Abstract
Introduction
Patients with short bowel syndrome (SBS) may exhibit enteric hyperoxaluria (EH), and the prevalence of oxalate nephropathy in SBS is likely underestimated. Plasma oxalate (POx) is a surrogate of systemic oxalate deposition and, consequently, may increase the risk of developing chronic kidney disease (CKD). The main objective of this study was to explore the distribution of POx levels in patients with SBS.
Methods
Patients followed for SBS were recruited prospectively in the OXAGO study (NCT04119765) to assess POx during their annual renal follow-up including iohexol clearance. The inclusion criteria were age ≥18 years, and SBS type 2 and type 3 for more than 6 months.
Results
A total of 47 patients were included but only 45 patients has a measured POx (55% males, 80% SBS type 2, 66% parenteral nutrition, 61% kidney stone history). POx levels were 6.8 ± 4.4 μmol/l, 29% of patients had POx ≥5 μmol/l. In the whole cohort, mean urinary oxalate (UOx) was 648±415 and 54% were >500 μmol/24h. In the group of patients with high POx levels (HPO), 24-hour urine oxalate was significantly higher than in the group with normal POx levels (NPO) (919 ± 566 vs. 526 ± 257 μmol/l; P = 0.003). Glomerular filtration rate (GFR) was 66 ± 22 ml/min per 1.73 m2, and 91% had CKD. GFR was significantly lower in the HPO than in the NPO group (49 ± 23 vs. 73 ± 18 ml/min per 1.73 m2; P = 0.0005.
Conclusion
Patients with SBS can display increased POx levels even with GFR >30 ml/min per 1.73 m2. POx may be an interesting biomarker to assess the severity of EH.
Keywords: enteric hyperoxaluria, plasma oxalate, short bowel
Graphical abstract
SBS results from the loss of a significant length of the small intestine (less than 180 cm), which leads to malabsorption of fluids, electrolytes, and nutrients.1,2 SBS can be divided in 3 categories as follows: (i) end-jejunostomy with no colon in continuity (type 1), (ii) jejuno-colic anastomosis with no ileocecal valve and a part of the colon in continuity (type 2), and (iii) jejuno-ileal anastomosis with both the ileocecal valve and the entire colon in continuity (type 3).1,2 This intestinal resection can occur after severe Crohn's disease, mesenteric ischemia, malignancy, or abdominal trauma.2 In this population, a decrease in GFR and renal perfusion has already been reported.3 Buchman et al.4 described reduced kidney function in approximately 50% of these patients and a decline of 3.5% per year in creatinine clearance. CKD progression is often multifactorial and can be related to intestinal failure as well as age, infections, dehydration, hypovolemic state, nephrolithiasis, and oxalate nephropathy. Indeed, oxalate stones are known to occur in patients with SBS type 2 or 3, and are linked to EH resulting from hyperabsorption of oxalate in the colon. The prevalence of oxalate renal stones in patients with SBS is from 15% to 60%.2
A recent review reported case series of oxalate nephropathy, due, most of the time, to EH.5 Among these patients, no nephrocalcinosis is described on renal ultrasounds. Buysschaert et al. retrospectively screened kidney biopsies and identified 1% with oxalate nephropathy; majority of patients with malabsorptive state.6 In all these case series, POx is not often measured although POx can be viewed as a biomarker helping to estimate systemic oxalate accumulation.7 POx is traditionally measured in primary (genetic) hyperoxaluria, an inherited disease leading to endogenous oxalate overproduction by the liver; in such cases, POx is often predictive of the severity of the disease.8,9 Oxalate is also considered as a uremic toxin10; therefore, its accumulation reflects the risk of GFR progression and the severity of systemic disease and cardiovascular outcomes, as recently published in the German 4D cohort in dialysis.11 Nevertheless, there has also been evidence demonstrating an association between 24-hour UOx levels and the risk of CKD progression.12,13 Assessing whether 24-hour urine oxalate or increased POx is a superior indicator for determining CKD risk presents a challenge; both measures could prove beneficial.
Oxalate nephropathy in SBS is likely underestimated, and the causality of plasma or urine oxalate is impossible to assess without renal biopsy, that is rarely performed in this clinical setting. Yang et al. reported a lower estimated GFR (eGFR) in patients with SBS with kidney stones than in patients without, highlighting that these patients could also have more calcium oxalate deposits in their tubules than expected.14 Bering et al.15 reported bone marrow oxalosis in patients with SBS, demonstrating the utility of estimating oxalate overload. Peringram reported an early increase in POx in EH, even for eGFR > 30 ml/min per 1.73m2.16 Therefore, we hypothesized that POx could be a biomarker of severity of renal involvement in patients with SBS.
The main objective of the study was to explore the distribution of POx in EH for patients with SBS and confirm previous observations of early increased POx in patients with EH. The second objective was to find associations between POx and renal, intestinal, or nutritional parameters.
