Clinical practice guideline for renal hypouricemia (1st edition)

Renal hypouricemia (RHUC) is a disease caused by dysfunction of renal urate reabsorption transporters; however, diagnostic guidance and guidelines for RHUC have been lacking, partly due to the low evidence level of studies on RHUC. This review describes a world-first clinical practice guideline (CPG) and its first version in English for this condition. It was developed following the “MINDS Manual for Guideline Development” methodology, which prioritizes evidence-based medicine. It was published in Japanese in 2017 and later translated into English. The primary goal of this CPG is to clarify the criteria for diagnosing RHUC; another aim is to work towards a consensus on clinical decision-making. One of the CPG’s unique points is that it contains textbook descriptions at the expert consensus level, in addition to two clinical questions and recommendations derived from a systematic review of the literature. The guidance shown in this CPG makes it easy to diagnose RHUC from simple blood and urine tests. This CPG contains almost all of the clinical foci of RHUC: epidemiology, pathophysiology, diagnostic guidance, clinical examinations, differential diagnosis, and complications, including exercise-induced acute kidney injury and urolithiasis. A CPG summary as well as a clinical algorithm to assist healthcare providers with a quick reference and notes from an athlete for both physicians and patients are included. We hope that this CPG will help healthcare providers and patients to make clinical decisions, and that it will promote further research on RHUC. Electronic supplementary material The online version of this article (10.1007/s13577-019-00239-3) contains supplementary material, which is available to authorized users.

This clinical practice guideline on renal hypouricemia from Japan is a world first. It is my sincere wish that researchers and healthcare providers will take this opportunity to use it to further develop their studies and clinical practice. Ishikawa et al. 5,6 named the concomitant kidney injury seen with renal hypouricemia (exercise-induced acute kidney injury) "ALPE" (Acute renal failure with severe Loin pain and Patchy renal ischemia after anaerobic Exercise) from its symptoms, and have researched it in detail. Moreover, causative genes (described below) 7,8 were identified in Japanese patients by Japanese researchers. Japanese researchers have made major contributions to studies on the development on this disease.

 Classification of renal hypouricemia
Serum urate is excreted from the renal glomeruli to the tubules as primary urine, which is then reabsorbed via urate transporters, including URAT1/SLC22A12 and GLUT9/SLC2A9, which are expressed on the proximal tubular epithelium. Dysfunctions of these transporters cause renal hypouricemia. One nonfunctional variant, W258X, of URAT1/SLC22A12 gene and two nonfunctional variants, R198C and R380W of the GLUT9/SLC2A9 gene, have been identified as causes of renal hypouricemia. Renal hypouricemia caused by variants of the URAT1/SLC22A12 gene and GLUT9/SLC2A9 gene is respectively termed renal hypouricemia type 1 (MIM: 220150) and renal hypouricemia type 2 (MIM: 612076).
Most cases of renal hypouricemia have been discovered by chance in health examinations that detect low serum uric acid level. Clinically, renal hypouricemia shows a relationship with a high risk of urolithiasis and exercise-induced acute kidney injury.

Introduction
 The need to develop a guideline Previous research suggests that renal hypouricemia is found in about 0.2% -0.5% of the general Japanese population. The disease concept of renal hypouricemia is, however, not fully established, even in general clinical practice and health examination settings. It is rare for renal hypouricemia to be treated before any symptoms appear, and its medical treatment depends on individual healthcare providers' decisions. Welldefined standards and concrete guidance are therefore needed before appropriate medical practice, including diagnosis and treatment, can be provided. This state of affairs prompted us to develop this clinical practice Guideline for renal hypouricemia, to provide clear diagnostic guidance, to improve recognition of the disease, and to assist with making clinical decisions. We hope that our efforts will assist clinicians to gain a correct picture of the nationwide prevalence of renal hypouricemia and to promote a more accurate understanding of it, such as by researching new variants other than type 1 and type 2. These points are the fundamental reasons behind the need to develop this Guideline.

