Absorptive Hyperoxaluria Leads to an Increased Risk for Urolithiasis or Nephrocalcinosis in Cystic Fibrosis

doi:10.1053/j.ajkd.2005.06.003

American Journal of Kidney Diseases

Volume 46, Issue 3, September 2005, Pages 440-445

https://doi.org/10.1053/j.ajkd.2005.06.003 Get rights and content

Background: Hyperoxaluria has been incriminated to account for the increased incidence of urolithiasis or nephrocalcinosis in patients with cystic fibrosis (CF). Hyperoxaluria presumably is caused by fat malabsorption and the absence of such intestinal oxalate-degrading bacteria as Oxalobacter formigenes. To better elucidate its pathophysiological characteristics, we prospectively studied patients with CF by determining these parameters and performing renal ultrasonography twice yearly. Methods: In addition to routine tests in urine (lithogenic and stone-inhibitory substances), the presence of O formigenes was tested in stool, plasma oxalate was measured, and a [¹³C₂]oxalate absorption test was performed in 37 patients with CF aged 5 to 37 years (15 females, 22 males) who were constantly hyperoxaluric before the study. Results: Hyperoxaluria (oxalate, 46 to 141 mg/1.73 m²/24 h [0.51 to 1.57 mmol/1.73 m²/24 h]; normal, <45 mg/1.73 m²/24 h [<0.5 mmol/1.73 m²/24 h]) was now found in 24 patients (64.8%). Plasma oxalate levels were elevated in 6 patients (7.92 to 19.5 μmol/L; normal, 6.3 ± 1.1 μmol/L). Oxalobacter species were detected in only 1 patient. Intestinal oxalate absorption was elevated (11.4% to 28.5%; normal, <10%) in 23 patients. Hypocitraturia was present in 17 patients (citrate, 0.35 to 2.8 g/1.73 m²/24 h [0.2 to 1.1 mmol/1.73 m²/24 h]; normal female, >2.8 mg/1.73 m²/24 h [>1.6 mmol/1.73 m²/24 h]; male, >3.3 mg/1.73 m²/24 h [>1.9 mmol/1.73 m²/24 h]). Urine calcium oxalate saturation was elevated in 17 patients (5.62 to 28.9 relative units; normal female, <5.5 relative units; male, <6.3 relative units). In 16% of patients, urolithiasis (n = 2) or nephrocalcinosis (n = 4) was diagnosed ultrasonographically. Conclusion: Absorptive hyperoxaluria and hypocitraturia are the main culprits for the increased incidence of urolithiasis and nephrocalcinosis in patients with CF. We advocate high fluid intake, low-oxalate/high-calcium diet, and alkali citrate medication, if necessary. Additional studies are necessary to determine the influence of Oxalobacter species or other oxalate-degrading bacteria on oxalate handling in patients with CF.

Section snippets

Methods

Eighty-two patients with CF (33 females, 49 males) with different grades of clinical severity currently are under our care. Of 63 initial patients with CF followed up since 1993,² 6 patients died of worsening pulmonary function. Of the surviving 57 patients, 2 patients underwent successful lung transplantation and 1 patient developed a testicular tumor. An additional 25 patients were included in our follow-up procedure since 1998. In all our patients, urine analysis for lithogenic and

Results

Hyperoxaluria was found in 24 patients (10 females, 14 males; oxalate range, 46 to 141 mg/1.73 m²/24 h [0.51 to 1.57 mmol/1.73 m²/24 h]; normal, <45 mg/1.73 m²/24 h [<0.5 mmol/1.73 m²/24 h]¹⁸). There was no specific difference in oxalate excretion between sex or age groups. Intestinal O formigenes was detected in only 1 patient.

