Controversies and practical management of patients with gout and chronic kidney disease.

Uric acid is a toxin retained with advancing kidney disease. Clinical manifestations of hyperuricemia include gout and systemic inflammation that are associated with increased risk for cardiovascular mortality. As many as one third of all patients with chronic kidney disease (CKD) have a history of gout, yet <25% of these patients are effectively treated to target serum urate levels of ≤6 mg/dL. A major reason for ineffective management of gout and hyperuricemia is the complexity in managing these patients, with some medications contraindicated, others requiring special dosing, potential drug interactions, and other factors. Consequently, many nephrologists do not primarily manage gout despite it being a common complication of CKD, leaving management to the primary physician or rheumatologist. We believe that kidney specialists should consider gout as a major complication of CKD and actively manage it in their patients. Here, we present insights from nephrologists and rheumatologists on a team approach to gout management that includes the nephrologist.

Caffeine inhibits both basal and insulin-activated urate transport.

OBJECTIVE: Caffeine, an adenosine receptor antagonist, is a potent central nervous system stimulant that also impairs insulin signaling. Recent studies have suggested that coffee consumption lowers serum urate (SU) and protects against gout, by unknown mechanisms. We hypothesized that caffeine lowers serum urate by affecting activity of urate transporters. METHODS: We examined the effect of caffeine and adenosine on basal and insulin-stimulation of net 14C-urate uptake in the human renal proximal tubule cell line PTC-05, and on individual urate transporters expressed in Xenopus laevis oocytes. RESULTS: We found that caffeine and adenosine efficiently inhibited both basal and insulin-stimulation of net 14C-urate uptake mediated by endogenous urate transporters in PTC-05 cells. In oocytes expressing individual urate transporters, caffeine (>0.2 mM) more efficiently inhibited the basal urate transport activity of GLUT9 isoforms, OAT4, OAT1, OAT3, NPT1, ABCG2 and ABCC4 than did adenosine, without significantly affecting URAT1 and OAT10. However, unlike adenosine, caffeine at lower concentrations (<0.2 mM), very effectively inhibited insulin-activation of urate transport activity of GLUT9, OAT10, OAT1, OAT3, NPT1, ABCG2 and ABCC4 by blocking activation of Akt and ERK. CONCLUSIONS: We postulate that inhibition of urate transport activity of the reabsorptive transporters GLUT9, OAT10, and OAT4 by caffeine is a key mechanism in its urate-lowering effects. Additionally, the ability of caffeine to block insulin-activated urate transport by GLUT9a and OAT10 suggests greater relative inhibition of these transporters in hyperinsulinemia.

Genetic and Physiological Effects of Insulin-Like Growth Factor-1 (IGF-1) on Human Urate Homeostasis.

SIGNIFICANCE STATEMENT: Hyperinsulinemia induces hyperuricemia by activating net renal urate reabsorption in the renal proximal tubule. The basolateral reabsorptive urate transporter GLUT9a appears to be the dominant target for insulin. By contrast, IGF-1 infusion reduces serum urate (SU), through mechanisms unknown. Genetic variants of IGF1R associated with reduced SU have increased IGF-1R expression and interact with genes encoding the GLUT9 and ABCG2 urate transporters, in a sex-specific fashion, which controls the SU level. Activation of IGF-1/IGF-1R signaling in Xenopus oocytes modestly activates GLUT9a and inhibits insulin's stimulatory effect on the transporter, which also activates multiple secretory urate transporters-ABCG2, ABCC4, OAT1, and OAT3. The results collectively suggest that IGF-1 reduces SU by activating secretory urate transporters and inhibiting insulin's action on GLUT9a. BACKGROUND: Metabolic syndrome and hyperinsulinemia are associated with hyperuricemia. Insulin infusion in healthy volunteers elevates serum urate (SU) by activating net urate reabsorption in the renal proximal tubule, whereas IGF-1 infusion reduces SU by mechanisms unknown. Variation within the IGF1R gene also affects SU levels. METHODS: Colocalization analyses of a SU genome-wide association studies signal at IGF1R and expression quantitative trait loci signals in cis using COLOC2, RT-PCR, Western blotting, and urate transport assays in transfected HEK 293T cells and in Xenopus laevis oocytes. RESULTS: Genetic association at IGF1R with SU is stronger in women and is mediated by control of IGF1R expression. Inheritance of the urate-lowering homozygous genotype at the SLC2A9 locus is associated with a differential effect of IGF1R genotype between men and women. IGF-1, through IGF-1R, stimulated urate uptake in human renal proximal tubule epithelial cells and transfected HEK 293T cells, through activation of IRS1, PI3/Akt, MEK/ERK, and p38 MAPK; urate uptake was inhibited in the presence of uricosuric drugs, specific inhibitors of protein tyrosine kinase, PI3 kinase (PI3K), ERK, and p38 MAPK. In X. laevis oocytes expressing ten individual urate transporters, IGF-1 through endogenous IGF-1R stimulated urate transport mediated by GLUT9, OAT1, OAT3, ABCG2, and ABCC4 and inhibited insulin's stimulatory action on GLUT9a and OAT3. IGF-1 significantly activated Akt and ERK. Specific inhibitors of PI3K, ERK, and PKC significantly affected IGF-1 stimulation of urate transport in oocytes. CONCLUSIONS: The combined results of infusion, genetics, and transport experiments suggest that IGF-1 reduces SU by activating urate secretory transporters and inhibiting insulin's action.

