid excretion. Potassium chloride was without effect. Effects of potassium citrate on urinary citrate, citrate clearance, and acid-base status tended to be more prominent than those of potassium bicarbonate, but these changes were not significant. Thus, the citraturic action of potassium citrate is largely accountable for by provision of an alkali load. Potassium itself had no effect in the absence of potassium deficiency.
Article
Citrate is pathogenetically important in stone formation, because it retards the crystallization of stone-forming calcium salts and because its level in urine is low in many patients with nephrolithiasis. Potassium citrate is useful therapeutically, because it can often restore normal urinary citrate. Hypocitraturia often results from dietary aberrations, including sodium excess, and exaggerated intake of animal proteins. Hypocitraturia is frequently accompanied by a low net gastrointestinal absorption of alkali. New drugs are under development as improvements or refinements of currently available potassium citrate. They are potassium citrate 10-mEq-tablet preparation, effervescent calcium citrate, and potassium-magnesium citrate.
Article
Each of 92 patients in a Swedish district served by only one hospital had been treated for their first renal stone in 1977 and was evaluated 10 years later. Recurrent stone formation during the observation period was observed in 26% of the patients, with no difference between men and women. Of all the patients who had sought medical advice in 1977 because of urinary stone colic, 51% were experiencing their first stone episode. Ten years later 37% of the original patients were still classified as single stone formers. The recorded recurrence rate was lower than that previously reported in the literature.
Article
Intracellular citrate is a central component of the tricarboxylic acid cycle; its excretion in the urine was utilized by Krebs and coworkers to demonstrate this biochemical pathway in whole animals. Subsequently, urinary citrate has been viewed as a “window” on renal metabolism [1]. Additionally, renal physiologists and biochemists have been intrigued for decades by the dramatic changes in urinary citrate which occur with changes in acid-base homeostasis. In recent years, renal handling of citrate and citrate excretion in the urine have attracted renewed interest because of several considerations. First, modern techniques in renal physiology (such as, transport studies in brush border membrane vesicles and perfused proximal tubules) have provided insights into the cellular and molecular mechanisms of citrate transport [2]. Also, excretion of urinary citrate (and other organic anions) has been recognized to influence systemic acid-base status, at least in certain species [3]. And perhaps most importantly, urinary citrate has been increasingly recognized as an important endogenous inhibitor of calcium nephrolithiasis [4]. This review will focus on the renal handling of citrate, particularly the mechanisms of citrate transport in the proximal tubule, and briefly discuss other aspects of citrate metabolism.
Article
The study was carried out in order to investigate citrate metabolism (i.e. serum levels, filtered load, tubular reabsorption, total and fasting urinary excretion) in a large group of normal subjects (n = 39) and kidney stone patients (n = 45). We found that mean serum citrate levels and filtered loads were similar in the two groups studied. On the other hand, both the 24-hour urinary citrate and the fasting citrate/creatinine ratio were significantly reduced, whereas the mean tubular reabsorption of citrate appeared to be significantly increased in kidney stone patients in respect to control subjects. A good correlation was found between the fasting and the 24-hour citrate/creatinine ratio in both normal subjects (r = 0.84, p less than 0.001) and kidney stone patients (r = 0.89, p less than 0.001). Our data indicate that the kidney appears to be involved in the pathogenesis of hypocitraturia in kidney stone patients and that a substantial proportion of these patients show a reduced urinary excretion of citrate. Finally, the evaluation of the fasting citrate/creatinine ratio may replace the measurement of the substance on the basis of a 24-hour urine collection.
Article
Among patients with urolithiasis, the recurrence rate is 10-23% per year. We have applied guidelines for critical appraisal to 46 publications addressing the efficacy of thiazides, orthophosphates, cellulose phosphate, allopurinol, magnesium and citrate as prophylaxis against recurrent urolithiasis. The 34 studies which do not have a randomly allocated control group are subject to methodologic deficiencies such as co-intervention, variable outcome measures, variable natural history, statistical regression to the mean, selection bias and incomplete follow-up of patients. These deficiencies make conclusions regarding the efficacy of an intervention suspect. Among the 12 randomized clinical trials are 5 thiazide, 2 orthophosphate, 4 allopurinol and 1 magnesium intervention. The methodologic and statistical questions addressed were: adequacy of randomization, clinical relevance of outcomes, description of patients, clinical and statistical significance, and completeness of follow-up. Based on these methodologic considerations, one could not conclude that orthophosphates, cellulose phosphate, magnesium or citrate were efficacious in preventing recurrent urolithiasis. Two of the 5 thiazide and 1 of the 4 allopurinol randomized clinical trials demonstrate convincing evidence for efficacy of these interventions. With the exception of pilot studies of new interventions, conclusions about efficacy of interventions claimed to decrease the urolithiasis recurrence rate should be based on methodologically sound randomized clinical trials.
