Abstract
Background
Primary hyperoxaluria (PH) type 3 (PH3) is caused by mutations in the hydroxy-oxo-glutarate aldolase 1 gene. PH3 patients often present with recurrent urinary stone disease in the first decade of life, but prior reports suggested PH3 may have a milder phenotype in adults. This study characterized clinical manifestations of PH3 across the decades of life in comparison with PH1 and PH2.
Methods
Clinical information was obtained from the Rare Kidney Stone Consortium PH Registry (PH1, n = 384; PH2, n = 51; PH3, n = 62).
Results
PH3 patients presented with symptoms at a median of 2.7 years old compared with PH1 (4.9 years) and PH2 (5.7 years) (P = 0.14). Nephrocalcinosis was present at diagnosis in 4 (7%) PH3 patients, while 55 (89%) had stones. Median urine oxalate excretion was lowest in PH3 patients compared with PH1 and PH2 (1.1 versus 1.6 and 1.5 mmol/day/1.73 m2, respectively, P < 0.001) while urine calcium was highest in PH3 (112 versus 51 and 98 mg/day/1.73 m2 in PH1 and PH2, respectively, P < 0.001). Stone events per decade of life were similar across the age span and the three PH types. At 40 years of age, 97% of PH3 patients had not progressed to end-stage kidney disease compared with 36% PH1 and 66% PH2 patients.
Conclusions
Patients with all forms of PH experience lifelong stone events, often beginning in childhood. Kidney failure is common in PH1 but rare in PH3. Longer-term follow-up of larger cohorts will be important for a more complete understanding of the PH3 phenotype.
Keywords: nephrocalcinosis, oxalate, primary hyperoxaluria, stone
KEY LEARNING POINTS
What is already known about this subject?
primary hyperoxaluria (PH) type 3 (PH3), which accounts for up to 10% of patients with PH, is the most recently identified type of PH; and
hyperoxaluria is present throughout life in PH3, though the severity of hyperoxaluria tends to be less than observed in PH1 and PH2.
What this study adds?
this study shows an early onset of stone-forming activity in PH3, which continues throughout all decades of life at a rate similar to those with PH1 and PH2; and
PH3 patients appear to have better preservation of kidney function over time when compared with PH1 and PH2. PH1 patients experienced advanced chronic kidney disease (CKD) across all decades of life, while PH3 patients were likely to progress to CKD Stage 3 only in later decades.
What impact this may have on practice or policy?
PH3 patients benefit from long term follow-up with attention to transition of care from childhood to adulthood.
ADDITIONAL CONTENT
An author video to accompany this article is available at: https://academic.oup.com/ndt/pages/author_videos.
INTRODUCTION
The primary hyperoxalurias (PHs) are inborn errors of metabolism that result in hepatic overproduction of oxalate that must then be excreted by the kidneys (typically >1 mmol/1.73 m2/day), and are caused by one of three enzyme deficiencies [1, 2]. Affected patients are at risk of frequent calcium oxalate stones, nephrocalcinosis and chronic kidney disease (CKD) [3, 4].
PH type 1 (PH1), the most common PH type, is caused by deficiency of the liver-specific peroxisomal enzyme alanine-glyoxylate aminotransferase, which results in overproduction of oxalate and glycolate [2, 5, 6]. PH1 is the most severe PH subtype with the highest average urinary oxalate excretion and greatest risk of nephrocalcinosis and end-stage kidney disease (ESKD) [6, 7]. PH2 is caused by deficiency of the enzyme glyoxylate reductase-hydroxypyruvate reductase, accounts for ∼10% of genetically characterized PH cases and may overall have a less severe disease course, although the risk of ESKD is still significant [8, 9]. PH3 is the most recently identified type, appears to account for ∼8–10% of PH and results from defects in the mitochondrial enzyme 4-hydroxy-2-oxoglutarate aldolase (HOGA) encoded by the hydroxy-oxo-glutarate aldolase 1 gene (HOGA1) [10–12]. HOGA catalyzes the final step of hydroxyproline metabolism from 4-hydroxy-2-oxoglutarate (HOG) to glyoxylate and pyruvate [11, 12]. It is believed that loss-of-function mutations in the HOGA1 gene are responsible for PH3, but the precise molecular mechanism by which these mutations cause hyperoxaluria remains elusive [13]. Prior studies suggested that PH3 patients had an earlier onset of symptomatic urinary stone disease (USD) compared with PH2 patients, and that stone activity may markedly decline or even completely remit in some patients by adulthood [14–16]. ESKD has been reported in just one PH3 patient to date [17].
