Endpoints for Clinical Trials in Primary Hyperoxaluria

Feature CJASN ePress. Published on March 12, 2020 as doi: 10.2215/CJN.13821119

Dawn S. Milliner,1 Tracy L. McGregor,2 Aliza Thompson,3 Bastian Dehmel,4 John Knight,5 Ralf Rosskamp,6 Melanie Blank,3 Sixun Yang,7 Sonia Fargue ,5 Gill Rumsby,8 Jaap Groothoff,9 Meaghan Allain,10 Melissa West,10 Kim Hollander,11 W. Todd Lowther,12 and John C. Lieske1

Abstract Patients with primary hyperoxaluria experience kidney stones from a young age and can develop progressive oxalate nephropathy. Progression to kidney failure often develops over a number of years, and is associated with systemic oxalosis, intensive dialysis, and often combined kidney and liver transplantation. There are no therapies Due to the number of approved by the Food and Drug Association. Thus, the Kidney Health Initiative, in partnership with the Oxalosis and contributing authors, Hyperoxaluria Foundation, initiated a project to identify end points for clinical trials. A workgroup of physicians, the affiliations are scientists, patients with primary hyperoxaluria, industry, and United States regulators critically examined the listed at the end of this article. published literature for clinical outcomes and potential surrogate end points that could be used to evaluate new treatments. Kidney stones, change in eGFR, urine oxalate, and plasma oxalate were the strongest candidate end Correspondence: points. Kidney stones affect how patients with primary hyperoxaluria feel and function, but standards for Dr. Dawn S. Milliner, measurement and monitoring are lacking. Primary hyperoxaluria registry data suggest that eGFR decline in most Division of Nephrology, Mayo patients is gradual, but can be unpredictable. Epidemiologic data show a strong relationship between urine oxalate Clinic Rochester, 200 andlong-termkidney functionloss.Urine oxalateisreasonablylikelyto predict clinical benefit, due to itscausal role First Street SW, in stone formation and kidney damage in CKD stages 1–3a, and plasma oxalate is likely associated with risk of Rochester, MN 55905. systemic oxalosis in CKD 3b–5. Change in slope of eGFR could be considered the equivalent of a clinically Email: Milliner. [email protected] meaningful end point in support of traditional approval. A substantial change in urine oxalate as a surrogate end point could support traditional approval in patients with primary hyperoxaluria type 1 and CKD stages 1–3a. A substantial change in markedly elevated plasma oxalate could support accelerated approval in patients with primary hyperoxaluria and CKD stages 3b–5. Primary hyperoxaluria type 1 accounts for the preponderance of available data, thus heavily influences the conclusions. Addressing gaps in data will further facilitate testing of promising new treatments, accelerating improved outcomes for patients with primary hyperoxaluria. CJASN 15: ccc–ccc, 2020. doi: https://doi.org/10.2215/CJN.13821119

Introduction This article discusses the pathophysiology of primary Primary hyperoxaluria is a rare disease, with ,1000 hyperoxaluria, current treatment strategies, approval individuals affected in the United States. There are pathways and end points in the United States, and the three types of primary hyperoxaluria that differ in their workgroup’s assessment of potential end points that severity and genetic cause. Each of the three known couldbeusedtoevaluatetheefficacy of new drugs primary hyperoxaluria types is caused by a defect in a for the treatment of primary hyperoxaluria. Because gene that governs the production of a different hepatic primary hyperoxaluria type 1 accounts for 70%–80% enzyme, and each result in the overproduction of of all diagnosed patients with primary hyperoxaluria oxalate by the liver. Because humans have no enzyme to date and appears to have the most severe clinical capable of degrading oxalate, it must be eliminated phenotype (2,3), knowledge is most extensive for primarily by the kidneys, with a small amount by the this primary hyperoxaluria type. Thus, data relevant gastrointestinal tract. Hyperoxaluria results in calcium to primary hyperoxaluria type 1 influenced recom- oxalate kidney stones, progressive oxalate nephropathy, mendations in this article more than other primary and kidney failure. To address the pressing need to hyperoxaluria types. evaluate new treatments for primary hyperoxaluria, the Kidney Health Initiative (KHI) (1), in partnership with the Oxalosis and Hyperoxaluria Foundation (OHF), Pathophysiology of Primary Hyperoxaluria initiated a project to identify end points that could be Primary hyperoxaluria is caused by deficiencies in used in clinical trials. Published literature was examined enzymes involved in the metabolism of glycolate, to identify candidate end points. Workgroup members glycine, and hydroxyproline within the liver. The with expertise in oxalate biology and pathophysiol- resulting excess of glyoxylate leads to the synthesis ogy, clinical nephrology and urology, and drug and release of oxalate into the bloodstream. In the development provided a critical analysis of each early stages of the disease, the increase in plasma candidate. Patients with primary hyperoxaluria, their oxalate is mitigated and compensated for by increased family members, and leadership of the OHF patient kidney excretion. Oxalate in the urine combines with advocacy organization provided input throughout. calcium to form stones, as well as crystals that cause

