British Journal of Urology (1991), 68,240-242 0 1991 British Journalof Urology

The Effect of Diclofenac Sodium on Urinary Concentration of Calcium, Uric Acid and Glycosamino- glycans in Traumatic Paraplegics

S. SHARMA, S. VAIDYANATHAN, S. K. THIND, R. NATH and A. SANKARANARAYANAN

Departments of Urology, Biochemistry and Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, India

Summary-Non-steroidal anti-inflammatory drugs (NSAID) have been shown to decrease calcium excretion in the experimental animal, in human volunteers and in calcium stone formers. Paraplegics tend to be hypercalciuric during the first 2 years after their injury and this is said to be a predisposing factor for stone formation in these patients. The effect of the NSAID diclofenac sodium was studied in 12 traumatic paraplegics who had sustained their injury 1 to 6 months previously; 24-h urine samples collected before and 2 weeks and 4 weeks after oral diclofenac sodium 50 mg tds were analysed for calcium, uric acid, glycosaminoglycans (GAGs) and volume. There were no significant changes in urinary volume, uric acid and GAGs excretion. However, urinary calcium concentration and 24-h calcium excretion decreased significantly following 2 weeks’ and 4 weeks’ treatment with diclofenac sodium.

The prevention of urological complications is a prime objective in the successful rehabilitation of patients with spinal cord injury. Urolithiasis is a well documented complication in traumatic para- plegics. Comarr (1955) reported an incidence of 6.8% for renal calculi and 28% for bladder calculi in adult paraplegics. Tori and Kewalramani (1 979) observed that 28% of children with a spinal cord injury developed renal tract stones and most of these (86%) formed during the first year following the injury. One of the predisposing factors for stone formation in these patients is hypercalciuria. Paraplegics are known to have elevated urinary calcium excretion during the first 2 years after their injury (Burr, 1978). The hypercalciuria begins about 10 days after paralysis, reaches a maximum at 10 weeks and persists for at least 6 months (Tori and Kewalramani, 1979). The peak incidence of stone formation occurred between 14 to 3 years after the spinal cord injury and has been related to the period of hypercalciuria, triggered perhaps by an episode of dehydration or infection with a urease-producing

Accepted for publication 21 September 1990

organism (Freeman, 1949; Guttman and Frankel, 1969; Burr and Nuseibeh, 1985). Eight of 10 patients with bladder calculi had hypercalciuria with positive urine cultures and the hypercalciuria was said to enhance stone formation due to infection with urea-splitting organisms (Tori and Kewalra- mani, 1979). Thus it is imperative to reduce urinary calcium excretion and concentration in these patients.

The prostaglandin synthetase inhibitor, indo- methacin, was found to reduce urinary calcium excretion and calcium concentration in both exper- imental animals and in hypercalciuric stone formers (Buck et al., 1983). More recently, diclofenac sodium has been used to good effect in the treatment of frequently relapsing calcium stone formers (Brundig and Borner, 1987). We therefore investi- gated the effect of diclofenac sodium therapy on the concentration and excretion of urinary calcium, uric acid and glycosaminoglycans in a group of traumatic paraplegics.

Patients and Methods

Twelve traumatic paraplegic patients were included in the study. Their spinal cord injuries had been

240

DICLOFENAC-SODIUM THERAPY IN TRAUMATIC PARAPLEGICS 24 1

sustained I to 6 months earlier. All were practising clean intermittent self-catheterisation. The urine was cultured and any urinary infections were treated prior to entry into the study. X-ray of the kidneys, ureters and bladder showed no evidence of urinary tract calculi in any patient and all had normal values of serum creatinine and calcium. A 24-h urine sample was collected (Sample 1) for base-line estimation of creatinine, calcium, uric acid and GAGs concentration and excretion. Diclofenac sodium was then prescribed in a dose of 50 mg 3 times a day for 4 weeks; 24-h urine samples were collected at 2 weeks (Sample 2) and at 4 weeks (Sample 3). Care was taken to ensure that no drug therapy was administered during the study period and the patients maintained their usual diet and fluid intake. The total volume of each 24-h urine sample was noted and an aliquot was preserved with a few crystals of thymol. Urinary calcium was determined by the method of Trindeir (1960), uric acid by the method of Henry (1961), creatinine as described by Natelson (1963) and GAGs were colorimetrically determined in terms (of glucuronic acid by the method of Hesse et al. (1986). The urinary concentration and excretion of calcium, uric acid, creatinine and GAGs is given as SI units. The significance of the changes in the urinary concentration of these substances after diclofenac sodium therapy was determined by Student’s t test for paired samples. The relationship between 24-h urinary excretion of uric acid and GAGs was determined by correlation coefficient.

Results

There were 10 male and 2 female patients in this study and their ages ranged from 21 to 48 years (mean 30.9 f 7.22). No adverse effects from diclo- fenac sodium therapy were noted. The results of the urine biochemistry prior to treatment and 2 weeks and 4 weeks following diclofenac sodium administration are shown in the Table. There was no significant change in the 24-h urinary volume after diclofenac sodium and no significant differ- ence in the urinary concentration of crleatinine, uric acid and GAGs after 2 and 4 weeks of treatment. The 24-h urinary excretion of calcium decreased from 4.58 k 1.54 mmo1/24 h to 3.35 k 1.49 mmol/ 24 h after 2 weeks (P<O.Ol) and to 3.22k 0.66 mmo1/24 h (P < 0.01) after 4 weeks of treat- ment with diclofenac sodium.

