#NephJC Chat

Tuesday June 30th, 2020 at 9 pm Eastern Daylight Time

Wednesday July 1st, 2020 at 9 pm Indian Standard Time

Wednesday July 1st, 2020 at 9 pm BST

N Engl J Med. 2020 Jun 25;382(26):2493-2503. doi: 10.1056/NEJMoa1916624.

Serum Urate Lowering With Allopurinol and Kidney Function in Type 1 Diabetes

Alessandro Doria 1, Andrzej T Galecki 1, Cathie Spino 1, Rodica Pop-Busui 1, David Z Cherney 1, Ildiko Lingvay 1, Afshin Parsa 1, Peter Rossing 1, Ronald J Sigal 1, Maryam Afkarian 1, Ronnie Aronson 1, M Luiza Caramori 1, Jill P Crandall 1, Ian H de Boer 1, Thomas G Elliott 1, Allison B Goldfine 1, J Sonya Haw 1, Irl B Hirsch 1, Amy B Karger 1, David M Maahs 1, Janet B McGill 1, Mark E Molitch 1, Bruce A Perkins 1, Sarit Polsky 1, Marlon Pragnell 1, William N Robiner 1, Sylvia E Rosas 1, Peter Senior 1, Katherine R Tuttle 1, Guillermo E Umpierrez 1, Amisha Wallia 1, Ruth S Weinstock 1, Chunyi Wu 1, Michael Mauer 1, PERL Study Group

PMID: 32579810 Full Text at NEJM

AND

N Engl J Med. 2020 Jun 25;382(26):2504-2513. doi: 10.1056/NEJMoa1915833.

Effects of Allopurinol on the Progression of Chronic Kidney Disease

Sunil V Badve 1, Elaine M Pascoe 1, Anushree Tiku 1, Neil Boudville 1, Fiona G Brown 1, Alan Cass 1, Philip Clarke 1, Nicola Dalbeth 1, Richard O Day 1, Janak R de Zoysa 1, Bettina Douglas 1, Randall Faull 1, David C Harris 1, Carmel M Hawley 1, Graham R D Jones 1, John Kanellis 1, Suetonia C Palmer 1, Vlado Perkovic 1, Gopala K Rangan 1, Donna Reidlinger 1, Laura Robison 1, Robert J Walker 1, Giles Walters 1, David W Johnson 1, CKD-FIX Study Investigators

PMID: 32579811 Full Text at NEJM

More information

Uric Aid Tweetorials

The summary is not enough. Check out these tweetorials on

Why did we lose the ability to handle excess uric acid?
What is mendelian randomization and what does it tell us here?

Correlation is Confusion not Causation: The Case of Uric Acid in CKD

This week, we will discuss the fresh-off-the-press trials from this week’s issue of the NEJM: PERL and CKD-FiX. These two trials examined if the uric acid and CKD link is causal: by measuring CKD progression after giving patients allopurinol. Be ready for another medical reversal.

The PERL study visual abstract

The CKD-Fix visual abstract

Introduction

Whether uric acid is a cause or symptom of kidney dysfunction is possibly the longest-standing unresolved debate in medicine. In 1683, Stephen Blankaart, a dutch physician, speculated that the increasing prevalence of gout was due to increased sugar consumption (Rivard et al., 2012). In 1848, Alfred Garrod published the first extensive manuscript describing gout, which identified the pathologic role of uric acid and detailed how “chronic gout” may silently affect the kidneys (see below).

More recent literature implicates uric acid as either an intermediary (as one of many factors that can influence hypertension) or a simple byproduct of CKD progression. How, in theory, would urate directly damage the kidney? Extracellular precipitation in the form of microscopic crystals and macroscopic urate stones can cause structural damage. There are also proposed intracellular mechanisms of injury relating to its oxidative properties (Johnson, 2013). Humans and other primates are prone to hyperuricemia because we lack uricase (see this Tweetorial for more on this). To lower uric acid levels, we must use xanthine oxidase inhibitors (XOIs) such as allopurinol and febuxostat, recombinant uricases such as rasburicase, and inhibitors of urate reabsorption such as probenecid.