PH3 cohort reports to date have been limited by relatively small patient numbers and short-term follow-up, with many still in the pediatric age range. Since this is a lifelong disease, it remains important to delineate manifestations later in life, especially with respect to USD and kidney function. Thus, this study was completed to better define the lifelong natural history of PH3 in comparison with PH1 and PH2.
MATERIALS AND METHODS
A retrospective review was performed of all PH patients who were enrolled in the Rare Kidney Stone Consortium PH (RKSC PH) registry through February 2019. The RKSC PH registry is a voluntary registry where patients from >40 nationalities are represented. The USA was the country of birth for 62% of participants in the cohort, followed by 16% of patients from South Asia (India and Pakistan). The registry was queried to obtain clinical and laboratory data in cohorts of PH patients [18]. Informed consent for registry participation was obtained from each subject after Mayo Clinic Institutional Review Board approval. Registry patients included in this study had molecular diagnostic testing that confirmed two mutant alleles in one of the known PH genes: AGXT (PH1), GRHPR (PH2) or HOGA1 (PH3) [12, 19, 20]. As of February 2019, there were 497 patients enrolled in the registry, of whom 463 received genetic testing for diagnosis. Twenty-seven were diagnosed by liver biopsy and seven patients were diagnosed based on biochemical profile. Most measurements (74%) for plasma oxalate were performed at the Mayo Clinic Renal Testing Laboratory [21, 22]. Median plasma oxalate concentration was similar when compared between Mayo Renal Testing Laboratory (n = 84, 11.7 µmol/L) and outside laboratories (n = 96, 9.9 µmol/L) and outside laboratories. Estimated glomerular filtration rate (eGFR) was calculated using the Full Age Spectrum equation [23]. Urine laboratory measurements were largely split between Mayo Clinic Renal Testing Laboratory (30%) and Litholink (25%), and the remaining 44% at other clinical laboratories. Stone analyses were performed by a variety of clinical testing laboratories. Twenty-four-hour urinary excretion rates of oxalate, calcium and other determinants of supersaturation were measured by standard laboratory methods. Since the population study included children as well as adults, excretion rates were corrected to 1.73 m2 for analyses. Supersaturation was calculated using the EQUIL2 program [24]. Urine and serum measurements were examined at the time of diagnosis and the latest available. Unless specified, urine and serum measurements detailed those obtained at the time of diagnosis. A stone clinical event was defined as pain or hematuria associated with a stone, stone passage or a procedure for stone management. Urologic procedures included extracorporeal shockwave lithotripsy, ureteroscopy, open or percutaneous stone surgery, and cystoscopies.
Statistical analyses
Results are expressed as the median (interquartile range) for continuous variables and as percentages for categorical variables. Spearman rank correlation was used to analyze correlations between baseline clinical and laboratory values and eGFR at diagnosis. Comparisons between groups were performed with a chi-square test for categorical variables and a Kruskal–Wallis test for continuous variables. The Kaplan–Meier method was employed to estimate development of ESKD and Cox proportional hazard models were used to compare groups. P-values <0.05 were accepted as statistically significant. All calculations were performed using SAS version 9.4 and R statistical software version 3.6.2.