Prescribing Patterns of Sodium-Glucose Cotransporter-2 Inhibitors in Patients with CKD: A Cross-Sectional Registry Analysis.

Background: Sodium-glucose cotransporter-2 inhibitors (SGLT-2i) reduce kidney disease progression and mortality in patients with chronic kidney disease (CKD), regardless of diabetes status. However, the prescribing patterns of these novel therapeutics in the CKD population in real-world settings remain largely unknown. Methods: This cross-sectional study included adults with stages 3-5 CKD included in the Mass General Brigham (MGB) CKD registry in March 2021. We described the adoption of SGLT-2i therapy and evaluated factors associated with SGLT-2i prescription using multivariable logistic regression models in the CKD population, with and without diabetes. Results: A total of 72,240 patients with CKD met the inclusion criteria, 31,688 (44%) of whom were men and 61,265 (85%) White. A total of 22,653 (31%) patients were in the diabetic cohort, and 49,587 (69%) were in the nondiabetic cohort. SGLT-2i prescription was 6% in the diabetic cohort and 0.3% in the nondiabetic cohort. In multivariable analyses, younger Black men with a history of heart failure, use of cardiovascular medications, and at least one cardiologist visit in the previous year were associated with higher odds of SGLT-2i prescription in both diabetic and nondiabetic cohorts. Among patients with diabetes, advanced CKD stages were associated with lower odds of SGLT-2i prescription, whereas urine dipstick test and at least one subspecialist visit in the previous year were associated with higher odds of SGLT-2i prescription. In the nondiabetic cohort, CKD stage, urine dipstick test, and at least one nephrologist visit in the previous year were not significantly associated with SGLT-2i prescription. Conclusions: In this registry study, prescription of SGLT-2i was low in the CKD population, particularly among patients without diabetes.

Zoledronic Acid-Associated Fanconi Syndrome in Patients With Cancer.

Zoledronic acid (ZA) is an antiresorptive agent typically used for fracture prevention in postmenopausal osteoporosis, malignancy-associated metastatic bone lesions, and as a treatment for hypercalcemia. ZA is excreted almost entirely by the kidney; as a result, a reduction in renal clearance can lead to its accumulation and potential renal toxicity. Although uncommon, acute kidney injury (AKI) from intravenous bisphosphonates has been described, with different patterns including tubulointerstitial nephritis, acute tubular necrosis, as well as focal segmental glomerulosclerosis. Here we present 4 patients with an underlying malignancy who each developed evidence of generalized proximal tubular dysfunction, also known as Fanconi syndrome, approximately 1 week after receiving treatment with ZA. On presentation, all patients had AKI, low serum bicarbonate levels, abnormal urinary acidification, hypophosphatemia, hypokalemia, and increased urine amino acid excretion or renal glycosuria. Based on the temporal association between ZA infusion and the development of these electrolyte abnormalities, each case is highly suggestive of ZA-associated Fanconi syndrome. Due to the severity of presentation, all required discontinuation of ZA and ongoing electrolyte repletion. Nephrologists and oncologists should be aware of this complication and consider ZA as a possible trigger of new-onset Fanconi syndrome.