acute and chronic tubular injury, induce inflammation significant risks (9–11). Therefore, new treatments are and fibrosis in the kidney parenchyma, and lead to loss of urgently needed. kidney function. Patients with primary hyperoxaluria typically experience kidney stones at a young age, have multiple recurrent stones, and often develop nephrocalci- Surrogate End Points and Approval Pathways in the nosis, progressive oxalate nephropathy, and kidney failure. United States Because oxalate is primarily eliminated by the kidneys, In the United States, the efficacy of a product (drug or advanced CKD results in high plasma oxalate concentra- biologic) in treating, mitigating, or preventing a disease can tions which exceed the saturation threshold for calcium be established by demonstrating an effect on a clinical oxalate. Calcium oxalate crystals can then deposit in skin, outcome, which reflects how a patient feels, functions, or retina, heart, vessels, bones, and other organ systems survives. Alternatively, product approval or licensure may (oxalosis), leading to severe morbidity that may eventually be based on a surrogate end point. Surrogate end points, cause death (3,4). In patients with primary hyperoxaluria which are often biomarkers such as a laboratory measure- who have kidney failure, dialysis cannot remove enough ment, radiographic image, or physical sign, are not direct oxalate to prevent progressive systemic oxalosis, and measures of clinical benefit, but instead are expected to kidney transplantation alone often fails due to recurrent predict the effect of a product on the clinical benefitof oxalate injury in the allograft (3). Figure 1 illustrates clinical interest.Surrogateendpointscanbecategorizedas manifestations observed in primary hyperoxaluria by validated, reasonably likely, or candidate, based on the kidney disease stage (upper bars), shaded from high strength of evidence supporting their use. A validated (blue) to low (gray) relative frequency. Of the three types surrogate end point is supported by strong scientific of primary hyperoxaluria, primary hyperoxaluria type 1 is evidence that a treatment effect on the surrogate end point the most severe form with more frequent nephrocalcinosis predicts the treatment effect on the clinical outcome of and kidney failure at earlier ages (2,3,5). As a population, primary interest. A reasonably likely surrogate end point is patients with primary hyperoxaluria type 1 have higher also supported by strong scientific evidence, but lacks urine oxalate than those with primary hyperoxaluria type sufficient evidence to serve as a validated surrogate end 2, followed by those with primary hyperoxaluria type 3 (2), point. Reasonably likely surrogate end points can be used and there is a wide variation among patients within each as a basis for accelerated approval of products intended to primary hyperoxaluria type and overlap between groups. treat a serious or life-threatening condition and that However, the mechanisms by which oxalate causes disease provide a meaningful advantage over available therapies. are believed to be the same in all types. For products granted accelerated approval, adequate and well controlled postmarketing confirmatory studies have generally been required to verify and describe the antic- Available Therapies and Unmet Need ipated clinical benefit(12–14). Current strategies to prevent stones and kidney damage target reduction of calcium oxalate crystal formation in the urinary tract through high urine volume and medications End Points for Clinical Trials in Primary Hyperoxaluria such as citrate and magnesium. Pyridoxine is a cofactor for In our evaluation of potential end points, the workgroup the alanine-glyoxylate aminotransferase (AGT) enzyme considered both clinical outcomes and surrogate end that is deficient in primary hyperoxaluria type 1. In certain points. Factors considered when assessing a clinical end primary hyperoxaluria type 1 genotypes characterized by point included its importance to patients and whether it mislocalization of AGT within hepatocytes, pharmacologic would be feasible to assess a treatment effect on the end doses of pyridoxine increase enzyme activity and thus point in a trial of reasonable duration. Factors considered reduce oxalate production (3,4,6). Large daily fluid intake when assessing a surrogate end point were (1) the biologic (e.g.,3.5–4 L/day in adults, with fluid prescription in plausibility of the relationship between the surrogate end children proportionate to body size) and a large pill burden point and clinical outcome of interest, including the extent compromise quality of life. Further, although these treat- to which the causal pathway of the disease is well un- ments may moderate the effects of hyperoxaluria, in many derstood and the relationship of the surrogate to this patients they do not prevent stone formation nor do they pathway; (2) the strength and consistency of the epidemi- eliminate kidney failure in primary hyperoxaluria types 1 ologic data supporting the relationship; and (3) whether and 2 (3,7). The burden of frequent symptomatic kidney treatment effects on the surrogate end point have been stones with associated hospitalizations and stone removal shown to predict treatment effects on the clinical outcome procedures, intensive dialysis if kidney failure ensues, of interest using different types of interventions. systemic oxalate deposition, and transplantation are enor- Although kidney failure is a meaningful end point, it is mous. The companion paper to this article, written by also one that is difficult to use in primary hyperoxaluria patients with primary hyperoxaluria and their family clinical trials because of the small size of the affected members, provides insights into the experience of living population and the long and variable time course for with this disease (8). At this time, there are no FDA- disease progression. Of the end points identified by the approved pharmacologic therapies for primary hyperox- workgroup (Table 1), kidney stones, rate of change in aluria. Liver transplantation can correct the metabolic GFR, urine oxalate, and plasma oxalate were identified deficiency in patients with primary hyperoxaluria types as the strongest end points for clinical trials (Figure 1). 1 and 2; this is an effective but extreme intervention, given In the sections that follow, each of these end points is that liver function is otherwise normal, and one that carries discussed. CJASN 15: ccc–ccc, July, 2020 Primary Hyperoxaluria Clinical Trial End Points, Milliner et al. 3

Figure 1. | Clinical manifestations observed in primary hyperoxaluria and candidate markers of progression vary by kidney disease stage. The consequences of hepatic oxalate overproduction (upper bars) are shaded to reflect high (purple) to low (gray) relative frequency, as best is known at this time. The clinical and biochemical markers (lower bars) are shaded to indicate those supported by clinical and experimental evidence (purple), while those with insufficient data and need for further research are shaded lighter (gray). Figure modified from the original provided courtesy of S. Hulton.

Kidney Stones as a Clinical End Point data, its role as a feasible clinical end point should be Stone burden is of particular interest in primary reconsidered. hyperoxaluria because stones are caused by high urine oxalate and often lead to pain, hospitalizations, and stone Slope of the Glomerular Filtration Rate as a Surrogate removal procedures. Although kidney stone disease di- End Point rectly affects the lives of patients with primary hyper- For rare causes of CKD, the efficacy of products intended oxaluria, work remains to develop reliable and safe to reduce the risk of progression to kidney failure may be methods for the assessment and quantification of stone established by showing a treatment effect on the rate of events, and to more fully define the natural history of decline in kidney function (GFR slope) or a sustained 30% stone burden at all CKD stages. Assessment of stone decline in GFR (12,18). In primary hyperoxaluria, loss of number and size is influenced by the type of imaging kidney function can begin in infancy and early childhood. modality used. Computerized tomography is recognized Among those with the most severe form, primary hyper- as the gold standard for stone detection (15,16), but oxaluria type 1, 50% will progress to kidney failure by 33 longitudinal studies require technique standardization years of age, and nearly all by 60 years of age (2). In most and entail recurring radiation exposure. Ultrasonography patients, kidney function is not typically lost at a rapid rate. for stone measurement yields varying results depending In a study by Tang et al. (7), the rate of loss of kidney upon the specific equipment used and sonographer function in a mixed group of patients with primary technique (17). Longitudinal data documenting changes hyperoxaluria type 1, primary hyperoxaluria type 2, and in kidney stone number or size regardless of technology primary hyperoxaluria type 3 ranged from 20.4 ml/min have not been reported in a primary hyperoxaluria per 1.73 m2 per year in those with no or prevalent cohort. Kidney stones are often asymptomatic for long nephrocalcinosis to 21.2 ml/min per 1.73 m2 per year in periods of time; thus, variability of stone symptoms must those with incident nephrocalcinosis. A small study (19) be considered when used as an end point for clinical reported a change of 21.7 ml/min per 1.73 m2 per year in trials. Further, neither definitions of symptomatic stone primary hyperoxaluria type 1 and 21.04 ml/min per events nor standards for radiographic assessment of 1.73 m2 per year in primary hyperoxaluria type 2. Fargue stone burden are commonly agreed upon. The effects et al. (20) reported a median decrease of 21.0 ml/min per of reduced GFR on stone burden are difficult to assess 1.73 m2 per year in 19 children with primary hyperoxaluria and have not been systematically described, and reduced type 1 who were .2 years of age at diagnosis. Clinical calcium and oxalate excretion in advanced CKD could experience suggests higher rates of GFR decline in those reduce stone activity. In sum, although stone burden is patients with primary hyperoxaluria who have more clinically meaningful, at the present time there are advanced CKD, particularly CKD stages 3b–4. Further, challenges related to its use as an end point in primary rapid declines in kidney function leading to kidney fail- hyperoxaluria. As the natural history of stone disease in ure over weeks to months occasionally occur in patients primary hyperoxaluria becomes informed by more robust with primary hyperoxaluria, sometimes precipitated by 4 CJASN

