Alkali action on the urinary crystallization of calcium salts: contrasting responses to sodium citrate and potassium citrate

Alkali therapy is used commonly to prevent recurrent stone formation in patients with distal renal tubular acidosis. We compared the effects of potassium citrate to those of sodium citrate in 6 well defined cases of incomplete distal renal tubular acidosis. The patients were studied during a control phase, during potassium citrate treatment (80 mEq. per day) and during sodium citrate treatment (80 mEq. per day) chosen in random order. Potassium citrate caused a decrease in urinary calcium and a significant increase in urinary citrate that resulted in a significant decrease in the urinary saturation of calcium oxalate. It did not alter the saturation of brushite and sodium urate. However, while sodium citrate also was able to increase the urinary citrate level, there was no decrease in the urinary calcium (owing to the increased sodium load). Thus, the urinary saturation of calcium oxalate did not decrease as much as with potassium citrate and the saturation of brushite increased significantly. Moreover, the urinary saturation of sodium urate increased significantly owing to the enhanced sodium excretion. The results suggest that potassium citrate therapy may retard the crystallization of calcium oxalate and may not cause calcium phosphate crystallization. In contrast, sodium citrate may have no effect or it sometimes may accentuate the crystallization of calcium salts. Thus, our study supports the potential clinical advantage of potassium citrate therapy over sodium alkali treatment in patients with incomplete distal renal tubular acidosis and recurrent calcium nephrolithiasis.     

Prevention of recurrent calcium stone formation with potassium citrate therapy in patients with distal renal tubular acidosis

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.     

Effect of chronic respiratory acidosis on urinary calcium excretion in the dog

It is currently believed that the two chronic acidemic disorders exert disparate effects on urinary calcium excretion: chronic metabolic acidosis induces consistent hypercalciuria, but no appreciable change or even a decrease in calcium excretion is reported to attend chronic respiratory acidosis. Whereas the effect of metabolic acidosis is well documented, little work has been carried out in chronic hypercapnia. In fact, most of the studies on chronic respiratory acidosis were short in duration, had employed only mild hypercapnia, or had failed to control carefully the prevailing metabolic conditions. We have carried out balance observations in nine dogs exposed to a 10% CO2 atmosphere in an environmental chamber for a period of two weeks. Chronic respiratory acidosis led to a significant increase in urinary calcium excretion from a mean control value of 0.4 +/- 0.1 mmol/day to 0.6 +/- 0.1 mmol/day during both week 1 and 2 of hypercapnia (P less than 0.05). Hypercalciuria occurred even though filtered load of calcium fell. Mean fractional excretion of calcium increased significantly during each week of hypercapnia averaging 0.60 +/- 0.12% during control, 1.05 +/- 0.13% during week 1, and 1.26 +/- 0.17% during week 2 of hypercapnic exposure (P less than 0.05). There were no changes in plasma levels of immunoreactive parathyroid hormone or 1,25-dihydroxyvitamin D3. These findings suggest that chronic respiratory acidosis, just like chronic metabolic acidosis, augments urinary calcium excretion by a direct depressive effect on the tubular reabsorption of calcium.     

Relationship between metabolic acidosis and calcium phosphate urinary stone formation in women

The relationship between the degree of metabolic acidosis and calcium phosphate stone formation was studied. Furthermore, the reasons why renal tubular acidosis (RTA) and primary hyperparathyroidism (PHPT) dominantly occur in women, and female stone formers more often produce calcium phosphate stone are discussed. Blood was slightly more acidotic in women than in men in both the urolithiasis and the control groups. Likewise, blood was significantly more acidotic and urinary pH significantly higher in patients with PHPT. Patients with RTA had severe metabolic acidosis, and urinary pH was highest among all groups. Calcium phosphate concentration was significantly higher in women than in men, and was also higher in patients with PHPT than in those with urolithiasis. All patients with RTA had pure calcium phosphate stones. The reasons why females are more acidotic and have more calcium phosphate in stones are suspected to be related to progesterone and urinary tract infection.     

