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.     

Defining hypercalciuria in nephrolithiasis

The classic definition of hypercalciuria, an upper normal limit of 200 mg/day, is based on a constant diet restricted in calcium, sodium, and animal protein; however, random diet data challenge this. Here our retrospective study determined the validity of the classic definition of hypercalciuria by comparing data from 39 publications analyzing urinary calcium excretion on a constant restricted diet and testing whether hypercalciuria could be defined when extraneous dietary influences were controlled. These papers encompassed 300 non-stone-forming patients, 208 patients with absorptive hypercalciuria type I (presumed due to high intestinal calcium absorption), and 234 stone formers without absorptive hypercalciuria; all evaluated on a constant restricted diet. In non-stone formers, the mean urinary calcium was well below 200 mg/day, and the mean for all patients was 127±46 mg/day with an upper limit of 219 mg/day. In absorptive hypercalciuria type I, the mean urinary calcium significantly exceeded 200 mg/day in all studies with a combined mean of 259±55 mg/day. Receiver operating characteristic curve analysis showed the optimal cutoff point for urinary calcium excretion was 172 mg/day on a restricted diet, a value that approximates the traditional limit of 200 mg/day. Thus, on a restricted diet, a clear demarcation was seen between urinary calcium excretion of kidney stone formers with absorptive hypercalciuria type I and normal individuals. When dietary variables are controlled, the classic definition of hypercalciuria of nephrolithiasis appears valid.     

Low urinary citrate excretion in nephrolithiasis

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.     

Lack of effect of prostaglandin inhibition on calcium excretion in normal volunteers

Recent data have shown that administration of indomethacin to patients with hypercalciuric nephrolithiasis decreased urinary calcium excretion, implying a possible pathogenic role for renal prostaglandins in hypercalciuria. To explore this hypothesis we administered indomethacin, ketoprofen and aspirin to normal volunteers for 6 days and assessed daily creatinine clearance and urinary excretion of sodium and calcium. In contrast to previous studies, subjects were maintained on a constant metabolic diet. These nonsteroidal anti-inflammatory drugs decreased urinary sodium excretion but had no effect on creatinine clearance or urinary calcium excretion. In summary, our data do not support an important physiologic role of renal prostaglandins in renal calcium excretion in normal subjects.     

A case report: primary hyperparathyroidism--comparison before and after parathyroidectomy by oral calcium tolerance test

To evaluate the cause of hypercalciuria, we carried out the oral calcium tolerance test before and after parathyroidectomy in a patient with primary hyperparathyroidism who had recurrent and multiple nephrolithiasis. Preoperative laboratory examination showed hypercalcemia, hypophosphetamia, hypercalciuria, decrease in % tubular reabsorption of phosphorus and strikingly elevated urinary cyclic AMP excretion. The oral calcium tolerance test indicated a significantly greater increase in serum calcium (delta serum calcium: 1.4 mg/dl vs 0.8 mg/dl) and a significantly greater suppression of urinary cyclic AMP excretion (delta U-cyclic AMP:-3.56 moles/gCre vs-1.17 moles/gCre) before parathyroidectomy than after. These results showed that hypercalciuria in this case was induced not only by the significant increase in the filtrated load of calcium but by the reduction in the resorption of calcium in the distal tubule caused by the significantly suppressed parathyroid hormone effect.     

The efficacy of dietary intervention on urinary risk factors for stone formation in recurrent calcium oxalate stone patients

PURPOSE: Nutrition is suggested to be the major environmental risk factor in idiopathic calcium oxalate stone disease. The study was designed to evaluate the effect of dietary intervention on urinary risk factors for recurrence in calcium oxalate stone formers. MATERIALS AND METHODS: A total of 76 men and 31 women with idiopathic calcium oxalate stone disease collected 24-hour urine on their habitual, self-selected diets and after 7 days on a balanced standardized diet according to the recommendations for calcium oxalate stone formers. RESULTS: On the usual diet, a urine volume of less than 2.0 l per 24 hours was present in 57.9%, hypercalciuria in 25.2%, hypomagnesuria in 18.7%, hyperoxaluria in 14.0%, hyperuricosuria in 41.3% and hypocitraturia in 57.0% of patients. The frequency of metabolic abnormalities and the risk of calcium oxalate stone formation decreased significantly on the ingestion of the balanced diet, due to the significant increase in urinary volume, pH and citrate excretion and the significant decrease in urinary calcium and uric acid excretion. No change occurred in urinary oxalate and magnesium excretion. CONCLUSIONS: The evaluation of urinary risk profiles of the patients on their usual dietary habits revealed a high risk for calcium oxalate stone formation. A low fluid intake and an increased intake of protein and alcohol were identified as the most important dietary risk factors. The shift to a nutritionally balanced diet according to the recommendations for calcium oxalate stone formers significantly reduced the stone forming potential.     