RESULTS
As of February 2019, there were 62 PH3 patients from 53 families enrolled in the RKSC registry (40 males, 22 females, 76% White, 8% Asian). Clinical characteristics by PH type are displayed in Table 1.
Table 1.
Clinical and laboratory characteristics of PH3 at clinical diagnosis compared with PH1 and PH2
| PH3 (n = 62) | PH1 (n = 384) | PH2 (n = 51) | |
|---|---|---|---|
| Age at diagnosis (years) | 4.9 (2.1, 13.7) | 11 (3.9, 30.4) | 9.5 (3.1, 23.4) |
| Age at first symptoms (years) | 2.7 (0.9, 8.7) | 4.9 (1.7, 13.6) | 5.7 (1.4, 15.2) |
| (n = 51) | (n = 325) | (n = 45) | |
| Prevalent nephrocalcinosis (%) | 6.5 | 25.5 | 15.7 |
| (n = 4) | (n = 98) | (n = 8) | |
| eGFR at diagnosis (mL/min/1.73 m2) | 96 (64, 125) | 48 (12, 74) | 83 (47, 98) |
| (n = 56) | (n = 333) | (n = 48) | |
| Plasma oxalate (μmol/L) (nL <1.6) | 2.1 (1.9, 2.7) | 12.5 (3.7, 50) | 4.3 (2.6, 12.6) |
| (n = 21) | (n = 221) | (n = 21) | |
| Urine oxalate (mmol/1.73 m2/24 h) (nL <0.46) | 1.1 (0.9, 1.3) | 1.6 (1.0, 2.5) | 1.5 (1.1, 2.0) |
| (n = 62) | (n = 242) | (n = 41) | |
| Urine calcium (mg/1.73 m2/24 h) (nL 100–300) | 111.6 (72.3, 162.1) | 51.4 (32.6, 92.5) | 98.2 (59.2, 157.9) |
| (n = 49) | (n = 191) | (n = 38) | |
| Urine citrate (mg/1.73 m2/24 h) (nL 320–1240) | 638.4 (416.8, 885.8) | 254.8 (113.5, 461) | 717 (320, 1098.5) |
| (n = 48) | (n = 190) | (n = 36) | |
| Urine calcium-oxalate supersaturation (DG) | 2.1 (1.9, 2.4) | 1.7 (0.8, 2.2) | 2.1 (1.4, 2.5) |
| (n = 43) | (n = 280) | (n = 32) |
All results presented as median (Q1, Q3). nL, normal limit.
PH3 patients were 4.9 years of age at clinical diagnosis compared with 11 years for PH1 and 9.5 years for PH2 (P = 0.07), and had a median age at first symptoms of 2.7 (0.9, 8.7) years versus 4.9 (1.7, 13.6) years for PH1 and 5.7 (1.4, 15.2) years for PH2 (P = 0.14). The median delay in diagnosis (time between first onset of symptoms and diagnosis) was 22 months for PH3, 25 months for PH1 and 12 months for PH2 (P = 0.19). Six (9.6%) PH3 patients were diagnosed by family screening and one who had no known affected family members was diagnosed based on a prenatal screening panel. Most PH3 patients (89%) had stones on initial evaluation. Overall, 26 PH3 patients had 41 stones analyzed at diagnosis or during follow-up. First-time stone analysis revealed 31% of stones were composed of calcium oxalate monohydrate (COM), 27% mixed COM and calcium oxalate dihydrate (COD) and 23% COM and COD mixed with calcium phosphate. Four stones were reported as calcium oxalate not otherwise specified and one stone was composed of sodium acid urate crystal. PH3 patients experienced recurring stone events throughout all decades of life, similar to PH1 and PH2. The number of stone events per patient per year of follow-up did not differ by PH type (Figure 1). Nephrocalcinosis was present in four (7%) PH3 patients at the time of diagnosis, compared with 26% for PH1 and 16% for PH2 (P = 0.002). During a median follow-up of 3.1 years, no PH3 patients developed incident nephrocalcinosis. There was no difference in urine chemistry between the PH3 groups with and without nephrocalcinosis. However, eGFR was found to be lower (60 mL/min/1.73 m2) in nephrocalcinosis group compared with those without nephrocalcinosis (97 mL/min/1.73 m2) (P = 0.052) (Supplementary data, Table S1). Plasma oxalate concentration at diagnosis was lowest in PH3 patients and highest in PH1 patients [median 2.1 (1.9, 2.7) µmol/L versus 12.5 (3.7, 50) µmol/L; P < 0.0001] (Table 1). In patients with eGFR >60 mL/min/1.73 m2, the median plasma oxalate in PH1 was slightly higher at 5.3 (n = 88) followed by PH2 at 3.0 (n = 14) and PH3 at 2.0 (n = 13) μmol/L (P < 0.05). eGFR at the time of diagnosis was highest for PH3 at 96 (64, 125) mL/min/1.73 m2, followed by 83 (47, 98) mL/min/1.73 m2 for PH2 and 48 (12, 74) mL/min/1.73 m2 for PH1 (P < 0.0001). Urine oxalate excretion was lowest in the PH3 group [median 1.1 (0.99, 1.3) mmol/1.73 m2/day] compared with PH1 [1.6 (1.0, 2.5) mmol/1.73 m2/day] and PH2 [1.5 (1.1, 2) mmol/1.73 m2/day] (P < 0.0005) (Table 1). Urine oxalate excretion in PH1 patients was examined based upon vitamin B6 responsiveness predicted by the AGXT c.508G>A mutation. Subjects with the homozygous c.508G>A mutations had lower urine oxalate excretion (0.5 mmol/1.73 m2/day) compared with heterozygotes (0.8 mmol/1.73 m2/day) and those without any c.508G>A mutation (1.1 mmol/1.73 m2/day) (Supplementary data, Table S2). Although median urine calcium excretion was not above the reference range in any of the PH types, PH3 patients had higher excretion [median 112 (72.3, 162.1) mg/day/1.73 m2] compared with PH1 [51.4 (32.6, 92.5) mg/day/1.73 m2] and PH2 [98.2 (59.2, 157.9) mg/day/1.73 m2] (P < 0.0001). Hypercalciuria (>4 mg/kg/day in children; >250 mg in adult men, 200 mg in women) was present at first measurement in 10% of PH3 patients compared with 2% of PH1 patients (P < 0.001). There were more PH3 patients on thiazides (23%) compared with PH1 (4.2%) (P < 0.0001). When analyzed across all PH types, a positive correlation between urine calcium excretion and stone events per year was observed (r = 0.12, P < 0.05). This association persisted within the PH3 subgroup, but was not statistically significant (r = 0.13, P = 0.39). Urinary citrate excretion rate was 638 (416.8, 885.8) mg/1.73 m2/24 h in the PH3 group and 255 (113.5, 461.4) mg/1.73 m2/24 h in PH1 (P < 0.0001). Median calcium oxalate supersaturation values (DG scores) were higher for both PH3 and PH2 as compared with PH1 [median 2.1 (1.9, 2.4) versus 1.7 (0.8, 2.2); P < 0.01]. There was a weak correlation between calcium oxalate supersaturation and stone events, which nearly achieved statistical significance (r = 0.15, P = 0.058). A scatter plot of first measured 24 h urinary oxalate excretion by age demonstrated marked hyperoxaluria (>1 mmol/1.73 m2) at all ages in the three PH groups (Figure 2).
FIGURE 1.
Stone events per patient per year during each decade of follow-up in PH3 (top panel), PH1 (middle panel) and PH2 (lower panel). The mean for each decade is shown as a black diamond.
FIGURE 2.
Scatter plot showing 24 h urine oxalate corrected for 1.73 m2 body surface area at first measurement in patients with PH1, PH2 and PH3 across the three groups of PH. Urine oxalate remains elevated at all ages in all PH types.
