Gout, Urate, and Crystal Deposition Disease

14 pages, 1221 KiB

Open AccessFeature PaperReview

Regulation of Urate Homeostasis by Membrane Transporters

by Tappei Takada, Hiroshi Miyata, Yu Toyoda, Akiyoshi Nakayama, Kimiyoshi Ichida and Hirotaka Matsuo

Gout Urate Cryst. Depos. Dis. 2024, 2(2), 206-219; https://doi.org/10.3390/gucdd2020016 - 19 Jun 2024

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Abstract

Uric acid is the final purine metabolite in humans. Serum urate levels are regulated by a balance between urate production, mainly in the liver, and its excretion via the kidneys and small intestine. Given that uric acid exists as a urate anion at [...] Read more.

Uric acid is the final purine metabolite in humans. Serum urate levels are regulated by a balance between urate production, mainly in the liver, and its excretion via the kidneys and small intestine. Given that uric acid exists as a urate anion at physiological pH 7.4, membrane transporters are required to regulate urate homeostasis. In the kidney, urate transporter 1, glucose transporter 9, and organic anion transporter 10 contribute to urate reabsorption, whereas sodium-dependent phosphate transport protein 1 would be involved in urate excretion. Other transporters have been suggested to be involved in urate handling in the kidney; however, further evidence is required in humans. ATP-binding cassette transporter G2 (ABCG2) is another urate transporter, and its physiological role as a urate exporter is highly demonstrated in the intestine. In addition to urate, ABCG2 regulates the behavior of endogenous substances and drugs; therefore, the functional inhibition of ABCG2 has physiological and pharmacological effects. Although these transporters explain a large part of the urate regulation system, they are not sufficient for understanding the whole picture of urate homeostasis. Therefore, numerous studies have been conducted to find novel urate transporters. This review provides the latest evidence of urate transporters from pathophysiological and clinical pharmacological perspectives. Full article

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33 pages, 6258 KiB

Open AccessConference Report

Gout, Hyperuricemia and Crystal-Associated Disease Network (G-CAN) Conference 2023: Early-Career Investigators’ Abstracts

by Gout, Hyperuricemia and Crystal-Associated Disease Network

Gout Urate Cryst. Depos. Dis. 2024, 2(2), 173-205; https://doi.org/10.3390/gucdd2020015 - 6 Jun 2024

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Abstract

The ninth annual international G-CAN research symposium was held in La Jolla, CA on the 7th and 8th of November 2023. This hybrid meeting, a live face-to-face and virtual live symposium, was attended by 191 participants. Over 20 research abstract submissions were received [...] Read more.

The ninth annual international G-CAN research symposium was held in La Jolla, CA on the 7th and 8th of November 2023. This hybrid meeting, a live face-to-face and virtual live symposium, was attended by 191 participants. Over 20 research abstract submissions were received from early-career investigators, for plenary oral and poster presentations. Here, we present the 20 accepted, lightly edited abstracts from the early-career presenters consenting to have their materials published. We thank and congratulate the presenters for their work and contributions to the meeting. Full article

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16 pages, 4093 KiB

Open AccessReview

SGLT2 Inhibitors and Uric Acid Homeostasis

by Ava M. Zapf and Owen M. Woodward

Gout Urate Cryst. Depos. Dis. 2024, 2(2), 157-172; https://doi.org/10.3390/gucdd2020014 - 31 May 2024

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Abstract

A relationship between metabolic disorders and hyperuricemia is well established. The nature of the relationship—risk factor, causal agent, or byproduct—remains unclear. Recent studies of sodium–glucose transporter 2 inhibitors (SGLT2i’s) have established that this pharmacological intervention is beneficial to patients with hyperglycemia and type [...] Read more.