To date, many clinical trials and systematic reviews have looked at whether there is a benefit to lowering uric acid levels. An umbrella review in the BMJ (Li et al., 2017) found a clear benefit only in gout and nephrolithiasis. Data evaluating the benefit of urate lowering in CKD is notoriously and problematically heterogeneous. Because of this uncertainty, nephrology practices diverge in terms of which patients are prescribed urate-lowering therapies. A more recent review article written by members of Richard Johnson’s group claimed that, if only the subset of RCTs that show progression of CKD in the control group are included, a benefit is observed (Sato et al., 2019). They conclude that in patients with progressing CKD (decrease in eGFR by >4 ml/min/1.73m2 per year), empiric allopurinol may be appropriate. However, several issues were raised in reply to this article, including questions about quality and biases of included studies (Steiger, Ma & Anders, 2020). Additionally, Mendelian randomization studies haven’t identified a causative role for urate in CKD (Jordan et al., 2019), which even proponents of the urate-causes-CKD theory have not been able to rectify (Sato et al., 2019). Ultimately, adequately powered RCTs are needed to settle the debate: does urate-lowering therapy provide significant benefit to the CKD population (Bose et al., 2013)? Enter the PERL and CKD-FIX studies.

PERL, covered first in the sections below, is a US-led study that examined whether CKD progression is halted with allopurinol in patients with Type 1 diabetes. CKD-FIX is an Australian-based study led by Sunil Badve (@badves) that looked at whether patients with advanced, progressive CKD benefit from allopurinol.

The Studies

PERL (Preventing Early Renal Loss in Diabetes)

Design

Double-blind, parallel group, multicenter, randomized, placebo-controlled clinical trial of allopurinol in 530 participants with Type 1 DiabetesConducted at 16 sites in the United States, Canada, and Denmark. Clinical trial registration: NCT02017171

Study Population
Inclusion criteria

Type 1 diabetes for more than 8 years
Between 18-70 years of age
Estimated GFR 40-99.9 ml/min/1.73m2 BSA
Evidence of diabetic kidney disease: defined as a urine albumin excretion rate (UAER) of 20-3333 µg/min or treatment with RAS blockers.
Evidence of decline in GFR of at least 3 ml/min/1.73m2 per year in previous 3-5 yrs
Serum urate level of ≥ 4.5mg/dL (268 µmol/L)

Exclusion criteria

History of gout or any other indication for urate lowering therapy such as with cancer chemotherapy. Cancer treatment within 2 years before screening.
Recurrent renal calculi.
Current use of azathioprine, 6-Mercaptopurine, didanosine, warfarin, tamoxifen, amoxicillin, ampicillin, and other drugs which interact with allopurinol.
Allergy to xanthine oxidase (XO) inhibitors or iodine-containing substances.
HLAb*58:01 positivity (associated with Stevens-Johnson syndrome/toxic epidermal necrolysis with allopurinol).
Kidney Transplant or non- diabetic kidney disease.
SBP/DBP >160/100 mmHg at screening or >150/95 at the end of run-in period.
History of hepatic disease including Hep B/C or elevated LFTs.
Hb <11 g/dL (males) , <10 g/dL (females) platelet count < 100,000/mm3
History of alcohol or drug abuse in past 6 months, or blood donation in the 3 months before screening
History of CHF, pulmonary insufficiency or HIV Current pregnancy or breastfeeding

Trial Procedures

Run-in phase: 9 weeks of RAS blocker (at least equivalent to 10mg of ramipril or 300mg of irbesartan) adjusted to BP target <140/90mmHg.
Randomization: oral placebo or allopurinol Allopurinol: minimum 100mg/day for 4 wks. Increased to: 400mg/day if eGFR was ≥ 50 ml/min/1.73m2300mg/day if eGFR was 25-49 ml/min/1.73m2200mg/day if eGFR was 15-24 ml/min/1.73m2
Stratified according to site, serum urate level (≤ 6 vs >6 mg/dL) and HbA1c (≤ 7.8 vs >7.8 %)
Treatment phase: 3 yrs plus 2 months washout period.
Trial Visits every 3-4 months included measurement of BP, serum creatinine (SCr), HbA1c as well as safety evaluations. GFR was measured by iohexol-based GFR (iGFR) method immediately before randomization, midway at 80 weeks, at the end of the intervention period at 156 weeks, and after the washout period at 164 weeks.

Outcomes

Primary outcome: iGFR after 3 yrs+2 months washout period, with adjustment for baseline iGFR.