Article
Fasting in rats decreases plasma citrate levels and reduces urinary citrate excretion by the kidney. After 72 h of fasting, the endogenous renal citrate clearance was decreased and the fractional citrate excretion was 0.026 +/- 0.008 compared with 0.218 +/- 0.030 in control fed rats. To determine whether these findings result from an adaptation in citrate transport across the plasma membrane of the renal tubular cell, Na+ gradient-dependent [14C]citrate uptake was examined in brush-border membrane vesicles (BBMW) prepared from kidneys of fed and 72-h fasted rats. The initial rate (10 s) of Na+ gradient-stimulated uptake of 100 microM citrate was significantly increased in BBMW from kidneys of fasted rats (380 +/- 24.9 pmol/mg prot) compared with fed rats (255 +/- 24.9 pmol/mg prot). Arterial acid-base parameters from conscious animals were similar between the two groups. There was no significant difference in Na+-independent citrate uptake or in L-glutamine uptake measured at 20 s in BBMV from the kidneys of fasted compared with fed rats. An adaptation occurs in the brush-border membrane of the renal tubular cell of fasting rats, unrelated to systemic acidosis, that may result in increased reabsorption of citrate.
Article
It generally is believed that conservative measures of high fluid intake and dietary modification in the setting of a stone clinic could favorably influence the course of renal stone disease. To establish the effect of specific medical treatment from the stone clinic effect, we compared the results of potassium citrate therapy to those of 11 reported conservative or placebo trials. The 54 patients receiving potassium citrate chosen for this comparison had mild to moderately severe stone disease (less than 1 stone per patient per year), similar to that encountered in conservative placebo trials (mean 0.54 stones per patient per year). New stone formation was virtually eliminated by potassium citrate therapy (a decrease from 0.52 to 0.02 stones per patient per year, a remission rate of 96 per cent, p less than 0.001), whereas it continued in 39 per cent of the patients during conservative or placebo trials. However, in patients participating in conservative or placebo trials new stone formation decreased by only 54 per cent (from 0.54 to 0.25 stones per patient per year). The superior response to potassium citrate suggested that this specific medical treatment exerted an additional favorable effect on the course of stone disease above the stone clinic effect.
Article
Several investigators have reported that hypocitraturia is frequent in patients with idiopathic kidney stones. In these studies, however, glomerular filtration rate, urinary tract infection, sex, diet, time of day, and medications, all potentially influential variables, were uncontrolled. Fifteen men, aged 30-52 yr, with recurrent idiopathic calcium oxalate stones and 15 normal age-matched men were studied. Patients with hyperparathyroidism, renal tubular acidosis, reduced creatinine clearance (less than 80 ml . min/1.73 M2), or urinary infection were excluded. Medications were stopped 2 weeks before the study began. A standard constant diet, furnishing 800 mg calcium and free of citrate, was fed for 20 days. During the last 10 days, 4.5 g sodium citrate were given orally. Eight-hour collections of urine were analyzed for calcium and citrate. Filtered load and net tubular reabsorption of citrate were also calculated. The 24-h urinary excretion of calcium was elevated in eight stone formers, and citrate excretion was depressed in seven. Five patients were both hypercalciuric anc hypocitraturic. The hypocitraturia resulted from excessive net tubular reabsorption of a normal filtered load of citrate. Urinary citrate was highest between 0800-1600 h, whereas calcium was highest between 1600-2400 h; both components were lowest between 2400-0800 h. The diurnal profiles of urinary calcium and citrate were similar in the stone formers and in the normal men. Oral sodium citrate did not influence urinary citrate in either group. These data suggest that in adult men, hypocitraturia may be a common predisposing factor for calcific nephrolithiasis.
Article
Citrate is an inhibitor of the crystallization of stone-forming calcium salts. Hypocitraturia, frequently encountered in patients with nephrolithiasis, is therefore an important risk factor for stone formation. Potassium citrate provides physiological and physicochemical correction and inhibits new stone formation, not only in hypocitraturic calcium nephrolithiasis but also in uric acid nephrolithiasis. Inhibition of stone recurrence has now been validated by a randomized trial. Ongoing research has disclosed additional causes of hypocitraturia (sodium excess, low intestinal alkali absorption, but not primary citrate malabsorption). Moreover, new insights on potassium citrate action have been shown, notably that some of absorbed citrate escapes oxidation and contributes to the citraturic response, that ingestion with a meal does not sacrifice physiological or physicochemical action, that orange juice mimics but does not completely duplicate its actions, that potassium citrate may have a beneficial bone-sparing effect, that it may reduce stone fragments following ESWL, and that danger of aluminum toxicity is not great in subjects with functioning kidneys. Finally, the research on potassium citrate has led to two promising products, calcium citrate as an optimum calcium supplement and potassium-magnesium citrate which may be superior to potassium citrate in the management of stone disease.