Methods
Study Design
We conducted a prospective pilot study approved by the Comité de Protection des Personnes Nord-Ouest III (n°2019-a02496-51) according to the Good Clinical Practice–International Conference on Harmonization guidelines and the Declaration of Helsinki. Informed consent was obtained from all participants. This OXAGO study was recorded as NCT04119765. Participants were included from February 2020 to May 2022.
Participants were recruited from Home Parenteral Nutrition Center for chronic intestinal failure where patients with SBS are followed-up with. The inclusion criteria were age ≥18 years, type 2 or type 3 short bowel for more than 6 months, and affiliated to a social health care. The exclusion criteria were primary hyperoxaluria suspicion and short bowel type 1 (patients without colon and not expected to have hyperoxaluria). Because we wanted to compare our SBS group to control group, we used prospectively previous published data from our unit to compare POx distribution.17
Outcomes
The primary outcome was POx distribution in type 2 and type 3 SBS. Secondary outcomes were association between POx and renal history, bowel length or remaining colon, UOx concentration, intestinal biomarkers, and vascular dysfunction.
Study Population
Patients’ demographic data were collected, including age, gender, body mass index, as well as medical and surgical history. The small bowel lengths and residual colon were obtained from the patients’ surgical reports. The duration of SBS was defined as the time interval between SBS diagnosis and the last hospital visit.
Patients were asked about their past history of kidney stones. Patients were classified as having nephrolithiasis if they had been definitively diagnosed with kidney stones after SBS diagnosis, or if symptomatic or asymptomatic kidney stones were confirmed on abdominal imaging (computed tomography, magnetic resonance imaging, or ultrasound). If available, stone analysis were also recorded.
Blood and Urine Analysis
Usual metabolic analyses were conducted for their annual follow-up, including measurement of sodium, potassium, chloride, bicarbonate, creatinine, calcium, phosphorus, parathyroid hormone, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, magnesium, uric acid, renin, aldosterone, albumin, prealbumin, C-reactive protein, citrulline, hydroxyproline, glycine, vitamin C, and B6. In addition, participants provided a 24-hour urine collection to measure the determinants of urinary supersaturation, such as creatinine, urea, sodium, potassium, calcium, citrate, oxalate, uric acid, phosphate, pH, density, and crystalluria. Renal function was eGFR and measured GFR (mGFR) by iohexol clearance, as previously described.18 CKD stage was defined using mGFR. For some patients, the following intestinal function tests and stool analyses were performed: D xylose test, breath test, fecal elastase, fecal calprotectine, alpha antitrypsine, and steatorrhea. Plasma renin activity is measured by chemiluminescence on an automated ISYS IDS system calibrated according to the international standard WHO 68/356 (1.67 mU/l = 1 ng/l).
POx and UOx
POx and UOx were measured using stable isotope dilution gas chromatography-mass spectrometry with 13C2-oxalate as internal standard.
Blood was collected in dry tube and sent in dry ice to the laboratpry within 1 hour. After centrifugation, serum was frozen at −80 °C and acidification to achieve pH <2 is performed the day of measurement. For UOx, 24-hour urine was collected and acidified with HCl to achieve pH <2. Liquid/liquid extraction using ethylacetate was performed before gas chromatography-mass spectrometry analysis and quantification using external calibration. Creatinine dosage was performed simultaneously, allowing to determine the ratio of oxalate to creatinine. Limit of quantification for oxalemia is 5 μmol/l and reference range is <5μmol/l. Oxaluria interpretation requires age-matched reference ranges.
Statistical Analysis
We evaluated the distribution of continuous variables by calculating mean ± SD and categorical variables by number (percentage) in the whole data set, as well as in subgroups according to study population characteristics. Groups were compared with nonparametric tests (Mann and Withney). The P-value for significance was 0.05. Statistical analysis was performed using GraphPad software (GraphPad Softwareversion9.1.2).
Results
Patients’ Characteristics
A total of 47 patients were included but only 45 POx levels were measured. Mean age was 60.5±15.3 years, 55% were male, body mass index was 22.3 ± 3.6 kg/m2, 80% were with type 2 of SBS, 66% benefited from parenteral nutrition. Among these patients, 58% had a history of kidney stone; mGFR was 66 ± 22 ml/min per 1.73 m2; most of them (91%) displayed CKD; 8.8% stage 4, 26.6% stage 3, 51.1% stage 2, and 13.3% with mGFR> 90 ml/min per 1.73 m2. Forty percent were considered to have sodium depletion based on renin values. All patients’ characteristics are described in Table 1. All nutrition characteristics are described in Table 2.
Table 1.