Secondary outcomes: baseline-adjusted iGFR after 3-yr intervention period; iGFR time trajectory as estimated from measurements conducted at baseline, at mid-trial, at the end of intervention, and at the end of washout period;baseline-adjusted serum creatinine-based eGFR (CKD-Epi equation) at 4 months;eGFR time trajectory with use of SCr obtained at intervals of 3-4 months doubling of SCr or progression to ESKD in a time-to-event analysis; baseline-adjusted urinary albumin excretion rate (UAER) after washout; baseline-adjusted UAER after 3 years;fatal or non fatal cardiovascular events (defined as death from cardiovascular causes, non fatal myocardial infarction, non fatal stroke, CABG, or PCI) in a time-to-event analysis.

Statistical analysis

It was estimated that 180 participants per group would provide the trial with 80% power to detect a prespecified effect of 3 ml/min/1.73m2 on the primary outcomes, assuming a two-sided type 1 error of 5% and a standard deviation of residual error of 10.1 ml/min/1.73m2 . Primary analysis was conducted in the intention-to-treat population, which included all the patients who had undergone randomization.
Effect of allopurinol on the primary outcome was evaluated with use of a linear model for correlated errors with a general or unstructured covariance matrix with the following covariates: stratification variables, baseline value of the dependent variable, kidney phenotype (albuminuric DKD vs normoalbuminuria with declining kidney function), and baseline UAER.

Funding

The trial was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and JDRF (previously known as the Juvenile Diabetes Research Foundation).

Results

PERL (Preventing Early Renal Loss in Diabetes)
Of 1625 persons screened, 1016 were ineligible, withdrew, or were lost to follow-up before the run-in phase, 609 entered the run-in phase, and 530 finished the run-in phase and were randomly assigned to receive either allopurinol (267 patients) or placebo (263 patients).

The mean age of the patients was 51.1 years, and the mean duration of diabetes was 34.6 years. The mean iGFR was 68.0 ml/min/1.73 m2 , and the mean eGFR was 74.7 ml/min/1.73 m2. The mean serum urate level was 6.1 mg/dL (360 μmol per liter), and the mean HbA1c was 8.2%. Ninety percent of the patients were on RAS inhibitors. More details are in Table 1.

The median adherence to the assigned regimen (assessed as the percentage of tablets taken) was 93.8% (IQR 86.3 to 97.4), with 85.4% of the participants having at least 80% adherence, and 94.9% of the patients having at least 70% adherence.
The serum urate level, which remained at baseline levels in the placebo group, decreased progressively in the allopurinol group from 6.1 mg/dL at baseline to 3.7 mg/dL at 16 weeks and remained at that level for the duration of the intervention period (mean, 3.9 mg/dL, equivalent to a 36% reduction from the baseline value); after the washout period, the serum urate level returned to a near-baseline value (mean, 5.9 mg/dL) (Fig. 1A).

Effect on HbA1c, BMI, systolic BP, and diastolic BP during the trial between two arms is shown in the following Supplemental figure S2. There was no significant difference in these parameters in allopurinol (red line) vs. placebo (blue line) groups.

Primary outcome

The iGFR in the intention-to-treat population (ITT) decreased at similar rates in the allopurinol group and in the placebo group (Fig. 1B).

When values were adjusted for the baseline values, the mean iGFR at the end of the 2-month washout period (the primary outcome) was virtually identical in the two groups (61.2 ml/min/1.73 m2 in each group, with a between-group difference of 0.001 ml/min/1.73 m2 ; 95% CI, −1.9 to 1.9) (Table 2).

There was no evidence of clinically meaningful effects with regard to the secondary outcomes of the baseline-adjusted iGFR at 4 months into the intervention and at the end of the intervention period, the slope of the iGFR, or the slope of the eGFR (Table 2). The UAER was 40% (95% CI, 0 to 80) higher at the end of the washout period and 30% (95% CI, 0 to 60) higher at the end of the intervention period in the allopurinol group than in the placebo group. Results in the time-to-event analyses of serum creatinine doubling or progression to end-stage kidney disease and of fatal or nonfatal cardiovascular events were inconclusive owing to small numbers of events.
Prespecified subgroup analyses of the primary outcome in the intention-to-treat population did not reveal significant heterogeneity in response to allopurinol (Fig. 2).