Article
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.
Article
We measured the effects of Tamm-Horsfall glycoprotein (THP) on calcium oxalate monohydrate (COM) crystal aggregation (Ac) in vitro as well as intrinsic viscosities (Vi) of THP at pH 5.7 and 200 mM NaCl and studied the effects of calcium and citrate on these parameters. THP were isolated from 24-h urines of seven male recurrent calcium stone formers (RCSF) and eight age-matched male healthy volunteers (N, normal). At basal conditions, RCSF-THP inhibited Ac by 28 +/- 10% and normal THP by 60 +/- 6% (P = 0.028). In the presence of calcium, increasing THP concentrations from 16 to 28 and 40 mg/l progressively lowered inhibition by RCSF-THP, but not by N-THP. At 40 mg/l, inhibition by N-THP was 27 +/- 9% vs. -43 +/- 8% by RCSF-THP (P = 0.001), i.e., all stone former THP promoted Ac. With an additional 3.5 mM of citrate, inhibition of Ac was 56 +/- 5% by normal and 34 +/- 6% by stone former THP (P = 0.021), and all seven stone former THP again inhibited Ac. Vi of RCSF-THP was higher than that of N at basal conditions (162 +/- 21 vs. 93 +/- 15 ml/g, P = 0.021) and in the presence of 5 mM calcium (352 +/- 54 vs. 118 +/- 17 ml/g, P = 0.001), i.e., RCSF-THP were more self-aggregated, but not when citrate was added (185 +/- 29 vs. 123 +/- 19 ml/g). (ABSTRACT TRUNCATED AT 250 WORDS)
Article
The role of net gastrointestinal (GI) alkali absorption in the development of hypocitraturia was investigated. The net GI absorption of alkali was estimated from the difference between simple urinary cations (Ca, Mg, Na, and K) and anions (Cl and P). In 131 normal subjects, the 24 h urinary citrate was positively correlated with the net GI absorption of alkali (r = 0.49, p < 0.001). In 11 patients with distal renal tubular acidosis (RTA), urinary citrate excretion was subnormal relative to net GI alkali absorption, with data from most patients residing outside the 95% confidence ellipse described for normal subjects. However, the normal relationship between urinary citrate and net absorbed alkali was maintained in 11 patients with chronic diarrheal syndrome (CDS) and in 124 stone-forming patients devoid of RTA or CDS, half of whom had "idiopathic" hypocitraturia. The 18 stone-forming patients without RTA or CDS received potassium citrate (30-60 mEq/day). Both urinary citrate and net GI alkali absorption increased, yielding a significantly positive correlation (r = 0.62, p < 0.0001), with the slope indistinguishable from that of normal subjects. Thus, urinary citrate was normally dependent on the net GI absorption of alkali. This dependence was less marked in RTA, confirming the renal origin of hypocitraturia. However, the normal dependence was maintained in CDS and in idiopathic hypocitraturia, suggesting that reduced citrate excretion was largely dietary in origin as a result of low net alkali absorption (from a probable relative deficiency of vegetables and fruits or a relative excess of animal proteins).
Article
Objective: To assess the influence of previous stone formation, urine and stone composition on the further course of the disease in recurrent calcium stone formers without pharmacological treatment. Method: The course of the disease was analysed during a prospective follow-up period by means of Kaplan-Meier estimates. At the start of follow-up the patients were subgrouped with regard to their previous history of stone formation expressed as stone age index (SAI = 100 x number of stones/age), urine composition, stone composition, and sex. In 223 of the patients was it possible to calculate AP(CaOx) index(s), a standardized estimate of the ion-activity product of calcium oxalate. Results: The 446 patients (329 men, 117 women) who were considered representative of an average population of recurrent calcium stone formers, had a 5-year recurrence risk of approximately 50%. Patients with an SAI <2 had a lower recurrence risk than those with an SAI >2 and a corresponding difference was recorded between patients with SAI levels <5 and >5. Furthermore, female patients had a lower risk of new stone formation than male patients. Patients with an AP(CaOx) index(s) of 1.5 or more had a significantly higher recurrence risk than those with a lower index, a difference that was most pronounced in female stone formers. A slightly higher risk of recurrent stone formation during the follow-up period could also be related to the presence of calcium phosphate in the stone, a high AP(CaP) index(s) (a standardized estimate of the ion-activity product of calcium phosphate) and a low concentration of citrate. Conclusion: AP(CaOx) index(s) and SAI were the most obvious predictors of the recurrence risk and these two variables, together with information on the sex distribution, might be useful for deriving an expected recurrence risk at a defined point of time in a group of recurrent stone formers. Such an estimate can be valuable for conclusions on the efficacy of different stone-preventive treatments when an appropriate control group is lacking.
