Incomplete renal tubular acidosis as a predisposing factor for calcium phosphate stones in neuropathic bladder: a case report

We present a male tetraplegic patient, who developed stones in neuropathic bladder six times within a span of three years. Unusual features of this case are: (1) This patient started developing stones in urinary bladder thirteen years after sustaining spinal cord injury. (2) He was performing intermittent catheterisation and did not have an indwelling catheter. (3) The presenting symptom of vesical lithiasis was abdominal spasms and not urine infection. (4) The major component of the stones was calcium phosphate; magnesium ammonium phosphate was completely absent in the calculus on four occasions. (5) Proteus species were not grown from urine at any time. (6) This patient failed to acidify urine below a pH of 5.3 after taking simultaneously furosemide (40 mg) and fludrocortrisone (1 mg), which suggested incomplete renal tubular acidosis type 1. We learn from this case that biochemical analysis of stones removed from urinary bladder may be useful. If the major component of vesical calculus is calcium phosphate, complete or incomplete renal tubular acidosis type 1 should be excluded, as it may be possible to reduce the risk of recurrence of calcium phosphate stones by oral potassium citrate therapy or, vegetable and fruit rich diet.

We learn from this case that biochemical analysis of stones removed from urinary bladder may be useful. If the major component of vesical calculus is calcium phosphate, complete or incomplete renal tubular acidosis type 1 should be excluded, as it may be possible to reduce the risk of recurrence of calcium phosphate stones by oral potassium citrate therapy or, vegetable and fruit rich diet.

Background
A study of bladder calculi in 500 persons treated at the University of Alabama in Birmingham Spinal Cord Injury Care System between 1973 and 1981 showed that bladder calculi were most likely to develop within one year of spinal cord injury. Patients developing bladder calculi prior to first definitive discharge were most likely to have neurologically complete lesions and Klebsiella infections at admission. Patients developing bladder stones within two years of hospital discharge were most likely to have indwelling urethral catheters and either Proteus or multipleorganism infections at discharge. [1] Thus indwelling urinary catheter and urine infections are major risk factors for vesical calculi in spinal cord injury patients. Patients, who develop vesical calculi, often present with catheter blockages or urine infections. These stones usually con-tain magnesium ammonium phosphate. When a spinal cord injury patient develops recurrent urine infections and vesical calculi, squamous metaplasia may be seen in the neuropathic bladder. Spinal cord injury patients, who develop recurrent nephrolithiasis, are advised to undergo biochemical evaluation, but patients with vesical calculi do not usually receive such advice, as metabolic abnormalities are uncommon in those who form stones only in the urinary bladder. Similarly, dietary modification or oral citrate therapy is recommended to patients with calcium phosphate kidney stones and not for those with bladder stones.
We report an adult male patient with tetraplegia, who developed recurrent bladder calculi. This case had several unusual features. The presenting symptom of vesical calculus was abdominal spasm. This patient was performing intermittent catheterisations and did not have long-term catheter drainage. He started developing bladder stones thirteen years after sustaining spinal cord injury. The major component of vesical calculi was calcium phosphate. Renal acidification test revealed incomplete renal tubular acidosis type 1.

