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Prevention of Recurrent Calcium Stone Formation with Potassium Citrate Therapy in Patients with Distal Renal Tubular Acidosis
Abstract
Distal renal tubular acidosis is a common cause of intractable calcium nephrolithiasis. We examined the effect of oral potassium citrate therapy in 9 patients with incomplete distal renal tubular acidosis diagnosed on the basis of an abnormal response to an oral ammonium chloride load. Patients were studied during a control phase and after 3 months of potassium citrate treatment (60 to 80 mEq. daily). Potassium citrate caused a significant increase in urinary pH and urinary citrate, and a decrease in urinary calcium. The urinary relative saturation ratio of calcium oxalate significantly decreased during treatment, while that of brushite did not change. Potassium citrate also was shown to inhibit new stone formation. During a mean treatment period of 34 months none of the 9 patients had new stones, although 39.3 plus or minus 79.7 (standard deviation) stones per patient formed during the 3 years preceding treatment. The results support the potential clinical advantage of potassium citrate therapy in patients with distal renal tubular acidosis and recurrent calcium nephrolithiasis.
... In addition to plasma bicarbonate, efficacy can be inferred by calcium and citrate urine excretion. 67,[87][88][89] Systemic and intracellular MA promote tubular reabsorption of citrate; urinary excretion, therefore, increases when the MA is corrected. 88,90 A significant inverse linear regression has been shown between calciuria (mg/kg per day) and plasma bicarbonate; most patients moreover normalized urine calcium when plasma bicarbonate was .21 ...
The term classic, type I renal tubular acidosis (RTA) or primary distal RTA is used to designate patients with impaired ability to excrete acid normally in the urine as a result of tubular transport defects involving type A intercalated cells in the collecting duct. The clinical phenotype is largely characterized by the complications of chronic metabolic acidosis, stunted growth, bone abnormalities, as well as nephrocalcinosis and nephrolithiasis that develop as the consequence of hypercalciuria and hypocitraturia. All these manifestations are preventable with early and sustained correction of metabolic acidosis with alkali therapy. The optimal target for plasma bicarbonate should be as close as possible to the range considered normal by current standards (between 23 and 28 mEq/l.). Most of the benefits of alkali therapy are tangible early in the course of the disease in childhood, but life-long treatment is required to prevent the vast array of complications attributable to chronic metabolic acidosis.
... Potassium citrate is used for urinary alkalization and the treatment of chronic metabolic acidosis and has a quick and temporary effect on systemic acid-base status (Papich, 2016b). Results of several human medicine studies show that dietary potassium citrate supplementation given orally significantly increases urinary pH (Doizi et al., 2018;Pak et al., 1986;Preminger et al., 1985). In dogs, a dosage of 40-60 mg/kg BW every 8-12 h is recommended for an alkalinizing effect (Adams & Syme, 2010). ...
Background
Urinary pH manipulation by therapeutic foods or supplements is part of the treatment for urolithiasis. The effectiveness of these diets and supplements should be studied to determine which of these strategies is most effective.
Hypothesis/Objectives
To assess the effect of the oral supplementation of potassium citrate, an ammonium chloride solution (Urical) and two dry therapeutic foods—Hill's® Prescription Diet® u/d® Canine (u/d diet) and Royal Canin® Urinary S/O dog (S/O diet)—on a dog's urinary pH at different time points over 8 h.
Animals
Seven healthy adult male research beagle dogs.
Methods
A prospective interventional study lasting 31 days. The dogs either received a supplement (potassium citrate or rical) with a dry adult maintenance diet (control diet) or the therapeutic diet (u/d diet or S/O diet). Each treatment had a duration of 2–5 days, with 2‐ to 4‐day washout periods in between. Urinary pH measurements were performed every 2 h between 07h00 and 15h00, with the food being given at 07h00 and 15h00, right after urine collection. The pH measurements obtained in each of the four treatments were compared to control (same dogs fed the control diet exclusively).
Results
When compared to the control diet at the same time points, biologically relevant changes in urinary pH (defined as ≥0.5) were: increase with potassium citrate at 7h00 and 13h00; increase with u/d diet at 9h00, 13h00, and 15h00; decrease with S/O diet at 9h00 and 11h00; Urical did not have a detectable effect on urinary pH.
Conclusions and Clinical Importance
The present study confirms that therapeutic foods S/O and u/d, and potassium citrate supplement affected acid‐base balance in healthy adult male beagle dogs, with the tested diets being more effective than the administered doses of the tested supplements at influencing urinary pH.