Table 1. Potential end points for clinical trials in primary hyperoxaluria

End Point Pros Cons

Clinical end points Stone events Affects how most patients with primary Standards for measurement and longitudinal hyperoxaluria feel and function monitoring lacking Accurate methods of measurement that do not rely on ionizing radiation are needed Reliability in CKD stages 3b–5 unknown

Kidney failure Important to patients, easy to measure May not have many events in a trial, particularly if trial is conducted in the available number of patients with a reasonable length of follow-up

Oxalosis Important to patients, severe morbidity May not have many events in a trial, particularly if trial is conducted in the available number of patients with a reasonable length of follow-up Surrogate end points Worsening kidney Accepted as surrogate end point for other May not detect change in patients with slow function (GFR slope) conditions progression Easy to measure Rapid decline would be highly supportive of clinically meaningful beneﬁt

Urine oxalate Causal role in stone formation and kidney Magnitude of change needed to predict clinical damage in CKD 1–3a and relationship beneﬁt across primary hyperoxaluria types between baseline urine oxalate and kidney warrants further study failure Available data support use of substantial change May not be useful in CKD 3b–5 due to reduced as surrogate end point for traditional approval kidney function to excrete oxalate in patients with primary hyperoxaluria type 1 with CKD 1–3a Lesser treatment effects or effects in patients with primary hyperoxaluria without very high baseline levels reasonably likely to predict clinical beneﬁt

Plasma oxalate Reasonably likely to predict clinical beneﬁt due Magnitude of change in plasma oxalate in CKD to causal role in systemic oxalosis in CKD stages 3b–5 likely to predict clinical beneﬁt stages 3b–5 requires further study Causal role in stone formation and kidney Value in CKD 1–3a for prediction of clinical damage (CKD stages 1–3a) outcome remains to be established Limited availability of laboratory measurement. Results vary by method

Data supporting these conclusions are heavily inﬂuenced by primary hyperoxaluria type 1, which accounts for the majority of patients with primary hyperoxaluria. Small numbers of patients with primary hyperoxaluria type 2 and primary hyperoxaluria type 3 in primary hyperoxaluria registries do not yet provide a similar strength of evidence for these biomarkers in other forms of primary hyperoxaluria.

acute events such as dehydration or an obstructive kidney function (2,3,7,21–23). In all primary hyperoxaluria types, stone (3,21). the urine becomes supersaturated, resulting in formation Additional research is needed to better define pop- of calcium oxalate crystals that aggregate within the ulations at greatest risk for progression and delineate the tubular lumen. The crystals can attach to the surface of course of disease in children and adults (Table 2). Given kidney tubular cells and become internalized, they then the limited ability to identify patients at high risk of migrate into the kidney interstitium (nephrocalcinosis) experiencing a significant loss of kidney function over where they induce inflammation, ultimately resulting in the course of a trial and the size of the affected progressive damage and CKD (3). In animal models of population, it is unclear whether GFR-based end points crystal nephropathy, prolonged activation of the intra- are, at present, feasible trial end points for primary renal inflammasome by calcium oxalate crystals appears hyperoxaluria. to be one mechanism that promotes the loss of kidney function (24,25). Nephrocalcinosis is also associated with Urine Oxalate as a Surrogate End Point risk of kidney failure in patients with primary hyper- Urine Oxalate as a Causal Factor in Stone Formation and oxaluria (7,26,27). Loss of Kidney Function. Persistently elevated urine ox- In all types of primary hyperoxaluria, calcium and oxalate alate levels cause kidney stone formation and also con- can also crystallize upon an anchored nidus in the kidney tribute to progressive kidney damage and loss of kidney papillum to form a stone (urolithiasis). Although higher CJASN 15: ccc–ccc, July, 2020 Primary Hyperoxaluria Clinical Trial End Points, Milliner et al. 5

Table 2. Gaps in data requiring additional research

CKD End Point Population Gaps in Data (Stage)

Kidney stones 1–3b Standards for deﬁnition of clinical stone event do not exist Standards for radiographic assessment of stone burden are not available Quantitative methods for stone assessments which avoid ionizing radiation not available 4–5a No reported studies

Slope of GFR 1–4 Changes in rate of decline by CKD stage are not well deﬁned Patient-patient variability is not well understood Discontinuity in eGFR formula performance as children transition to adulthood (52)

Urine oxalate excretion 1–3a Correlation between spot urine oxalate/creatinine and 24-h urine oxalate excretion not established Conﬁrmation of the relationship of urine oxalate excretion and incident ESKD in a validation cohort Relationshipofurineoxalateandplasmaoxalateovertherangeof GFRnotwelldescribed Interplay between urine oxalate and plasma oxalate and the development of intrarenal calcium oxalate crystals and kidney damage are poorly understood Quantitative effect of reduction of urine oxalate on GFR and stone burden is not known 3b–5a Effect of low GFR on urine oxalate has not been described; urine oxalate expected to decrease at low GFR due to declining kidney function.

Plasma oxalate 1–3aa Not widely used in clinical practice; minimal data available concentration Biologic variation not characterized Association with later irreversible morbidity and mortality not studied 3b–5 Biologic variation not well characterized Standards for sample collection, processing, and measurement are lacking Interpretation requires correction for GFR due to kidney clearance Dynamic equilibrium between plasma oxalate and tissue oxalate stores is poorly understood Predictive value of elevated plasma oxalate on clinical end points including risk for ESKD not deﬁned Magnitude of decrease in plasma oxalate needed to achieve a meaningful clinical beneﬁt not known Quantitative effect of plasma oxalate on systemic oxalosis is not known

Evidence supporting the association of potential end points with disease progression differs by CKD stage. Urine oxalate is a more useful biomarker when kidney function is preserved but is expected to decrease as GFR falls to low levels. Plasma oxalate becomes the biomarker of choice when the failing kidney is no longer able to adequately excrete oxalate into the urine (CDK stages 3b–5). Additional study is needed to determine whether plasma or urine oxalate performs better as a biomarker in CKD stage 3. aMinimal data available.