A relationship between metabolic disorders and hyperuricemia is well established. The nature of the relationship—risk factor, causal agent, or byproduct—remains unclear. Recent studies of sodium–glucose transporter 2 inhibitors (SGLT2i’s) have established that this pharmacological intervention is beneficial to patients with hyperglycemia and type 2 diabetes mellitus (T2D) and also against the common cardio and renal comorbidities associated with diabetes. Hyperuricemia, or high plasma uric acid levels, is one of the comorbidities mitigated with SGLT2i treatment, raising the potential for using SGLT2i’s as part of the treatment for gout and hyperuricemia. However, the mechanisms underlying the lower plasma urate levels and increased uricosuria produced with SGLT2i’s remains poorly understood. Here, we review the renal physiology of glucose and uric acid transport, the renal consequences of hyperglycosuria and diabetes, the benefits and physiology of SGLT2i use, and discuss several potential mechanisms that may be responsible for the favorable uricosuric effect observed in those treated with SGLT2i’s. Full article

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Figure 1
Renal uric acid and glucose transport physiology. (A) After being freely filtered by the glomerulus, (1) uric acid is reabsorbed from the tubular fluid by apically expressed OAT4 and OAT10 and (2) reabsorbed back into the blood by basolateral SLC2A9. (3) OAT1 and OAT3 at the basolateral membrane are responsible for transporting uric acid from the blood into the cell for (4) re-secretion into the tubular fluid by apical NPT1 and NPT4. The apical high-capacity/low-affinity glucose transporter SGLT2 reabsorbs approximately 90% of the filtered glucose within the early proximal tubule along with one sodium ion per glucose molecule, where glucose is reabsorbed into the blood by basolateral GLUT2. (B) The late proximal tubule (S3 segment) is the chief site of uric acid reabsorption. The majority of the freely filtered uric acid is (5) reabsorbed from the tubular fluid in exchange for lactate by the apical transporter URAT1 and is (6) reabsorbed back into the blood by basolateral expressed SLC2A9. Basolateral OAT1 and OAT3 reabsorb uric acid from the blood back into the cell for (7) re-secretion into the tubular fluid through the specific uric acid secretory transporter ABCG2. The low-capacity/high-affinity glucose transporter SGLT1 is responsible for reabsorbing the remaining <10% of glucose from the tubular fluid using two sodium ions per glucose molecule and is similarly reabsorbed into the blood by basolateral GLUT1/2. Abbreviations: OA− = organic anions; Pi = inorganic phosphate; UA = uric acid; OAT = organic anion transporter; NPT = sodium/phosphate transporter. Images were created using Biorender.com. Full article ">Figure 2
SGLT2i mediated uricosuria mechanisms of action. (A) Chloride delivery hypothesis: Reabsorption of NaCl, Na–glucose, and NaHCO3− is inhibited by SGLT2i treatment in the early proximal tubule (S1) through the apical transporters SGLT2 and NHE3. As a result, sodium and chloride ions in the tubular fluid accumulate and are delivered to the downstream S3 segment, where apical URAT1 and ABCG2, the reabsorptive urate and secretory transporters are located. The increased delivery of chloride ions effectively inhibits URAT1 transporter activity, preventing the reabsorption of tubular urate, and thus, increasing urinary urate excretion by the kidneys. (B,C) Metabolism hypothesis: In the normal functioning proximal tubule, gluconeogenesis is energetically favored for cellular ATP production over glycolysis, where glucose is made by the proximal tubule cell instead of being used as the substrate for ATP production. (B) During the state of hyperglycemia, increased transporter activity of SGLT2 leads to increased sodium and glucose reabsorption from the tubular fluid. As a result, the excess glucose is used for glycolysis for pyruvate production and ultimately, Acetyl-CoA and entry into the TCA cycle, replacing fatty acid oxidation (FAO)-generated Acetyl-CoA. The increase in pyruvate production results in significant increases in intracellular lactate concentrations. The excess lactate also enters the tubular fluid, where the apical Na+/lactate cotransporter SMCT1 is expressed. As a result, more sodium and lactate are reabsorbed back into the cell, sustaining high intracellular lactate levels and trans-stimulating the reabsorption of urate via URAT1, resulting in a pathological positive feedback loop. (C) SGLT2 inhibition by an SGLT2i prevents the excess reabsorption of glucose, reducing glycolysis and stimulating gluconeogenesis, together significantly suppressing intracellular lactate. As a result of the decreased intracellular lactate levels, the trans-stimulation of URAT1 and urate reabsorption is significantly diminished, and thus, increases urinary urate excretion. Figures were created using Biorender. Full article ">

