Renal tubular acidosis in recurrent renal stone formers

Renal tubular acidosis (RTA) is a well-known metabolic disturbance that may promote recurrent renal stone formation. However, its incidence, screening criteria and association with other lithogenic metabolic abnormalities are not established in recurrent nephrolithiasis. 10 of 50 consecutive recurrent renal stone formers had a persistent fasting morning urinary pH above 6.0 and/or a basal plasma bicarbonate concentration below 20.0 mM. Acid and alkaline loads disclosed RTA in 3 patients: 1 patient had incomplete type-1 distal RTA in addition to hyperoxaluria; a second patient showed complete type-2 proximal RTA, hyperoxaluria and renal hypercaliuria; and a third patient had incomplete proximal RTA without any other metabolic derangement. These results reinforce the importance of RTA as an isolated metabolic abnormality among recurrent renal stone formers. In addition, RTA appears to be more commonly associated with other lithogenic metabolic derangements than has been previously suspected. The extensive metabolic protocol used in this study provides a useful tool in the diagnosis and therapeutic considerations of recurrent nephrolithiasis.     

Tubular defects in patients forming calcium-containing stones.

The study of renal function, primarily the tubular function, in 55 patients with idiopathic, recurrent renal stones showed a large number of abnormalities. 49% of the patients, especially the women were affected. The most common defect was a reduced acidification capacity of varying degrees of severity in 64% of the woman and in 20% of the men. Impairment of the acidification capacity of the distal tubule was found in 18% and of the proximal tubule in 11% of the patients. Inability to dilute the urine after water loading was found in 17% and tubular proteinuria also in 17% of the patients. Most patients with an impaired tubular function had a severe stone disease. The defects in acidification and dilution capacity ought to be of pathogenetic importance for stone formation and should be considered in the selection of preventive therapy.     

Pathophysiology of incomplete renal tubular acidosis in recurrent renal stone formers: evidence of disturbed calcium,bone and citrate metabolism

Summary Urinary acidification, bone metabolism and urinary excretion of calcium and citrate were evaluated in 10 recurrent stone formers with incomplete renal tubular acidosis (RTA), 10 recurrent stone formers with normal urinary acidification (NUA) and 10 normal controls (NC). Patients with iRTA had lower plasma standard bicarbonate after fasting (P<0.01) and lower urinary excretion of titratable acid (P<0.05) and citrate (P<0.01) compared with NUA patients and NC, and higher urinary excretion of ammonia (P<0.05) compared with NC (P<0.05). Hypercalciuria was found in 6 of 10 patients with iRTA compared with 3 of 10 with NUA, and O of 10 NC. The citrate/calcium ratio in urine was significantly reduced in iRTA compared with the value in NUA (P<0.01), and in NUA compared with NC (P<0.05). Biochemical markers of bone formation (serum osteocalcin) and bone resorption (urinary hydroxyproline) were significantly increased in iRTA compared with NUA and NC (P<0.01), indicating increased bone turnover in stone formers with iRTA. Stone formers with iRTA thus presented with disturbed calcium, bone and citrate metabolism-the same metabolic abnormalities which characterize classic type 1 RTA. Mild non-carbonic acidosis during fasting may be a pathophysilogical factor of both nephrolithiasis and disturbed bone metabolism in stone formers with iRTA     

A study of recurrent stone formers with special reference to renal tubular acidosis

Forty-five patients with recurrent renal stone were examined for distal renal tubular acidosis (dRTA) defects by acid challenge test (150 mg ammonium chloride/kg body weight). Their 24-h urine samples were analysed for creatinine, calcium, oxalic acid, inorganic phosphorus, uric acid, magnesium and citric acid. One-hour urine samples before acid load and hourly samples for the 7 h following acid challenge test were collected and analysed for creatinine, calcium, citric acid, inorganic phosphorus, titratable acidity, and ammonium. The incidence of distal RTA defect was 22.2% in the patients examined. The major biochemical characteristics in RTA patients compared with patients without RTA were: (a) significantly higher urinary pH, (b) significantly lower excretion of citric acid, (c) no significant difference in calcium excretion and (d) a tendency toward lower titratable acidity and ammonium excretion.     