The urinary concentration of calcium decreased from 4.4 k 2 mmol/L to 3.32 f 1.44 mmol/L at 2 weeks (P<O.O2) and to 3.32 t 2.6 rnmol/L at 4

weeks (P ~ 0 . 0 5 ) . There was no correlation between the urinary uric acid and GAGs concentration in the three 24-h urine samples. There was no significant difference in the urinary concentration of calcium between sample 2 and sample 3.

Discussion

The non-steroidal anti-inflammatory agent, indo- methacin, was shown significantly to reduce urinary calcium excretion in normal volunteers and in hypercalciuric stone formers (Buck et al., 1981, 1983). The present study has shown that diclofenac sodium decreases both calcium concentration and excretion in traumatic paraplegics and the drug produced no significant adverse effects. Renal prostaglandin activity appears to be an important factor in the mechanism of calciuria in stone formers. Prostaglandins have been shown to influ- ence the tubular transport of calcium while NSAIDs appear to inhibit calcium binding by cell mem- branes (Northover, 1973; Buck et al., 1983). The inhibition of prostaglandin-mediated renal lcr hy- droxylase activity for the synthesis of 1,25 (OH)*D3 could be another mechanism for the reduction in urinary calcium excretion with diclofenac sodium (Wark et al., 1981).

The incidence of renal tract stone formation in traumatic paraplegics has varied between 20 and 68% (Guttmann, 1973). In astudyof 351 paraplegics from World War I1 a stone incidence of 22% was reported (Guttman, 1973). However, in 476 patients treated with intermittent self-catheterisation the incidence was only 1.7% (Guttman and Frankel, 1969). The increased risk of stone formation in paraplegics is far from resolved, especially in developing countries where the medical and nursing care of paraplegics leaves much to be desired. In addition to the control of infection and eradication of urinary stasis, a reduction in the excretion and concentration of calcium would help to reduce the risk of stone formation. Prostaglandin synthetase inhibition with NSAIDs presents a new strategy in the treatment of calcium urolithiasis (Brundig and Borner, 1987). There is a choice of a very wide range of NSAIDs at the present time, but diclofenac sodium appears to have the low& risk of side effects and interactions. The twisting of the 2 aromatic rings towards one another is regarded as its most important structural parameter. Special importance for drug-receptor interaction is attrib- uted to the specific steric configuration. Long-term treatment is not followed by cumulation in the serum, and kidney function need not be a consid-

242 BRITISH JOURNAL OF UROLOGY

Table Urinary Concentration and Excretion of Lithogenic Substances and Inhibitor before and after Therapy with Diclofenac Sodium (50 mg tds)

~

Parameter

~ - ~ ~ ~ ~~~

After 2 weeks After 4 weeks Before therapy ojtherapy of therapy

~

24-h urine volume (ml) Creatinine (c)

Calcium (c)

Uric acid (c)

GAGs(c)

(el

( 4

( 4

( 4

1188k53 7.04 k 2.48 8.36 f 2.94 4.37 f 2.08 4.58 k 1.54 1.82k0.99 2.16k1.17 0.07 f 0.077

0.083 k0.091

~

1208f65 6.63 f 2.04 8.01 k2.46 3.32+ 1.44* 3.35k1.491 2.11 kO.81 2.55 f 0.97 0.06 f 0. f 048 0.07 k0.057

~

1425 k 76 7.43 f 2.21

10.58 k 3.14 3.32 f 2.67t 3.22 & 0.661 1.89k1.15 2.69k 1.64 0.07 k0.05 0.09 k 0.07

c = concentration (mmol/L) e = excretion (mmo1/24 h) Valuesare expressedasmean fS.D. * P<O.O2, t PiO.05 , 3 P<O.O1.

eration for repeated dosage as the drug is rapidly

Thus diclofenac sodium holds promise in decreas- ing the occurrence of urolithiasis in spinal cord injury patients by lowering the urinary calcium concentration and 24-h urinary excretion of cal- cium. However, its clinical potential in the prophy- laxis of nephrolithiasis in traumatic paraplegics needs to be evaluated by longitudinal clinical studies.

' eliminated (Brundig and Borner, 1987).

Acknowledgements We thank Dr A. K. Hemal, Assistant Professor of Urology, PGIMER, Chandigarh, and Dr H. Sidhu, Lecturer in Biochem- istry, Panjab University, Chandigarh, for their valuable help.

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The Authors S. Sharma, PhD, Research Officer. S. Vaidyanathan, MS, MCh, MAMS, PhD, Associate Professor

S. K. Thind, PhD, Scientist Emeritus, Biochemistry. R. Nath, PhD, FAMS, Professor of Biochemistry. A. Sankaranarayanan, PhD, Associate Professor of Pharmacol-

of Urology.

ogy.

Requests for reprints to: S. Vaidyanathan, Department of Urology, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India.