13 pages, 677 KiB

Open AccessReview

Gout and Gout-Related Comorbidities: Insight and Limitations from Population-Based Registers in Sweden

by Panagiota Drivelegka, Lennart TH Jacobsson and Mats Dehlin

Gout Urate Cryst. Depos. Dis. 2024, 2(2), 144-156; https://doi.org/10.3390/gucdd2020013 - 7 May 2024

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Abstract

Population-based databases in Nordic countries offer unique opportunities for large-scale population-based epidemiological studies. The personal identity number enables researchers to link different registers at the individual level, which can be used for large-scale epidemiological population-based studies. This review outlines how these opportunities have [...] Read more.

Population-based databases in Nordic countries offer unique opportunities for large-scale population-based epidemiological studies. The personal identity number enables researchers to link different registers at the individual level, which can be used for large-scale epidemiological population-based studies. This review outlines how these opportunities have been used so far in the field of gout research, as well as the potential challenges and limitations. Their major advantage is that they cover the entire population, minimizing problems such as selection bias and loss to follow-up. This has enabled us to provide information on gout regarding risk factors; occurrence; association with comorbidities in relation to gout onset; treatment patterns; as well as its effect on other outcomes, such as sick leave and mortality. Validity issues, missing data, and legal issues are some of the challenges that researchers need to deal with. Choosing the most appropriate combination of databases to use for a specific question is crucial in order to maximize validity and adjust for confounders. Despite challenges and potential limitations, the Swedish registers have provided valuable epidemiological results and will continue to play an important role in the years to come. Full article

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11 pages, 3813 KiB

Open AccessBrief Report

Sex-Specific Differences in Cytokine Production Capacity in Patients with Gout Compared to Controls

by Medeea Badii, Orsolya I. Gaal, Ioana Hotea, Valentin Nica, Andreea M. Mirea, Dragoş Mărginean, HINT Consortium, Cristina Pamfil, Simona Rednic, Radu A. Popp, Tania O. Crişan and Leo A. B. Joosten

Gout Urate Cryst. Depos. Dis. 2024, 2(2), 133-143; https://doi.org/10.3390/gucdd2020012 - 22 Apr 2024

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Abstract

Gout, an inflammatory disease orchestrated by interleukin-1β activation and release, is more prevalent in men. The clinical profiles of patients with gout report differences by sex. This study aims to investigate sex-specific cytokine profiles in circulation and in stimulated peripheral blood mononuclear cells [...] Read more.

Gout, an inflammatory disease orchestrated by interleukin-1β activation and release, is more prevalent in men. The clinical profiles of patients with gout report differences by sex. This study aims to investigate sex-specific cytokine profiles in circulation and in stimulated peripheral blood mononuclear cells (PBMCs) of patients with gout and controls. Participants included in the gout group met the criteria of the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR). The control group included individuals with varying levels of serum urate and absence of gout. PBMCs were stimulated in vitro for 24 h with various TLR ligands. Cytokines were determined in culture supernatants and plasma. Plasma IL-1Ra and high-sensitivity C-reactive protein (hsCRP) were higher in men with gout compared to men without gout whereas no significant differences in circulating cytokines were observed in women. PBMCs of patients with gout showed higher cytokine production of IL-1β, IL-1Ra, and TNF-α following 24 h stimulation, predominantly observed in women. We identified sex-specific cytokine production in gout in response to in vitro stimulation. While men with gout had higher levels of circulating cytokines, stimulated PBMCs of women with gout show an enhanced capacity for cytokine production. These data may suggest potentially different regulatory mechanisms of inflammation in men and women with gout. Full article