Hyperkalemic renal tubular acidosis: effect of furosemide in humans and in rats

Furosemide increases urinary acidification in control subjects and in certain patients with normokalemic or hypokalemic distal renal tubular acidosis (RTA). We studied the effect of furosemide in 14 patients with hyperkalemic distal RTA. In a group of patients with pure selective aldosterone deficiency, furosemide increased net acid and K excretion in a fashion indistinguishable from controls. This effect of furosemide was observed both in the presence and in the absence of acute mineralocorticoid administration. In another group of patients with hyperkalemic distal RTA, furosemide failed to decrease urine pH and to increase net acid excretion despite acute mineralocorticoid administration. Plasma aldosterone was variable in this group in that some patients had appropriate levels of aldosterone for the degree of hyperkalemia, whereas in the other patients the levels were low. The failure of these patients to respond to furosemide, despite pharmacologic doses of mineralocorticoid, suggests that these patients had a defect in H+ secretion other than that attributable to aldosterone deficiency alone. To gain insight into the mechanism whereby furosemide increases urinary acidification, we studied control and amiloride-treated rats pretreated with mineralocorticoid. In response to furosemide, control rats had a significantly lower urine pH and higher net acid and K excretion than that observed in amiloride-treated rats. These data suggest that furosemide increases H+ and K excretion, at least in part, by creating a favorable electric gradient for secretion of these ions since these effects were blunted in presence of inhibition of distal Na transport by amiloride.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

A distal (type 1) renal tubular acidosis case that mimic coronary ischemia

Abstract

Introduction: Type 1 (distal) renal tubular acidosis (RTA) is a rare clinical condition characterized with defect of urinary acidification in distal tubulus. If diagnosis delays, RTA may cause metabolic and clinical complications and comorbidities. We describe here a type 1 distal RTA case with symptoms mimicking coronary ischemia. Case report: A 46-year-old woman admitted with complaints of chest pain, palpitation, walking disability, fatigue and nausea. On physical examination muscles were weaken 3/5 in four extremities. An electrocardiogram revealed supraventricular tachycardia and ST depression on precordial V2-6 derivations. An acute coronary syndrome diagnosis made based on anginal symptoms, supraventricular tachycardia, ST depression on V2-6 derivations and elevated cardiac enzymes. Urgent coronary angiography was normal except a 30% narrowing in LAD. She had recurrent nephrolithiasis and had operated because of hydronephrosis. She had two episodes of fatigue and walking disability previously. Hyperchloremic metabolic acidosis with normal anion gap determined in blood gas analyze. Patient diagnosed with type I RTA with the signs and symptoms of recurrent nephrolithiasis, fatigue, severe hypokalemia (1.8?mmol/L), hyperchloremic metabolic acidosis with normal anionic gap, alkaline urine (pH 8) and positive urinary anionic gap (13.7?mmol/L). Sodium bicarbonate infusion and potassium replacement therapy administered. Clinical and laboratory signs of the patient dissolved during treatment. Conclusion: Type 1 RTA should be considered in acidotic patients admitted with hypokalemia and coronary symptoms. Urinary and blood gas analyses should be done beside cardiac tests initially. Therefore, a precise diagnosis may be possible without the possible complications of unnecessary coronary interventions.     

Pathophysiology of the renal acidification defect present in the syndrome of familial hypomagnesaemia-hypercalciuria

A distal acidification defect is frequently observed in the syndrome of familial hypomagnesaemia-hypercalciuria and hence this condition can be confused with prirnary distal renal tubular acidosis (RTA). This study demonstrates that in four unrelated patients with familial hypomagnesaemia-hypercalciuria the acidification defect is functionally different from that present in primary distal RTA. All patients exhibited hypomagnesaemia, hypermagnesuria, hypercalciuria, hyposthenuria, nephrocalcinosis and slight reduction of glomerular filtration rate (GFR). A moderate degree of metabolic acidosis was also present and basal data showed an inappropriately high urine pH (5.7–5.9) and a positive urine anion gap (Na+KCl=11–28 mmol/l). Stimulation of distal acidification induced a fall in urine pH (4.7–5.6), but ammonium excretion remained low despite factoring by GFR (26–46 mol/min per 1.73 m², 35–54 mol/100 ml GF). The urine to bloodPCO₂ gradient also remained low after sodium bicarbonate loading (1.3–17.7 mmHg). These results are best explained by both defective ammonia transfer to the deep nephron and impaired hydrogen ion secretion at the level of the medullary collecting duct, and probably are secondary effects of the medullary interstitial nephropathy.     