urine oxalate correlated with a greater number of stones on primary hyperoxaluria type 2 compared with primary radiographic images in one study (7), the relationship of hyperoxaluria type 1, and even lower in primary hyper- urine oxalate to clinical stone events or stone burden has not oxaluria type 3 (2,3,5,7). Nonetheless, an analysis of the been otherwise reported. Obstructing stones or stone re- OxalEurope primary hyperoxaluria type 2 registry data moval procedures can contribute to the loss of kidney clearly indicates that this patient population has signif- function in individual patients. However, in contrast to icant disease burden and morbidity (5). These observa- nephrocalcinosis, the number of stones and symptomatic tions suggest that more severe disease expression in primary stone events do not appear associated with kidney survival hyperoxaluria may be related to higher urine oxalate in primary hyperoxaluria at a population level (7). excretion rates. Epidemiologic Data. Epidemiologic data on the rela- Analysis of data from the Rare Kidney Stone Consortium tionship between urine oxalate and loss of kidney function (RKSC) primary hyperoxaluria registry of 297 patients with is derived from primary hyperoxaluria registries, observa- all types of primary hyperoxaluria (65% primary hyper- tions in secondary causes of hyperoxaluria, and in a large oxaluria type 1) demonstrated that kidney outcomes cohort of patients with CKD with other forms of kidney correlated with baseline urine oxalate excretion stratiﬁed disease. Analyses of primary hyperoxaluria registry data by quartile, with a kidney failure hazard ratio for quartile 4 show a strong relationship between urine oxalate and loss (Q4) versus Q1–Q3 of 3.4 (95% CI, 1.4 to 7.9). The 20-year of kidney function (21). Primary hyperoxaluria type 1 kidney survival was 96% for patients whose oxalate accounts for a majority of subjects. Data in primary excretion rate at primary hyperoxaluria diagnosis was hyperoxaluria type 2 and primary hyperoxaluria type 3 ,1.11 mmol/1.73 m2 per 24 hours, in contrast to 42% for are more limited but show urine oxalate, risk of neph- those with excretions $2.45 mmol/1.73 m2 per 24 hours rocalcinosis, and risk of kidney failure to be less in (21). When urine oxalate excretion rates over time were 6 CJASN

analyzed as a continuous time-dependent covariate, the type 1 in patients with CKD 1–3a. Lesser treatment effects or risk of kidney failure was greater with increasing urine effectsinpatientswithoutveryhigh baseline levels could also oxalate levels, yielding a hazard ratio of 1.8 (95% CI, 1.2 to translate into clinical benefit and possibly serve as a reasonably 2.5) per 1 mmol/1.73 m2 per 24-hour increase. In a separate likely surrogate and basis for accelerated approval, but the primary hyperoxaluria registry analysis (7), urine oxalate magnitude of reduction needed is unclear at this time. excretion rates in patients with primary hyperoxaluria were Urine oxalate appears to be the preferred end point in higher among those with nephrocalcinosis (2.0 mmol/24 hours) CKD 1–3a because urine oxalate is a causal factor in kidney versus those without nephrocalcinosis (1.3 mmol/24 hours), stones and nephrocalcinosis in these patients with higher P,0.01, again demonstrating a relationship between urine GFR. Changes in urine oxalate over the disease course have oxalate and kidney damage. In a large population of not been well described in patients who have progressed to patients who did not have primary hyperoxaluria with CKD stages 3b–5. Urine oxalate is expected to decrease as baseline CKD stages 2–4, higher 24-hour urinary oxalate GFR falls to very low levels (GFR,15 ml/min per 1.73 m2); excretion was an independent risk factor for CKD progres- ultimately excretion will cease with oligoanuria. The effects sion and kidney failure (23). In a review of 108 patients with of very low levels of kidney function on stone burden and secondary forms of hyperoxaluria, 55% required dialysis due nephrocalcinosis have not been systematically described. to biopsy-proven oxalate nephropathy (28). Timed 24-hour urine collections are needed for the most Importantly, although it is difficult to draw definitive accurate measurement of urine oxalate excretion rate but conclusions from these cross-sectional analyses, the data are challenging, especially in children. Additional work to support the principle that those patients with the highest quantitate the relationship between spot urine oxalate/ levels of urine oxalate are at greatest risk for primary urine creatinine measurements (39) or shorter duration hyperoxaluria disease progression, an important consider- collection with 24-hour urine oxalate excretion is needed. In ation for use of urine oxalate as a surrogate end point. The pediatric patients, urine oxalate measurements must ac- workgroupacknowledgesthatthisconclusionisdrivenby count for changes in reference ranges due to maturation primary hyperoxaluria type 1 data, which represent the of kidney function and growth throughout infancy and majority of primary hyperoxaluria cases, and that direct childhood. evidence of the relationship between urine oxalate and clinical outcome for primary hyperoxaluria type 2 and Plasma Oxalate as a Surrogate End Point primary hyperoxaluria type 3 is not yet available. Plasma Oxalate as a Causal Factor in Loss of Kidney Treatment Effects. Currently, the only treatment di- Function and Systemic Oxalosis. Plasma oxalate directly rectly targeting urine oxalate reduction is pyridoxine, reflects hepatic synthesis of oxalate. When kidney function which appears to increase the enzyme activity of a subset (GFR) is normal, the overproduction of oxalate is balanced of mutant AGT forms found in primary hyperoxaluria type by kidney excretion. Thus, plasma oxalate remains within 1 (29,30). Approximately 30% of patients with primary the normal range, or mildly elevated, at the expense of hyperoxaluria type 1 show some degree of responsive- markedly increased urine oxalate (40). As GFR declines, ness (31,32). A retrospective review demonstrated mean plasma oxalate increases due to dependence on the kidney urine oxalate reduction on pyridoxine of 73% from a for elimination. When plasma oxalate exceeds 35–50 mmol/L, baseline of 1.5 mmol/1.73 m2 per day among six patients physicochemical properties favor crystallization, leading to with primary hyperoxaluria type 1 who were homozygous systemic calcium oxalate crystal deposition (41,42). Crystal for the most common pyridoxine-responsive AGT muta- injury to tissue (43) can cause bone fractures, impaired tion (G170R); four achieved normal urine oxalate excretion erythropoiesis, infiltrative cardiomyopathy, arrhythmias, (33). In the same study, eight patients who were hetero- peripheral neuropathy, retinopathy, and ischemic ulcers zygous achieved a 45% reduction from a baseline of (4,44). Thus, in CKD stages 3b–5 (GFR,45 ml/min per 2.2 mmol/1.73 m2 per day. Pyridoxine effect was sustained 1.73 m2), elevated plasma oxalate is directly related to the during 6.5 and 8.4 years of follow-up, respectively. Pri- pathophysiology of oxalosis. In contrast, although oxa- mary hyperoxaluria registry studies confirm that patients late overproduction is a key causal factor in loss of kidney with primary hyperoxaluria type 1 who have the G170R function, plasma oxalate in isolation may not track well mutation have better preservation of kidney function than with the loss of kidney function at higher eGFR levels those patients without this mutation (2,34). Similarly, in four (.45 ml/min per 1.73 m2) because of the ability of the of five patients with late diagnosis of primary hyperoxaluria kidney to excrete the excess load. but with urine oxalate excretions normal or near normal after Epidemiologic Data. In patients with primary hyper- initiation of pyridoxine (,0.5 mmol/1.73 m2 per day), stable oxaluria, plasma oxalate increases from normal/modestly kidney function was maintained during a median of 8.5 years increased (2–10 mmol/L; normal is 1–3 mmol/L with most after a kidney-alone transplant (35). The only graft loss assays) when GFR is well preserved (.60 ml/min per occurred at 13.9 years post-transplant. Normalization of 1.73 m2) to markedly increased (.90–100 mmol/L) in oxalate excretion and stabilization of kidney function has patients with CKD stage 5 (3,4,40) (Figure 2). Plasma also been observed after pre-emptive liver transplanta- oxalate concentrations that exceed the supersaturation tion, and nephrocalcinosis has resolved after liver-alone threshold for calcium oxalate are typically observed transplant in a few reported cases (36–38). in patients with primary hyperoxaluria with GFR Recommendation for Urine Oxalate. Available data #30–40 ml/min per 1.73 m2 (CKD 3b–5) (40,45). Only support a substantial change in urine oxalate (e.g., near patients with primary hyperoxaluria who have advanced normalization) as a surrogate end point and basis for tradi- CKD and markedly increased plasma oxalate experience tional approval for the treatment of primary hyperoxaluria clinically overt systemic deposition of calcium oxalate CJASN 15: ccc–ccc, July, 2020 Primary Hyperoxaluria Clinical Trial End Points, Milliner et al. 7