Urine HOG excretion was markedly elevated in the PH3 group [median 110 (76, 181) mg/g creatinine (Cr); P < 0.0001], while urinary HOG excretion was essentially absent in PH1 and PH2 patients. Urinary HOG decreased with age as shown in Figure 3. As expected, PH2 patients had the highest urine glycerate excretion at 674 mg/g Cr (P < 0.0001) while urine glycolate excretion was highest in PH1 patients (101 mg/g Cr; P < 0.008).
FIGURE 3.
Scatter plot showing correlation between urinary HOG and age in PH3 patients (normal limit <10 mg/g Cr).
Median eGFR at diagnosis was 96 (64, 125) mL/min/1.73 m2 for the PH3 group followed by 48 (12, 74) and 83 (47, 98) mL/min/1.73 m2 for the PH1 and PH2 groups (P < 0.0001; Table 1). At age 40 years, 97.1% [95% confidence interval (CI) 91.8–100.0%] of PH3 patients had not progressed to ESKD, compared with 36.2% (95% CI 30–43%) of PH1 and 65.8% (95% CI 48.8–88.8%) of PH2 patients (Figure 4). Supplementary data, Figure S5 depicts CKD stages by decade of life at first and last follow-up for each PH type. Among the 40–60 years age group, only one-seventh had CKD 3, and among those >60 years of age, three had CKD 3 and only one had CKD 4. Overall, more PH1 patients experienced CKD 5 across all decades of life, while PH3 patients were likely to develop CKD 3 in later decades.
FIGURE 4.
Kaplan–Meier curve showing ESKD for the three PH groups with ESKD defined as eGFR <15 mL/min/1.73 m2, initiation of dialysis or kidney transplant.
The most commonly observed homozygous mutations in our PH3 population were c.944_946delAGG (n = 12, 19%) and c.700 + 5G>T (n = 10, 16%). Age at diagnosis (P = 0.28) did not differ between these two genotypes. In addition mean eGFR at diagnosis and at last follow-up, urinary oxalate or other urinary excretions did not differ by genotype.
DISCUSSION
This study compares the phenotype of a cohort of PH patients of all three known types. A trend toward earlier diagnosis was observed in PH3 (median 4.9 years of age) compared with PH1 and PH2. Eighty-nine percent of PH3 patients had stones present at intitial evaluation. Consistent with prior reports, PH3 patients had a lower urine oxalate excretion than other PH types [16, 17, 25]. We also observed higher urine citrate and urine calcium excretion. Nonetheless, in our cohort PH3 patients experienced stone events throughout life at rates similar to those with PH1 and PH2. In addition, we did not find that clinical kidney stone events changed over the decades of life for any PH type and thus there was no evidence for a clinical remission. While progressive CKD was common in PH1 patients, it was not often observed in the PH3 population.
Studies on stone composition in PH patients are limited [26–28]. Daudon et al. observed that pure COM stones were usually observed in a largely PH1 cohort [26, 27]. Further, in a recent report of a European PH2 cohort, 28 out of 30 stones were predominantly COM [9]. In contrast, in our PH3 cohort 36% of the calcium oxalate stones were a mixture of COD and COM, consistent with several PH3 patients reported from Germany [28]. Among the general stone-forming population, it has been reported that hypercalciuria favors COD while hyperoxaluria favors COM [28, 29]. A prior study by Monico et al. demonstrated that the urine calcium excretion of PH3 patients is often in a high normal or even elevated range, in marked contrast to the low urine calcium excretion typically observed in PH1 [25]. In the current cohort, urine calcium excretion was also highest in the PH3 group, and roughly twice that of the PH1 group (Table 1). Thus the higher ratio of calcium to oxalate in PH3 versus PH1 may favor COD. Mixed calcium oxalate and calcium phosphate stones, found in 23% of our PH3 cohort, but rarely observed in PH1 or PH2, may also reflect differences in urine composition by PH type.