Association of acidic urine pH with impaired renal function in primary gout patients: a Chinese population-based cross-sectional study.

BACKGROUND: Patients with gout frequently have low urinary pH, which is associated with the nephrolithiasis. However, the specific distribution of urinary pH and potential relationship of acidic urine pH to broader manifestations of kidney disease in gout are still poorly understood. METHODS: A 2016-2020 population-based cross-sectional study was conducted among 3565 gout patients in the dedicated gout clinic of the Affiliated Hospital of Qingdao University to investigate the association between low urinary pH and kidney disease. We studied patients that we defined to have "primary gout", based on the absence of > stage 2 CKD. All subjects underwent 14 days of medication washout and 3-day standardized metabolic diet. We obtained general medical information, blood and urine biochemistries, and renal ultrasound examination on the day of the visit. The primary readouts were urine pH, eGFR, nephrolithiasis, renal cysts, microhematuria, and proteinuria. Patients were assigned into 5 subgroups (urine pH ≤5.0, 5.0 6.9), aligning with the clinical significance of urine pH. RESULTS: Overall, the median urine pH and eGFR of all patients was 5.63 (IQR 5.37~6.09), and 98.32 (IQR 86.03~110.6), with acidic urine in 46.5% of patients. The prevalence of nephrolithiasis, microhematuria, and proteinuria were 16.9%, 49.5%, and 6.9%, respectively. By univariate analysis, eGFR was significantly associated with age, sex, duration of gout, tophus, body mass index, systolic blood pressure, diastolic blood pressure, fasting blood glucose, total cholesterol, serum utare, hypertension, diabetes, and urine pH. On multivariable analysis, eGFR was associated with age, sex, diastolic blood pressure, serum uric acid, hypertension, diabetes, and urine pH. Acidic urine pH, especially urine pH < 5.0, was significantly associated with the prevalence of kidney disease, including > stage 1 CKD, nephrolithiasis, kidney cyst, and microhematuria. Patients with 6.2 ≤ urine pH ≤ 6.9 and SU ≤ 480 µmol/L had the highest eGFR with the lowest prevalence of nephrolithiasis, microhematuria, and proteinuria. CONCLUSIONS: Approximately half of gout subjects had acidic urine pH. Urine pH < 5.0 was associated with significantly increased nephrolithiasis, renal cyst, microhematuria, and proteinuria. The results support prospective clinical investigation of urinary alkalinization in selected gout patients with acidic urine pH.

Genetic and Physiological Effects of Insulin on Human Urate Homeostasis.

Insulin and hyperinsulinemia reduce renal fractional excretion of urate (FeU) and play a key role in the genesis of hyperuricemia and gout, via uncharacterized mechanisms. To explore this association further we studied the effects of genetic variation in insulin-associated pathways on serum urate (SU) levels and the physiological effects of insulin on urate transporters. We found that urate-associated variants in the human insulin (INS), insulin receptor (INSR), and insulin receptor substrate-1 (IRS1) loci associate with the expression of the insulin-like growth factor 2, IRS1, INSR, and ZNF358 genes; additionally, we found genetic interaction between SLC2A9 and the three loci, most evident in women. We also found that insulin stimulates the expression of GLUT9 and increases [14C]-urate uptake in human proximal tubular cells (PTC-05) and HEK293T cells, transport activity that was effectively abrogated by uricosurics or inhibitors of protein tyrosine kinase (PTK), PI3 kinase, MEK/ERK, or p38 MAPK. Heterologous expression of individual urate transporters in Xenopus oocytes revealed that the [14C]-urate transport activities of GLUT9a, GLUT9b, OAT10, OAT3, OAT1, NPT1 and ABCG2 are directly activated by insulin signaling, through PI3 kinase (PI3K)/Akt, MEK/ERK and/or p38 MAPK. Given that the high-capacity urate transporter GLUT9a is the exclusive basolateral exit pathway for reabsorbed urate from the renal proximal tubule into the blood, that insulin stimulates both GLUT9 expression and urate transport activity more than other urate transporters, and that SLC2A9 shows genetic interaction with urate-associated insulin-signaling loci, we postulate that the anti-uricosuric effect of insulin is primarily due to the enhanced expression and activation of GLUT9.