 Goals
The first goal is to clarify the criteria for diagnosing renal hypouricemia, a prime requirement for troublefree diagnosis of renal hypouricemia; and to enable appropriate decision-making, based on the results of blood examinations, as well as the selection of additional tests that will lead to a rapid and definitive diagnosis. Another goal is to work towards a consensus on clinical decision-making: the effects of drugs, including xanthine oxidoreductase inhibitors, and their application to the treatment of renal hypouricemia have up to now been controversial.
The use of a clinical practice Guideline should enable healthcare providers to remain informed and to gain a fuller picture of the status of renal hypouricemia. Various analyses and feedback to clinical settings based on this Guideline will also contribute to a more accurate understanding of the disease.
Why does the pathophysiology in peripheral blood and tubules of renal hypouricemia result in clinical symptoms such as exercise-induced acute kidney injury and urolithiasis? How is a sudden burden placed on the kidneys during strenuous exercise, and how can we counteract it? Research in these areas must be performed to acquire sufficient evidence. Trials must also be conducted to elucidate the mechanism of action of drugs, the benefits obtained by administering them, and whether or not adverse effects occur. Appropriate prevention of concomitant diseases is dependent on first clarifying their frequencies, risk factors, and conditions. Such prevention is one of the major goals of this guideline.
 Hopes for the future As described above, we hope that making this Guideline available to healthcare providers and individuals involved, including patients, will help to reveal the actual prevalence of renal hypouricemia, and lead to the discovery of novel genetic factors other than type 1 and type 2, especially in Japan, where the frequency of this disease appears to be relatively high. We also hope that this Guideline will encourage the development of novel therapies and preventive methods, not only for patient groups whose diagnosis and treatment are relatively well known, but also for those for whom truly effective treatments remain to be discovered.
We have developed this Guideline based on the "MINDS Manual for Guideline Development" to secure the largest possible number of scientific bases. I am grateful to all the Guideline Development Committee Members, who I hope will accept our heartfelt thanks again for all their help, and to those at the MINDS Guideline Center from whose advice we benefited. Hypouricemia is a clinical finding often found by chance during health examinations. One pathognomonic finding of RHUC is a low serum uric acid (S UA ) level, although the threshold for suspecting RHUC has not been determined: so far, for example, the definition of hypouricemia is S UA ≤ 2 mg/dl in some studies and S UA ≤ 3 mg/dl in others. A clear cutoff value for diagnosing RHUC, one cause of hypouricemia, is therefore necessary.

Components of CQ P (Patients, Problem, Population) Sex
Not specified Age Excluding infants Problem Hypouricemia (before definite diagnosis of RHUC)

Physiographic factor
Not specified Others Centrally focused on Japanese individuals

List of I (Interventions) or C (Comparisons, Controls, Comparators)
 To consider the differential diagnosis of hypouricemia when his/her S UA is ≤ 2 mg/dl.  To consider the differential diagnosis of hypouricemia when his/her S UA is ≤ 3 mg/dl.  To consider the differential diagnosis of hypouricemia when his/her S UA is ≤ 4 mg/dl.

List of O (Outcomes) Outcome
Benefit or Harm Magnitude (points)

O1
To obtain valuable findings to suspect RHUC Benefit 8 Developed CQ CQ1: Should individuals with a serum uric acid level of ≤ 2.0 mg/dl be considered for differential diagnosis of hypouricemia? in these Tables describes only the finallyadopted ones for CQs. The "magnitude" was evaluated on a scale of 1 to 10 points).

5.
SRT conducted a literature search using the following methods.  RHUC patients often suffer from recurrent concomitant diseases, such as exercise-induced acute kidney injury (EIAKI) and urolithiasis. To prevent these concomitant diseases, patients are usually recommended to drink a lot (especially before exercise), to avoid intense exercise, and/or to limit exercise when taking non-steroid anti-inflammatory drugs. Moreover, in addition to using urinary alkalinizers to prevent urolithiasis, administration of xanthine oxidoreductase (XOR) inhibiters before exercise is also assumed to prevent EIAKI. The clinical effectiveness of XOR inhibitors, however, remains unclear and needs to be investigated. evaluations, on a scale of 1 -5 (1 = "disagree," 3 = "neutral," and 5 = "agree").