Safety

There were 354 serious adverse events; 171 serious adverse events occurred in the allopurinol group and 183 occurred in the placebo group. The percentages of participants with at least one serious adverse event were similar in the two groups (93 of 267 patients [34.8%] in the allopurinol group and 82 of 263 [31.2%] in the placebo group) (Table S4), as were the percentages of patients who discontinued allopurinol or placebo because of such events (16 patients [6.0%] and 11 patients [4.2%], respectively) (fig S1).
Although uncommon, there were numerically more fatal serious adverse events in the allopurinol group than in the placebo group (in 10 patients vs. 4). No major imbalances between the two groups were observed in the distribution of serious adverse events according to the body system.

CKD-FIX (Controlled Trial of Slowing of Kidney Disease Progression from the Inhibition of Xanthine Oxidase)

Design

Investigator-initiated, randomized, double-blind, placebo-controlled trial with a total of 363 participants with CKD Stage 3 or 4.
Conducted at 31 centers in Australia and New Zealand.
Clinical trial registry: 343216

Study Population

Inclusion criteria

Adult (age ≥ 18 years)
CKD stage 3 or 4 (eGFR 15 to 59 mL/min/1.73 m2 inclusive); AND
Random urine albumin to creatinine ratio (UACR) ≥265 mg/g (≥30 mg/mmol) OR
Evidence of progression of CKD (decrease in eGFR ≥ 3.0 mL/min/1.73 m2 in the last year)

Exclusion criteria

History of clinically established gout;
History of hypersensitivity to allopurinol;
Kidney transplant recipients;
Concurrent treatment with azathioprine, 6-mercaptopurine, theophylline, cyclophosphamide, cyclosporine, probenecid, phenytoin, or chlorpropamide;
Indication for allopurinol, including tophus or tophi on clinical examination or imaging study, uric acid nephropathy, uric acid nephrolithiasis or urolithiasis;
Current non-skin cancer malignancy;
Unresolved acute kidney injury in last 3 months;
Current pregnancy or breastfeeding;
Any uncontrolled psychological illness or condition which interferes with their ability to understand or comply with the requirements of the study; or
Elective or imminent initiation of maintenance dialysis or kidney transplantation expected in the next 6 months.

Trial Procedures

Patients were randomized 1:1 to receive allopurinol or placebo with an adaptive allocation algorithm designed to minimize imbalance between the treatment groups in the following variables: trial center, CKD stage 3 or 4, albuminuria (UACR, ≥530 or <530mg/g [≥60 or <60mg/mmol]), and diabetes mellitus status (present or absent).

eGFR was determined by the CKD-EPI creatinine equation. Sensitivity analyses were conducted with the use of the CKD-EPI equation, based on cystatin C alone and in combination with creatinine, and the Modification of Diet in Renal Disease equation

Follow up period was 104 weeks (2 years), which includes the initial dose escalation phase of 12 weeks and subsequent 92-week follow-up phase.

During the dose escalation phase, the starting dose of allopurinol (100 mg) or placebo was one tablet by mouth daily and could be increased every 4 weeks to a maximum of three tablets daily if all the criteria for dose adjustment were met. (Table S2.) Criteria for Study Medication Dose Adjustment:

No new onset skin rash or reaction;
Haemoglobin >80 g/L;
Neutrophil count >2.0 x 109 /L;
Eosinophil count ≤0.60 x 109 /L or <20% of previous value if baseline eosinophil count >0.60 x 109 /L;
Platelet count >100 x 109 /L;
Alanine transaminase (use aspartate transaminase if alanine transaminase is not available) <3 times upper limit of normal;
Serum creatinine >20% increase of previous value; and,
The treating physician feels increasing dose is safe based on the clinical circumstances.

Dose adjustment on the basis of serum urate level was not permitted at any time during the trial.

During the follow-up phase, patients underwent assessment in the clinic every 16 weeks.

Patients were withdrawn from the trial earlier than 104 weeks if they received dialysis for more than 30 days or underwent kidney transplantation.

Outcomes

Primary outcome:
- Change in eGFR from randomization to 104 weeks
Secondary outcomes:
- Composite of 40% reduction from baseline in eGFR, ESKD (dialysis for ≥30 days or kidney transplant), or death from any cause
- Composite of 30% reduction from baseline in eGFR, ESKD, or death from any cause
- individual components of the composite kidney outcomes;
- blood pressure, albuminuria, and serum urate level;
- cardiovascular events;
- hospitalization for any cause;
- quality-of-life summary scores on the 36-Item Short-Form Health Survey.