Patients’ characteristics
| Characteristics (mean ± SD) | Patients (N = 45) |
|---|---|
| Age (yr) | 60.5 ± 15.3 |
| Male, % | 50 % |
| BMI (kg/m2) | 22.3 ± 3.6 |
| Plasma oxalate (μmol/l) | 6.8 ± 4.4 |
| mGFR (ml/min per 1.73 m2) | 66 ± 22 |
| HCO3- (mmol/l) | 24 ± 4 |
| Potassium (mmol/l) | 4.2 ± 0.6 |
| Calcium (mmol/l) | 2.25 ± 0.14 |
| Phosphate (mmol/l) | 1.0 ± 0.2 |
| PTH (ng/l) (Normal value 15–65) | 57 ± 37 |
| 25OHvit D (nmol/l) | 65 ± 32 |
| Na reabsorption fraction (%) | 99.2 ± 0.7 |
| Cl reabsorption fraction (%) | 98.9 ± 0.6 |
| Increased renin (%) | 40 % |
| Urine volume (l) | 1.2 ± 0.6 |
| Urine sodium (mmol/24h) | 103 ± 61 |
| Urine calcium (mmol/kg/j) | 0.03 ± 0.3 |
| Urine citrate (mmol/24h) | 0.6 ± 0.84 |
| Urine oxalate (μmol/24h) | 648 ± 415 |
| Positive crystalluria | 38% |
| Kidney stone history | 58% |
| Intestinal characteristics and function | |
| Type 2 SBS | 80% |
| SBS vintage (mo) | 117 ± 113 |
| Parenteral nutrition | 66% |
| Underlying disease | |
| Mesenteric ischemia, % (n) | 40% (18) |
| volvulus, % (n) | 31% (14) |
| neoplasia, % (n) | 9% (4) |
| Inflammatory bowel, % (n) | 4% (2) |
| Others, % (n) | 16% (7) |
| Remaining small bowel length (cm) | 86 ± 40 |
| Mean partial colon (%) | 72% |
| Fecal elastase (n = 30) (μg/g) | 206 ± 174 |
| Alpha-1-antitrypsin clearance (n = 32) (ml/day) | 22 ± 22 |
| Steatorrhea to lipid absorption ratio (n = 27) (g/day) | 43 ± 22 |
| D xylose absorption test (n = 33) (mmol/l) | 0.52 ± 0.33 |
| Bacterial overgrowth, n (%) | 22 (66%) |
| Medications | |
| calcium, n (%) | 27 (57 %) |
| Pancreatic enzymes, n (%) | 18 (39%) |
| Vitamin C, n (%) | 24 (51%) |
| Oral antibiotics for intestinal bacterial overgrowth, n (%) | 13 (29%) |
25OHvit D, 25 hydroxyvitamin D; BMI, body mass index; HCO3-, bicarbonates; mGFR, measured glomerular filtration rate; PTH, parathyroid hormone; SBS, short bowel syndrome.
Results are expressed in mean ± SD or %.
Table 2.
Nutrition characteristics
| Nutrition characteristics | |
| Patients with parenteral nutrition (%) | 66% |
| Parenteral nutrition | |
| Number a week | 2.7 ± 2.3 |
| Volume (ml)/bag | 1473 ± 575 |
| Calories (Kcal)/bag | 1272 ± 505 |
| Glucose (g)/bag | 165 ± 78 |
| Lipides (g/bag) | 45 ± 16 |
| Amino acids (g/bag) | 54 ± 17 |
| Per os | |
| Volume (ml/d) | 2112 ± 849 |
| Calories (Kcal/d) | 2135 ± 805 |
| Carbohydrate intake (g/d) | 247 ± 86 |
| Lipid intake (g/d) | 84 ± 44 |
| Proteins (g/d) | 86 ± 33 |
| Total volume | |
| Total volume (i.v. + per os) ml/d | 3095 ± 1208 |
POx Distribution
Mean POx was 6.8 ± 4.4 μmol/l (min. POx <5 μmol/l–max. POx 26 μmol/l) (Figure 1a). Among all patients, 29% had a POx ≥5 μmol/l for a mean of 11.5 ± 6.1 μmol/l (Figure 1b).
Figure 1.
Plasma oxalate distribution. (a) Plasma oxalate (POx) distribution. Mean plasma oxalate was 6.8 ± 4.4 μmol/l; (b) plasma oxalate repartition between patients with measurable POx (grey) and patients with POx < 5 umol/l. Among all patients, 29 % of patients had a plasma oxalate ≥5 μmol/l for a mean of 11.5 ± 6.1 μmol/l.
Because Pox seems higher than expected, we compared POx concentration to a CKD cohort that we included in a previous study and considered as a control group.13 In the CKD control group, POx was ≥5 μmol/l only when eGFR was below 10 ml/min per 1.73 m2 (Figure 2a). In our current study, POx was elevated even for eGFR at 81 ml/min per 1.73 m2 (Figure 2b); and was higher in our current study than in our previous study. We matched mGFR between patients with SBS and the control group and we found a significant difference between POx (POx 5±0 μmol/l for the control group [mGFR of 61 ± 24 ml/min per 1.73 m2] vs. POx 6.8 ± 4.4 μmol/l for SBS group [66 ± 22 ml/min per 1.73 m2); P = 0.02; Figure 2c]).
Figure 2.