9.
The results of external reviews are described below.
Prior to publication of the Guideline, the c. To clarify the facilitators and barriers to the Guideline's application.
• We described them.
d. To provide tools on how the recommendations can be put into practice.

• We provided "A Brief Summary of this
Guideline" as an abstract.
Public comments were also solicited via the GUIDE system provided by MINDS (http://minds.jcqhc.or.jp/guide/pages/GuideT opHome.aspx) for the month from Nov. 8 th to Dec. 8 th 2016. We found no comments requesting revisions or modifications.
In the light of these comments (or lack of them), the finalized Guideline was approved and completed at the Third Conference.
The Guideline draft was also read through and evaluated by an RHUC patient, and her comments were added to the Guideline as "Notes from an Athlete."

10.
We considered the facilitators and barriers to the Guideline's application to be as follows.  7 In fact, the frequency of patients of diabetes mellitus was not higher in those with hypouricemia than in those without 3 .
Although there was no information provided on liver disease, the averages of AST, ALT, and γ-GTP in hypouricemic subjects did not differ from those in the SUA > 2.0 mg/dl groups 3 . There was also no information on the use of urate-lowering agents, but there were no differences in the frequency of hypouricemia among different age groups in males 3 , whereas increasing numbers of males receive frequent urate-lowering therapy as they age 8 . As described above, the prevalence of hypouricemia reported by Wakasugi et al. 3 is thought to reflect the prevalence of RHUC.
As described above, the prevalence of hypouricemia in females is about double that seen in males. Wakasugi et al. 3 first investigated the prevalence of hypouricemia with age, and revealed that its prevalence decreased with rising age in females (Fig. 1). The age-dependent decrease in the prevalence of hypouricemia in females seems to have been due to the menopause, which causes a loss in the urate-lowering effect of female sex hormones. The rate of prevalence of hypouricemia in females in their 40s was 0.6% ( Fig. 1).
Although menopausal status was not investigated in the study by Wakasugi et al., 3 Fig. 2A). There is another urate transporter called the urate excretion transporter, which secretes urate from the blood vessel side to the primary urine side (tubular side).
Dysfunctional variants of urate reabsorption transporter increase urate excretion (Fig. 2B, C), which results in lowered serum uric acid (S UA ) level: this is the basic pathophysiology of renal hypouricemia (RHUC).
The first report on this disease was published in 1950 3 , and the first report from Japan was in 1975 4 .
From the very beginning, this disease has been noted to be common in Japanese and Jews 5 .
Subsequent studies identified the causative genes of RHUC 6,7 , and its molecular pathophysiology is now almost fully known.

Fig. 1 Metabolism of urate
Urate is an end metabolite of purine bodies in humans. Purine bases are supplied from de novo pathways, which produce new purine bases, and are also supplied from salvage pathways that re-use purine bases. They are finally metabolized to urate by XOR, but humans cannot metabolize it due to a lack of uricase activity: the uricase gene has changed into a pseudo-gene during the evolutionary process. (See Abbreviations for details.)    Table 1 takes these facts into account.

2.
Renal hypouricemia is a type of overexcretion-type hypouricemia. Hypouricemia (serum uric acid (S UA ) level of ≤ 2.0 mg/dl (120 µmol/l)) and increased fractional excretion of uric acid (FE UA ) and/or uric acid clearance (C UA ) by repeated tests are necessary for diagnosis of renal hypouricemia.

4.
Fanconi syndrome and xanthinuria are included as differential diagnoses of hypouricemia.

Summary
Renal hypouricemia (RHUC), which is classified as a type of overexcretion hypouricemia, is caused by increased urate excretion in the kidney despite the absence of tubular disorders 1-4 . It results from defective urate reabsorption transporters at the renal proximal tubules. Defects in the two urate reabsorption transporters URAT1/SLC22A12 and GLUT9/SLC2A9 are currently believed to be its causes [5][6][7][8] . RHUC itself is usually asymptomatic, but is reported to have complications, including exercise-induced acute kidney injury (EIAKI) and urolithiasis 6,[9][10][11]  Refer to Chapter 2 of the "Guideline for the management of hyperuricemia and gout (2 nd edition)" for the details of these measuring methods and their normal range. Table 2 and
* There is a possibility of mild RHUC even with an S UA of 2.1 -3.0 mg/dl (121 -180 µmol/l). Repeated tests of Required Factors #1 and #2 above are therefore desirable, especially when confirming any of the Reference Factors 1) to 3) shown below.