Safety outcome: all serious adverse events and drug reactions. Specific safety outcomes of interest were erythema multiforme, the Stevens– Johnson syndrome, toxic epidermal necrolysis, minor rash, hypersensitivity syndrome, aplastic anemia, and thrombocytopenia.

Statistical analysis

Under the assumption of an annual decline in eGFR of 3 ml/min/1.73 m2, 15 loss to follow-up (5%), and drop-in and drop-out rates of 5%, 620 patients (310 in each group) were planned to be enrolled to provide 90% power to detect a 20% attenuation in the decline in eGFR after 2 years of follow-up.

The estimate of treatment effect was the difference between the allopurinol group and the placebo group in the annual change in eGFR. This estimate included the time to discontinuation for informative reasons (death or end-stage kidney disease), analyzed with a Weibull parametric survival model with random effects.

Funding

Funded by the National Health and Medical Research Council of Australia and the Health Research Council of New Zealand

Results

CKD-FIX (Controlled Trial of Slowing of Kidney Disease Progression from the Inhibition of Xanthine Oxidase)

From March 2014 through December 2016, a total of 369 patients (60% of the target number) were randomly assigned to the allopurinol group (185 patients) or the placebo group (184 patients). A decision was made by the trial steering committee to stop further recruitment because of a slower than anticipated recruitment rate that rendered the number of participants unlikely to reach the projected target within a reasonable time frame.

At the end of the 12-week dose-escalation phase, 126 (69%), 17 (9%), and 9 (5%) of the 182 patients in the allopurinol group were taking three tablets, two tablets, and one tablet of allopurinol once daily, respectively; the corresponding numbers in the placebo group were 126 (70%), 27 (15%), and 10 (6%) of 181 patients. During the 104-week follow-up period, 54 patients (30%) in the allopurinol group and 45 patients (25%) in the placebo group discontinued the assigned regimen.

In total, 132 patients (73%) in the allopurinol group and 144 patients (80%) in the placebo group completed the 104-week follow-up period. The patients who had been assigned to the allopurinol group took allopurinol for a mean of 75.8 weeks (83% of 91.5 weeks of follow-up), and the patients who had been assigned to the placebo group took placebo for a mean of 83.0 weeks (88% of 94.2 weeks of follow-up).

Primary Outcome

The change in the eGFR did not differ significantly between the allopurinol group (−3.33 ml/min/1.73 m2 per yr [95% CI, −4.11 to −2.55]) and the placebo group (−3.23 ml/min/1.73 m2 per yr [95% CI, −3.98 to −2.47]), with a mean difference of −0.10 ml/min/1.73 m2 per yr [95% CI, −1.18 to 0.97] (P=0.85; Fig 1).

Results for the primary outcome were consistent across a wide range of prespecified subgroups (Fig. S2).

Secondary outcomes

The secondary composite outcome of a 40% decrease in eGFR, end-stage kidney disease, or death from any cause occurred in 63 patients (35%) in the allopurinol group and 51 patients (28%) in the placebo group (risk ratio, 1.23; 95% CI, 0.90 to 1.67; hazard ratio, 1.34; 95% CI, 0.92 to 1.93) (Table 2).

Similar results were observed for the composite outcome of a 30% decrease in the eGFR, end-stage kidney disease, or death from any cause (risk ratio, 1.13; 95% CI, 0.89 to 1.44; hazard ratio, 1.23; 95% CI, 0.90 to 1.69).

Mean serum urate level

The mean difference in the serum urate level, with adjustment for baseline values, was −2.7 mg/dL (95% CI, −3.0 to −2.5) (−160 μmol/L; 95% CI, −180 to −150) (Fig. 2A above, and table below).