Recently, Allard et al. reported two PH3 patients who developed nephrocalcinosis [15]. Nephrocalcinosis was detected in our PH3 cohort as well, but only in 7%, and much less frequently than in the PH1 population (26%). In addition, no incident cases of nephrocalcinosis occurred in the PH3 group during follow-up, unlike in PH1 and PH2 patients [30]. Thus, although PH3 patients presented with USD somewhat earlier in life compared with PH1 and PH2, and manifested similar stone recurrence rates throughout life, they had a lower prevalence of nephrocalcinosis. This may suggest different pathophysiologic mechanisms for nephrolithiasis versus nephrocalcinosis. Within the PH3 group, subjects with nephrocalcinosis had lower eGFR compared with those without nephrocalcinosis (Supplementary data, Table S1). However, we found no difference in urine chemistry between PH3 with and without nephrocalcinosis.
Calcium oxalate supersaturation in the final urine is expected to reflect kidney stone risk. Indeed, across all PH types, calcium oxalate supersaturation was higher than normal and the frequency of kidney stone events was similarly high. Although oxalate concentration is a major determinant of urine calcium oxalate supersaturation calculated by EQUIL2 [24], calcium oxalate supersaturation was in fact lower in PH1 when compared with PH2 or PH3, in part due to a lower urinary calcium excretion. Thus, it is not clear that EQUIL2 calculated supersaturation captures all features of stone formation risk in these severly hyperoxaluric patients.
PH3 patients in our cohort demonstrated lower urine oxalate and better kidney outcome than PH1, illustrated by the relatively modest CKD stage progression over decades of life compared with PH1 or PH2 (Supplementary data, Figure S5). We previously reported that the magnitude of hyperoxaluria is a primary risk factor for renal function loss across PH types [31]. Indeed oxalate induced kidney injury is an important factor in progressive CKD in enteric hyperoxaluria, and appears to play a role in CKD progression broadly [32, 33]. Recently, the Kidney Health Initiative, in partnership with the Oxalosis and Hyperoxaluria Foundation (OHF), identified urinary oxalate as one of the potential endpoints for clinical trials in PH [34].
In general, kidney function was relatively well-preserved in the PH3 population, confirming previous observations. In our cohort, nonetheless, there were a number of PH3 patients at CKD Stages 3–4 by the fifth decade of life (Supplementary data, Figure S5). A significant proportion of PH3 patients >40 years of age had CKD Stage 3 or higher, which is higher than the prevalence of CKD Stage 3 in the general population [35]. Allard et al. reported a modest eGFR decline in two of seven PH3 patients diagnosed in childhood [15]. Both patients presented with bilateral obstructive USD requiring urologic procedures, including open surgery in one patient. So far there has been only one reported PH3 patient with ESKD. That patient had recurrent stone removal surgeries and a complicated post-surgical course, which could have contributed to the decline of his GFR [17]. Thus the role of large and obstructive stones and the risk of progressive CKD in PH3 patients would benefit from further study. Once a PH3 patient develops CKD, the persistent hyperoxaluria could put them at greater risk of relatively rapid progression to ESKD.
Lifelong hyperoxaluria and recurring stones with risk of impaired kidney function beginning in childhood substantiate the need for early diagnosis of PH3 and long-term follow-up. Urine oxalate is valuable for screening, but alone does not differentiate among PH types. It has been suggested that screening of family members with PH could be beneficial [36]. Urinary HOG was markedly elevated in PH3 patients Figure 3. In recent studies by Ventzke et al. and Greed et al., urinary HOG was found to be an excellent biomarker for PH3 diagnosis [37, 38]. Thus based upon this study and previous publications, urinary HOG quantification appears to be an excellent screening test for PH3 that is sufficiently stable for routine clinical assays as employed in our study. 4-Hydroxy-glutamate (4OHGlu) has emerged as an alternative PH3 biomarker that may have advantages in biobanked samples subjected to prolonged freezing or multiple freeze–thaw cycles. Since HOG and 4OHGlu appear low to undetectable in PH1, concurrent screening for glycolate and HOHG or 4OHGlu could help biochemically differentiate between PH1 and PH3 [38]. Of course, genetic screening as employed here is the gold standard to identify the etiology in PH, and can identify other monogenic causes of USD that can phenocopy PH [39].