Development of metaphylaxis in calcium urolithiasis: A restriction of conventional drug therapy

Between 1978 and 1992 (mean 9.2 years), metaphylaxis was introduced to 110 patients originally hospitalized for recurrent urinary calcium stones (mostly bilateral or multiple). Patients with hyperparathyroidism or with sponge kidney were excluded from the study. Until 1984, the condition had been treated mostly using conventional drug metaphylaxis (thiazides and allopurinol in 75% and 57%, respectively). After that year, there was a gradual decrease in the number of patients treated with thiazides (to 15%) and allopurinol (to 10%). This was associated with a steep rise in the proportion of patients treated with inhibitors (magnesium to 36% and citrates to 30%), or exclusively with non-medicamentous therapy (to 31%). These fundamental changes in approach have not reduced the effectiveness of metaphylaxis, and recurrence rates in individual years have not changed significantly either. Metaphylaxis was successful in 105 patients (95%) and the rate of recurrence has declined from 0.9 to 0.08 stones per year. The restriction of conventional drug metaphylaxis has entailed a marked decrease in the incidence of side effects of therapy and, consequently, a reduced need for follow-up tests and outpatient follow-up.     

Inhibitors of urinary stone formation in 40 recurrent stone formers

The excretion of four inhibitors of urinary stone formation (zinc, magnesium, citrates and glycosaminoglycans (GAG) was studied in 20 normal controls and 40 recurrent calcium stone formers who were placed on a fixed diet restricted in calcium, oxalates and purines. We were unable to show any abnormality in the excretion of Zn, Mg or GAG. In 11 patients, a low level of urinary citrate was a significant feature that was associated in most cases with a urinary pH value above 6. Citrate concentration (per litre) and output (per 24 h) were found to be lower than in the controls in 19 and 33% respectively of the determinations. The overall ratio of average urinary citrate concentration in patients and controls was 0.56, a figure in agreement with previous data.     

Alkali citrate for preventing recurrence of calcium oxalate stones

The use of alkali citrates for preventing the recurrence of calcium oxalate stones was investigated in two trials. In trial I, alkali citrates were given continuously for 18 months to 8 patients who had shown a tendency to recurrent stone formation. In trial II, 12 similar patients were given intermittent therapy for 12 months. The expected changes in urine chemistry were checked at intervals of 3 months. Recurrent stone formation (2 episodes) was observed in only 1 patient (in trial II) during alkali citrate administration; before therapy this patient had suffered an average of 10 attacks of stone formation annually. In the light of the experience gained in these trials, continuous administration of alkali citrates is recommended; the duration of treatment should be tailored to individual needs, but it should not be prolonged indefinitely. Besides having well-attested effectivity of stone prevention, this mode of therapy carries a relatively low incidence of side effects.     

Bone histology and bone mineral density after correction of acidosis in distal renal tubular acidosis