... According to Hodgkinson, hypocitraturia is a unique urinary chemical disorder observed in kidney stone patients [18]. Several studies have demonstrated the effectiveness of potassium citrate in preventing urinary tract stones [19][20][21][22][23]. Based on the results of our study, citrates and pyridoxine can be beneficial in treating kidney stones with hypocitraturia. ...
... Systemic and/or intracellular acidosis leads to increased citrate reabsorption in the proximal tubule and reduced urinary citrate excretion. Long-term alkali therapy not only corrects the acid retention and normalizes urinary citrate and calcium, but also reduces clinical stone recurrences by more than fivefold [25,122]. ...
The aim of this study was to construct the fourth in a series of guidelines on the treatment of urolithiasis by the International Alliance of Urolithiasis (IAU) that by providing a clinical framework for the metabolic evaluation, prevention, and follow-up of patients with urolithiasis based on the best available published literature. All recommendations were summarized following a systematic review and assessment of the literature in the PubMed database from January 1976 to June 2022. Each generated recommendation was graded using a modified GRADE methodology. Guideline recommendations were developed that addressed the following topics: initial evaluation, metabolic testing, dietary measures, medical management, and follow-up of recurrent stone formers. It was emphasized by the Panel that prevention of new stone formation is as important as the surgical removal of the stones. Although general preventive measures may be effective in reducing stone recurrence rates in some patients, specific medical and dietary management should be well considered and eventually applied in an individualized manner based on the outcomes of metabolic work-up, stone analysis and some certain patient related factors. A detailed follow-up of each case is essential depending on the metabolic activity of each individual patient.
... Incomplete dRTA has been associated to recurrent calcium kidney stones in adults (50), nephrocalcinosis (50,51), as well as to osteopenia or osteoporosis (52)(53)(54). In these cases, alkali therapy has shown to reduce stone formation and increase bone mass (54,55). It has also been reported in sickle-cell disease (56), interstitial nephropathies (57) and autoimmune diseases [especially, Sjögren disease (58)]. ...
The kidney plays a fundamental role in acid-base homeostasis by reabsorbing the filtered bicarbonate and by generating new bicarbonate, to replace that consumed in the buffering of non-volatile acids, a process that leads to the acidification of urine and the excretion of ammonium (NH4+). Therefore, urine pH (UpH) and urinary NH4+ (UNH4+) are valuable parameters to assess urinary acidification. The adaptation of automated plasma NH4+ quantification methods to measure UNH4+ has proven to be an accurate and feasible technique, with diverse potential indications in clinical practice. Recently, reference values for spot urine NH4+/creatinine ratio in children have been published. UpH and UNH4+, aside from their classical application in the study of metabolic acidosis, have shown to be useful in the identification of incomplete distal renal tubular acidosis (dRTA), an acidification disorder, without overt metabolic acidosis, extensively described in adults, and barely known in children, in whom it has been found to be associated to hypocitraturia, congenital kidney abnormalities and growth impairment. In addition, a low UNH4+ in chronic kidney disease (CKD) is a risk factor for glomerular filtration decay and mortality in adults, even in the absence of overt metabolic acidosis. We here emphasize on the need of measuring UpH and UNH4+ in pediatric population, establishing reference values, as well as exploring their application in metabolic acidosis, CKD and disorders associated with incomplete dRTA, including growth retardation of unknown cause.
Renal tubular acidosis (RTA) can lead to renal calcification in children, which can cause various complications and impair renal function. This review provides pediatricians with a comprehensive understanding of the relationship between RTA and renal calcification, highlighting essential aspects for clinical management. The article analyzed relevant studies to explore the prevalence, risk factors, underlying mechanisms, and clinical implications of renal calcification in children with RTA. Results show that distal RTA (type 1) is particularly associated with nephrocalcinosis, which presents a higher risk of renal calcification. However, there are limitations to the existing literature, including a small number of studies, heterogeneity in methodologies, and potential publication bias. Longitudinal data and control groups are also lacking, which limits our understanding of long-term outcomes and optimal management strategies for children with RTA and renal calcification. Pediatricians play a crucial role in the early diagnosis and management of RTA to mitigate the risk of renal calcification and associated complications. In addition, alkaline therapy remains a cornerstone in the treatment of RTA, aimed at correcting the acid-base imbalance and reducing the formation of kidney stones. Therefore, early diagnosis and appropriate therapeutic interventions are paramount in preventing and managing renal calcification to preserve renal function and improve long-term outcomes for affected children. Further research with larger sample sizes and rigorous methodologies is needed to optimize the clinical approach to renal calcification in the context of RTA in the pediatric population.