2.
Differential diagnosis with myoglobinuric acute kidney injury which occurs after exercise is necessary.

EIAKI cases generally show transient acute kidney injury (AKI)
, and receive common treatment for AKI.

EIAKI carries a good short-term prognosis, although its long-term prognosis is unknown,
and recurrence is also reported.

5.
For the prevention of EIAKI, some studies recommend drinking a large volume of water before exercise, limiting exercise while taking non-steroid anti-inflammatory drugs, and/or avoiding any strenuous exercise.

6.
There are some reports in which allopurinol, a xanthine oxidoreductase inhibiter, was administered as a preventive method based on a hypothetic mechanism of its pathogenesis; however, convincing evidence for its efficacy is lacking.

Summary
Renal hypouricemia (RHUC) patients often suffer from one of its concomitant diseases, exerciseinduced acute kidney injury (EIAKI), that is, acute kidney injury (AKI) with loin pain and without findings of increased serum creatine kinase and myoglobin after strenuous (anaerobic) exercise.
Although its mechanism of pathogenesis remains to be clarified, recent diagnostic imaging suggests a relationship with renal ischemia. Other studies have shown a reversible resistance index using ultrasonography of renal blood flow in EIAKI patients 11 . There is also a study 2 that reports, using delayed CT, a wedge-shaped residue of contrast agent in the kidney lasting a few hours to several days after injection of 40 ml contrast agent during the return period of kidney function (serum creatinine of 1.5 -3.0 mg/dl), whereas myoglobinuric AKI displays a diffuse residue.
Conducting contrast-enhanced CT in AKI patients, of course, needs particular attention. There is a study 12

2.
If uric acid stones develop, dissolution therapy by urinary alkalization is also effective.

3.
To prevent urolithiasis, fluid intake that will achieve a urine volume of at least 2,000 ml daily is recommended.

4.
Citrate compounds can be prescribed to renal hypouricemia patients with urinary stones to maintain urinary pH at an optimal level of 6.0 -7.0 to prevent stone occurrence.

Summary
Renal hypouricemia (RHUC) often causes urinary stones, such as uric acid or calcium oxalate stones. Ultrasonotomography and computed tomography are used as diagnostic imaging tools.
Plain film of the kidneys, ureter, and bladder (KUB) is not useful, because uric acid stones are radiolucent. Urinalysis, including urine pH, crystal in urinary sediment, and urinary urate excretion during 24-hour urine collection, is useful for diagnosis. Analysis of delivered stones is also desirable to know which kind of stones they are.
Dissolution therapy of uric acid stones by urinary alkalinization is also effective. It is mandatory for fluid intake that will achieve a urine volume of at least 2,000 ml daily to prevent urinary stones.
Urine alkalinization using citrate compounds is necessary to maintain urinary pH between 6.0 and 7.0. If uric acid stones are suspected using the imaging diagnosis described above, dissolution therapy by administering urinary alkalinizers is also likely to be effective, even in patients with RHUC 18 .

Consensus
However, it will take a long time for the stones to dissolve completely.
The risk factors for urinary stones that are concomitant with hyperuricemia and gout are (1) low urinary volume or poor intake of water, (2) increased urinary urate excretion, (3) and presence of aciduria 5 . These are the same as for urinary stones caused by RHUC.  Table 1 Representative reports on the epidemiological distribution of serum uric acid (S UA ) level.

Note 1)
The tested population is that without the W258X mutation: a dysfunctional mutation of the urate reabsorption transporter gene URAT1/SLC22A12 which causes renal hypouricemia type 1. Therefore, most RHUC cases should be excluded from this population. (RHUC cases not caused by W258X are, however, included.) Note 2) Most of the tested population is male, since they were recruited from Self-Defense Forces (military) personnel.