Relationship between plasma oxalate and mGFR. (a) Plasma oxalate concentration (POx) in function of measured GFR (mGFR) in the control cohort of patients with chronic kidney disease without malabsorption. POx was ≥5 μmol/l only when eGFR was below 10 ml/min per 1.73 m2. (b) Plasma oxalate concentration (POx) in function of measured GFR (mGFR) in the SBS cohort; (c) comparison of POx between matched mGFR control patients and patients with SBS. (POx 5 ± 0 μmol/l for control group [mGFR of 61 ± 24 ml/min per 1.73 m2] vs. POx 6.8 ± 4.4 μmol/l for SBS group [66 ± 22 ml/min per 1.73 m2]; P = 0.02).
Renal Determinants of POx Level
In the group of patients with HPO, 24-hour UOx was significantly higher (919 ± 566 μmol/l) than in the NPO group (526 ± 257 μmol/l) (P = 0.003; Figure 3a). Excretion fraction increase in HPO was higher than in the NPO group (153% ± 9% vs. 100% ± 5%; Figure 3b). Mean mGFR was 49±23 ml/min per 1.73 m2 and was significantly lower in the HPO group than in the NPO group (73 ± 18 ml/min per 1.73 m2; P = 0.0005) (Figure 3c). There was a significant inverse association between mGFR and P)x (r = −0.56; P < 0.0001).
Figure 3.
Renal determinants of plasma oxalate level. (a) In the group of patients with high plasma oxalate (HPO), 24-hour urine oxalate was significantly higher (919 ± 566 μmol/l) versus normal plasma oxalate group (NPO) (526 ± 257 μmol/l); P = 0.003. (b) Excretion fraction in HPO is increased more than in the NPO group (153% ± 9% vs. 100% ± 5%). (c) Mean mGFR was 49 ± 23 ml/min per 1.73 m2 and was significantly lower in the HPO group than in the NPO group (73 ± 18 ml/min per 1.73 m2; P = 0.0005).
Mean UOx in the SBS cohort was 648±415 and 54% had an UOx >500 μmol/24h, that we can consider as an EH. There was no difference in history of kidney stone between the groups with HPO (P = 0.5; RR 0.7 (0.36–1.66)). There was no difference in 24-hour urine calciuria, citraturia, sodium, and protein consumption between both groups. There was no difference in hydration status between the groups either, although we did find an association between sodium reabsorption fraction and PRA (r = 0.4; P = 0.03). All urine characteristics are described in Table 3.
Table 3.
Urine characteristics between HPO and NPO groups
|
Characteristics |
Plasma oxalate <5 μmol/l NPO (n = 32) |
Plasma oxalate ≥5 μmol/l HPO (n = 13) |
P value |
|---|---|---|---|
| Age (y) | 59.4 ± 14.9 | 64.5 ± 15.9 | NS |
| Male, % | 54% | 53% | NS |
| BMI (kg/m2) | 22.9±3.7 | 20.9±3.10 | 0.03 |
| Plasma oxalate (μmol/l) | 4.9 ± 0.3 | 11.5 ± 6.1a | <0.0001 |
| mGFR (ml/min per 1.73 m2) | 73 ± 18 | 49 ± 21a | <0.0005 |
| HCO3- | 24 ± 4 | 24 ± 5 | NS |
| Potassium | 4.2 ± 0.5 | 4.2 ± 0.7 | NS |
| Chloride (mmol/l) | 107 ± 3 | 106 ± 4.6 | NS |
| Calcium (mmol/l) | 2.25 ± 0.12 | 2.25 ± 0.19 | NS |
| Phosphate (mmol/l) | 0.99 ± 0.19 | 1.05 ± 0.22 | NS |
| PTH (ng/l) | 56 ± 37 | 59 ± 38 | NS |
| 25OHvit D (nmol/l) | 63 ± 31 | 71 ± 35 | NS |
| Na reabsorption fraction (%) | 99.99 | 98.5 ± 1a | 0.0002 |
| Cl reabsorption fraction (%) | 99.2 ± 0.5 | 98.4 ± 0.6a | < 0.0001 |
| Renin (ng/l) | 35 ± 68 | 66 ± 154 | NS |
| Increased renin (%) | 37% | 53 % | NS |
| Urine volume (l) | 1.1 ± 0.6 | 1.5 ± 0.5a | 0.03 |
| Urine sodium (mmol/24h) | 101 ± 54 | 126 ± 73 | NS |
| urine calcium (mmol/kg/j) | 0.04 ± 0.04 | 0.03 ± 0.02 | NS |
| Urine citrate (mmol/24h) | 0.6 ± 0.92 | 0.6 ± 0.6 | NS |
| Urine oxalate (μmol/24h) | 526 ± 257 | 919 ± 566a | 0.003 |
| Urine glycolate | 173 ± 115 | 109 ± 83 | NS |
| Positive crystalluria | 40% | 31 % | NS |
| Kidney stone history | 47% | 46% | NS |
| CRP (mg/l) | 2.9 ± 3.7 | 1.4 ± 1.5 | NS |
| Treatment with calcium, n (%) | 27 (60%) | 18 (40%) | NS |
BMI, body mass index; HPO, high plasma oxalate; NPO, normal plasma oxalate.
For P < 0.05 between NPO and HPO group.