A short ammonium chloride loading test was used in the investigation of renal acidification capacity of 51 patients with idiopathic recurrent renal stones containing calcium. Many of these patients had suffered from prolonged and severe stone disease. In 31% of the patients an impaired acidification with varying degrees of severity was found. Eight patients had defects suggesting distal renal tubular acidosis (RTA). One case with the complete and two cases with the incomplete form of RTA were found. A further five patients, who were all able to acidify their urine to an acid pH, had milder defects in the excretion of titratable acid and/or ammonium ions which may indicate an early stage of distal tubular acidosis. Six patients were suspected of having a proximal acidification defect, as they showed delayed responses to the ammonium chloride induced acidosis.
As earlier investigations of renal acidification capacity were poorly standardized it was considered important to develop a clinically useful method. The ability of the kidneys to acidify urine was studied in 19 normal persons by short ammonium chloride loading. Ammonium chloride was given in a dose of 150 mmol/m2 body surface in one of four different ways: whole tablets, crushed tablets, capsules and in solution. The degree of acidosis developed in each subject was measured in arterialized capillary blood samples. Urine was analysed for pH, titratable acid, ammonium ions (TA and NH4+) and phosphate. The excretion of TA, NH4+ and phosphate increased with the degree of acidosis in blood whilst urine pH decreased. The critical level appeared to lie around a base excess of -6 mmol/l below which all subjects could acidify their urine to a pH below 5.0. For clinical applications a frame of reference with tolerance limits is given for acidification capacity related to the degree of acidosis expressed as base excess.
A method is described for quantitatively determining the inhibitory activity of pure components, isolates, or mixtures of components (such as urine) on the growth of calcium oxalate crystals. Results with known calcium phosphate crystal growth inhibitors--magnesium, citrate, and pyrophosphate--suggest that these components contribute little to the ability to normal urine to inhibit the growth of calcium oxalate crystals. As yet unidentified urinary components seem to be responsible for most of this activity. The urinary crystal growth inhibitors appear to function by adsorbing on the surface of the growing crystals, thereby preventing the further incorporation of lattice ions. The fit of experimental data to the Langmuir absorption isotherm supports this conclusion.
The understanding of the formation of urinary stones centers around three main mechanisms: the urinary concentration of stone-forming ions, the role of promoters, and the role of inhibitors of crystal formation and crystal aggregation. With respect to the promoting activity, lately emphasis has shifted from the role of the organic matrix to that of one salt inducing by epitaxy the precipitation of another salt. Among the inhibitors, it has become necessary to distinguish between those affecting crystal formation and those affecting crystal aggregation. For measuring the inhibitory activity, the various techniques and their relevance have been reviewed. It has been found that the main inhibitors for calcium phosphate and calcium oxalate precipitation are citrate, pyrophosphate, and perhaps magnesium. Those for calcium phosphate and calcium oxalate aggregation are glycosaminoglycans, pyrophosphate, and citrate. Among the synthetic inhibitors, the diphosphonates are the most powerful for both processes. The role and the therapeutic implications of these various concepts have been discussed.
Clearance and micropuncture studies have been performed in dogs to examine the effects of acute and chronic metabolic acidosis and acute alkalosis on tubular sodium and calcium transport. Acute metabolic acidosis, induced by the infusion of hydrochloric acid, decreased proximal fluid reabsorption and increased the fractional delivery of sodium and calcium to the distal tubule, but not to the final urine. In comparison with normal dogs, dogs with chronic metabolic acidosis (induced by feeding ammonium chloride) showed an increase in proximal fluid reabsorption and a dissociation of calcium from sodium reabsorption more distally, leading to an increased delivery of calcium relative to sodium at the distal tubule and in the final urine. The infusion of sodium bicarbonate to correct chronic metabolic acidosis, both in intact and thyroparathyroidectomized (TPTX) dogs, reduced proximal fluid reabsorption and caused a selective enhancement of calcium reabsorption relative to sodium in the more distal nephron, resulting in a reversal of the dissociation observed in acidosis, both at the distal tubule and in the final urine. By contrastin fusion of sodium chloride in parathyroid-intact acidotic dogs did not reduce proximal fluid reabsorption or enhance tubular calcium reabsorption. In nonacidotic dogs, both intact and TPTX, infusion of sodium bicarconate to induce acute alkalosis resulted in selhese data demonstrate the presence of a component of tubular calcium reabsorption situated beyond the proximal tubule, which is inhibited by chronic (but not acute) metabolic acidosis and enhanced by metabolic alkalosis (or bicarbonate infusion) independently of parathyroid hormone.