Case presentation
A Caucasian male, born in 1943, sustained fracture dislocation of seventh cervical and first thoracic vertebrae with tetraplegia in 1992, when he lost control of motorbike. Internal fixation and fusion of cervico-dorsal junction was performed. He was managing his bladder by a penile sheath. In 1997, this person was taught the technique of self-catheterisation. He started performing intermittent catheterisations.
Intravenous urography was performed as a routine test on 06 August 1997, and it showed marked prostatic calcification. Kidneys, ureters and bladder were normal. Intravenous urography was performed during a routine followup on 30 June 1999; and no radio opaque calculi were seen. Both kidneys excreted the contrast; normal kidney, pelvicalyceal systems, ureters and bladder. As the patient developed frequent urine infections, intravenous urography was performed on 31 January 2000. No radio opaque renal or vesical calculi were seen; prostatic calcification was present. Both kidneys excreted contrast; normal kidneys, pelvicalyceal system, ureters and bladder. There was no significant residual urine.
In September 2004, this person developed spasms of abdomen, cold sweats and headache. He was moving his bowels every day in the evening and was using Carbalax suppositories. Intravenous urography was performed on 05 November 2004. Kidneys and ureters were normal. Multiple diverticula arising from the bladder were noted.
This patient attended spinal unit on 24 January 2005 with spasm of abdomen. Chest X-ray, which was taken on 04 March 2005, showed clear lungs. X-ray of abdomen revealed moderate faceal loading of the colon. Ultrasound scan of abdomen showed multiple gallstones; common bile duct was not dilated. Ultrasound examination of urinary tract revealed a simple cyst in the upper pole of right kidney; no renal calculi; no renal scarring or hydronephrosis. There was a calculus in the urinary bladder. Intravenous urography revealed prostatic calcification and a vesical calculus. (Figure 1) Pelvicalyceal systems and ureters were normal. Diverticula were seen in the bladder.  (Table 2) The stone was found to contain 100% calcium phosphate.  This patient performed intermittent catheterisations about six times a day; he preferred ready to use, sterile, pre-lubricated SpeediCath catheters size 12 French (Coloplast Ltd, Peterborough PE2 6FX, United Kingdom) for self-catheterisations because the catheter package already contained water for lubrication and it was user-friendly. With regular intermittent catheterisations, this patient remained continent and was able to discard penile sheath and leg bag. Asymptomatic bacteriuria was observed on several occasions and organisms isolated from urine are listed in Table 3 Since this patient developed repeatedly stones in urinary bladder, we carried out biochemical tests of blood and urine to look for underlying metabolic abnormality, if any. When biochemical tests were carried out, this patient had started taking orange juice in large quantities in the hope of preventing further formation of urinary stones.
Results of biochemical tests are given below. Reference range is mentioned within parenthesis.   In summary, this patient had citrate level in urine at the bottom of the reference range. Urine pH was 6.1, which would be conducive to calcium phosphate stone formation. We carried out urinary acidification test to look for distal renal tubular acidosis after taking written informed consent from the patient.

24-hours urine
Urinary acidification was assessed by simultaneous administration of furosemide (40 mg) and fludrocortisone (1 mg). A baseline urine sample was taken followed by oral administration of furosemide (40 mg) and fludrocortisone (1 mg). Fluid intake was ad libitum. Urine was collected hourly for the next six hours. The results of urine acidification test are given in Table 4. The minimum pH value of urine was 5.56, which was noted four hours after ingestion of furosemide and fludrocortisone. Failure to acidify urine to a pH of less than 5.3 is consistent with incomplete distal renal tubular acidosis.
Therapeutic options were: (1) to prescribe potassium citrate or sodium citrate; (2) to advise the patient to take vegetables and fruits daily. Both potassium citrate and sodium citrate were available on prescription and therefore, the patient did not have to pay for these medicines.
But the patient would have to buy fruits, vegetables or fruit juices. We were concerned about the possible side effect of sodium citrate therapy, as supplementation of sodium can potentially affect blood pressure especially when taken for a prolonged period. The patient decided to take more citrus fruits in his diet every day. He was given  [3] revealed that 71 subjects were diagnosed with Proteus in their urine at some point during the study period, and 19 of them (27%) were also diagnosed with stones (P = 0.045). Other organisms associated with the presence of stones included Enterococcus, Klebsiella, Pseudomonas, Morganella, and Providencia (P < 0.05). In this patient, Proteus was not grown in urine at any time, but this patient had asymptomatic bacteriuria with Escherichia coli, Enterococcus faecalis, Klebsiella aerogenes, and Pseudomonas aeruginosa.