Figure 2. | Plasma oxalate increases exponentially as eGFR declines below 60 ml/min per 1.73 m2. Plasma oxalate values and eGFR taken from the latest visit of 128 patients with primary hyperoxaluria (PH) who were .2 years of age (PH type 1, n596; PH2, n514; PH3, n518) were plotted. Plasma oxalate values are relatively stable in the eGFR range of .60 ml/min per 1.73 m2, and then they increase exponentially as eGFR declines. Plasma oxalate concentration was measured by ion chromatography. The CKD Epidemiology Collaboration (CKD-EPI) equation was used to calculate eGFR in adults, and the modified Schwartz equation at ,18 years of age. The model was fit using a third degree polynomial regression (plotted as a black line). Both quadratic and cubic terms were statistically significant by the likelihood ratio test (P,0.001 for both). The 95% confidence interval of the regression model is indicated by the shaded region. Data shown is from the Rare Kidney Stone Consortium Primary Hyperoxaluria Registry. in multiple body tissues, resulting in severe disease and oxalosis is limited to anecdotal experience with inten- ultimately death (3,4,45). Although the risk and manifesta- sive dialysis regimens and the resolution of disease man- tions of oxalosis are most severe in primary hyperoxaluria, ifestations after transplantation. Plasma oxalate decreases lesser elevations in plasma oxalate in patients with kidney rapidly after liver transplantation (48), with gradual reso- failure from any cause can be associated with a mild form of lution of oxalosis reported (37). Studies of treatment re- systemic calcium oxalate deposition (46,47). In patients with sponse to plasma oxalate reduction in patients with primary primary hyperoxaluria who have preserved GFR (CKD 1–3a), hyperoxaluria who have CKD stages 1–3a are lacking. theroleofplasmaoxalateindisease progression has not been Recommendation for Plasma Oxalate. Available data studied. This may, in part, be related to the small number support the use of a substantial change in plasma oxalate in of laboratories performing plasma oxalate measurements, patients with CKD stages 3b–5 and markedly elevated differences in measurement methods, and infrequent mea- plasma oxalate levels as a reasonably likely surrogate for surement of plasma oxalate in earlier stages of CKD. atreatment’s effect on systemic manifestations of the Treatment Effects. Evidence that reduction in plasma disease. Among patients with CKD 1–3a, the major util- oxalate reduces the risk or severity of subsequent systemic ity for plasma oxalate may be as a readily obtainable 8 CJASN

biomarker that reflects the net effect of oxalate burden and investment of the pharmaceutical industry. Although work urinary oxalate excretion (49). Limited data are available remains, patients with primary hyperoxaluria and their on the magnitude of change in plasma oxalate required to physicians can face the future with optimism. confer clinical benefit. Further, in advanced systemic oxalosis, the exchange of oxalate between tissue stores Acknowledgments and plasma is poorly understood (41,42,47). Additional In February 2018, the OHF conducted a workshop for members of research is needed to address these gaps in the data. the hyperoxaluria community, including patients and care partners, scientists, and clinicians. Clarity regarding end points for clinical Other Markers Considered as Potential Surrogate End Points trials of new agents for primary hyperoxaluria was identified as a Nephrocalcinosis, urine calcium oxalate supersatu- high priority. Participants and other volunteers from the primary ration (50), and primary hyperoxaluria metabolites hyperoxaluria community, selected by the OHF and KHI as mem- (glycolate, glycerate, dihydroxyglutarate, and 4-hydroxy- bers of the KHI Workgroup, collated literature for each potential end 2-oxoglutarate) (51) were also considered as potential point and presented the findings. The workgroup then deliberated surrogate end points. Progression of nephrocalcinosis and and worked to a consensus on the feasibility and utility of each end its relationship with kidney function has not been studied. point. Further, the absence of quantitative methods for nephro- We would like to acknowledge workgroup members and par- calcinosis measurement is a current barrier for its use as a ticipants of the RKSC and OxalEurope, including Kyle Wood, marker of disease progression. Measurements of primary Barbara Cellini, Felicity Enders, Lisa Vaughan, Amanda Gentile, hyperoxaluria metabolites and calculation of calcium oxalate supersaturation are currently performed by only a few Elisabeth Lindner, Dayna LeSueur, Anna Twigg, Frits van Alphen, laboratories and not widely used in clinical practice. Thus, and Yaacov Frishberg for their support over the duration of this there have been no studies in primary hyperoxaluria project. We would also like to acknowledge Kim Hollander and cohorts that demonstrate a correlation of these parameters Julie Bertarelli from the OHF (www.ohf.org) for their initiation of with stone burden or with progression of disease. this project and continued support along with the patients with Among patients with primary hyperoxaluria who have primary hyperoxaluria and their families who motivated this work. CKD stages 3b–5, severity of systemic oxalosis was con- This work was supported by the KHI, a public-private partnership sidered. New imaging techniques show promise for as- between the American Society of Nephrology (ASN), the US FDA, . sessment of systemic calcium oxalate burden (e.g.,retinal and 100 member organizations and companies to enhance patient imaging with spectral domain optical coherence tomogra- safety and foster innovation in kidney disease. KHI funds were used phy, speckle tracking echocardiography, cardiac elastog- to defray costs incurred during the conduct of the project, including raphy, and quantification of calcium oxalate deposits in project management support that was expertly provided by ASN bone through computed tomography or magnetic reso- staff members, M.A. and M.W. There was no honorarium or other nance imaging). There is limited experience in the use of financial support provided to KHI workgroup members. these imaging techniques in patients with primary hyper- The authors of this paper had final review authority and are fully oxaluria, and no systematic studies to define their responsible for its content. KHI makes every effort to avoid actual, usefulness in disease progression. Thus, in the absence potential, or perceived conflicts of interest that may arise as a result of standardized and reproducible measures of severity, of industry relationships or personal interests among the members assessment of oxalosis requires additional research. of the workgroup. More information on KHI, the workgroup, or the conflict of interest policy can be found at www.kidneyhealth- initiative.org. Conclusion The views and opinions expressed in this publication are those of To address the pressing need to evaluate new treatments the authors and do not necessarily reflect the official policies of any for primary hyperoxaluria, KHI, in partnership with KHI member organization, the US Department of Veterans Affairs, OHF, initiated a project to identify end points that could or the US Department of Health and Human Services, nor does any be used in clinical trials. The workgroup, which included mention of trade names, commercial practices, or organization experts in primary hyperoxaluria, patients living with imply endorsement by the US Government. primary hyperoxaluria and their families, industry, and United States regulators, considered potential clinical Disclosures outcomes, as well as possible surrogate end points that Dr. Lieske is currently employed by Mayo Clinic. Dr. Lieske re- could be used to establish the efficacy of new treatments. ports receiving grants from Allena, Alnylam, Dicerna, OxThera, The strengths and limitations of the end points considered Retrophin, and Siemens; receiving honoraria from Alnylam, by the group are summarized in Table 1, and important American Board of Internal Medicine (ABIM), Dicerna, Orfan, gaps in the data are discussed in Table 2. Available evidence OxThera, and Retrophin; serving as a consultant for ABIM, Allena, supports urine oxalate in CKD stages 1–3a and plasma Alnylam, Dicerna, Orfan, OxThera, Retrophin, and Siemens; and oxalate in CKD stages 3b–5 as end points for clinical trials in serving as a scientific advisor or member of ABIM, Kidney In- primary hyperoxaluria. ternational, and the Oxalosis and Hyperoxaluria Foundation; all We are at a tipping point in the development of new outside of the submitted work. Dr. Milliner is currently employed treatments for patients with primary hyperoxaluria, made by Mayo Clinic. Dr. Milliner reports receiving grants from Allena, possible by decades of dedicated patient participation in Alnylam, Dicerna, and OxThera; receiving honoraria from Alnylam; registries and clinical studies, the OHF in their support serving as a consultant for Allena, Alnylam, Dicerna, and OxThera; of primary hyperoxaluria patient and research communi- serving in an advisory committee for Alnylam, a monitoring com- ties, basic and clinical investigators, and the more recent mittee for a clinical trial conducted by Dicerna, on a data safety CJASN 15: ccc–ccc, July, 2020 Primary Hyperoxaluria Clinical Trial End Points, Milliner et al. 9