Management of gout in chronic kidney disease: a G-CAN Consensus Statement on the research priorities.

Gout and chronic kidney disease (CKD) frequently coexist, but quality evidence to guide gout management in people with CKD is lacking. Use of urate-lowering therapy (ULT) in the context of advanced CKD varies greatly, and professional bodies have issued conflicting recommendations regarding the treatment of gout in people with concomitant CKD. As a result, confusion exists among medical professionals about the appropriate management of people with gout and CKD. This Consensus Statement from the Gout, Hyperuricemia and Crystal-Associated Disease Network (G-CAN) discusses the evidence and/or lack thereof for the management of gout in people with CKD and identifies key areas for research to address the challenges faced in the management of gout and CKD. These discussions, which address areas for research both in general as well as related to specific medications used to treat gout flares or as ULT, are supported by separately published G-CAN systematic literature reviews. This Consensus Statement is not intended as a guideline for the management of gout in CKD; rather, it analyses the available literature on the safety and efficacy of drugs used in gout management to identify important gaps in knowledge and associated areas for research.

Assessing the Causal Relationships Between Insulin Resistance and Hyperuricemia and Gout Using Bidirectional Mendelian Randomization.

OBJECTIVE: Hyperuricemia is closely associated with insulin resistance syndrome (and its many cardiometabolic sequelae); however, whether they are causally related has long been debated. We undertook this study to investigate the potential causal nature and direction between insulin resistance and hyperuricemia, along with gout, by using bidirectional Mendelian randomization (MR) analyses. METHODS: We used genome-wide association data (n = 288,649 for serum urate [SU] concentration; n = 763,813 for gout risk; n = 153,525 for fasting insulin) to select genetic instruments for 2-sample MR analyses, using multiple MR methods to address potential pleiotropic associations. We then used individual-level, electronic medical record-linked data from the UK Biobank (n = 360,453 persons of European ancestry) to replicate our analyses via single-sample MR analysis. RESULTS: Genetically determined SU levels, whether inferred from a polygenic score or strong individual loci, were not associated with fasting insulin concentrations. In contrast, genetically determined fasting insulin concentrations were positively associated with SU levels (0.37 mg/dl per log-unit increase in fasting insulin [95% confidence interval (95% CI) 0.15, 0.58]; P = 0.001). This persisted in outlier-corrected (ß = 0.56 mg/dl [95% CI 0.45, 0.67]) and multivariable MR analyses adjusted for BMI (ß = 0.69 mg/dl [95% CI 0.53, 0.85]) (P < 0.001 for both). Polygenic scores for fasting insulin were also positively associated with SU level among individuals in the UK Biobank (P < 0.001). Findings for gout risk were bidirectionally consistent with those for SU level. CONCLUSION: These findings provide evidence to clarify core questions about the close association between hyperuricemia and insulin resistance syndrome: hyperinsulinemia leads to hyperuricemia but not the other way around. Reducing insulin resistance could lower the SU level and gout risk, whereas lowering the SU level (e.g., allopurinol treatment) is unlikely to mitigate insulin resistance and its cardiometabolic sequelae.

Mutations in HOGA1 do Not Confer a Dominant Phenotype Manifesting as Kidney Stone Disease.