Urine cytology photomicrograph shows benign epithelial cells with a background of neutrophil ploymorphs
Calcium phosphate calculi in urinary bladder are rare, as magnesium ammonium phosphate, which is associated with urine infection, is the common vesical calculus in patients, who have indwelling catheters. Calcium phosphate stones in kidneys are seen in patients with renal tubular acidosis type 1. Typically patients with complete renal tubular acidosis type 1 have metabolic acidosis, alkaline urine, decreased urinary citrate, and hypercalcuria. Persons with incomplete renal tubular acidosis type 1 may not markedly manifest any of these abnormalities. Investigation of this patient revealed little that was abnormal, however he was found to have a basal urine pH of 6.1, which would be conducive to calcium phosphate cal-culi formation. Therefore, we performed urinary acidification test by simultaneous administration of furosemide (40 mg) and fludrocortisone (1 mg). The short ammonium chloride test, which involves the oral ingestion of a quantity of ammonium chloride and serial measurements of urine pH, is adopted internationally as the 'gold standard' diagnostic test for distal renal tubular acidosis. However, although the ammonium chloride test lasts eight hours and does not require blood testing, it can be unpleasant for some patients, because gastric irritation, nausea, and vomiting are common. Walsh and associates [4] showed that simultaneous administration of furosemide (to increase distal tubular sodium delivery) and fludrocortisone (to enhance principal cell sodium reabsorption and alpha intercalated cell hydrogen ion secretion) provided a sufficient and consistent stimulus to unmask an acidification defect in distal renal tubular acidosis, without the need for ammonium chloride. Simultaneous administration of furosemide and fludrocortisone provided an easy, effective, and well-tolerated alternative to the standard ammonium chloride urinary acidification test for the diagnosis of distal renal tubular acidosis. Following administration of furosemide (40 mg) and fludrocortisone (1 mg), the urine pH decreased to less than 5.3 in all healthy volunteers whereas all patients with previously diagnosed distal renal tubular aciodosis failed to acidify their urine to pH less than 5.3. Ammonium chloride test and furosemide/fludrocortisone test assess urinary acidification in different ways: the former by providing an acid load for the distal nephron to excrete and the latter by producing direct and indirect stimulation of distal nephron hydrogen ion secretion.
When calcium phosphate calculi, which are rare, are found in urinary bladder, it is advisable to exclude complete or incomplete renal tubular acidosis type 1. In case a patient has renal tubular acidosis, it is possible to reduce the risk of recurrence of calcium phosphate stones by increasing citrate intake or taking vegetable and fruit rich diet. [5] Spinal cord injury patients, who have indwelling catheters and develop vesical calculi, present with catheter blockages and urine infections. This patient was performing intermittent catheterisations and developed calcium phosphate stones in urinary bladder. The initial presenting symptom of vesical calculi in this patient was abdominal spasms. Doctors caring for spinal cord injury patients should be aware of the unusual symptoms, which are seen in spinal cord injury patients with various diseases. Hyperhidrosis may be the presenting symptom of renal calculi in a patient with spinal cord injury. [6] This case raises an important question to which we do not have an answer. ‚ Why did this patient with incomplete renal tubular acidosis develop calcium phosphate stones in urinary bladder and not in the kidneys?
We shall submit a follow-up of this patient after 18 months to inform the readers whether the diet rich in vegetables and fruits has been useful in preventing recurrence of calcium phosphate stones in urinary bladder.

Conclusion
We learn from this case that abdominal spasms may be the presenting feature of calcium phosphate stones in urinary bladder of spinal cord injury patients, as these stones, unlike magnesium ammonium phosphate stones, are not associated with recurrent urine infections. It is advisable to send specimens of stones removed from urinary bladder for biochemical analysis. If the major component of vesical calculus is found to be calcium phosphate, complete or incomplete renal tubular acidosis type 1 should be excluded, as it may be possible to reduce the risk of recurrence of calcium phosphate stones by oral potassium citrate therapy or vegetable and fruit rich diet.