Effect of high protein diet on stone-forming propensity and bone loss in rats

BACKGROUND: High protein diets are believed to cause kidney stone formation and bone loss, but the mechanisms mediating these changes are unknown. The purpose of this study was to create an animal model of animal protein excess and to evaluate the response of kidney and bone to the dietary protein load. METHODS: Rats (12 per group) were pair-fed with a high (48%) and low (12%) casein diets that were otherwise identical in their content of sodium, potassium, calcium, phosphorus, and magnesium. RESULTS: Compared with the low casein group, the high casein group delivered a substantial acid load during 59 days of study, since it significantly decreased urinary pH, and increased urinary ammonium, titratable acidity, and net acid excretion. Animals on high casein diet also had higher urinary volumes. On the high casein diet, urinary calcium excretion was significantly higher and urinary citrate excretion and concentration was significantly lower. On the high casein diet, urinary saturation of calcium phosphate was higher. Serum calcitriol concentration did not significantly differ between the two groups. Histomorphometric analysis of femur procured after 59 days on the diet showed marked increase in bone resorption in the high casein group. Hypocitraturia was associated with increased activity of sodium-citrate cotransporter in renal cortical brush-border membranes (BBM) in the high casein group. CONCLUSION: Both the kidney and bone contribute to the pathogenesis of hypercalciuria during high casein diet in rats. Hypocitraturia is probably renal in origin. This rat model will be useful in elucidating the mechanisms by which high protein intake increases the risk of nephrolithiasis and bone loss in human beings.     

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.     

The ClC-5 knockout mouse model of Dent's disease has renal hypercalciuria and increased bone turnover.

Dent's disease is a nephrolithiasis disorder associated with hypercalciuria and low molecular weight proteinuria that is caused by mutations in the voltage-gated chloride channel ClC-5. Because the exact cause of hypercalciuria in this disease is unknown and could come from a renal, intestinal, or bone origin, we have investigated overall calcium handling in the ClC-5 knockout mouse (ClC-5 KO). On a high calcium diet, ClC-5 KO mice had elevated serum 1alpha,25-dihydroxyvitamin D3 (1alpha,25D3), alkaline phosphatase (AP), osteocalcin (OC), and urinary deoxypyridinoline (DPD), but serum parathyroid hormone (PTH), calcium, and intestinal calcium uptake was similar to that of wild-type (WT) mice. A 30-fold decrease in dietary calcium intake caused elevation of serum PTH and urinary cyclic adenosine monophosphate in ClC-5 KO mice and decreased the renal calcium excretion, which still remained 2-fold above that of WT mice. On this low calcium diet, both groups of mice had the same serum 1alpha,25D3, with similar increments in intestinal calcium absorption, serum AP, OC, and urinary DPD. These data indicate that the hypercalciuria in the ClC-5 KO mice on low and high calcium diets is of bone and renal origin and is not caused by increased intestinal calcium absorption, despite an elevated serum 1alpha,25D3. These mice data suggest that young patients with this disease may have a propensity for altered bone homeostasis that should be monitored clinically.     

Prevalence of fasting hypercalciuria associated with increased citraturia in the ambulatory evaluation of nephrolithiasis

BACKGROUND: Nephrolithiasis is a common, high costing pathology of the urinary tract. The most common urinary abnormalities are fasting hypercalciuria, hypercalciuria and hypocitraturia. This study aimed to identify the principal urinary abnormalities in our patients. METHODS: Ninety-eight patients (pts) (43 females, 55 males) with recurrent calcium nephrolithiasis underwent metabolic evaluation. In two 24-hr urine collections the following parameters were evaluated: calcium, phosphate, sodium, potassium, chloride, magnesium, citrate, oxalate, uric acid, creatinine (Cr), urea, ammonium and pH; blood measurement of calcium, phosphate, sodium, potassium, chloride, magnesium, uric acid, Cr, urea, acid-base balance ionized calcium and intact parathyroid hormone (iPTH) were also performed. A first morning voided urine sample was collected for measuring the urinary cross-links and fasting calciuria. The tubular threshold of phosphate (TmP) was calculated according to Walton and Bijovet. Metabolic evaluation was repeated in 63/98 pts after 7 days on a low calcium diet. RESULTS: The most common urinary abnormalities were fasting hypercalciuria in 51/96 pts (53.1%), hypercalciuria in 33/97 pts (34%) and hypocitraturia in 29/98 pts (29%); 24/33 pts (73%) with hypercalciuria had fasting hypercalciuria. Hypercalciuria was partially corrected on the calcium-restricted diet, while fasting hypercalciuria was not. Urine citrate levels were significantly higher in patients with fasting hypercalciuria. CONCLUSIONS: Fasting hypercalciuria was the most frequent urinary abnormality and it was not corrected with a calcium-restricted diet. In fasting hypercalciuric patients, increased bone resorption activity could be responsible for higher citraturia levels.     

