Dent's disease: can we slow its progression?

Helen K Burgess, Satishkumar A Jayawardene and Nestor Velasco

Renal Unit, Mayday University Hospital, London Road, Thornton Heath, Surrey CR7 7YE, UK

Sir,

Dent's disease is a syndrome of low molecular weight proteinuria, hypercalciuria, aminoaciduria and hypophosphataemia. It was first described by Dent and Friedman in 1964 in two unrelated boys with rickets [1]. The condition is familial, affecting both males and females in equal numbers, but males are more severely affected than females. In males, it tends to present in childhood or early adult life with symptoms of renal calculi, rickets or even with renal failure. It is still unclear as to exactly why and what proportion of sufferers progress to end-stage renal failure (ESRF). The nephrolithiasis associated with Dent's disease usually takes the form of nephrocalcinosis [2]. It is thought that the decline in renal function may be partially due to the infection and obstruction associated with nephrocalcinosis. This however, cannot be the sole reason, as some patients have reached ESRF with no evidence of it [2]. In renal transplant recipients, there is no recurrence of stone disease within the renal allograft, suggesting an intrinsic renal problem [3]. In the largest study of patients with Dent's disease, nine out of 15 men and one out of 10 women reached ESRF (at a mean age of 47 years) [2]. At present there is no strategy for the treatment of patients other than supportive measures.

Case History.

In November 1993, a family consisting of both parents and their three sons was referred to the renal clinic following a routine health check with their General Practitioner. This had revealed proteinuria on dipstix testing in all members of the family except the youngest son. The parents showed only trace protein but the two elder sons had 3+ and 2+ protein on urinalysis. Of note in the family history was a maternal uncle who was also being investigated for proteinuria.

Case 1.

At presentation the eldest son was 16 years old. He was asymptomatic and normotensive with no abnormalities on physical examination. Initial investigations revealed a normal serum sodium of 140 mmol/l (NR 135–145 mmol/l), serum potassium of 4.7 mmol/l (NR 3.4–5.2 mmol/l), serum urea concentration of 5.0 mmol/l (NR 1.7–8.3 mmol/l), and serum creatinine concentration of 157 µmol/l (NR 63–107 µmol/l). A 24-h urine collection revealed a creatinine clearance of 92 ml/min (NR 80–120 ml/min) and proteinuria of 3.45 g/24 h (NR 0–0.1 g/24 h). A renal ultrasound was unremarkable and a renal biopsy failed to establish a diagnosis. The patient had normal audiometry and slit lamp eye examination. In 1997, the maternal uncle was suspected of having Dent's disease. At this time the patient's urine was positive for aminoaciduria and he had an elevated urinary calcium excretion (24.13 mmol/24 h (NR 2.5–7.5 mmol/24 h)).

The patient was therefore diagnosed with Dent's disease and started on hydrochlorthiazide (25 mg per day) in an attempt to reduce his hypercalciuria. Prior to treatment, the patient had abnormal renal function (urea 7.8 mmol/l and creatinine 157 µmol/l) but a normal serum calcium level (2.27 mmol/l (NR 2.15–2.55 mmol/l)). His creatinine clearance had deteriorated to 62 ml/min and his proteinuria was still significant at 3.06 g/24 h. His calcium excretion was elevated at 25.18 mmol/24 h. At this time his height was 1.85 m and weight 83.4 kg.

Over the last 2 years, whilst taking his thiazide diuretic, the patient's calcium excretion has reduced to 18.21 mmol/24 h, then to 9.61 mmol/24 h, and most recently to 14.46 mmol/24 h. His most recent blood tests show normal electrolytes (sodium 144 mmol/l, potassium 3.7 mmol/l) and unchanged renal function (urea 6.3 mmol/l, creatinine 153 µmol/l). He has reported no adverse effects of the diuretic such as hypotension or dehydration, and has had no symptoms to suggest renal calculi.

Case 2.