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Baseline characteristics. (A) Box plots split into women (F) and men (M) with and without gout. (B) Box plots of only patients with gout split into women (F) and men (M). Unpaired two-sample Wilcoxon test (also known as Wilcoxon rank sum test or Mann–Whitney test); outlier samples are indicated by the red (A) and black (B) dots. (C) Comorbidities distribution in patients with gout split by sex. Full article ">Figure 2
Association of cytokine production in PBMCs and sex in patients with and without gout. (A) Percentage of women (F) and men (M) in both groups. (B) Experimental design. (C,D) p-values of association between gout and cytokine levels in all patients or split by sex. In all patients, age and sex have been added as co-variates, rather when split by sex, only age was added as a covariate. All p-values were calculated using linear regression and cytokine data were log transformed. Grey color belongs to non-significant p-values (>0.05). (E,F) Sample distribution example of basal IL-1Ra levels (RPMI) and in stimulation with C16 and MSU in all patients or split by sex. (G,H) Sample distribution of IL-1β and IL-1Ra levels after stimulation with LPS low dose and MSU in all patients or split by sex; On the y-axis, values are presented without commas for numbers exceeding four digits. Full article ">Figure 3
Circulating markers. (A) Box plots for high-sensitive CRP and plasma IL-1Ra for patients with and without gout. (B) Box plots split into women (F) and men (M). Unpaired two-sample Wilcoxon test (also known as Wilcoxon rank sum test or Mann–Whitney test); Black (A) and red (B) dots mark outlier samples. Full article ">

25 pages, 1161 KiB

Open AccessReview

Circadian Rhythms in NLRP3 Inflammasome Regulation: Possible Implications for the Nighttime Risk of Gout Flares

by Raewyn C. Poulsen and Nicola Dalbeth

Gout Urate Cryst. Depos. Dis. 2024, 2(2), 108-132; https://doi.org/10.3390/gucdd2020011 - 15 Apr 2024

Cited by 1 | Viewed by 900

Abstract

Gout flares more frequently start late at night or in the early morning compared to during the day. The reasons for this are unknown. Activation of the NLRP3 inflammasome in monocytes/macrophages is central to initiation of gout flares. Here, we review the mechanisms [...] Read more.

Gout flares more frequently start late at night or in the early morning compared to during the day. The reasons for this are unknown. Activation of the NLRP3 inflammasome in monocytes/macrophages is central to initiation of gout flares. Here, we review the mechanisms by which circadian clocks control the NLRP3 inflammasome and the implications of this for the nighttime pattern of gout flares. Several hormones involved in inflammation regulation, e.g., glucocorticoids, melatonin and melanocortins, are under circadian control, with both circulating hormone levels as well as the expression of their receptors on target tissues showing time-of day differences. In addition, the NLRP3 inflammasome is also under the control of the macrophage circadian clock, leading to time-of-day differences in expression of NLRP3 inflammasome components and susceptibility to inflammasome-activating stimuli. MSU crystal exposure leads to altered expression of circadian clock components in macrophages, leading to time-of-day-specific loss of repression of NLRP3 inflammasome activity. Taken together, there is clear evidence that circadian clocks regulate the NLRP3 inflammasome and that this regulation may be compromised by MSU crystal exposure in gout. Circadian control of the inflammasome may be one of the factors contributing to nighttime susceptibility to gout flares. Full article