The spectrum of metabolic abnormalities in patients with cystine nephrolithiasis

To elucidate the pathophysiology of mixed stone formation in cystinuria, 27 patients with documented cystine nephrolithiasis underwent an inpatient evaluation under a constant dietary regimen. All patients had homozygous cystinuria, since the daily urinary cystine excretion exceeded 250 mg. per gm. creatinine. Hypercalciuria was noted in 5 patients (18.5 per cent), 4 of whom had fasting hypercalciuria. Hyperuricosuria was found in 6 patients (22.2 per cent) and it was not caused by a consumption of a diet rich in animal proteins, since urinary pH was higher and urinary sulfate lower than in control subjects. Serum uric acid was slightly lower and uric acid clearance was higher in hyperuricosuric patients than in control subjects. Hypocitraturia was found in 12 patients (44.4 per cent) and it was associated with defective renal acidification in 4 of 5 patients in whom it was tested. Thus, hypercalciuria, hyperuricosuria and hypocitraturia frequently accompany cystinuria in patients with cystine nephrolithiasis. These conditions might be renal in origin, rather than a result of dietary or environmental aberrations. They may contribute to the formation of calcium and uric acid stones, which sometimes complicate cystine nephrolithiasis.     

Osteoporosis and urolithiasis

Several studies have indicated that up to 60% of idiopathic calcium stone formers present hypercalciuria. Many authors have described reduced bone mineral density (BMD) in stoneformers with hypercalciuria, but osteopenia has also been found in normocalciuric patients. Moreover, Jaeger's group found that bone mass was reduced in all patients with calcium stone disease, independently of hypercalciuria. Many factors may contribute to the pathogenesis of osteopenia in stone formers. A predominant role has been given to the low-calcium diet that is still prescribed in nephrolithiasis. Also slight metabolic acidosis, which is frequently present in stone formers eating a diet rich in animal protein, can contribute to bone loss. Finally, some authors described a pathogenetic role for cytokines, prostaglandins and vitamin D receptor gene polymorphisms.     

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.     

Dietary protein levels affect the excretion of oxalate and calcium in patients with absorptive hypercalciuria type II

A total of 12 patients with absorptive hypercalciuria type II and 11 normal controls participated in a study to evaluate the effects of dietary protein levels on urinary calcium and oxalate excretion before and after a 1 gm. dose of oxalate. Two test periods were used during which calcium (less than 400 mg. per day) and oxalate were restricted. The first test was done under conditions of low dietary protein (12 per cent total caloric intake, 60 gm.) and the second test was done at a high protein level (25 per cent, 125 gm. protein). Twelve-hour urine specimens were obtained after dinner on day 3 of each diet (low and high protein) and again on day 4 when 1 gm. oxalate (spinach) was added to the dinner meal. The specimens were analyzed for calcium, oxalate and relative calcium oxalate saturation (concentration product ratio). There were no significant differences between the controls and subjects with absorptive hypercalciuria type II in oxalate excretion before the oxalate load on the low protein (controls 31.4 +/- 4.2 standard error, expressed as mmol. oxalate per mol. creatinine, and absorptive hypercalciuria type II 23.1 +/- 3.1) and high protein (controls 30.4 +/- 4.2 and absorptive hypercalciuria type II 28.8 +/- 5.9) diets. After the oxalate bolus the positive changes in oxalate excretion were 11.8 +/- 4.8 (low protein) and 17.8 +/- 4.7 (high protein) for controls, and 11.4 +/- 4.4 (low protein) and 31.8 +/- 5.2 (high protein) for patients with absorptive hypercalciuria type II. Thus, the increases in post-load urinary oxalate levels observed for controls and patients were greater on the high protein than on the low protein diets. After the oxalate load the increases in urinary oxalate and calcium oxalate supersaturation were significantly greater for patients with absorptive hypercalciuria type II than for control subjects for the high protein but not the low protein diets (p less than 0.05).     