Our study has limitations. HOGA1 mutations as a cause of PH was first recognized just 10 years ago. Thus, the number of patients is small due to its rarity and lack of access to affordable genetic testing [36]. Furthermore, PH3 mutation carrier frequency is estimated at 1:185 based on population data, suggesting that there are PH3 individuals who either remain undiagnosed or do not have clinical manifestations [3, 17]. PH3 is often diagnosed in children, and the relatively short duration of follow-up of this life-long disease limit our current conclusions, particularly regarding long-term kidney function. The RKSC PH registry is a voluntary retrospective registry and therefore this cohort may not represent all patients with PH3. Moreover, comprehensive data at regular time points were not available for all patients due to voluntary reporting at the time of medical care. Urinary HOG values were unfortunately not available for all patients, and we did not have complete information on stone composition. Urine oxalate was measured in several commercial laboratories, with only a quarter of measurements performed at the Mayo Clinic. However, this study of a larger PH3 cohort includes follow-up well into adulthood for some. This provides a more complete picture of lifelong expression of PH3 disease than has been available to date.
In conclusion, PH3 is marked by persistent stone activity throughout life starting early in childhood. Though kidney function is better preserved in PH3 than PH1 or PH2, the risk of CKD progression over a lifetime remains a concern. Long term follow-up with attention to transition of care from childhood to adulthood is important.
SUPPLEMENTARY DATA
Supplementary data are available at ndt online.
Supplementary Material
ACKNOWLEDGEMENTS
We thank all of the patients and families who have participated in the RKSC PH registry as well as the many physicians who collected detailed clinical records. Further, we thank the study coordinators who collected the clinical data and biological samples, and particularly thank referring nephrologists Dr Baum, Dr Greenbaum, Dr Saland, Dr Bartosh and Dr Chandra. The RKSC is a part of the National Institutes of Health Rare Diseases Clinical Research Network. Funding for this project has been provided by U54-DK083908 from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). This work was further supported by the OHF. This work was partially presented as two abstracts at the Annual Meeting of the American Society of Nephrology, 2019 (Washington, DC) and at the OHF International Hyperoxaluria Workshop (Boston, MA) 2019.
AUTHORS’ CONTRIBUTIONS
D.S.M., J.C.L. and P.C.H. contributed to study design, and manuscript writing and review; A.C.G., L.H., D.O., J.B.O. and B.M.S. contributed to data acquisition and manuscript review; J.K.V. and R.A.M. provided statistical support, data acquisition and manuscript writing; D.J.S. contributed to manuscript review and writing; and P.S. contributed to manuscript writing, editing and reviewing.
CONFLICT OF INTEREST STATEMENT
D.O. has received lecture fees from the Chilren’s National Hospital and receives grant funding from NIH and Marriott Foundation. D.J.S. has received consulting fees from Advicenne, and lecture fees from Retrophin. J.C.L. receives consulting fees from the American Board of Internal Medicine, and grant support from Alnylam, Allena, Retrophin, OxThera, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and Dicerna. D.S.M. has received consulting fees from OxThera, Dicerna, Allena and Alynam, and grant funding from OxThera and Alnylam.
Contributor Information
Prince Singh, Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA.
Jason K Viehman, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA.
Ramila A Mehta, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA.
Andrea G Cogal, Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA.
Linda Hasadsri, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
Devin Oglesbee, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
Julie B Olson, Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA.
Barbara M Seide, Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA.
David J Sas, Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA; Division of Pediatric Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA.
Peter C Harris, Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA; Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA.
John C Lieske, Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
Dawn S Milliner, Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA; Division of Pediatric Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA.
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