A method is described for the determination of oxalic acid in 0.5 ml of urine. Oxalic acid is co-precipitated with calcium sulphate, reduced to glycollic acid by boiling with dilute sulphuric acid and a zinc pellet and estimated colorimetrically with chromotropic acid. Up to 12 samples can be conveniently analysed in a normal working day.Normal men excreted from 17 to 43 mg of (anhydrous) oxalic acid per day (mean = 30.9 mg). Normal women excreted similar amounts but children under 14 had lower values.These values, which agree well with results obtained by isotope dilution analysis, are generally higher than have been obtained previously by chemical methods and possible reasons for this difference are discussed.
Renal tubular function was studied in 318 consecutive recurrent renal stone formers. Impaired acidification capacity was found in 19% of the patients, and tubular proteinuria in 13% of the patients. Most of the patients with defective acidification of the urine had the incomplete form of renal tubular acidosis (RTA), rpoximal and distal defects being equally common. The incidence of impaired acidification was much higher in the female (38%) than in the male (13%) stone formers. A further analysis of the clinical picture in patients with acidification defects revealed a more severe stone disease than among other stone formers. Characteristic findings were an early onset, multiple recurrences were an increased need for surgery. Stone analyses showed a high frequency of calcium phosphate stones. Investigations of renal tubular functions appear to be a valuable adjunct in the evaluation of recurrent renal stone disease.
Using the ambulatory protocol previously described, 241 patients with nephrolithiasis were evaluated. They could be categorized into 10 groups from the results obtained. Absorptive hypercalciuria type I (87 per cent male) comprised 24.5 per cent and was characterized by normocalcemia, normal fasting urinary calcium (less than 0.11 mg/100 ml glomerular filtration), an exaggerated urinary calcium following an oral calcium load (greater than 0.20 mg/mg creatinine), normal urinary cyclic adenosine monophosphate (AMP) (less than 5.4 nmol/100 ml glomerular filtration) and serum parathyroid hormone (PTH), and hypercalciuria (greater than 200 mg/day during a calcium- and sodium-restricted diet). Absorptive hypercalciuria type II (50 per cent male) accounted for 29.8 per cent; its biochemical features were the same as those for absorptive hypercalciuria type I, except for normocalciuria during a restricted diet and low urine volume (1.42 +/- 0.55 SD liter/day). Renal hypercalciuria (56 per cent male), disclosed in 8.3 per cent, was represented by normocalcemia and high values for fasting urinary calcium (0.160 +/- 0.054 mg/100 ml glomerular filtration), urinary cyclic AMP (6.80 +/- 2.10 nmol/100 ml glomerular filtration) and serum PTH. Primary hyperparathyroidism (57 per cent female), accounted for 5.8 per cent, typically included hypercalcemia, hypophosphatemia, hypercalciuria and high urinary cyclic AMP. Hyperuricosuric calcium urolithiasis (100 per cent male) comprised 8.7 per cent, and was characterized by hyperuricosuria (776 +/- 164 mg/day) and urinary pH exceeding pK for uric acid (5.91 +/- 0.33). In enteric hyperoxaluria (60 per cent female), encountered in 2.1 per cent of cases, urinary oxalate was increased (6.29 +/- 13.2 mg/day). Noncalcium-containing stones were found in 2.1 per cent of the patients with uric acid lithiasis (100 per cent male) and in another 2.1 per cent of the patients with infection lithiasis (60 per cent female). These conditions were typified by low urinary pH (5.29 +/- 0.12) and high urinary pH (6.69 +/- 1.16), respectively. Renal tubular acidosis was found in one patient (male, 0.4 per cent). In 10.8 per cent of the patients (81 per cent male), no metabolic abnormality could be found, although urine volume was low (1.41 +/- 0.51 liter/day). Hypercalciuria could not be differentiated between absorptive hypercalciuria and renal hypercalciuria in 5.4 per cent of the patients. Thus, this ambulatory protocol disclosed a physiologic disturbance in nearly 90 per cent of the cases and provided a definitive diagnosis in 95 per cent of the patients.