Intestinal Determinants of POx
The remaining small bowel length was not different between groups (77 ± 33 vs. 91 ± 43 cm, P = 0.3; respectively); however, the length of the remaining colon had a trend to be higher in the HPO group (82 ± 14 vs. 67 ± 30 cm for HPO and NPO, respectively; P = 0.08). The SBS vintage was not different between both groups.
In the group with sugar malabsorption (D Xylose 60 min <0.73 mmol/l), UOx was significantly higher (961 ± 313 μmol/24h) than in the group without sugar malabsorption (496 ± 313 μmol/24h) (P = 0.0063). There was a significant correlation between sugar malabsorption measured by D xylose test and UOx (r = 0.41; P = 0.001). There was no difference between POx in sugar malabsorption group (7.2 ± 5.3 μmol/l vs. 5.7 ± 2.33 μmol/l). However, there was a trend to have more patients with a HPO level (33% vs. 22%). The fecal elastase tends to be lower in HPO group (110 ± 116 vs. 235 ± 81 for HPO and HPO, respectively; P = 0.07). We found no difference in HPO frequency between the group with intestinal bacterial overgrowth (36%) and with no intestinal bacterial overgrowth (27%) group.
All intestinal functional testing between HPO and NPO group are described in Table 4.
Table 4.
Intestinal functional tests between HPO and NPO groups
| Functional tests | Plasma oxalate <5 μmol/l NPO (n = 32) |
Plasma oxalate ≥5 μmol/l HPO (n = 13) |
P value |
|---|---|---|---|
| Type 2 SBS | 84% | 69 % | NS |
| SBS vintage (months) | 115 ± 115 | 123 ± 109 | NS |
| Remaining small bowel length (cm) | 91 ± 43 | 77 ± 33 | |
| Length of remaining colon (%) | 67 ± 30 | 82 ± 14 | 0.08 |
| Parenteral nutrition (%) | 63 | 77 | NS |
| Plasma citrulline/creatinine | 0.41 ± 0.26 | 0.18 ± 0.14a | 0.04 |
| Fecal elastase (μg/g) | 235 ± 181 | 110 ± 116 n = 7 | 0.07 |
| Alpha-1-antitrypsin clearance (ml/d) | 19 ± 14 | 28 ± 34 | NS |
| Steatorrhea (%) (steatorrhea/lipides intake) (IQR) | 42 ± 21 | 48 ± 23 | NS |
| D xylose absorption test (mmol/l) | 0.52 ± 0.36 | 0.52 ± 0.24 | NS |
| Bacterial overgrowth, n (%) | 75 % | 61% | NS |
| Vitamin C (μmol/l; normal: 25–85) | 50 ± 30 | 37 ± 23 | NS |
| Vitamin B6 (nmol/L; normal: 35–110) | 171 ± 86 | 150 ± 3 | NS |
| Glycine (μmol/l; normal: 168–397) | 344 ± 110 | 379 ± 81 | NS |
| Hydroxyproline (μmol/l; normal: 5–20) | 14 ± 6.5 | 18 ± 7a | 0.04 |
HPO, high plasma oxalate; IQR, interquartile range; NPO, normal plasma oxalate; SBS, short bowel syndrome.
For P < 0.05 between NPO and HPO group.
Nutrition Determinants of POx Level
There was no significant difference in the proportion of parenteral nutrition in both groups (77% vs. 62% for HPO and NPO, respectively; P = 0.4). Estimated calories per day intake was not different between the groups. There was no difference in the amount of amino acids, carbohydrates, lipids, or proteins between groups. There was no correlation between UOx and intake of carbohydrate, lipid, and protein.
Plasma vitamin C and vitamin B6 level were not different between groups, but interestingly hydroxyproline level was significantly higher in the HPO group (18 ± 7) than in the NPO group (14 ± 6.5; P = 0.04).
Discussion
In this study, we have showed that POx levels can increase earlier in EH compared to other causes of CKD. We have also described that patients with SBS are at a high risk of developing EH (54%), kidney stones (58%), and CKD.
Healthy individuals typically maintain POx levels between 1 and 5 μmol/l.19 Previous studies have reported limited information on POx values in CKD. As expected, in our study, eGFR was significantly lower in the HPO group and correlated with POx levels. However, POx levels remained high despite mGFR being above 30 ml/min per 1.73 m2 (median of 49 ml/min per 1.73 m2), suggesting that the elevated POx level cannot be solely attributed to a decrease in renal function.