BACKGROUND: The association between chronic metabolic acidosis and alterations in bone cell functions has been demonstrated in vitro and in animal studies. However, the causal role of acidosis and the effects of alkaline therapy on bone histology and bone mineral density in chronic metabolic acidosis have never been systematically demonstrated in humans. This study was conducted to examine the alterations in bone mineral density and bone histology before and after correction of acidosis among patients with distal renal tubular acidosis (dRTA) METHODS: Correction of metabolic acidosis by potassium citrate was done in non-azotemic dRTA patients, 6 females and 4 males, who had never received long-term alkaline therapy before enrolling into this study. Blood chemistries, serum intact parathyroid hormone, and 24-hour urine collection for the determination of urinary calcium, phosphate, sodium, potassium, bone mineral density determination, and transiliac bone biopsy were done in all patients at baseline and after one year of potassium citrate therapy. RESULTS: Significant elevations in serum bicarbonate (16.5 +/- 3.0 vs. 24.6 +/- 2.8 mEq/L, P < 0.05) and urinary potassium excretion (35.2 +/- 7.9 vs. 55.4 +/-3.5 mEq/L, P < 0.05) were observed after potassium citrate therapy. No significant alterations in other serum and urine electrolytes were found after the therapy. Serum intact parathyroid hormone level was also significantly elevated after one year of treatment (12.8 +/- 7.3 vs. 26.2 +/- 8.7 pg/mL, P < 0.05). Bone formation rate was significantly suppressed at baseline and was normalized by the treatment (0.02 +/- 0.02 vs. 0.06 +/- 0.03 microm(3)/microm(2)/day, P < 0.05). There were non-significant elevations in trabecular bone volume, osteoblastic and osteoclastic numbers. Bone mineral densities in dRTA patients were also significantly decreased below normal values in most studied areas at baseline and were significantly elevated at the trochanter of femur (0.677 +/- 0.136 vs. 0.748 +/- 0.144 g/c m(2), P < 0.05) and total femur (0.898 +/- 0.166 vs. 0.976 +/- 0.154 g/c m(2), P < 0.05) after the treatment. CONCLUSIONS: This study demonstrates that alkaline therapy corrects abnormal bone cell function and elevates bone mineral density in dRTA patients, indicating the causal role of acidosis in the alterations of bone cell functions and reduction in bone mineral density. Parathyroid gland activity also may be involved in the adaptation of the body to chronic metabolic acidosis.     

远端肾小管酸中毒的诊断和治疗

报告远端肾小管酸中毒１６例，其中完全型２例，不完全型１４例。完全型有高氯低钾性酸中毒，不完全型无酸中毒，但氯化铵负荷试验阳性。在口服枸橼酸钾期间，两型均观察到尿钙明显降低，尿ｐＨ和枸橼酸显著升高，完全型代谢性酸中毒得到纠正。对远端肾小管酸中毒的诊断和治疗进行了讨论。     

Long-term treatment of calcium nephrolithiasis with potassium citrate

The long-term effects of potassium citrate therapy (usually 20 mEq. 3 times daily during 1 to 4.33 years) were examined in 89 patients with hypocitraturic calcium nephrolithiasis or uric acid lithiasis, with or without calcium nephrolithiasis. Hypocitraturia caused by renal tubular acidosis or chronic diarrheal syndrome was associated with other metabolic abnormalities, such as hypercalciuria or hyperuricosuria, or occurred alone. Potassium citrate therapy caused a sustained increase in urinary pH and potassium, and restored urinary citrate to normal levels. No substantial or significant changes occurred in urinary uric acid, oxalate, sodium or phosphorus levels, or total volume. Owing to these physiological changes, uric acid solubility increased, urinary saturation of calcium oxalate decreased and the propensity for spontaneous nucleation of calcium oxalate was reduced to normal. Therefore, the physicochemical environment of urine following treatment became less conducive to the crystallization of calcium oxalate or uric acid, since it stimulated that of normal subjects without stones. Commensurate with the aforementioned physiological and physicochemical changes the treatment produced clinical improvement, since individual stone formation decreased in 97.8 per cent of the patients, remission was obtained in 79.8 per cent and the need for surgical treatment of newly formed stones was eliminated. In patients with relapse after other treatment, such as thiazide, the addition of potassium citrate induced clinical improvement. Thus, our study provides physiological, physicochemical and clinical validation for the use of potassium citrate in the treatment of hypocitraturic calcium nephrolithiasis and uric acid lithiasis with or without calcium nephrolithiasis.     