Family history of renal stones in recurrent stone patients

A survey was carried out on the family history of renal stones among 380 patients in an out-patient stone clinic, most of whom had experienced frequent recurrences. In 55.4% of patients at least one first-degree relative had experienced renal stones. A positive family history was more common in females (64.7%) than in males (51.0%) and was particularly apparent in those who had multiple recurrences. It was also significantly more common in female patients with evidence of renal tubular defects (incomplete forms of renal tubular acidosis). Among the ordinary stone patients 18% of the fathers and 8% of the mothers had also formed renal stones. The corresponding figures for female stone patients with renal tubular defects were 40 and 33% respectively. These findings indicate that tubular dysfunction could be an inherited trait that predisposes to the formation of renal stones. Hypercalciuria or hyperuricosuria was not over-represented among stone formers with a positive family history.     

Distal renal tubular acidosis and the potassium enigma

Severe hypokalemia is a central feature of the classic type of distal renal tubular acidosis (RTA), both in hereditary and acquired forms. In the past decade, many of the genetic defects associated with the hereditary types of distal RTA have been identified and have been the subject of a number of reviews. These genetic advances have expanded our understanding of the molecular mechanisms that lead to distal RTA. In this article, we review data published in the literature on plasma potassium from patients with inherited forms of distal RTA. The degree of hypokalemia varies depending on whether the disease is autosomal autosomal-recessive or dominant, but, interestingly, it occurs in defects caused by mutations in genes encoding the AE-1 exchanger, the carbonic anhydrase II gene, and genes encoding different subunits of the H+ adenosine triphosphatase. This shows that a unique defect involving the H+/K+-adenosine triphosphatase leading to renal potassium wastage cannot explain the hypokalemia seen in virtually all types of classic distal RTA.     

The impact of cystinuria on renal function

PURPOSE: Patients with cystinuria frequently have recurrent renal calculi and may subsequently require multiple stone removing procedures during their lifetime which could have an impact on overall renal function. We determined the potential impact of cystinuria and cystine stone formation on the level of renal function compared to calcium oxalate stone formers. MATERIALS AND METHODS: Clinical data on 40 cystinuric patients followed at 2 medical centers and 45 such individuals in a large stone population data base were analyzed. These results were compared to data on 3,964 calcium oxalate stone formers enrolled in this data base. RESULTS: Mean serum creatinine plus or minus standard deviation for stone forming cystinuric patients was significantly higher than that of the calcium oxalate cohort (1.13 +/- 0.28 versus 1.01 +/- 0.28 mg./100 ml., p = 0.0001). A significantly greater percentage of cystinuric patients (5.8%) had an abnormally increased serum creatinine compared to the calcium oxalate stone formers (2.2%, p = 0.046). Male gender, increasing number of open surgical stone removing procedures and nephrectomy were significant variables associated with an increased serum creatinine (p = 0.0010, p = 0.0038, p = 0.0133, respectively). An increasing number of open surgical stone removing procedures had a significant positive correlation with performance of nephrectomy in the cystinuric population (p = 0.0166). A significantly greater percentage of cystinuric patients compared to the calcium oxalate cohort were subjected to nephrectomy (14.1% versus 2.9%, p = 0.007). CONCLUSIONS: Cystinuric patients have higher serum creatinine levels than calcium oxalate stone formers and they are at more risk for renal loss. When stone removal is required, a minimally invasive approach is preferred.     

Urinary acidification in renal stone patients from northeastern Thailand.

Hypokalemia, hypokaliuria and hypocitraturia are common findings in patients with renal stone disease in Northeastern Thailand. However, hyperchloremic metabolic acidosis seldom is seen. Therefore, we studied renal acidification in 29 renal stone disease patients who were living in rural Northeast Thailand. Baseline blood and average 24-hour urine biochemical parameters were measured. Hypokalemia, hypokaliuria and hypocitraturia were found in 10%, 83% and 93% of the patients, respectively. By multiple regression, urinary citrate excretion correlated positively with serum potassium and urinary potassium excretion, and negatively with urinary ammonium (r = 0.640, p = 0.005). An abnormal response to acid loading was found in only 1 patient. Thus, hypokaliuria and hypocitraturia in our renal stone disease subjects were infrequently due to distal renal tubular acidosis. Perhaps potassium depletion might be a contributing factor in these metabolic abnormalities.     

Comparison of fibronectin content in urinary macromolecules between normal subjects and recurrent stone formers.