Because we did not have a control group in this prospective study, we added a previous cohort of patients with CKD without SBS. In this previous study conducted by our team, we reported a very late increase of POx for participants with impaired renal function16; all patients with a GFR >30 ml/min per 1.73 m2 had POx levels <5.0 μmol/l (Figure 2a) compared to our prospective cohort of patients with SBS, where 13 patients had POx ≥5 μmol/l. In Figure 2b, we highlight that elevated oxalate levels were found for patients with mGFR >45 ml/min per 1.73 m2, which is not a common finding. Moreover, when we matched mGFR between the groups, we found a significant increase of POx in patients with SBS. These results are in line with those of Perimpam et al., showing that some patients with EH had POx levels >5.0 μmol/l despite an eGFR >30 ml/min per 1.73 m2 compared to control or routine urinary stone disease.15 Miliner et al.19 showed also in patients with primary hyperoxaluria a statistically significant inverse correlation between eGFR and Pox, with POx elevated at early stages of CKD (stages 1–3b) for some, demonstrating that a correlation is present before substantial kidney loss. Some patients with SBS may behave like patients with genetic hyperoxaluria. European guidelines do not recommend measuring POx for primary hyperoxaluria diagnosis when eGFR is greater than 30 ml/min per 1.73 m2, mainly to avoid false negative results that could have deleterious effects on diagnosis and management of patients with true genetic hyperoxaluria, and we share this opinion.20 However in some specific populations, once the diagnosis is established, Pox could be measured more promptly to detect the severity of the disease earlier, namely systemic oxalosis.
In patients with severe malabsorption, POx is a risk factor for oxalate nephropathy, although no causality can be established in this present study. Indeed, we did not provide any histological data that could have helped demonstrate a causal relationship between POx and oxalate nephropathy. Kidney biopsies are often challenging to perform in these patients with SBS. In a previous study, Buysschaert et al.6 retrospectively screened kidney biopsies and identified 1% with oxalate nephropathy. Most cases were attributed to EH, accounting for 75%, with only 1 patient having SBS. In this paper, POx was not provided but its measurement, would have been interesting. This publication highlighted a poor renal prognosis, emphasizing the necessity for prognostic biomarkers.21
Kidney and nephrolithiasis assessments in patients with secondary hyperoxaluria, particularly those with an EH are very difficult to obtain due to overestimation of GFR with CKD-Epidemiology Collaboration equations,17 nonaccess to mGFR, and difficulty to obtain oxaluria excretion. Therefore, we need to consider that POx can be a useful value not for diagnosis but for prognosis in this specific setting of SBS. Indeed, in some diseases, even with an eGFR >30 ml/min per 1.73 m2, POx concentration could serve as a useful biomarker to assess the risk of kidney stones and kidney disease progression.19,22 Moreover, POx is a surrogate marker for the severity of primary hyperoxaluria and systemic oxalate accumulation. Previous studies have demonstrated that oxalate can inhibit kidney epithelial cell proliferation, exert toxic effects on renal epithelial cells, cause direct tubular damage, and ultimately promote fibrosis.22 It is important to consider that measuring POx is challenging and not routinely performed in most centers.23 In addition, significant intermeasurement variability has been documented.24
Our patients with SBS display high UOx (62%), 46% had calciuria <0.02 mmol/kg/j and 80% had hypocitraturia, that are all the hallmarks of EH, but also decreased GFR. We demonstrated a significant number of patients with EH in these SBS cohort. We also show a significant increase in UOx levels in the HPO group, likely due to the increase in filtered oxalate load. The median UOx in this group was 737 μmol/24h; thus, we propose a cutoff of 750 μmol/24h for measuring POx regardless of the GFR in EH. Our results are in line with previous reports; Lieske et al. described a mean of 700 μmol/24h for patients with kidney stone 8 months after bariatric surgery and D’Costa et al. described a mean of 615 μmol/24h.25,26 As a reminder, the cut-off level of UOx proposed in adults for ruling out primary hyperoxaluria is 460 μmol/24h.21
In EH, patients with SBS exhibit probably the most severe malabsorption state. These patients are well-known to be at a high risk of developing kidney stones. In total, 58% of patients in our study had a history of kidney stones or positive crystalluria. This proportion of kidney stones in patients with SBS is higher than other malabsorption states; Lieske et al. described 11% of kidney stones after bariatric surgery and D’Costa reported 23%.25,26 Kidney stones have been reported in patients with SBS, resulting in adverse clinical outcomes.27, 28, 29
Regardless of eGFR, we investigated other potential factors that could explain the early elevation of Pox in some patients. One interesting finding was the significant difference in plasma hydroxyproline levels between individuals with normal and HPO levels. It has been shown that hydroxyproline, which is a byproduct of collagen catabolism, contributes approximately 15% of UOx in healthy individuals.30 The reason for the elevated hydroxyproline levels in these patients remains to be determined. Furthermore, we confirmed a positive association between the severity of malabsorption and POx levels, as demonstrated by the positive correlation between POx and citrulline-to-creatinine ratio.
There are some limitations to this study. We only described 45patients; however, these severe SBS cases are rare, and we were able to collect information about different intestinal tests. Our POx concentration could not be measured below 5 μmol/l, which limits our ability to establish a more precise association. It would be very interesting to have a follow-up of mGFR slope in these patients with SBS to be able to better study causality and logistic regression model.
This study is mainly descriptive and does not allow to answer the question of causality. However, we see an interest in measuring POx in a very specific kind of CKD population, especially patients with severe malabsorption.
