High levels of UOCR (>32 mg/g) were present in 23% of the patients. An intermeasure agreement between both urine samples was excellent: all normo-oxaluric patients had a normal second oxaluria measure and all hyperoxaluric patients except one again were hyperoxaluric.
Comparison of clinical and biological variables in hyperoxaluric and normo-oxaluric patients showed that pancreatic atrophy (P = .006), clinical steatorrhea at inclusion (P = .004), excessive alcohol intake (P = .04), and long-term diabetes (P <.001) were clinical characteristics more frequent in patients with UOCR >32 mg/g. These patients had a longer duration of disease (9.9 vs 6.3 years), and were more frequently on pancreatic enzymes (73 vs 43%) when compared to normo-oxaluric patients, although these differences were not significant. Among the biological findings, low carotenoids level (P = .04), higher UPCR (P = .02), low fecal elastase-1 level (P <.001), and high fecal acid steatocrit (P = .001) were associated with hyperoxaluria (Tables 1 and 2).
The regression analysis explained 52.7% of the variance of the oxaluria measures with only clinical steatorrhea, high steatocrit level, and pancreatic atrophy as significant predictive variables (Table 3). Inclusion of “pancreatic enzyme therapy” as a binary covariate in the regression analysis, after having removed the nonsignificant covariates, did not modify these associations (data not show). The presence of clinical steatorrhea, steatocrit level >31%, and pancreatic atrophy was associated with a positive predictive value of 100% and a negative predictive value of 86% of having hyperoxaluria.
Altogether, these data show a high prevalence of hyperoxaluria in patients with CP and a significant association with markers of exocrine dysfunction.
Follow-up data on renal function were available in 7/11 (64%) patients with UOCR >32 mg/g and in 27/37 (73%) patients with normo-oxaluria at baseline. The mean duration of follow-up was 904 days, with no difference between patients with or without hyperoxaluria (P = .59). The mean annual decline in eGFR was highly variable in this limited number of patients with longitudinal follow-up, and values of –6.4 ± 3.4 and –0.1 ± 1.9 mL/min/1.73 m2 were observed in patients with UOCR >32 mg/g or ≤32 mg/g, respectively (P = .10). Annual change in eGFR closely correlated with the baseline level of UOCR (Spearman, r = 0.39, P = .02). UOCR >32 mg/g was significantly and independently associated with a higher risk of eGFR loss during follow-up after adjustment for established determinants of renal function decline, including gender, diabetes, bicarbonate level, baseline eGFR, and UPCR (Table 4).
Our study shows for the first time the high prevalence of hyperoxaluria among prevalent patients with CP seen at the outpatient clinic, with almost a quarter of them affected. Enteric hyperoxaluria has also been reported in other malabsorptive disorders such as chronic inflammatory bowel disease, short bowel syndrome, and bariatric surgery.[24–27] In comparison, hyperoxaluria was present in about half of patients following modern bariatric surgery.
We also found a baseline UOCR >32 mg/g to be associated with mean annual eGFR decline rate during follow-up, although this needs to interpreted with caution because of the limited number of patients and the high inter-individual variability in eGFR changes. The clinical expression of hyperoxaluria is extremely variable and depends on its severity, chronicity, etiology, and on the presence of other factors.[10,29] Hyperoxaluria leads to urinary calcium oxalate supersaturation, and eventually the formation and retention of calcium oxalate crystals. This may result in diffuse renal calcifications (nephrocalcinosis) or stones (nephrolithiasis).[10,30–31] Also, calcium oxalate crystal deposits in renal tubules may induce epithelial lesions and tubular necrosis, and crystals can migrate into the interstitium triggering inflammation.[10,32] This “acute oxalate nephropathy” has been reported in patients with inflammatory bowel disease, celiac disease, jejunoileal and gastric bypass, CP, gastrointestinal lipase inhibitor use, and pancreatic carcinoma.[6,24,33–35] Previously impaired renal function, hypovolemia, and poor adherence to pancreatic enzymatic substitution treatment are suspected to increase the risk of developing oxalate nephropathy in patients with CP and hyperoxaluria.[36–37] Further large-scale, prospective studies will be needed to properly examine the impact of high urinary oxalate levels on long-term kidney function in patients with CP.
We used spot urine samples normalized to creatinine to determine oxaluria. This has recently emerged as a reliable and easy alternative to 24-hour urine oxalate quantification, much alike the now universally adopted urinary albumin to creatinine ratio in the context of chronic kidney disease.[38–40] Studies have shown the absence of significant diurnal pattern of UOCR.[39,41] Additionally, there was a good agreement between the 2 oxaluria measures in our patients.
The limitations of our study are the inclusion of prevalent CP patients, half of them already under treatment. This should intuitively have limited the extent of steatorrhea, thereby limiting the oxaluria. Thus, our results may be an underestimate of the actual prevalence of hyperoxaluria in CP. Although 72-hour fecal fat excretion is still considered as the gold standard for the diagnosis of fat malabsorption, its use is limited in the clinical setting. Several studies have shown acid steatocrit performed on a random stool sample to have a good sensitivity and specificity for the detection of steatorrhea.[13,42,43] Another drawback is the absence of restrictive dietary measures adopted during urine collection. However, Stauffer found urinary oxalate to be not significantly different in normal subjects on controlled diets versus those ingesting a regular diet with added tea. Moreover, we showed a good reproducibility of the oxaluria levels in our patients.
Altogether, we prospectively demonstrated a high (around 25%) prevalence of hyperoxaluria in a selected cohort of CP patients. Hyperoxaluria is associated with clinical and biological signs of intestinal malabsorption and exocrine pancreatic insufficiency, and possibly with eGFR change during a mean follow-up of 2.5 years. Further studies are needed to determine the clinical significance of hyperoxaluria in patients with CP and identify those most likely to benefit from treatment in order to prevent renal complications, including dietary counseling, pancreatic enzyme replacement therapy, use of oxalate binders, and sufficient hydration.
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