OBJECTIVES: Fibronectin (FN: 230 kD) is a multifunctional alpha(2)-glycoprotein distributed throughout the extracellular matrix and body fluids. Recent studies have shown that a variety of molecules, including FN, inhibit the endocytosis of calcium oxalate (CaOx) crystals in vitro. We recently reported that FN was oversecreted from the renal tubular cells as a result of the stimulation of CaOx crystals, and inhibited the aggregation of CaOx crystals and the adhesion of CaOx crystals to the renal tubular cells. In the present study, we investigated the difference of FN content in urinary macromolecules (UMMs) between normal subjects and recurrent stone formers. MATERIALS AND METHODS: Urinary parameters in relation to urolithiasis of normal subjects and recurrent stone formers were measured. Proteins in extracted UMMs from urine of normal subjects and recurrent stone formers were measured with a BioRad protein assay, GAGs in each UMMs with a modified DMB assay and the FN content with the ELISA method. RESULTS: In urinary parameters, citrate was significantly higher in urine from normal subjects (female) than normal subjects (male) or recurrent stone formers, and the other parameters showed no differences between each group. The protein concentrations in UMMs showed no differences between each group. Normal subjects (male and female) showed a significantly higher concentration of GAGs than recurrent stone formers (with and without silent stone). Compared with normal subjects and recurrent stone formers without silent stones, higher FN levels were found in recurrent stone formers with silent stones. Normal subjects showed a significantly higher concentration of FN than recurrent stone formers without silent stones. No difference in FN level was shown between normal subjects (male) and normal subjects (female). CONCLUSION: Recurrent stone formers with silent stones showed a significantly higher concentration of FN in UMMs than normal subjects. This finding suggests that FN might be oversecreted from the renal tubular cells as a result of the stimulation of CaOx stones in vivo. Recurrent stone formers without silent stones showed a significantly lower concentration of FN in UMMs than normal subjects. From this finding it is suggested that FN might play a role as a potent inhibitor of CaOx urolithiasis in a clinical setting.     

Prevalence and characterization of renal tubular acidosis in patients with osteopenia and osteoporosis and in non-porotic controls.

BACKGROUND: Chronic metabolic acidosis may increase alkali mobilization from the bone and thus promote the development of osteoporosis. The objective of the current study was to compare urinary acidification in patients with reduced bone mineral content with that in control subjects with normal bone density. METHODS: Forty-six subjects (41 females, 5 males) with osteopenia or osteoporosis were studied. In none of the subjects were overt metabolic acidosis, derangement of potassium homeostasis, or renal insufficiency present. Distal tubular acidification was studied by means of oral ammonium chloride loading test (0.1 g/kg body weight) and the oral frusemide test (40 mg). In addition the frusemide test was performed in 20 healthy age- and sex-matched controls (17 females, 3 males). RESULTS: In all control subjects a urinary pH <5. 5 was observed following the ingestion of 40 mg frusemide. In contrast, in patients with reduced bone mineral density incomplete renal tubular acidosis type I (RTA I) was diagnosed in 10 of 46 subjects (22%) by oral ammonium chloride loading test. Disorders possibly related to RTA I were detected in eight of these 10 patients. Thirty-six patients had a normal urinary pH response following oral ammonium chloride loading. Oral frusemide, 40 mg, failed to lower urinary pH <5.5 in sixteen patients (35%), these included 10 subjects with incomplete RTA I, and six subjects with a normal oral ammonium chloride loading test. An abnormal frusemide test was found in 35% of patients with reduced bone mass and in none of the normal controls (chi(2)=7.39; P<0.01). With the ammonium chloride test as the gold standard for diagnosis of distal RTA, the frusemide test showed a sensitivity of 1.0 (95% CI, 0.69-1.0) and a specificity of 0.89 (95% CI, 0.78-0.96) for the diagnosis of distal RTA. Patients with incomplete RTA I were younger than those without incomplete RTA I (42+/-16 vs 54+/-14 years; P=0.025; mean+/-SD). Basal serum bicarbonate concentrations and capillary pH did not differ between the groups. CONCLUSION: Incomplete RTA I may be prevalent in a significant proportion of patients suffering from osteopenia or osteoporosis. The outcome of the frusemide test suggests either a defect of the H(+)ATPase in the cortical collecting tubule (CCT) or a defective Na(+) reabsorption in the CCT. Prospective studies are needed to further elucidate the impact of incomplete RTA I on the development of reduced bone mineral content.     

