Gout is a chronic inflammatory disease caused by precipitation of urate crystals in the joints, kidneys, and urinary tract. Independent of urate deposition disorders, recent studies have shown a ...positive association between circulating uric acid (UA) levels and cardiovascular (CV) diseases. These results indicate that UA is a precipitating factor of both gout and the progression of CV diseases, including hypertension and/or chronic kidney disease (CKD). A large body of evidence has shown that UA-lowering therapies are effective in preventing the progression of hypertension/CKD and that a causal relationship exists between serum UA level and CV diseases. Despite the urgent need for effective UA-lowering drugs that can be used to obtain better therapeutic outcomes and prognosis, only few drugs have been developed in the past decades. Recently, febuxostat and topiroxostat, which are xanthine oxidoreductase inhibitors, were developed and used in clinical practice. Of note, after the approval of lesinurad, which is a urate transporter-1 (URAT-1) inhibitor, in the United States in 2015, dotinurad (Fig.
1
), a novel promising drug with selective UA reabsorption inhibitory property, was recently developed in Japan in 2018. Dotinurad is indicated for patients with hyperuricemia/gout as most patients with hyperuricemia are classified into “underexcretion type”, which requires the inhibition of URAT-1 to excrete excess UA via the kidney. Focusing on dotinurad, the present study highlighted the multifaceted preliminary new trials that assessed for drug efficacy and safety, pharmacokinetics (PK) according to age and gender, the presence or absence of liver and kidney disorders, drug interactions with NSAID, and non-inferiority of dotinurad to either febuxostat or benzbromarone. A series of studies included in this supplemental review indicate that dotinurad reduces serum UA levels, and its efficacy and safety are similar to those of other UA-lowering agents currently used even in hyperuricemic patients with various clinical conditions. Moreover, two exploratory studies with a small sample size were conducted to compare PK parameters between patients with overproduction- and underexcretion-type hyperuricemia, and results showed that the effects of UA-lowering agents were comparable between the two subtype groups.
Fig. 1
Chemical structural formula of dotinurad
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background: This review considers anew the etiology of the cardio-renal protective effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors by extending the discussion to renal congestion, ...inherent in diabetic kidney disease (DKD) even at an early stage of nephropathy in which heart failure (HF) or salt and water accumulation is asymptomatic. Summary: The interstitial fluid (IF) space of the kidney space plays a crucial role for tubulointerstitial inflammation, renal hypoxia, and ischemic injury, which often leads to renal progression. In DKD, as a result of hyperglycemic milieu, excessive salt and water can be accumulated in the IF space, creating renal congestion. I hypothesize that SGLT2 inhibitors cause a shift in extracellular water from the IF space to the intravascular space to compensate for the SGLT2 inhibitor-induced hypovolemia. This decrease in IF volume ameliorates the IF space milieu and may reduce inflammation, hypoxia, and ischemic injury. Message: The present review proposes a novel theory; unlike other hypoglycemic agents or diuretics, SGLT2 inhibitor could protect DKD from failing by improving latent renal congestion even without symptomatic HF.