Hyperchloremic acidosis and imperforate anus

The predominant electrolyte imbalance associated with enterourinary fistulas is hyperchloremic acidosis. The mechanism is the absorption of urinary electrolytes across the colonic mucosa. One of the genitourinary associated anomalies of a high imperforate anus is a rectourinary fistula. There have been 5 cases of hyperchloremic acidosis as a complication of an imperforate anus with a rectourinary fistula reported in the literature to date. An additional case is presented with a clinical analysis of the previously reported cases. The important factors in the development of hyperchloremic acidosis in patients with an imperforate anus are 1) the presence of a rectourinary fistula, 2) an initial diverting colostomy permitting a long segment of colonic mucosa for the absorption of urinary electrolytes, 3) distal urinary tract obstruction allowing significant volumes of urine to flow into the colonic segment and 4) the presence of urinary tract infection contributing to the urinary obstruction. Management should consist of vigorous electrolyte therapy, decreasing the retrograde flow of urine into the colon by temporary catheterization and early repair of the fistulous tract.     

Acid loading during treatment with sevelamer hydrochloride: mechanisms and clinical implications

Short-term and long-term studies indicate that patients treated with sevelamer hydrochloride have lower serum bicarbonate levels than patients treated with calcium-containing phosphate binders. This observation has previously been attributed to withdrawal of a source of base with discontinuation of calcium carbonate or calcium acetate. However, understanding of the chemistry of sevelamer hydrochloride suggests at least three potential mechanisms whereby it might induce a dietary acid load. Moreover, preliminary results from an animal model demonstrate that treatment with sevelamer hydrochloride results in a fall in urine pH, as well as an increase in urinary ammonium and calcium excretion consistent with an increase in net acid excretion. Chronic metabolic acidosis in maintenance dialysis patients is associated with major systemic effects. It is independently associated with an increased risk of death in dialysis patients. Metabolic acidosis has both catabolic and antianabolic effects that may lead to a net negative nitrogen balance and total body protein balance. Metabolic acidosis also leads to physiochemical dissolution of bone and promotes cell-mediated bone resorption due to enhanced osteoclast activity and reduced osteoblast activity. It may also exacerbate secondary hyperparathyroidism and renal osteodystrophy. Given the long-term risks of chronic metabolic acidosis in maintenance dialysis patients, Kidney/Dialysis Outcome Quality Initiative (K/DOQI) guidelines have recently recommended maintaining predialysis serum levels of CO2 above 22 mmol/L in order to improve bone histology, and to ameliorate excess protein catabolism.     

Acid-base status determines cyclosporine-induced hypercalciuria

OBJECTIVE: Cyclosporine (CsA) causes tubular dysfunction characterized by polyuria, calcium wasting, distal tubular acidosis, and hyperkalemia. The hypercalciuria induced by CsA administration is associated with an inhibition of calbindin D(28k) expression. It has also been shown that chronic metabolic alkalosis increased the expression of Ca(2+) transport proteins accompanied by diminished urine Ca(2+) excretion. The aim of this study, therefore, was to determine the effect of acid-base status on CsA-induced hypercalciuria. METHODS: Experiments were performed on male Sprague-Dawley rats. Metabolic alkalosis and acidosis were induced respectively by adding 0.28 mol/L NaHCO(3) and 0.28 mol/L NH(4)Cl in the drinking water for 7 days; control rats received regular tap water. Seven days after NaHCO(3) or NH(4)Cl administration, rats were treated with CsA (25 mg/kg, IP) daily for 14 days. To estimate glomerular filtration rate (GFR) over time, animals were placed in metabolic cages. Fractional urinary calcium excretion was determined by standard formula. RESULTS: The CsA group showed decreased serum calcium and increased fractional urinary calcium excretion compared with the control group. Creatinine clearance was also significantly reduced. Metabolic alkalosis alone did not affect GFR, but significantly prevented an increase in fractional urinary calcium excretion induced by CsA, whereas chronic metabolic acidosis resulted in the exact opposite effect. CONCLUSIONS: It is essential for nephrologists to fully understand the mechanisms of CsA-induced renal injury. In this study, metabolic alkalosis reduced CsA-induced hypercalciuria. Further studies are needed to elucidate whether this effect may be achieved pharmacologically by the expression of Ca(2+) transport proteins.     