monitoring board for a clinical trial conducted by OxThera, and on the Consortium: Patients with Primary Hyperoxaluria type 2 have editorial board for Urolithiasis, all outside of the submitted work. significant morbidity and require careful follow-up. Kidney Int 96: 1389–1399, 2019 Dr. Milliner also has ongoing work with OHF outside of the submitted 6. Fargue S, Lewin J, Rumsby G, Danpure CJ: Four of the most work.Ms.AllainandMs.WestarecurrentlyemployedbytheAmerican common mutations in primary hyperoxaluria type 1 unmask the Society of Nephrology. Dr. Blank, Dr. Thompson, and Dr. Yang are cryptic mitochondrial targeting sequence of alanine:glyoxylate currently employed by the FDA. Dr. Dehmel is currently employed by aminotransferase encoded by the polymorphic minor allele. JBiol and reports ownership interest in OxThera outside of the submitted Chem 288: 2475–2484, 2013 7. Tang X, Bergstralh EJ, Mehta RA, Vrtiska TJ, Milliner DS, Lieske JC: work.Dr. FargueservesonthescientificadvisorycouncilforOHFandis Nephrocalcinosis is a risk factor for kidney failure in primary currently employed by the University of Alabama, Birmingham, out- hyperoxaluria. Kidney Int 87: 623–631, 2015 side of the submitted work. Dr. Groothoff is currently employed by the 8. Lawrence J, Wattenberg DJ: Primary hyperoxaluria: The patient and Academic Medical Center, Amsterdam, and reports serving as a con- caregiver perspective. Clin J Am Soc Nephrol 15: XXX–XXX, 2019 sultant for Alnylam and Dicerna, outside of the submitted work. 9. Watt KD, Pedersen RA, Kremers WK, Heimbach JK, Charlton MR: Evolution of causes and risk factors for mortality post-liver Dr. Groothoof is supported by presentation fees from Alnylam and transplant: Results of the NIDDK long-term follow-up study. Am J grantsfromAlnylam,Dicerna,andUniQure.Ms.Hollanderiscurrently Transplant 10: 1420–1427, 2010 employedbytheOHF.Ms.Hollanderreportsreceivinggrantsonbehalf 10. Rawal N, Yazigi N: Pediatric liver transplantation. Pediatr Clin of the OHF from Allena, Alnylam, Bridge Biopharma, Captozyme, North Am 64: 677–684, 2017 Dicerna, EveryLife Foundation, Intella Therapeutics, Invitae Corpo- 11. Diaz-Nieto R, Lykoudis P, Robertson F, Sharma D, Moore K, Malago M, Davidson BR: A simple scoring model for predicting ration, Novome Biotechnologies, Orfan, and OxThera; personal fees early graft failure and postoperative mortality after liver trans- from Allena, Alnylam, and Dicerna; and nonfinancial support from plantation. Ann Hepatol 18: 902–912, 2019 Allena, Alnylam, Dicerna, KHI, and OxThera; all outside of the sub- 12. Thompson A, Lawrence J, Stockbridge N: GFR decline as an end mitted work. Dr. Knight is currently employed by the University of point in trials of CKD: Aviewpoint from the FDA. Am J Kidney Dis 64: 836–837, 2014 Alabama, Birmingham. Dr. Knight reports receiving grants from Al- 13. Thompson A, Carroll K, A Inker L, Floege J, Perkovic V, Boyer- nylam, Chinook Therapeutics, Intella Therapeutics, and Synlogic Op- Suavet S, W Major R, I Schimpf J, Barratt J, Cattran DC, S Gillespie erating Company, Inc.; receiving personal fees from Chinook B, Kausz A, W Mercer A, Reich HN, H Rovin B, West M, Nachman Therapeutics; and has a pending patent for treating primary or idio- PH: Proteinuria reduction as a surrogate end point in trials of IgA pathic hyperoxaluria with small molecule inhibitors of lactate de- nephropathy. Clin J Am Soc Nephrol 14: 469–481, 2019 14. U.S. Department of Health and Human Services: Guidance for hydrogenase. Dr. Lowther is currently employed by Wake Forest Industry: Expedited Programs for Serious Conditions—Drugs and School of Medicine. Dr. Lowther reports receiving grants from Chinook Biologics, Silver Spring, MD, Food and Drug Administration, Therapeutics and Paredox Therapeutics, having ownership interest in 2014 Chinook Therapeutics, and serving on the editorial board of the Journal 15. Fowler KA, Locken JA, Duchesne JH, Williamson MR: US for of Biological