Article
The knowledge of the natural history (i.e. the course of the disease without metaphylaxis is the base for establishing rational guidelines for metaphylaxis in urolithiasis. This review is based on a Medlinetrade mark Search (1966-1999) and the proceedings of the Bonn-Vienna and European symposia on urolithiasis. Only 31 references were sufficient for the purpose of this review. In idiopathic calcium stone disease, stone frequency without metaphylaxis is 0.10-0.15 stones per patient per year. The average recurrence rate is 30-40%. Recurrence rate increases with age and observation time. Risk for recurrence is highest during the first 4 years after the first stone episode. More than 50% of all recurrent stone formers have only one recurrence during their lives. 10% of recurrent stone formers have more than 3 recurrences. Risk factors for recurrence are: male sex, multiple and lower calyx stones, early onset, familial history, complications after stone removal. Metabolic evaluation is a poor predictor of the risk for recurrence. Renunciation of metaphylaxis is justified in first stone formers with idiopathic calcium oxalate and apatite stones. All patients, however, should be advised to increase their fluid intake.
Article
Urinary citrate is a potent inhibitor of renal stone formation. Its excretion is regulated by Na(+)/dicarboxylate cotransporter-1 (NaDC-1), which is expressed on the apical membrane of renal proximal tubules. Many patients with calcium urolithiasis exhibit hypocitraturia, however, the mechanisms are not perfectly understood. We examined whether or not the I550V polymorphism in human NaDC-1 gene (hNaDC-1) influenced urinary citrate excretion. I550V polymorphism was investigated in 105 patients with recurrent renal calcium stone formation (RSF) and 107 age-matched healthy volunteers with non-renal stone formation (NSF), using polymerase chain reaction (PCR) restriction fragment length polymorphism analysis and two 24-h urine samples. Overall and in the RSF groups, subjects with a BB (homozygous for the digested Bcl-I allele) genotype exhibited a significantly lower urinary citrate excretion level than subjects with a bb (homozygous for the undigested allele) genotype. Genotype distributions between subjects with hypocitraturia and normocitraturia were significantly different, with the BB genotype being more frequently observed in subjects with hypocitraturia - both overall and in each of the RSF and NSF groups. Although the BB genotype was observed more frequently in the RSF group than in the NSF group, no statistical differences among the distributions of the three genotypes (BB, Bb [heterozygous] and bb) were observed between the RSF and NSF groups. These results suggest that the B allele of I550V polymorphism of hNaDC-1 may be associated with a reduction in urinary citrate excretion and contribute to hypocitraturia in recurrent renal stone formers.
Article
The present study was performed to examine the efficacy of a selective treatment according to the guidelines for the prevention of recurrence in calcium oxalate stone patients and to assess risk factors for stone recurrence. To investigate the effect of specific diagnostic and therapeutic measures, 134 recurrent calcium oxalate stone formers participated in a prospective study for two years with regular follow-ups of at least every six months. Depending on the results of analysis of 24-hour urine, nutrition record and metabolic situation, selective recommendations were given concerning diet and medication. Throughout the follow-up period, 57 (43%) of the patients experienced relapses. In recurrence-free patients, the significant increase in urinary volume, as well as urinary pH, potassium and citrate excretion, three indexes of compliance with alkalization, resulted in a significant decrease in the calculated risk of calcium oxalate stone formation. In patients with recurrences during follow-up, the relative supersaturation with calcium oxalate increased significantly, mainly due to the significant rise in urinary oxalate excretion exceeding the significant increases in urinary volume, pH, potassium and citrate excretion. Multiple logistic regression analysis revealed previous ESWL treatment and a history of multiple stones as independent predictors of the risk for recurrence. The results indicate that compliance with drinking advice and alkalization therapy was highest among both, patients with and without recurrences, compared with all other therapeutic measures. The increase in oxalate excretion is identified as the major urinary risk factor for relapse during follow-up in recurrent calcium oxalate stone disease.
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