Renal acidification defects in medullary sponge kidney

Thirteen patients with medullary sponge kidney underwent a short ammonium chloride loading test to investigate their renal acidification capacity. All but 1 presented with a history of recurrent renal calculi and showed bilateral widespread renal medullary calcification on X-ray examination. Nine patients had some form of renal acidification defect; 8 had the distal type of renal tubular acidosis, 2 the complete and 6 the incomplete form. One patient had proximal renal tubular acidosis. These findings, which suggest that renal acidification defects play an important role in the pathogenesis of renal calculi in medullary sponge kidney, have considerable therapeutic implications.     

Secondary erythrocytosis associated with distal renal tubular acidosis

AIMS: Diagnosis and classification of renal tubular acidosis (RTA) have traditionally been made on the basis of functional studies. Despite recent expanding knowledge about the molecular abnormalities involved in renal bicarbonate (HCO3-) and H+ transport, the pathophysiology of secondary erythrocytosis in association with distal RTA remains obscure. CASE HISTORY: A 2-month-old boy with severe hyperchloremic metabolic acidosis with positive urine anion gap was diagnosed with distal RTA. Replacement therapy with sodium bicarbonate and potassium citrate succeeded in improving his metabolic acidosis and growth. His renal function remained normal. He had persistent erythrocytosis. CONCLUSION: Secondary erythrocytosis is a rarely reported association of distal RTA. It may increase the risk of thromboembolism.     

Case of hypoparathyroidism, deafness and renal dysplasia (HDR) syndrome associated with nephrocalcinosis and distal renal tubular acidosis

Hypoparathyroidism, deafness and renal dysplasia (HDR) syndrome is an autosomal dominant disorder characterized by hypoparathyroidism, sensorineural deafness and renal dysplasia. Herein, we report a case of HDR syndrome associated with nephrocalcinosis and distal renal tubular acidosis. A 34-year-old woman was admitted to investigate recurrent stone formation and bilateral nephrocalcinosis. As a 3-year-old child, she had been diagnosed with HDR syndrome without chromosome evaluation. She had spontaneous stone passages on several occasions. On laboratory examination, serum calcium and intact parathyroid hormone at lower levels. Urinary citrate excretion was extremely low at 51.6 mg/day. On an ammonium chloride loading test, complete distal renal tubular acidosis was proved. To prevent the nephrocalcinosis from deteriorating, she was given potassium-sodium citrate. Since administration, she has not experienced spontaneous stone passage or renal colic. Nephrocalcinosis and recurrent urolithiasis will strongly affect renal prognosis in this case and we consider that citrate medication is an effective therapy in avoiding progress of her nephrocalcinosis.     

Recurrent nephrolithiasis in renal tubular acidosis. Metabolic profiles,therapy and course

13 patients with recurrent urolithiasis and distal renal tubular acidosis (RTA I) were investigated for lithogenic metabolic disorders. Treatment was given and the patients observed for periods of up to 10 years.     

Calcium nephrolithiasis and distal tubular acidosis in type 1 glycogen storage disease

A 36-year-old man was admitted to hospital due to right flank pain as a result of ureteral stones. He had been followed up for type 1 glycogen storage disease since the age of 11 years. He had four episodes of spontaneous stone birth during the previous 2 years, and each stone was composed mainly of calcium oxalate. Intravenous pyelography showed right hydronephrosis due to ureteral stones and bilateral multiple renal stones. We carried out transurethral ureterolithotripsy (TUL) on the right ureteral stones. The composition was a mixture of calcium oxalate and calcium phosphate. Laboratory evaluation demonstrated the association of distal renal tubular acidosis (RTA). These observations suggest that hypocitraturia and distal RTA are strongly correlated to recurrence of calcium nephrolithiasis. The patient's serum uric acid and urinary citrate excretion levels normalized after allopurinol and potassium citrate administration.     

Infrequency of primary hyperparathyroidism in renal stone formers

Repeated measurements of serum calcium and immunoreactive parathyroid hormone were performed in 1433 renal stone formers systematically referred from Accident and Emergency Departments and from Departments of Urology and Nephrology, irrespective of their serum calcium. Primary hyperparathyroidism was found in 23 patients and confirmed in 19/20 patients who underwent neck surgery, including 8 with intermittent hypercalcaemia. Our data suggest that when selection bias is minimised, primary hyperparathyroidism is found in about 2% of renal stone formers in a western country such as Belgium.