There were no significant between-group differences in the UAER (geometric mean difference, −9%; 95% CI, −24 to 10) (Fig. 2B),

There were no significant between-group difference in systolic blood pressure (mean difference, −1.79 mm Hg; 95% CI, −4.69 to 1.11) or diastolic blood pressure (mean difference, −3.21 mm Hg; 95% CI, −6.82 to 3.40) (Figs. S3 and S4), or health-related quality of life (mean difference in 36-Item Short-Form Health Survey quality-of-life summary score, −4.4; 95% CI, −10.5 to 1.6)

*Figure S3 and S4 from CKD-FiX, NEJM 2020*

Adverse Events

Serious adverse events occurred at similar frequencies in the two groups (170 events among 84 participants [46%] in the allopurinol group and 167 events among 79 participants [44%] in the placebo group) (Table 3). Eleven participants (6%) in the allopurinol group and 6 (3%) in the placebo group died. There were no significant differences in the risks of non serious adverse drug reactions, including rash.

Discussion

There is a longstanding debate regarding whether urate-lowering drugs could slow the progression of CKD. Data from multiple observational studies and small RCTs are contradictory and, as a whole, inconclusive (Li et al., 2017). These two trials were designed to settle the issue. PERL randomized adults with Type 1 diabetes, early-to-moderate DKD on RASi, and serum urate ≥ 4.5 mg/dL (268 µmol/L) to maximal tolerated dose allopurinol vs. placebo for 3 years. CKD-FIX enrolled adults with progressive, moderate-to-advanced CKD (of any etiology), who were also randomized to receive either maximally tolerated allopurinol or placebo for 2 years. Both studies came to the same conclusion: allopurinol was not effective in reducing the rate of progression of kidney disease. These findings are consistent with the FEATHER (Febuxostat versus Placebo Randomized Controlled Trial Regarding Reduced Kidney Function in Patients with Hyperuricemia Complicated by Chronic Kidney Disease Stage 3) trial, which examined the role of another xanthine oxidase inhibitor, febuxostat, on CKD progression (Kimura, 2018), though in a population with little progression of CKD.

Strength

PERL: well-designed — rigorous protocol, adequate power (80%), robust imputation method, high participant adherence (sustained 36% reduction in serum urate levels)
PERL: accurate data reporting — iGFR used
PERL: representative population — rate of GFR decline in control group consistent with literature for T1DKD
CKD-FIX: robust outcome measures — consistent results across primary and secondary outcomes
Both studies: longitudinal — At 2- and 3-years in length, these have been the longest RCTs studying the effect of allopurinol on CKD progression to date. It seems unlikely that a trial of even longer duration would reveal differences between groups given the virtual absence of a treatment effect over the 2-3 years.

Limitations

PERL: many patients are not hyperuricemic at baseline (critique raised in a Tweet by David S. Goldfarb (@weddellite) and in a response article by Richard Johnson’s group)
- Two smaller, positive RCTs (Siu et al., 2006, N = 54 and Goicoechea et al., 2010, N = 113) had much higher baseline serum urate levels — 9.5 mg/dL and 7.6 mg/dL, respectively.
- CKD-FIX did not have a minimal enrollment cutoff for urate levels. As a result, some participants were normouricemic, but overall the study population had a baseline mean serum urate level of 8.2 mg/dL.
CKD-FIX: insufficient power as a result of incomplete enrollment (difficulty recruiting patients who met criteria, possibly indicating limitations in the generalizability of results)
CKD-FIX: nonadherence — 30% of patients stopped taking allopurinol, though there was still a sustained mean reduction of serum level of 35% (similar to PERL; 36%)

Conclusion

The PERL and CKD-FIX trials show that allopurinol treatment does not significantly attenuate CKD progression in their study populations. Is this the end of the story? The castle of the crumbling urate-CKD hypothesis has been built on the back of confounded epidemiological studies and small underpowered trials with extraordinary results. Though individually these two trials are not without limitations, they are complimentary in nature by avoiding the same set of problems. These are the best data we have and they do not support allopurinol use for asymptomatic hyperuricemia.

Of course this does not mean that allopurinol prescriptions should stop. Appropriate allopurinol use, such as for gout prophylaxis, should not cease. But do we need more trials? The overall literature no longer supports more trials. In addition to these two largest trials in this area, the Mendelian randomization studies (eg (Jordan et al., 2019) also make it clear that the coherent point of view no longer supports a causal role for uric acid in CKD progression any more.

Summary prepared by:

Anju Yadav MD FASN,

Thomas Jefferson University, Philadelphia, PA

Caitlyn Vlasschaert MD MSc,

Queen’s University, Kingston, Ontario, Canada

NSMC interns, Class of 2020