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The hierarchical circadian clock network. In humans, the circadian clock network consists of a central clock located in the suprachiasmatic nucleus in the hypothalamus and peripheral clocks located in all other cells in the body. The central clock comprises a series of transcription and translation feedback loops (TTFLs). The core components of the circadian clock are the proteins BMAL1 and CLOCK and members of the PERIOD and CRYPTOCHROME families. BMAL1 and CLOCK dimerize and promote PERIOD and CRYPTOCHROME transcription. PERIOD and CRYPTOCHROME dimerize and inhibit the actions of BMAL1:CLOCK, resulting in the expression of BMAL1 and CLOCK oscillating in anti-phase with PERIOD and CRYPTOCHROME. Other auxiliary feedback loops also contribute to regulating this cycle, one of which is made up of the transcriptional regulator REV-ERBα and members of the ROR family. REV-ERBα represses BMAL1 expression, whereas ROR promotes it. The same TTFL machinery is present in nucleated cells throughout the body. Clocks in these tissues are termed “peripheral clocks”. The central clock is directly regulated by light sensed through the eye, and this synchronizes its cycling with the day/night cycle. Most peripheral clocks are not light sensitive and instead are regulated by physiological rhythms generated by the central clock (such as circulating levels of hormones, e.g., glucocorticoids) as well as rhythms in the local tissue environment, e.g., nutrient availability driven by daily feeding/fasting cycles. Full article ">Figure 2
NLRP3 inflammasome activation. NLRP3 inflammasome activation occurs by a two-step process involving, first, priming, then assembly of the inflammasome. Priming stimuli include pathogen-associated and damage-associated molecular patterns (DAMPs/PAMPs) which act on toll-like receptors. Although MSU crystals can serve as DAMPs and reliably activate inflammasome priming in vitro, this does not always occur in vivo and instead other DAMPs/PAMPs stimulate the priming step. Toll-like receptor activation leads to activation of nuclear factor kappa B (NF-κB) and upregulation of NLRP3 and Pro-IL-1β gene transcription. NLRP3 inflammasome priming can also be stimulated by pathways independent of TLR activation. A range of other regulators also contribute to controlling NLRP3 and Pro-IL-1β expression. The assembly step in the NLRP3 inflammasome activation process requires a second stimulus. MSU crystals as well as a number of other factors, such as ATP, can stimulate the assembly step. This leads to activation and oligomerization of NLRP3 protein, followed by recruitment of ASC and caspase 1, resulting in NLRP3 inflammasome assembly. Assembly of the inflammasome triggers caspase 1 activation by self-cleavage. Active caspase 1 drives the maturation and secretion of IL-1β and IL-18. Full article ">

7 pages, 230 KiB

Open AccessReview

Calcium Pyrophosphate and Basic Calcium Phosphate Crystal Arthritis: 2023 in Review

by Augustin Latourte, Hang-Korng Ea and Pascal Richette

Gout Urate Cryst. Depos. Dis. 2024, 2(2), 101-107; https://doi.org/10.3390/gucdd2020010 - 5 Apr 2024

Cited by 3 | Viewed by 972

Abstract

Calcium-containing crystal deposition diseases are extremely common in rheumatology. However, they are under-explored compared to gout or other inflammatory rheumatic diseases. Major advances have been made in 2023 that will undoubtedly stimulate and facilitate research in the field of calcium pyrophosphate (CPP) deposition [...] Read more.

Calcium-containing crystal deposition diseases are extremely common in rheumatology. However, they are under-explored compared to gout or other inflammatory rheumatic diseases. Major advances have been made in 2023 that will undoubtedly stimulate and facilitate research in the field of calcium pyrophosphate (CPP) deposition disease (CPPD): the ACR/EULAR classification criteria for CPPD and a semi-quantitative OMERACT score for ultrasound assessment of the extent of CPP deposition have been validated and published. A large randomized controlled trial compared the efficacy and safety of colchicine and prednisone in acute CPP arthritis. Preclinical studies have elucidated the pro-inflammatory and anti-catabolic effects of basic calcium phosphate (BCP) crystals on mononuclear cells and chondrocytes. The association between osteoarthritis (OA) and IA calcifications has been the subject of several epidemiological publications, suggesting that calcium crystals are associated with a greater risk of progression of knee OA. Research in the field of calcium crystal deposition diseases is active: the areas of investigation for the coming years are broad and promising. Full article

15 pages, 3588 KiB

Open AccessReview

Optimising the Use of Ultrasound in Gout: A Review from the Ground Up

by Emilio Filippucci, Edoardo Cipolletta, Silvia Sirotti and Georgios Filippou

Gout Urate Cryst. Depos. Dis. 2024, 2(2), 86-100; https://doi.org/10.3390/gucdd2020009 - 4 Apr 2024

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Abstract

The use of ultrasonography (US) has considerable potential for the diagnosis and monitoring of gout due to its capacity to detect monosodium urate deposits. In the last decade, a critical amount of scientific data has become available. Consensus-based definitions for ultrasonographic elementary lesions [...] Read more.