Chemistry and the scientific advisory boards for Chinook detecting renal calculi with nonenhanced CT as a reference standard. Radiology 222: 109–113, 2002 Therapeutics and the Oxalosis and Hyperoxaluria Foundation, all 16. Fulgham PF, Assimos DG, Pearle MS, Preminger GM: Clinical outside of the submitted work. Dr. McGregor is currently employed by, effectiveness protocols for imaging in the management of ureteral has received travel support from, and has ownership interest in Al- calculous disease: AUA technology assessment. JUrol189: nylam Pharmaceuticals outside of the submitted work.Dr. Rosskampis 1203–1213, 2013 currently employed by and has ownership interest in Dicerna outside of 17. Dunmire B, Lee FC, Hsi RS, Cunitz BW, Paun M, Bailey MR, Sorensen MD, Harper JD: Tools to improve the accuracy of kidney the submitted work. Dr. Rumsby serves as a consultant for OxThera stone sizing with ultrasound. J Endourol 29: 147–152, 2015 outside of the submitted work. 18. Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Perrone RD, Koch G, Ouyang J, McQuade RD, Blais JD, Czerwiec FS, Sergeyeva O; REPRISE Trial Investigators: Tolvaptan in later-stage Funding autosomal dominant polycystic kidney disease. N Engl J Med 377: This work was supported by KHI, which is partially funded by a 1930–1942, 2017 US FDA grant 2R18FD005283-06 and ASN. This work was also sup- 19. Milliner DS, Wilson DM, Smith LH: Phenotypic expression of ported by the OHF and the Rare Kidney Stone Consortium of the primary hyperoxaluria: Comparative features of types I and II. National Institute of Diabetes and Digestive and Kidney Diseases Kidney Int 59: 31–36, 2001 20. Fargue S, Harambat J, Gagnadoux MF, Tsimaratos M, Janssen F, (U54DK083908), which is a part of the Rare Diseases Clinical Research Llanas B, Berthe´le´me´ JP, Boudailliez B, Champion G, Guyot C, fi Network of the Of ce of Rare Diseases Research, National Center for Macher MA, Nivet H, Ranchin B, Salomon R, Taque S, Rolland Advancing Translational Sciences of the National Institutes of Health. MO, Cochat P: Effect of conservative treatment on the renal outcome of children with primary hyperoxaluria type 1. Kidney Int 76: 767–773, 2009 21. Zhao F,Bergstralh EJ, Mehta RA, Vaughan LE, Olson JB, Seide BM, References Meek AM, Cogal AG, Lieske JC, Milliner DS; Investigators of Rare 1. Archdeacon P, Shaffer RN, Winkelmayer WC, Falk RJ, Roy- Kidney Stone Consortium: Predictors of incident ESRD among Chaudhury P: Fostering innovation, advancing patient safety: the patients with primary hyperoxaluria presenting prior to kidney kidney health initiative. Clin J Am Soc Nephrol 8: 1609–1617, 2013 failure. Clin J Am Soc Nephrol 11: 119–126, 2016 2. Hopp K, Cogal AG, Bergstralh EJ, Seide BM, Olson JB, Meek AM, 22. Curhan GC, Taylor EN: 24-h uric acid excretion and the risk of Lieske JC, Milliner DS, Harris PC; Rare Kidney Stone Consortium: kidney stones. Kidney Int 73: 489–496, 2008 Phenotype-genotype correlations and estimated carrier frequencies 23. Waikar SS, Srivastava A, Palsson R, Shafi T,Hsu CY,Sharma K, Lash of primary hyperoxaluria. JAmSocNephrol26: 2559–2570, 2015 JP,Chen J, He J, Lieske J, Xie D, Zhang X, Feldman HI, Curhan GC; 3. Cochat P, Rumsby G: Primary hyperoxaluria. N Engl J Med 369: Chronic Renal Insufficiency Cohort study investigators: Associ- 649–658, 2013 ation of urinary oxalate excretion with the risk of chronic kidney 4. Hoppe B, Beck BB, Milliner DS: The primary hyperoxalurias. disease progression. JAMA Intern Med 179: 542–551, 2019 Kidney Int 75: 1264–1271, 2009 24. Knauf F, Asplin JR, Granja I, Schmidt IM, Moeckel GW, David RJ, 5. Garrelfs SF, Rumsby G, Peters-Sengers H, Erger F, Groothoff J, Flavell RA, Aronson PS: NALP3-mediated inflammation is a Beck B, Oosterveld MJS, Pelle A, Neuhaus T, Adams B, Cochat P, principal cause of progressive renal failure in oxalate nephrop- Salido E, Lipkin GW, Hoppe B, Hulton SA; OxalEurope athy. Kidney Int 84: 895–901, 2013 10 CJASN