In conclusion, this study confirms that 54% patients with intestinal failure due to an SBS have an EH and 29% can exhibit an early increase in POx, even with an eGFR >30 ml/min per 1.73 m2. POx could be a valuable biomarker in these patients with severe malabsorption, particularly to detect the risk for hyperoxaluria and the risk of early renal progression.
Disclosure
SL, JB, and NA report support from Alnylam for travel grant, consultancy, and as speaker. CA reports support from Alnylam for travel grant and consultancy. All the other authors declared no competing interests.
Acknowledgments
The authors thank the “l'académie de médecine” for its financial support.
Data Availability Statement
We will send raw data on request. Data described in the manuscript will be made available upon request pending approval.
Author Contributions
CG contributed to acquisition of data; analysis and interpretation of data. CC did critical revision of the manuscript for important intellectual content, analysis and interpretation of data and conception and design of the study. CA contributed to conception and design of the study, and critical revision of the manuscript for important intellectual content. NA did critical revision of the manuscript for important intellectual content. CB did critical revision of the manuscript for important intellectual content. ML did critical revision of the manuscript for important intellectual content and analysis and interpretation of data. FG-E did critical revision of the manuscript for important intellectual content. JB did critical revision of the manuscript for important intellectual content and analysis and interpretation of data. LD-D did critical revision of the manuscript for important intellectual content and analysis and interpretation of data. AdM did critical revision of the manuscript for important intellectual content and analysis and interpretation of data. SL contributed to the conception and design of the study, acquisition of data, analysis and interpretation of data, and drafting of the manuscript.
References
- 1.Pironi L., Arends J., Baxter J., et al. ESPEN endorsed recommendations. Definition and classification of intestinal failure in adults. Clin Nutr. 2015;34:171–180. doi: 10.1016/j.clnu.2014.08.017. [DOI] [PubMed] [Google Scholar]
- 2.Thompson J.S., DiBaise J.K., Iyer K.R., Yeats M., Sudan D.L. Postoperative short bowel syndrome. J Am Coll Surg. 2005;201:85–89. doi: 10.1016/j.jamcollsurg.2005.02.034. [DOI] [PubMed] [Google Scholar]
- 3.Boncompain-Gérard M., Robert D., Fouque D., Hadj-Aïssa A. Renal function and urinary excretion of electrolytes in patients receiving cyclic parenteral nutrition. JPEN J Parenter Enter Nutr. 2000;24:234–239. doi: 10.1177/0148607100024004234. [DOI] [PubMed] [Google Scholar]
- 4.Buchman A.L., Moukarzel A., Ament M.E., et al. Serious renal impairment is associated with long-term parenteral nutrition. JPEN J Parenter Enter Nutr. 1993;17:438–444. doi: 10.1177/0148607193017005438. [DOI] [PubMed] [Google Scholar]
- 5.Rosenstock J.L., Joab T.M.J., DeVita M.V., Yang Y., Sharma P.D., Bijol V. Oxalate nephropathy: a review. Clin Kidney J. 2022;15:194–204. doi: 10.1093/ckj/sfab145. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Buysschaert B., Aydin S., Morelle J., Gillion V., Jadoul M., Demoulin N. Etiologies, clinical features, and outcome of oxalate nephropathy. Kidney Int Rep. 2020;5:1503–1509. doi: 10.1016/j.ekir.2020.06.021. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Shah R.J., Vaughan L.E., Enders F.T., Milliner D.S., Lieske J.C. Plasma oxalate as a predictor of kidney function decline in a primary hyperoxaluria cohort. Int J Mol Sci. 2020;21:3608. doi: 10.3390/ijms21103608. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Marangella M., Petrarulo M., Cosseddu D., Vitale C., Linari F. Oxalate balance studies in patients on hemodialysis for type I primary hyperoxaluria. Am J Kidney Dis. 1992;19:546–553. doi: 10.1016/s0272-6386(12)80833-x. [DOI] [PubMed] [Google Scholar]
- 9.Marangella M., Vitale C., Petrarulo M., et al. Bony content of oxalate in patients with primary hyperoxaluria or oxalosis-unrelated renal failure. Kidney Int. 1995;48:182–187. doi: 10.1038/ki.1995.283. [DOI] [PubMed] [Google Scholar]