This communication provides a current overview on the renal protective effects of sodium–glucose cotransporter 2 (SGLT2) inhibitors in diabetics. Following the epoch-making publications, the CANVAS ...Program and the EMPA-REG OUTCOME trial, numerous literature has discussed the mechanisms by which SGLT2 inhibition exerts its cardio-renal protective effects. Some of them reached agreement, while others did not. This review focuses on the hemodynamic aspect and the remaining potential factors relevant to the renal protection which have not been so much taken up by other review papers. Questions unanswered include factors of uric acid, lipids, erythropoiesis and oxidative stress, salt and sympathetic nerve, and the Na–H exchanger in heart and kidney.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Glucagon-like peptide‒1 (GIP‒1) receptor agonists (GLP‒1 RAs) are incretin derivative hypoglycemic agents that augment endogenous insulin secretion to improve glucose metabolism in patients with ...diabetes. Recent clinical studies based on the guidelines of the United States Food and Drug Administration suggest that GLP‒1 RAs have cardio-renal protective effects. For example, beneficial effects on major cardio-vascular events have been observed in the LEADER, SUSTAIN‒6, REWIND, HARMONY trials. In addition, renal protective effects have been proven in the ELIXA, LEADER, SUSTAIN‒6, and REWIND trials. Despite this clinical evidence, the precise pharmacological mechanisms of the cardio-renal protective effects of GLP‒1 RAs are unclear. Therefore, the present narrative review article assessed the assumptive mechanisms of GLP‒1 RAs. The GLP‒1 RAs act on the central and visceral vagal nervous systems to suppress appetite and reduce body weight and thereby help improve insulin resistance and decrease salt burden potentially underlying in patients with diabetes. In the kidney, GLP‒1 RAs inhibit Na reabsorption by inhibiting Na‒H exchanger 3 in the proximal tubule, which induces water and natriuresis. The GLP‒1 RAs also stimulate atrial natriuretic peptide, potentiating natriuresis, leading to a blood pressure lowering. In addition, GLP‒1 RAs improve proteinuria presumably via antioxidant, anti-inflammatory, anti-fibrotic, and anti-atherosclerotic effects. Whether GLP‒1 RAs provide glomerular protection through the Na‒H exchanger 3‒induced optimization of tubulo-glomerular feedback and the macula densa system is still a matter for debate. In conclusion, this narrative review article provides new insights into the mechanisms of the cardio-renal protective effects of GLP‒1 RAs.
Treatment of asymptomatic hyperuricemia is not commonly implemented. However, it is unclear whether urate deposition that begins during asymptomatic hyperuricemia can induce nephropathy. Dysfunction ...of ATP-binding cassette subfamily G member 2 (ABCG2), a urate efflux transporter, leads to elevated serum uric acid concentration (SUA). We investigated the association between asymptomatic hyperuricemia and decreased estimated glomerular filtration rate (eGFR), and the impact of ABCG2 on this relationship.
Retrospective cohort study.
1,885 Japanese adults undergoing routine health care follow-up between 2007 and 2017 who had eGFR ≥60 mL/min/1.73 m2, of which 311 had asymptomatic hyperuricemia (SUA >7.0 mg/dL). Study participants were classified into 3 categories of estimated ABCG2 function (full, 75%, and ≤50% function).
Baseline SUA and estimated ABCG2 function.
Change in eGFR over time.
Linear mixed-effect models were used to analyze the relationship between asymptomatic hyperuricemia, ABCG2 function, and eGFR decline.
Asymptomatic hyperuricemia was negligibly associated with eGFR decline overall. However, among those with eGFR 60-89 mL/min/1.73 m2 and ≤50% ABCG2 function, eGFR decline was associated with asymptomatic hyperuricemia (P = 0.03). ABCG2 was not associated with eGFR reductions when the SUA was <6.0 mg/dL. Among participants with SUA ≥6.0 mg/dL and eGFR 60-89 mL/min/1.73 m2, ≤50% ABCG2 function was associated with approximately 1.2-fold faster eGFR decline compared with fully functional ABCG2 (P = 0.02). Among the participants with SUA ≥6.0 mg/dL and eGFR 60-89 mL/min/1.73 m2, the adjusted eGFR slopes (given as mean ± standard error of the mean, in mL/min/1.73 m2 per year) were −0.946 ± 0.049, −1.040 ± 0.046, and −1.148 ± 0.069 for full, 75%, and ≤50% ABCG2 function, respectively.
Lack of measurement of urinary urate and uremic toxins that are known to be transported by ABCG2, and no independent validation cohort.
Asymptomatic hyperuricemia was not associated with eGFR decline, except when in the presence of ≤50% ABCG2 function.