Alkalizitrate in der Urologie

Alkaline citrates have been used as an efficient therapy in hypocitraturic calcium nephrolithiasis, uric acid lithiasis, cystinuria, and renal tubular acidosis. Furthermore, alkaline citrates are very effective in treating and preventing hyperchloremic metabolic acidosis in patients with urinary diversion. The main physiological effects during urolithiasis therapy have been significant increases in urinary pH, in citrate and potassium, and a decrease in calcium excretion. This paper reviews current indications, therapy modalities, and metaphylactic use reported in the literature and/or recommended by the Deutsche Gesellschaft für Urologie (DGU) and the European Association of Urology (EAU). It is intended to give useful advice for the urologist's daily practice.     

儿童特发性高钙尿症52例临床分析

目的探讨特发性高钙尿症（IH）的临床特点及与泌尿系结石的关系。方法分析52例确诊为IH患儿的临床资料特点,并结合文献讨论其与泌尿系结石发生的关系。结果52例患儿均有不同程度血尿。其中41例患儿行腹部B超和X线平片检查及静脉肾盂造影检查,发现肾结石5例。调查52例患儿家族史发现15例家族中有泌尿系结石患者,6例同胞中有类似血尿患者,较正常对照组家族的尿结石发病率明显增高（P〈0．05）。52例患儿进行钙负荷试验,其中肠道吸收亢进型29例．肾脏漏出型23例。结论除血尿外,泌尿系结石也是IH的常见临床表现,尤其见于高钙尿状态持续时间较长者。IH与家族泌尿系结石的发病有密切关系,有遗传倾向。     

Complete distal renal tubular acidosis in systemic lupus: clinical and laboratory findings

We report two patients with systemic lupus erythematosus (SLE) who were found to have complete (acidotic) distal renal tubular acidosis (DRTA). One patient had nephrocalcinosis and renal magnesium wasting with tetany; the other patient had nephrolithiasis and nephrotic syndrome secondary to membranous glomerulopathy. Both patients had decreased urinary citrate excretion but neither had hypercalciuria. We discuss the association of DRTA with immunologic disorders and the possible role of hypocitraturia in promoting renal calcification in these patients. We suggest that patients with renal calcification be evaluated for DRTA, and that patients found to have DRTA be further evaluated for signs, symptoms, and laboratory evidence of immunologic disorders.     

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.     

The effects of oral furosemide on the response of urinary excretion of cyclic adenosine monophosphate and phosphate to parathyroid extract in normal subjects

We studied the effects of oral furosemide, 80 mg/day for 7 days, on the response of urinary excretion of phosphate and cyclic AMP to exogenous parathyroid extract (PTE) in 6 normal subjects. All 6 subjects had marked increases in urinary calcium and a significant increase in urinary cyclic AMP from the control to the furosemide periods: this suggests that furosemide-induced hypercalciuria produced elevated parathyroid activity. After treatment with furosemide, the response of urinary cyclic AMP and phosphate to PTE was blunted. During the subsequent calcium infusion (4 mg/kg), urinary cyclic AMP was suppressed to subnormal values, and the response to PTE returned to normal. The evidence suggests that furosemide may blunt the response to PTE, perhaps as a result of the elevated parathyroid activity produced by furosemide-induced hypercalciuria and lowering of plasma-ionized calcium. This blunting effect of furosemide on the response of urinary phosphate and cyclic AMP to PTE should be considered in the evaluation of parathyroid function in patients taking furosemide.     

The diagnosis of hypercalciuria in children

Calcium loading tests were performed in 21 children with hypercalciuria, haematuria and/or nephrolithiasis and 10 control subjects. Comparisons of 24-h calcium excretion before and after loading were evaluated rather than fasting urinary calcium to urinary creatinine ratio. The differences in calcium excretion before and after loading clearly distinguished absorptive from renal hypercalciuria. A difference higher than 0.035 mmol/kg indicated absorptive hypercalciuria in 6 of 21 patients, whereas in the remaining 15 much lower differences indicated renal hypercalciuria. Resorptive hypercalciuria caused by low serum values of 25-hydroxyvitamin D was considered in 6 of the 15 patients with renal hypercalciuria. These patients had low values of phosphate reabsorption (TmP/GFR) and could be clearly separated by high values of calcium reabsorption (TmCa/GFR), in contrast to patients with renal hypercalciuria who had normal values of TmP/GFR and low values of TmCa/GFR. The correct treatment and prevention of nephrolithiasis caused by hypercalciuria in children should be based on accurate diagnosis; this can be achieved by using the calcium loading test described in this report.