Plasma oxalate levels were elevated in 6 patients with hyperoxaluria (7.92 to 19.5 μmol/L; normal, <6.3 ± 1.1 μmol/L¹²). All patients had normal kidney function, with an

Discussion

Patients with CF have an increased risk for urolithiasis or nephrocalcinosis.1, 2, 3, 4, 5, 6, 7, 8, 9 We and others suggested that this is caused primarily by secondary hyperoxaluria resulting from fat malabsorption and the lack of such intestinal oxalate-degrading bacteria as O formigenes.2, 3, 10 We now show that the secondary hyperoxaluria is caused by increased intestinal absorption of oxalate in the majority of patients with hyperoxaluria (79%). In comparison to previous data, we now

Acknowledgment

The authors thank Ernst Leumann, Zurich, Switzerland, for editorial advice; Gabriele Benz-Bohm for renal ultrasound examinations; S. van Koningsbruggen for her support in patient recruiting; nurses of the CF centers of the University of Cologne for obtaining urine and stool samples; and A. Gradehand (University of Cologne), B. Bär, and M. Klöckner (University of Bonn) for laboratory assistance.

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A6 is physically or structurally associated with cystic fibrosis transmembrane conductance regulator (CFTR) (Lohi et al., 2003; Wang et al., 2006). Moreover, in patients with cystic fibrosis, CFTR dysregulation was observed to be associated with enhanced oxaluria (Gibney and Goldfarb, 2003; Hoppe et al., 2005; Knauf et al., 2017). The present study shows that enhanced estrogen level attenuates oxalate or bicarbonate transporting activity through A6 in A549 lung cancer cells.
Estrogen therapy has used to prevent bone loss in postmenopausal women. Although therapeutically enhanced estrogen levels have been suggested, patients are exposed to greater risks of nephrolithiasis and cancer. It has been known that oxalate or bicarbonate transporter SLC26A6 is involved in oxalate homeostasis and its deletion results in kidney stone formation and addressed that patients with kidney stones possess higher cancer risk. Thus, the mechanism of the interaction between estrogen and SLC26A6 and the effect of SLC26A6 on cancer cells should be elucidated. In this study, we investigated whether β-estradiol treatment modulates SLC26A6 expression and its bicarbonate or oxalate transporting activity and affects the proliferative and migratory ability of A549 cells. The β-estradiol stimulation attenuated oxalate or bicarbonate transporting activities through SLC26A6. Knockdown of SLC26A6 reduced transporter activity whereas enhanced cellular migration. β-estradiol-mediated cellular migration was independent of SLC26A6 transporter activity, whereas enhanced SLC26A6 expression attenuated cellular migration even in the presence of β-estradiol treatment. These results indicate β-estradiol treatment enhances cancer cell migration and dysregulates oxalate transport by inhibiting SLC26A6 activity, suggesting reduced oxalate transporting activity may involve in the oxalate homeostasis.
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The objective of this chapter is to provide an overview of our current understanding of the mechanisms underlying absorption of predominant anions [chloride and short-chain fatty acids (SCFAs)] and the regulation of anion transporters in the mammalian intestine. As a result of the availability of knockout mouse models and models of intestinal diseases, novel mechanisms regulating the expression, trafficking, and function of the key anion transporters in response to various physiological and pathophysiological conditions have been elucidated. New data on the fine structural details of the anion transporters (such as the N-glycosylation) and the role of some of these anion transporters as tumor suppressors have come to surface. This has been reviewed in detail in this chapter. In addition, this chapter also reviews briefly the anion transporters involved in the absorption of sulfate and oxalate. However, mechanisms of absorption of phosphate will not be included here and will be presented in another chapter of this book. Since, the general mechanisms of intestinal electrolyte transport and the physiology of their integration are being addressed elsewhere in the book, the focus of the current chapter is, therefore, more on recent advances in the molecular identity and regulation of the transporters involved in Cl⁻ and SCFA⁻ absorption under normal and disease states.