Metabolic acidosis after bladder replacement: comparison of severity and reversibility in ileal and colonic reservoirs

Metabolic acidosis developed frequently after ureterosigmoidostomy and rectosigmoid bladder construction but has been reported rarely after the newer methods of continent urinary diversion which also employ intestinal reservoirs. We created an animal model in which to compare the metabolic effects of bladder replacement with segments of ileum or colon and the potential for reversing these derangements with nicotinic acid and chlorpromazine. One year after six dogs' bladders were replaced by colon (three) or ileum (three), all dogs appeared in excellent health and were free of urinary tract obstruction and clinical infection. Both groups of dogs were severely acidotic with diminished arterial pH and arterial and venous total CO2 concentrations although normal serum electrolytes and creatinine concentrations were maintained. Both groups of dogs absorbed approximately one half the urinary sodium, chloride and urea presented to their intestinal reservoirs. After treatment with nicotinic acid and chlorpromazine, the metabolic status of both groups of animals improved. Although nicotinic acid reduced urinary excretion of electrolytes more effectively than chlorpromazine, nicotinic acid was not more effective for reversing metabolic acidosis. When nicotinic acid was provided as an adjunct to sodium bicarbonate therapy in two animals acidosis was corrected at reduced doses of sodium bicarbonate. Based upon this work in an animal model, there does not appear to be a metabolic advantage to intestinal reservoirs which incorporate ileum versus colon. However, asymptomatic patients with normal serum electrolytes and creatinine concentrations may be acidotic. The effects of long term mild acidosis are unknown. However, if therapy is required to prevent diminution of whole body buffers or changes in bone density specific therapy with nicotinic acid or chlorpromazine may reduce the requirement for alkali for correction of metabolic acidosis.     

Reversible low-molecular-weight proteinuria in patients with distal renal tubular acidosis

Four patients with untreated renal tubular acidosis had a urinary excretion of low-molecular-weight (LMW) proteins which was restored to normal by alkali therapy. Hypokalaemic proximal tubular damage in untreated patients with distal renal tubular acidosis is believed to be the cause of LMW proteinuria. An examination of urinary excretion of LMW proteins is useful for determining hypokalaemic proximal tubular dysfunction, as well as the efficiency of alkali therapy.     

Influence of dietary animal protein on renal stone disease

The effect of dietary protein load on the incidence of nephrolithiasis was studied in rats and men. Three groups of adult male Wister rats were fed with a standard protein diet, a high protein diet, or a low protein diet for 4 weeks. In the high protein group, calcium excretion was significantly increased and citrate excretion was remarkably decreased. This group also exhibited low grade metabolic acidosis due to catabolism of excess amino acids, and increases in urinary cyclic AMP excretion and bone resorption. These findings indicate that protein-induced hypercalciuria is due to low grade metabolic acidosis, which directly affects renal handling of calcium. Long-term calcium loss in the urine may lead to negative calcium balance and hyperfunction of the parathyroid gland may induce bone resorption. The influence of 40 g animal protein load on urinary risk factors of calcium stone formation was investigated in 23 healthy males and 26 patients with nephrolithiasis. All subjects were given control diets each day containing 60 g protein for a week and during the next week each received an additional 40 g animal protein. In the controls, added dietary protein resulted in decreased urinary citrate and increased urinary uric acid, with no change in urinary calcium or cyclic AMP excretion. In contrast, the patients showed increased urinary calcium and cyclic AMP as well as decreased urinary citrate. Further examination of the patients revealed that the significant increases of calcium and cyclic AMP excretion occurred only in hypercalciuric patients, who seemed to be classified into renal hypercalciuria.(ABSTRACT TRUNCATED AT 250 WORDS)     