- 10.Duranton F., Cohen G., De Smet R., et al. Normal and pathologic concentrations of uremic toxins. J Am Soc Nephrol. 2012;23:1258–1270. doi: 10.1681/ASN.2011121175. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Pfau A., Ermer T., Coca S.G., et al. High oxalate concentrations correlate with increased risk for sudden cardiac death in dialysis patients. J Am Soc Nephrol. 2021;32:2375–2385. doi: 10.1681/ASN.2020121793. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Waikar S.S., Srivastava A., Palsson R., et al. Association of urinary oxalate excretion with the risk of chronic kidney disease progression. JAMA Intern Med. 2019;179:542–551. doi: 10.1001/jamainternmed.2018.7980. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Puurunen M., Kurtz C., Wheeler A., et al. 24-hour urine oxalate and risk of chronic kidney disease. Nephrol Dial Transplant. 2023 doi: 10.1093/ndt/gfad221. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Yang J., Sun H., Wan S., et al. Risk factors for nephrolithiasis in adults with short bowel syndrome. Ann Nutr Metab. 2019;75:47–54. doi: 10.1159/000502329. [DOI] [PubMed] [Google Scholar]
- 15.Bering J.L., Wiedmeier-Nutor J.E., Sproat L., DiBaise J.K. Bone marrow oxalosis with pancytopenia in a patient with short bowel syndrome: report of a case and review of the literature. JPEN J Parenter Enter Nutr. 2023;47:165–170. doi: 10.1002/jpen.2453. [DOI] [PubMed] [Google Scholar]
- 16.Perinpam M., Enders F.T., Mara K.C., et al. Plasma oxalate in relation to eGFR in patients with primary hyperoxaluria, enteric hyperoxaluria and urinary stone disease. Clin Biochem. 2017;50:1014–1019. doi: 10.1016/j.clinbiochem.2017.07.017. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Selistre Lda S., Cochat P., Rech D.L., Parant F., Souza VC de, Dubourg L. Association between glomerular filtration rate (measured by high-performance liquid chromatography with iohexol) and plasma oxalate. J Bras Nefrol. 2018;40:73–76. doi: 10.1590/1678-4685-JBN-3743. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Lemoine S., Guebre-Egziabher F., Sens F., et al. Accuracy of GFR estimation in obese patients. Clin J Am Soc Nephrol. 2014;9:720–727. doi: 10.2215/CJN.03610413. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Ermer T., Eckardt K.U., Aronson P.S., Knauf F. Oxalate, inflammasome, and progression of kidney disease. Curr Opin Nephrol Hypertens. 2016;25:363–371. doi: 10.1097/MNH.0000000000000229. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Milliner D.S., Cochat P., Hulton S.A., et al. Plasma oxalate and eGFR are correlated in primary hyperoxaluria patients with maintained kidney function-data from three placebo-controlled studies. Pediatr Nephrol. 2021;36:1785–1793. doi: 10.1007/s00467-020-04894-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Groothoff J.W., Metry E., Deesker L., et al. Clinical practice recommendations for primary hyperoxaluria: an expert consensus statement from ERKNet and OxalEurope. Nat Rev Nephrol. 2023;19:194–211. doi: 10.1038/s41581-022-00661-1. [DOI] [PubMed] [Google Scholar]
- 22.Knauf F., Asplin J.R., Granja I., et al. NALP3-mediated inflammation is a principal cause of progressive renal failure in oxalate nephropathy. Kidney Int. 2013;84:895–901. doi: 10.1038/ki.2013.207. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Pfau A., Wytopil M., Chauhan K., et al. Assessment of plasma oxalate concentration in patients with CKD. Kidney Int Rep. 2020;5:2013–2020. doi: 10.1016/j.ekir.2020.08.029. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Hillebrand P., Hoppe B. Plasma oxalate levels in primary hyperoxaluria type I show significant intra-individual variation and do not correlate with kidney function. Pediatr Nephrol. 2020;35:1227–1233. doi: 10.1007/s00467-020-04531-5. [DOI] [PubMed] [Google Scholar]
- 25.Lieske J.C., Mehta R.A., Milliner D.S., Rule A.D., Bergstralh E.J., Sarr M.G. Kidney stones are common after bariatric surgery. Kidney Int. 2015;87:839–845. doi: 10.1038/ki.2014.352. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.D’Costa M.R., Kausz A.T., Carroll K.J., et al. Subsequent urinary stone events are predicted by the magnitude of urinary oxalate excretion in enteric hyperoxaluria. Nephrol Dial Transplant. 2021;36:2208–2215. doi: 10.1093/ndt/gfaa281. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.McConnell N., Campbell S., Gillanders I., Rolton H., Danesh B. Risk factors for developing renal stones in inflammatory bowel disease. BJU Int. 2002;89:835–841. doi: 10.1046/j.1464-410x.2002.02739.x. [DOI] [PubMed] [Google Scholar]
- 28.O’Connor R.C., Worcester E.M., Evan A.P., et al. Nephrolithiasis and nephrocalcinosis in rats with small bowel resection. Urol Res. 2005;33:105–115. doi: 10.1007/s00240-004-0460-4. [DOI] [PubMed] [Google Scholar]
- 29.Johnson E., Vu L., Matarese L.E. Bacteria, bones, and stones: managing complications of short bowel syndrome. Nutr Clin Pract. 2018;33:454–466. doi: 10.1002/ncp.10113. [DOI] [PubMed] [Google Scholar]
- 30.Fargue S., Milliner D.S., Knight J., Olson J.B., Lowther W.T., Holmes R.P. Hydroxyproline metabolism and oxalate synthesis in primary hyperoxaluria. J Am Soc Nephrol. 2018;29:1615–1623. doi: 10.1681/ASN.2017040390. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
We will send raw data on request. Data described in the manuscript will be made available upon request pending approval.