The younger son was aged 15 years at presentation. He also had no symptoms or physical signs in 1993. At this time, his renal function showed serum electrolytes (sodium 137 mmol/l, potassium 4.5 mmol/l) and a serum urea concentration of 6.8 mmol/l and a serum creatinine concentration of 197 µmol/l. Creatinine clearance was reduced at 57 ml/min and he had proteinuria of 2.90 g/24 h. A renal ultrasound was unremarkable and a renal biopsy was not performed in this case. He had normal audiometry and slit lamp eye examination. In 1997, he was also diagnosed with Dent's disease when his urine was positive for aminoaciduria and his urinary calcium excretion 13.38 mmol/24 h. A KUB X-ray showed early nephrocalcinosis. He was also started on a thiazide diuretic to reduce his hypercalciuria. In this case, bendrofluazide at 2.5 mg per day was prescribed. Prior to treatment his serum electrolytes were normal (sodium 139 mmol/l, potassium 3.8 mmol/l), and his renal function still abnormal (serum urea concentration 7.2 mmol/l, serum creatinine concentration 194 µmol/l). His corrected serum calcium was 2.34 mmol/l. At this time his height was 1.77 m and his weight was 75.5 kg.

Over the following 2 years, the patient's calcium excretion improved to 10.95 mmol/24 h and then to 9.5 mmol/24 h. His most recent results showed a calcium excretion of 4.8 mmol/24 h and an improved creatinine clearance of 66 ml/min. His serum sodium concentration was normal but his serum potassium was slightly low at 3.1 mmol/l. His serum urea concentration and serum creatinine concentration were essentially unchanged (8.2 mmol/l and 181 µmol/l, respectively). His 24-h proteinuria was lower at 1.44 g/24 h. He has also had no side effects from his thiazide diuretic, and has had no symptoms attributable to renal calculi.

Discussion.

The term Dent's disease comprises a whole group of familial tubular syndromes including: X-linked recessive nephrolithiasis with renal failure, X-linked recessive hypophosphataemic rickets, and both Japanese and idiopathic low molecular weight proteinuria [4]. These all share a common aetiology, having now been shown to be due to genetic mutations in the renal chloride channel CLCN5. Loss of function of this channel causes a proximal tubular defect and leads to the hypercalciuria and nephrolithiasis of Dent's disease. The exact mechanism for this and the low molecular weight proteinuria is still not fully understood [5]. There is however, evidence that the CLCN5 channel is expressed in the proximal tubule and the thick ascending limb of the loop of Henle, which are both sites of calcium transport [6].

Although Dent's disease is now well reported and the genetic mutations responsible have been identified, there is still no clear strategy for the management of patients with this condition. Thiazide diuretics have been used for many years in the prevention of the recurrence of nephrolithiasis. They have also been successful in the treatment of idiopathic hypercalciuria in children and have been found to reduce these patients' daily urinary calcium excretion [7]. They act on the distal renal tubule to enhance the reabsorption of calcium at this point, therefore reducing the hypercalciuria and decreasing the risk of progression to renal calculi [8,9].

Thiazide diuretics have also been used anecdotally in patients with Dent's disease. In one report in 1980, hydrochlorthiazide was used in a case of hypercalciuric rickets. It succeeded in reducing the daily urinary calcium excretion but was associated with such severe nausea and weakness that it had to be discontinued [10]. The authors felt that their patient was similar to those described by Dent and Friedman [1]. Another patient with Dent's disease was studied as an inpatient to assess daily changes in his urinary calcium excretion whilst on treatment with hydrochlorthiazide. After 4 days of treatment, his calcium excretion had fallen from 11.7–12.2 mmol/24 h to 0.6–2.0 mmol/24 h, at which point his diuresis was so marked that he became symptomatic and required sodium and potassium replacement and treatment was stopped. Subsequent follow-up revealed that a strict dietary restriction of calcium was not sufficient to control his hypercalciuria [2]. Only one case has reported any success with thiazide diuretics. This was a patient with bilateral renal calculi, whose urinary calcium excretion was reduced from 10.1 mmol/24 h to 4.5 mmol/24 h by the administration of bendrofluazide. Ten years after diagnosis, his plasma creatinine had risen from 152 µmol/l to 340 µmol/l and he required laser treatment for his renal calculi [2].

Thiazide diuretics were used in our two cases with reasonable success in reducing urinary calcium excretion, although in only one of the patients was urinary calcium excretion reduced to normal levels. There were no significant side effects. In addition to this, after 2 years of treatment, there had been no deterioration in renal function. There is no long-term information regarding the use of thiazide diuretics in Dent's disease. It is conceivable that by reducing hypercalciuria we can reduce the risk of nephrolithiasis/nephrocalcinosis and hopefully slow down the natural progression to ESRF.

References

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