Calcium metabolism in acidotic patients induced by carbonic anhydrase inhibitors: responses to citrate

Calcium metabolism and its response to citrate were examined in 51 patients with glaucoma receiving carbonic anhydrase inhibitors (acetazolamide or methazolamide). Metabolic acidosis, hypocitraturia and increased incidence of nephrolithiasis were induced by both drugs. However, the acidosis was milder with methazolamide administration. Normocalciuria was observed in 29 patients and was shown to be a result of low filtered calcium. Renal hypercalciuria in 16 patients was associated with elevated parathyroid hormone but nephrogenic cyclic adenosine monophosphate remained within normal limits. Citrate in the form of potassium citrate (4.3 mmol.) and sodium citrate (4.0 mmol.) did not correct the metabolic acidosis or hypocitraturia but consistently decreased fasting and 24-hour urinary calcium excretion in patients with renal hypercalciuria. This event did not occur in patients with normocalciuria or absorptive hypercalciuria. These results suggest that a small amount of citrate could reverse renal hypercalciuria without correcting the metabolic acidosis.     

Hypocitraturia as a pathogenic risk factor in the mixed (calcium oxalate/uric acid) renal stones.

A small group of patients with nephrolithiasis who forms mixed (calcium oxalate and uric acid) calculi presents particular problems in their clinical management. In 3,158 stones analyzed in our laboratory, we found 158 mixed calculi in 86 of the patients. In this work, the clinical and biochemical results obtained from 27 patients with mixed stones were compared with those from 27 control patients with calcium oxalate renal lithiasis. A significant difference was found in oxalate and citrate urinary elimination (mean +/- SD) in mixed stone formers versus pure calcium oxalate stone formers: oxaluria (mg/24 h: 38 +/- 15 vs. 28 +/- 12; p less than 0.01) and citraturia (mg/24 h: 214 +/- 139 vs. 437 +/- 303; p less than 0.01). Citraturia was decreased in a high proportion (77%) in mixed stone formers, and only a reduced percentage of them (23%) presented normal values, although in the low limit of normality. As treatment and prophylactic measure, we proposed oral administration of citrates in mixed stone patients because citrate inhibits spontaneous nucleation of calcium salts and crystal growth, and it also increases the urinary pH with a consequent increase in uric acid solubility.     

Life threatening hyperkalemia and acidosis secondary to trimethoprim-sulfamethoxazole treatment.

We present a 77-year-old male with moderate chronic renal insufficiency from diabetic nephropathy who developed severe metabolic acidosis and life threatening hyperkalemia on treatment with regular dose of trimethoprim-sulfamethoxazole (TMP-SMZ) for urinary tract infection. The metabolic acidosis and hyperkalemia resolved upon appropriate medical intervention and discontinuation of TMP-SMZ. While hyperkalemia has commonly been reported with high dose of TMP-SMZ, severe metabolic acidosis is quite uncommon with regular dose TMP-SMZ. We emphasize that patients with renal tubular acidosis (RTA), renal insufficiency, aldosterone deficiency, old age with reduced renal mass and function, and angiotensin converting enzyme (ACE)-inhibitor therapy are at high risk of developing these severe and potentially life threatening complications.     

The in-vivo effect of sodium-potassium citrate on the crystal growth rate of calcium oxalate and other parameters in human urine

Summary In this study, an efficient microtechnique (gel crystallization method) was used to investigate the in-vivo effect of sodium-potassium citrate on the crystal growth rate of calcium oxalate (Vcr) in human urine samples of 6 healthy volunteers. With a daily dose of 3x11 mmol of alkali citrate, Vcr decreased by 70%. This could have been due to the decrease of calcium excretion, which caused 50–60% of the total change, and to the increase of citrate and pH, each contributing about 20–25% to the decline of Vcr. The findings explain the clinical advantages of alkali citrates in the prevention of recurrent calcium oxalate stone formation.