PURPOSE: The etiology of calcium-oxalate kidney stone formation remains elusive. Biallelic mutations in HOGA1 are responsible for primary hyperoxaluria type 3 and result in oxalate overproduction and kidney stone disease. Our previous study showed that carriers of HOGA1 mutations have elevated urinary levels of oxalate precursors. In this study we explored the possibility that mutations in HOGA1 confer a dominant phenotype in the form of kidney stone disease or hyperoxaluria. MATERIALS AND METHODS: An observational analytic case control study was designed to determine the prevalence of pathogenic HOGA1 mutations among adults with calcium-oxalate kidney stone disease. Given the high prevalence of HOGA1 mutations among Ashkenazi Jews, this group was evaluated separately. Carrier frequency of any of the 52 reported pathogenic mutations was compared to data derived from gnomAD for the corresponding ethnic group. Sanger sequencing of HOGA1 gene was performed on DNA samples from the following groups: 60 Ashkenazi Jews and 86 nonAshkenazi calcium-oxalate stone formers, 150 subjects with low and 150 with high urinary oxalate levels. RESULTS: The carrier prevalence of pathogenic mutations among the Ashkenazi Jews was 1.7% compared to 2.8% in the corresponding control group (p=0.9 OR=0.6 95% CI 0.01-3.51). We did not detect any mutation among the nonAshkenazi study group. No correlation was detected between hyperoxaluria and HOGA1 variants. CONCLUSIONS: This study shows that mutations in HOGA1 do not confer a dominant phenotype in the form of calcium-oxalate kidney stone disease or hyperoxaluria.

Incidence of Hyponatremia in Patients With Indwelling Peritoneal Catheters for Drainage of Malignant Ascites.

Importance: Indwelling peritoneal catheters (IPCs) are frequently used to drain tense, symptomatic, malignant ascites. Large-volume drainage may lead to hyponatremia owing to massive salt depletion. To date, no studies have examined the epidemiology of hyponatremia after placement of an IPC. Objective: To evaluate the incidence of hyponatremia after IPC placement, the risk factors associated with its development, and how it is managed. Design, Setting, and Participants: This cohort study retrospectively reviewed the medical records of 461 patients who had IPCs placed during the period between 2006 and 2016 at a tertiary care hospital in Boston, Massachusetts, of whom 309 patients met the inclusion criteria. Data analysis was performed from June to November 2019. Main Outcomes and Measures: Main outcomes were the incidence of hyponatremia (with a serum sodium level <135 mEq/L) after IPC placement, the risk factors for its development, and how it was managed. We also examined the clinical course of a subset of 21 patients with hypovolemic hyponatremia. Results: Of the 309 eligible patients with laboratory results both before IPC placement and 2 days or more after IPC placement, 189 (72.1%) were female, and the mean (SD) age was 59 (12) years. The overall incidence of hyponatremia after IPC placement was 84.8% (n = 262), of whom 21 patients (8.0%) had severe hyponatremia. The mean (SD) decrease in serum sodium level before vs after IPC placement was 5 (5.1) mEq/L and decreased by 10 mEq/L or more among 52 patients (16.8%). Patients with hyponatremia prior to IPC placement had an 8-fold higher adjusted odds of having persistent hyponatremia after IPC placement (odds ratio, 7.9; 95% CI, 2.9-21.7). Patients with hepatopancreatobiliary malignant neoplasms were more likely to develop hyponatremia (78 of 262 patients with hyponatremia [29.8%] vs 7 of 47 patients without hyponatremia [14.9%]). Hyponatremia was either unrecognized or untreated in 189 patients (72.1%). Conclusions and Relevance: Although the placement of an IPC is often a palliative measure, hyponatremia is common and is often untreated or unrecognized. Patients at highest risk, such as those with hyponatremia at baseline and those with hepatopancreatobiliary malignant neoplams, should be evaluated carefully prior to IPC placement and may warrant closer monitoring after placement. In all cases, hyponatremia should be evaluated and managed within the context of a patient's overall goals of care.

Genomic dissection of 43 serum urate-associated loci provides multiple insights into molecular mechanisms of urate control.