CQ1
Recommen dation 1 Table 1 shows typical reports obtained through a systematic review of the literature which examined the epidemiological distribution of S UA , which suggest that there are considerable numbers of people, especially female, with an S UA of 2.0 -3.0 mg/dl (120 -180 µmol/l) that do not show RHUC.
Otherwise, this population seems to be adequately excluded with a cutoff value of S UA set at ≤ 2.0 mg/dl. Moreover, few RHUC cases with concomitant diseases (exercise-induced acute kidney injury [EIAKI] and urolithiasis) had a normal S UA of > 2.0 mg/dl 7-10 .
However, re-examination of S UA sometimes shows a low S UA of ≤ 2.0 mg/dl even they initially showed S UA of > 2.0 mg/dl 11,12 . Furthermore, there is a study reporting that heterozygous carriers of the URAT1/SLC22A12 gene show various values of S UA (often > 3.0 mg/dl) 5 . Therefore, because individuals with variants in their urate transporter genes often show an S UA of > 2.0 mg/dl [5][6][7][8][9]13,14 , reexamining S UA several times and searching for genetic variants (if necessary) would be helpful, especially if they have a past history of EIAKI and/or urolithiasis, or a family history of hypouricemia.
When their S UA values are ≤ 1.0 mg/dl, RHUC and xanthinuria should be considered as a differential diagnosis. Xanthinuria, however, is easily distinguished because its disease frequency is much lower than that of RHUC, and because xanthinuria results in little urinary urate excretion and little fractional excretion of uric acid. Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and diabetes mellitus are known to be causes of secondary hypouricemia. However, they are relatively distinguishable from RHUC because they often show S UA of > 2.0 mg/dl and other findings such as hyponatremia and hyperglycemia 12,15 . Likewise, secondary hypouricemia caused by Wilson's disease or Fanconi syndrome, respectively, is also relatively identifiable due to the presence of other clinical evidence, including hypoceruloplasminemia or hyperaminoaciduria/hyperphosphatemia. Hypouricemia caused by drugs or tumors is distinguishable from RHUC by its clinical course.

 References
Patients with renal hypouricemia (RHUC) often suffer from recurrence of its concomitant diseases, including exercise-induced acute kidney injury (EIAKI) and urolithiasis. To prevent this, patients are usually recommended to drink a lot (especially before exercise), to avoid strenuous exercise, and/or to avoid all exercise when taking non-steroid anti-inflammatory drugs, sometimes combined with the administration of urinary alkalinizers to prevent urolithiasis. The administration of xanthine oxidoreductase (XOR) inhibiters (as of 2015, allopurinol, febuxostat, and topiroxostat are available in Japan) before exercise is also assumed to prevent EIAKI. The clinical effectiveness of XOR inhibitors, however, remains unclear and needs to be investigated.
Since urate has a strong antioxidant effect, it might mitigate vasopressor effects in the kidney caused by oxygen radicals produced during anaerobic exercise. This has prompted a hypothesis to explain why EIAKI is concomitant with RHUC: namely, that low serum uric acid levels in RHUC patients lead to lower antioxidant effects (the scavenger effect), which results in prolonged renal ischemia due to continuous vasopressor effects in the kidney. Some, but not much, of the literature provides evidence for this hypothesis, as listed below.