Comprehensive morpho-constitutional analysis of urinary stones improves etiological diagnosis and therapeutic strategy of nephrolithiasis
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Type Ie stones are also indicative of specific pathogenic conditions associated with marked hyperoxaluria resulting from an intestinal dysfunction of diverse origins. This ‘enteric hyperoxaluria’ is observed in inflammatory bowel diseases, especially after ileal resection for Crohn's disease, in children with cystic fibrosis with a severe pancreatic deficit [8], and after bariatric surgery such as jejuno-ileal bypass or Roux-en-Y gastrojejunal bypass, which sometimes may result in heavy hyperoxaluria [9–13]. Type Ie calculi exhibit a locally budding, mammillary or rough brown-yellow pale surface, and a heterogeneous structure, with a mixture of poorly organized brown-yellow pale areas and of locally concentric dark brown layers with a radiating organization.
The generalized use of physical methods, X-ray diffraction and Fourier transform infrared spectroscopy (FTIR) decisively improved urinary stone analysis by allowing to accurately identify the chemical nature, crystalline phases and relative proportions of stone constituents. Such compositional analysis is sufficient to identify stone diseases involving a single specific component such as cystine, 2,8-dihydroxyadenine (DHA), struvite, uric acid, ammonium hydrogen urate or a drug. However, for common calcium nephrolithiasis, which represents by far the largest part of urinary stones throughout the world, the simple identification of calcium oxalate (CaOx) and/or calcium phosphate (CaP) as constituents provides incomplete etiologic information because a same elemental stone composition may result from different lithogenic processes.
A more comprehensive method combining careful morphologic examination of the surface and the section of stones with detailed FTIR analysis of the nature, location, crystalline phases and a respective proportion of stone constituents, therefore termed ‘morpho-constitutional’ analysis, as used in our laboratory for four decades provides more complete etiologic information. In common idiopathic CaOx nephrolithiasis, the predominance of the monohydrate form (COM) was shown to be associated with elevated urine Ox concentration, whereas the dihydrate form (COD) was associated with hypercalciuria, thus orienting dietary and/or pharmacological intervention. A major contribution of the method is to immediately orient the diagnosis of rare, but severe, diseases leading to a loss of renal function, when stone analysis reveals a peculiar morphology of common constituents. The most salient examples are the type Ic morphology of COM stones, pathognomonic of primary hyperoxaluria, type Ie morphology, which is highly suggestive of absorptive hyperoxaluria as seen in inflammatory bowel diseases and pathologies inducing steatorrhea, type IIId morphology of ammonium urate stones, which orientates towards chronic diarrhea with dietary imbalance and loss of electrolytes, and type IVa2 morphology of carbapatite, specific of distal renal tubular acidosis of congenital or acquired origin, and distinctive aspect of 2,8-DHA stones. In conclusion, the proposed morpho-constitutional method should be recommended for routine stone analysis, inasmuch as it is simple, rapid, reliable, clinically relevant and cost-effective.
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Originally published online as doi:10.1053/j.ajkd.2005.06.003 on August 1, 2005.

Supported in part by grants Un 91/3 and He 1132/11-4 from the Deutsche Forschungsgemeinschaft. H.S. is affiliated with Ixion Biotechnology Inc, Alachua, FL, which performs specific studies in Oxalobacter research.

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Original investigationPathogenesis and treatment of kidney disease and hypertensionAbsorptive Hyperoxaluria Leads to an Increased Risk for Urolithiasis or Nephrocalcinosis in Cystic Fibrosis

Section snippets

Methods

Results

Discussion

Acknowledgment

J Pediatr

J Urol

J Urol

Kidney Int

J Chromatogr B

Clin Chim Acta

J Urol

J Urol

Kidney Int

Kidney Int

Gastroenterology

J Urol

Urinary excretion substances in cystic fibrosisRisk of urolithiasis?

Pediatr Nephrol

Oxalate and calcium excretion in cystic fibrosis

Arch Dis Child

Original investigation
Pathogenesis and treatment of kidney disease and hypertension
Absorptive Hyperoxaluria Leads to an Increased Risk for Urolithiasis or Nephrocalcinosis in Cystic Fibrosis