High serum urate is a prerequisite for gout and associated with metabolic disease. Genome-wide association studies (GWAS) have reported dozens of loci associated with serum urate control; however, there has been little progress in understanding the molecular basis of the associated loci. Here, we employed trans-ancestral meta-analysis using data from European and East Asian populations to identify 10 new loci for serum urate levels. Genome-wide colocalization with cis-expression quantitative trait loci (eQTL) identified a further five new candidate loci. By cis- and trans-eQTL colocalization analysis, we identified 34 and 20 genes, respectively, where the causal eQTL variant has a high likelihood that it is shared with the serum urate-associated locus. One new locus identified was SLC22A9 that encodes organic anion transporter 7 (OAT7). We demonstrate that OAT7 is a very weak urate-butyrate exchanger. Newly implicated genes identified in the eQTL analysis include those encoding proteins that make up the dystrophin complex, a scaffold for signaling proteins and transporters at the cell membrane; MLXIP that, with the previously identified MLXIPL, is a transcription factor that may regulate serum urate via the pentose-phosphate pathway and MRPS7 and IDH2 that encode proteins necessary for mitochondrial function. Functional fine mapping identified six loci (RREB1, INHBC, HLF, UBE2Q2, SFMBT1 and HNF4G) with colocalized eQTL containing putative causal SNPs. This systematic analysis of serum urate GWAS loci identified candidate causal genes at 24 loci and a network of previously unidentified genes likely involved in control of serum urate levels, further illuminating the molecular mechanisms of urate control.

Molecular Pathophysiology of Uric Acid Homeostasis.

Uric acid, the end product of purine metabolism, plays a key role in the pathogenesis of gout and other disease processes. The circulating serum uric acid concentration is governed by the relative balance of hepatic production, intestinal secretion, and renal tubular reabsorption and secretion. An elegant synergy between genome-wide association studies and transport physiology has led to the identification and characterization of the major transporters involved with urate reabsorption and secretion, in both kidney and intestine. This development, combined with continued analysis of population-level genetic data, has yielded an increasingly refined mechanistic understanding of uric acid homeostasis as well as greater understanding of the genetic and acquired influences on serum uric acid concentration. The continued delineation of novel and established regulatory pathways that regulate uric acid homeostasis promises to lead to a more complete understanding of uric acid-associated diseases and to identify new targets for treatment.

The Shared Genetic Basis of Hyperuricemia, Gout, and Kidney Function.

Increased urate levels and gout correlate with chronic kidney disease with consensus that the primary driver of this relationship is reduced kidney function. However, a comparison of results of genome-wide association studies in serum urate levels and kidney function indicate a more complex situation. Approximately 20% of loci are shared-comprised of those in which the urate-raising allele associates with reduced kidney function, the vice versa situation, and those in which the signals/alleles are different. Although there is very little known regarding the molecular basis of the shared genetic relationship, it is clear that there is no major role for urate transporters and associated transportasome machinery. Some loci, however, do provide clues. The ATXN2 locus, with a shared signal, is one of only a small number of master regulators of expression by chromatin interaction, regulating expression of genes relevant for cholesterol and blood pressure. This suggests a role for systemic metabolic alteration. At HNF4A there is genetic heterogeneity with different genetic variants conferring risk to hyperuricemia and chronic kidney disease, suggesting different pathways. Interestingly, the shared loci congregate in the olfactory receptor pathway. The genome-wide association studies have generated a range of experimentally testable hypotheses that should provide insights into the shared pathogenesis of hyperuricemia/gout and chronic kidney disease.

The Management of Gout in Renal Disease.

Gout, a debilitating inflammatory arthritis, currently affects more than 9 million Americans. Hyperuricemia, the laboratory abnormality associated with the development of gout, also occurs in a significant number of patients with chronic kidney disease (CKD), a condition that affects approximately 14% of the US population. Several recent studies have attempted to provide a definitive link between the presence of hyperuricemia and progression of CKD; however, the treatment of asymptomatic hyperuricemia in CKD is not supported by recent randomized controlled trials. The pharmacology of acute gout flares and urate lowering is complicated in patients who also have evidence of CKD, primarily because of an increased risk of medication toxicity. Recipients of kidney transplants are particularly at risk of debilitating gout and medication toxicity. We review the available data linking CKD, gout, and hyperuricemia, providing practice guidelines on managing gout in CKD patients and kidney transplant recipients. We advocate for much greater involvement of nephrologists in the management of gout in renal patients.