The use of ultrasonography (US) has considerable potential for the diagnosis and monitoring of gout due to its capacity to detect monosodium urate deposits. In the last decade, a critical amount of scientific data has become available. Consensus-based definitions for ultrasonographic elementary lesions in gout have been developed, tested, and validated, as well as a semiquantitative scoring system for their quantification. Many scanning protocols have been proposed in different clinical scenarios. In this review, we formulate a set of practical suggestions for the use of the US in daily practice. We discuss the current knowledge to indicate which joints and structures are to be scanned and which elementary findings are to be evaluated according to the clinical scenario. While for some clinical settings, a quite definite scanning protocol can be indicated, others still need to be further investigated, and how to obtain the best out of the US is still entrusted to the individual experience. Full article

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Double-contour sign (arrowheads). Hand, fifth finger, metacarpophalangeal joint. Dorsal longitudinal (A) and transverse (B) views. m = metacarpal head; p = proximal phalanx; t = finger extensor tendon. Images were acquired using a 6–18 MHz linear probe. Full article ">Figure 2
Double-contour sign (arrowheads). Knee, trochlear hyaline cartilage of the femur. Anterior transverse (A) and longitudinal (B) views. f = femoral trochlea; ti = tibia; pt = patellar tendon; h = Hoffa’s fat pad. Images were acquired using a 3–11 MHz linear probe. Full article ">Figure 3
Tophaceous deposit (arrows). Hand, third finger, metacarpophalangeal joint. Dorsal longitudinal (A) and transverse (B,C) views. Transverse views (B,C) were acquired at the level of the solid (B) and dashed (C) lines, respectively m = metacarpal bone; p = proximal phalanx; t = finger extensor tendon. Images were acquired using a 6–18 MHz linear probe. Full article ">Figure 4
Tophaceous deposit (arrows and arrowhead). Hand, second finger, metacarpophalangeal joint. Radial aspect longitudinal (A) and transverse (B) views. m = metacarpal head; p = proximal phalanx. Note the heterogeneous texture of the tophus, which is made up of different areas with variable degrees of echogenicity. A part of the tophus generates an acoustic shadow and a pseudo interruption of the underlying bone profile. Images were acquired using a 6–18 MHz linear probe. Full article ">Figure 5
Tophaceous deposits (arrows). (A) Foot, second digit, metatarsophalangeal joint. Dorsal longitudinal view. (B) Hand, third finger, proximal interphalangeal joint. Dorsal longitudinal view. Both images show representative examples of hard tophi with complete and partial impairment of the ultrasound beam penetration and, consequently, of the underlying bony cortex visualisation. While in A, the tophus is intra-articular with a clear visualisation of the overlying extensor tendon of the finger, in B, the tophus is periarticular and englobes the finger extensor tendon that is barely detectable inside the tophaceous texture (arrowheads). mt = metatarsal bone; pp = proximal phalanx; mp = middle phalanx. Images were acquired using a 6–18 MHz linear probe. Full article ">Figure 6
Aggregates within the tibialis anterior tendon. Ankle, tibialis anterior tendon. Anterior longitudinal (A) and transverse (B) views. Note the important derangement of the tendon fibrillar echotexture due to urate deposits appearing as iperechoic spots and dots (arrowheads). Images were acquired using a 6–18 MHz linear probe. Full article ">

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Gout Urate Cryst. Depos. Dis., Volume 2, Issue 2 (June 2024) – 8 articles

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