25. Mulay SR, Kulkarni OP, Rupanagudi KV, Migliorini A, Darisipudi 39. Clifford-Mobley O, Tims C, Rumsby G: The comparability of MN, Vilaysane A, Muruve D, Shi Y, Munro F, Liapis H, Anders HJ: oxalate excretion and oxalate:creatinine ratio in the investigation Calcium oxalate crystals induce renal inflammation by NLRP3- of primary hyperoxaluria: Review of data from a referral centre. mediated IL-1b secretion. J Clin Invest 123: 236–246, 2013 Ann Clin Biochem 52: 113–121, 2015 26. Takayama T, Nagata M, Ichiyama A, Ozono S: Primary hyper- 40. Hoppe B, Kemper MJ, Bo¨kenkamp A, Langman CB: Plasma calcium- oxaluria type 1 in Japan. Am J Nephrol 25: 297–302, 2005 oxalate saturation in children with renal insufficiency and in children 27. van Woerden CS, Groothoff JW, Wanders RJ, Davin JC, Wijburg with primary hyperoxaluria. Kidney Int 54: 921–925, 1998 FA: Primary hyperoxaluria type 1 in The Netherlands: Prevalence 41. Marangella M, Cosseddu D, Petrarulo M, Vitale C, Linari F: and outcome. Nephrol Dial Transplant 18: 273–279, 2003 Thresholds of serum calcium oxalate supersaturation in relation to 28. Lumlertgul N, Siribamrungwong M, Jaber BL, Susantitaphong P: renal function in patients with or without primary hyperoxaluria. Secondary oxalate nephropathy: A systematic review. Kidney Int Nephrol Dial Transplant 8: 1333–1337, 1993 Rep 3: 1363–1372, 2018 42. Hoppe B, Kemper MJ, Bo¨kenkamp A, Portale AA, Cohn RA, 29. Fargue S, Rumsby G, Danpure CJ: Multiple mechanisms of action Langman CB: Plasma calcium oxalate supersaturation in children of pyridoxine in primary hyperoxaluria type 1. Biochim Biophys with primary hyperoxaluriaandend-stagerenalfailure. KidneyInt Acta 1832: 1776–1783, 2013 56: 268–274, 1999 30. Cellini B, Montioli R, Oppici E, Astegno A, Voltattorni CB: The 43. Kusmartsev S, Dominguez-Gutierrez PR, Canales BK, Bird VG, chaperone role of the pyridoxal 59-phosphate and its implications Vieweg J, Khan SR: Calcium oxalate stone fragment and crystal for rare diseases involving B6-dependent enzymes. Clin Biochem phagocytosis by human macrophages. J Urol 195: 1143–1151, 47: 158–165, 2014 2016 31. Cochat P, Hulton SA, Acquaviva C, Danpure CJ, Daudon M, De 44. Birtel J, Herrmann P,Garrelfs SF,Dulz S, Atiskova Y,Diederen RM, MarchiM,FargueS,GroothoffJ,HarambatJ,HoppeB,JamiesonNV, Gliem M, Brinkert F, Holz FG, Boon CJF, Hoppe B, Charbel Issa P: KemperMJ,MandrileG,MarangellaM,PiccaS,RumsbyG,SalidoE, The ocular phenotype in primary hyperoxaluria type 1. Am J Straub M, van Woerden CS; OxalEurope: Primary hyperoxaluria Ophthalmol 206: 184–191, 2019 Type 1: indications for screening and guidance for diagnosis and 45. Marangella M, Petrarulo M, Vitale C, Daniele PG, Sammartano S, treatment. Nephrol Dial Transplant 27: 1729–1736, 2012 Cosseddu D, Linari F: Serum calcium oxalate saturation in patients 32. Hoyer-Kuhn H, Kohbrok S, Volland R, Franklin J, Hero B, Beck BB, on maintenance haemodialysis for primary hyperoxaluria or ox- Hoppe B: Vitamin B6 in primary hyperoxaluria I: First prospective trial alosis-unrelated renal diseases. Clin Sci (Lond) 81: 483–490, 1991 after 40 years of practice. Clin J Am Soc Nephrol 9: 468–477, 2014 46. Morgan SH, Purkiss P,Watts RW, Mansell MA: Oxalate dynamics 33. Monico CG, Rossetti S, Olson JB, Milliner DS: Pyridoxine effect in in chronic renal failure. Comparison with normal subjects and type I primary hyperoxaluria is associated with the most common patientswith primary hyperoxaluria. Nephron 46: 253–257, 1987 mutant allele. Kidney Int 67: 1704–1709, 2005 47. Marangella M, Vitale C, Petrarulo M, Tricerri A, Cerelli E, Cadario 34. Harambat J, Fargue S, Acquaviva C, Gagnadoux MF, Janssen F, A, Barbos MP, Linari F: Bony content of oxalate in patients with Liutkus A, Mourani C, Macher MA, Abramowicz D, Legendre C, primary hyperoxaluria or oxalosis-unrelated renal failure. Kidney Durrbach A, Tsimaratos M, Nivet H, Girardin E, Schott AM, Int 48: 182–187, 1995 Rolland MO, Cochat P: Genotype-phenotype correlation in 48. Bergstralh EJ, Monico CG, Lieske JC, Herges RM, Langman CB, primary hyperoxaluria type 1: The p.Gly170Arg AGXT mutation HoppeB,MillinerDS;IPHRInvestigators:Transplantationoutcomes is associatedwith a better outcome. Kidney Int 77: 443–449, 2010 in primary hyperoxaluria. Am J Transplant 10: 2493–2501, 2010 35. Lorenz EC, Lieske JC, Seide BM, Meek AM, Olson JB,Bergstralh EJ, 49. Perinpam M, Enders FT, Mara KC, Vaughan LE, Mehta RA, Milliner DS: Sustained pyridoxine response in primary hyper- Voskoboev N, Milliner DS, Lieske JC: Plasma oxalate in relation to oxaluria type 1 recipients of kidney alone transplant. Am J eGFR in patients with primary hyperoxaluria, enteric hyperoxaluria Transplant 14: 1433–1438, 2014 and urinary stone disease. Clin Biochem 50: 1014–1019, 2017 36. Kemper MJ, Nolkemper D, Rogiers X, Timmermann K, Sturm E, 50. Werness PG, Brown CM, Smith LH, Finlayson B: EQUIL2: A MalagoM,BroelschCE,Burdelski M,Mu¨ller-WiefelDE:Preemptive BASIC computer program for the calculation of urinary saturation. liver transplantation in primary hyperoxaluria type 1: Timing and J Urol 134: 1242–1244, 1985 preliminary results. J Nephrol 11[Suppl 1]: 46–48, 1998 51. Clifford-Mobley O, Hewitt L, Rumsby G: Simultaneous analysis of 37. Galanti M, Contreras A: Excellent renal function and reversal of urinary metabolites for preliminary identification of primary nephrocalcinosis 8 years after isolated liver transplantation in an hyperoxaluria. Ann Clin Biochem 53: 485–494, 2016 infant with primary hyperoxaluria type 1. Pediatr Nephrol 25: 52. Rule AD, Kremers WK: What is the correct approach for com- 2359–2362, 2010 paring GFR by different methods across levels of GFR? Clin J Am 38. Perera MT, Sharif K, Lloyd C, Foster K, Hulton SA, Mirza DF, Soc Nephrol 11: 1518–1521, 2016 McKiernan PJ: Pre-emptive liver transplantation for primary hyperoxaluria (PH-I) arrests long-term renal function de- Published online ahead of print. Publication date available at terioration. Nephrol Dial Transplant 26: 354–359, 2011 www.cjasn.org.

AFFILIATIONS

1Division of Nephrology, Mayo Clinic, Rochester, Minnesota; 2Alnylam Pharmaceuticals, Cambridge, Massachusetts; 3Division of Cardiovascular and Renal Products, Ofﬁce of New Drugs, Center for Drug Evaluation and Research, and 7Division of Vaccines and Related Products Applications, Ofﬁce of Vaccines Research and Review, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland; 4OxThera AB, Stockholm, Sweden; 5Department of Urology, The University of Alabama at Birmingham, Birmingham, Alabama; 6Dicerna Pharmaceuticals, Cambridge, Massachusetts; 8University College London Hospitals, London, United Kingdom; 9Department of Pediatric Nephrology, University of Amsterdam Medical Center, Amsterdam, Netherlands; 10American Society of Nephrology, Washington, DC; 11Oxalosis and Hyperoxaluria Foundation, New Paltz, New York; and 12Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, North Carolina