The renal blood flow of two RHUC patients was examined using Xanthine oxidase (XO), the oxidase form of XOR, produces oxygen radicals as well as urate along the urate synthesis metabolic pathway. While XOR inhibitors are usually used as urate-lowering therapy to act as urate-synthesis inhibitors, they also inhibit the production of oxygen radicals. It is therefore possible that XOR inhibitors mitigate the deterioration of renal hemodynamics in RHUC patients.
There are a few studies that provide evidence of the usefulness of administering XOR inhibitors to RHUC patients to prevent EIAKI. All of these are case reports.
 Exercise stress tests were performed with Pakistani RHUC patients, and renal dysfunction was induced, but it could be prevented by premedication with allopurinol (300 mg/day for five days).
Four healthy controls did not show renal dysfunction in the exercise stress tests 4 .
 In a report from the USA, an RHUC patient, a 400 meter-sprinter, had experienced EIAKI, but after recovering, EIAKI did not recur following track meetings after premedication with allopurinol (300 mg/day for three days) 5 .
 Healthy controls including athletes prescribed with allopurinol before exercise showed decreased serum values of enzymes released from dead cells (such as creatinine kinase) and myoglobin levels, indicating reduced damage to skeletal muscle 6 .
As described above, there are a few reports that suggest the potential for the use of allopurinol to prevent EIAKI in RHUC patients. There are, however, no reports featuring Japanese/East Asians, randomized intervention studies, or studies with multiple patients. Moreover, no studies were found in which the amount and duration of allopurinol were evidenced.
It is not appropriate to administer XOR inhibitors to all RHUC patients to prevent EIAKI. This is because not all RHUC patients suffer from EIAKI, and because administration of XOR inhibitors could cause adverse events. Administering XOR inhibitors, however, may provide significant benefits, especially to those at risk of EIAKI, such as individuals with a past history of EIAKI and/or athletes, taking into account the fact that common and relatively low-cost drugs are reported, in a few studies, to prevent the serious concomitant diseases of EIAKI.
We cannot find any evidence on whether the risk of adverse effects from XOR inhibitors is higher in RHUC patients than in patients with other diseases treated with XOR inhibitors, such as hyperuricemia.
In response to the discussion above, to the clinical question (CQ) "Should xanthine oxidoreductase (XOR) inhibitors be administered to prevent exercise-induced acute kidney injury (EIAKI) in patients with renal hypouricemia (RHUC)?," our conclusion is "We cannot definitively state that XOR inhibitors should be administered to prevent EIAKI in RHUC patients." We also present our recommendation that "Administration of XOR inhibitors should be decided by taking into account both benefits and harms, especially for patients known to be at high risk, such as athletes or individuals with Notes from an Athlete RHUC patients rarely notice that they have this condition, because they experience no problems in their daily life. However, athletes or people who engage in intense physical activity can face serious health problems if they don't know about this condition. My own experience is that throughout elementary, junior high, and high school, I often felt nauseous after short-distance running and sports tests. My teachers were concerned, and thought it might be due to sudden and vigorous exercise without warm-up, but the actual cause was the heavy load on my kidneys due to RHUC. As an adult, to prepare for mixed martial arts matches, I had to lose weight, which placed great demands on my internal organs. I then engaged in fierce fights.
Afterwards, I suffered exercise-induced acute kidney injury (EIAKI), which caused me to feel ill and vomit repeatedly. Sometimes couldn't eat normally for a couple of weeks.
Looking back, I can see that my body was repeatedly sending me warning messages, but not knowing that I had RHUC, I couldn't respond appropriately, and as a result I injured my health many times. After martial arts fights I felt sick, and whenever I saw other fighters staying energetic, even after fights, I often thought that I was getting more tired and injured because I hadn't prepared hard enough for the fights, and blamed myself for my lack of dedication. As the Guideline shows, knowing about RHUC and its effects helped me to make the right treatment decisions, and as a result, I don't feel so sick now during intensive training for fights or even after fights.
I hope that more medical institutions will make use of the information in the Guideline to anticipate and prevent urinary stones and EIAKI, for example, and that they will chose and prescribe painkillers and cold remedies that apply less stress on the kidneys. In addition, I hope that, having read this Guideline, sports medicine practitioners will be better able to

Appendix
inform patients on what type and intensity of exercise is appropriate for EIAKI patients, provide them with appropriate treatment, and that they will no longer misdiagnose the backache characteristic of EIAKI as simple muscle pain or tiredness.
Last but certainly not least, I'd like to send a message to my fellow sufferers of RHUC. If you focus on preserving your health, you can enjoy life like everyone else, for example, by engaging in ordinary daily activities of course, but also sports, marathons, and even martial arts! It is very important to be aware of your daily levels of physical activity and to remember the characteristics of RHUC. The Guideline tells us, for example, what type of care we need to take before exercise, what intensity of exercise we can stand, and what we need to be aware of after intense physical activity. It is easy to forget, at normal levels of physical activity, that we have RHUC, because it has no symptoms, but to prevent disease complications, this is something we need pay close attention to every day.