The impact of sodium chloride and volume depletion in the chronic kidney disease of congenital chloride diarrhea

Abstract

Congenital chloride diarrhea is due to mutations in the intestinal Cl(-)/HCO(3)(-) exchange (SLC26A3) which results in sodium chloride and fluid depletion leading to hypochloremic and hypokalemic metabolic alkalosis. Although treatment with sodium and potassium chloride offers protection from renal involvement in childhood, the long-term renal outcome remains unclear. Here we describe two cases of congenital chloride diarrhea-associated end-stage renal disease with transplantation. Further, we show that there is a high incidence of mild chronic kidney disease in 35 other patients with congenital chloride diarrhea. The main feature of the renal injury was nephrocalcinosis, without hypercalciuria or nephrolithiasis with small sized kidneys and commensurately reduced glomerular filtration rates. This suggests that diarrhea-related sodium chloride and volume depletion, the first signs of non-optimal salt substitution, promote urine supersaturation and crystal precipitation. The poor compliance with salt substitution along with long-lasting hypochloremic and hypokalemic metabolic alkalosis is likely to induce progressive calcification and renal failure. Both our patients developed nephrocalcinosis in the transplanted kidneys suggesting that this complication is a consequence of intestinal SLC26A3 deficiency. Interestingly, the transporter is expressed in the distal nephron but the recurrence of nephrocalcinosis in the transplanted kidney suggests that it does not play a significant renal role in this syndrome.

Transcellular oxalate and Cl−absorption in mouse intestine is mediated by the DRA anion exchanger Slc26a3, and DRA deletion decreases urinary oxalate

“…Absorptive and secretory processes for oxalate along the nephron could participate in determining urinary oxalate excretion, but the contribution of DRA to this is likely to be minimal, as it is frequently not detected in renal tissues. DRA expression has only been reported for the human kidney (43), whereas studies with mouse (37; unpublished observations), rat (3), and rabbit (24) renal cortex failed to detect the Slc26a3 gene product. The impact of intestinal DRA on oxalate homeostasis in humans does not appear to be as dramatic as seen here in mice, since Cl Ϫ -losing diarrhea patients have been reported to have a median daily excretion ratio of oxalate to creatinine of 0.012 (43), which is similar to that reported (30) for a population of healthy adults (0.016).…”

“…Urinary oxalate excretion in KO mice was 30% of that measured in WT mice, highlighting the contribution of transcellular intestinal absorption to oxalate homeosta- sis. Since there is little evidence for a significant presence of the DRA protein in renal tissues (43), the reduction of oxalate excretion in DRA KO mice is most likely associated with the decrease in intestinal absorption. Finally, DRA KO mice exhibited a 60% reduction of serum oxalate, which was significantly lower than in the controls.…”

Congenital Chloride Losing Diarrhea

“…In addition, it has been shown that butyrate is also able to inhibit both basal and adenosine 3_,5_-cyclic monophosphatestimulated Cl_ secretion in a dose-dependent manner [41]. Finally, the trophic effects elicited by short chain fatty acids on intestinal mucosa (mediated through circulatory, hormonal, and neural mechanisms) could contribute to improvement in diminishing severity of diarrhea in the CLD patient [37,41].…”

“…It is easily administered, useful in preventing severe dehydration episodes, and may be a promising therapeutic approach for a long-term treatment in this rare and severe condition [37].…”

“…Chronic hypovolemia itself causes a series of secondary effects. An increase in renin and angiotensin concentrations, with secondary hyperaldosteronism, results in vascular changes in the kidney resembling those seen in hypertension, even when these patients have normal blood pressure [37]. Chronic potassium depletion results in impaired functioning of renal tubular and intestinal absorptive cells [37,38].…”