The urate transporter ABCG2 is a protein that regulates serum urate concentrations; when dysfunctional, it can lead to elevated serum concentrations of this compound (ie, hyperuricemia). Although persistent hyperuricemia induces gout and kidney injury, the effects on organs during the asymptomatic phase have yet to be established. Therefore, to clarify the relationship between ABCG2, asymptomatic hyperuricemia, and kidney function, we conducted a retrospective cohort study of 1,885 healthy participants, including 311 participants with asymptomatic hyperuricemia. We found that the coexistence of asymptomatic hyperuricemia and severe ABCG2 dysfunction was associated with the age-dependent decline in kidney function. We concluded that asymptomatic hyperuricemia represents a risk factor for chronic kidney disease, at least in individuals with highly dysfunctional ABCG2. This new finding highlights the potential importance of ABCG2 in the pathogenesis of hyperuricemia-induced kidney injury.
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Abstract
The long-term clinical experiences with recombinant human erythropoietin (rHuEPO) and its analog derivatives have clearly proven that correction of anemia with erythropoiesis stimulating ...agent (ESA) not only reduces blood transfusion and improves patients’ QOL but has multiple benefits for the concurrent complications of CKD such as Cardio-Renal–Anemia (CRA) syndrome and/or malnutrition-inflammation-atherosclerosis (MIA) syndrome.
Unlike ESA, the newly available agent, hypoxia-inducible factor (HIF) stabilizer, stimulates endogenous erythropoietin (EPO) by mimicking hypoxia with HIF prolyl hydroxylase domain enzyme (HIF-PHD) inhibition. The phase 2 and 3 clinical studies have shown that HIF stabilizers are as efficacious as ESA in ameliorating renal anemia. Whether the same clinical benefits on CRA and MIA syndrome hold true in patients given HIF stabilizers is a matter for future debate. Given that HIF stabilizers act on the multiple target genes, the use of this novel agent may lead to unwanted adverse events.
Launching HIF stabilizers into the treatment of renal anemia provokes a concern about how this alternative treatment will be taken up in the daily clinical practice. However, guideline-oriented strategies on how to use HIF stabilizer is not available at this limited point due to scant clinical information. Nevertheless, this opinion-based review provides a future insight into the management of renal anemia with HIF stabilizer by reference to the past experiences with ESA. HIF stabilizers can preferably be indicated for CRA syndrome at pre-dialysis stage, ESA resistant anemia at advanced CKD stage, and perhaps for dysregulated iron metabolism akin to MIA syndrome in patients on dialysis.
The Japanese Society for Dialysis Therapy (JSDT) guideline committee, chaired by Dr Y. Tsubakihara, presents the Japanese guidelines entitled “Guidelines for Renal Anemia in Chronic Kidney Disease.” ...These guidelines replace the “2004 JSDT Guidelines for Renal Anemia in Chronic Hemodialysis Patients,” and contain new, additional guidelines for peritoneal dialysis (PD), non‐dialysis (ND), and pediatric chronic kidney disease (CKD) patients.
Chapter 1 presents reference values for diagnosing anemia that are based on the most recent epidemiological data from the general Japanese population. In both men and women, hemoglobin (Hb) levels decrease along with an increase in age and the level for diagnosing anemia has been set at <13.5 g/dL in males and <11.5 g/dL in females. However, the guidelines explicitly state that the target Hb level in erythropoiesis stimulating agent (ESA) therapy is different to the anemia reference level. In addition, in defining renal anemia, the guidelines emphasize that the reduced production of erythropoietin (EPO) that is associated with renal disorders is the primary cause of renal anemia, and that renal anemia refers to a condition in which there is no increased production of EPO and serum EPO levels remain within the reference range for healthy individuals without anemia, irrespective of the glomerular filtration rate (GFR). In other words, renal anemia is clearly identified as an “endocrine disease.” It is believed that defining renal anemia in this way will be extremely beneficial for ND patients exhibiting renal anemia despite having a high GFR. We have also emphasized that renal anemia may be treated not only with ESA therapy but also with appropriate iron supplementation and the improvement of anemia associated with chronic disease, which is associated with inflammation, and inadequate dialysis, another major cause of renal anemia.
In Chapter 2, which discusses the target Hb levels in ESA therapy, the guidelines establish different target levels for hemodialysis (HD) patients than for PD and ND patients, for two reasons: (i) In Japanese HD patients, Hb levels following hemodialysis rise considerably above their previous levels because of ultrafiltration‐induced hemoconcentration; and (ii) as noted in the 2004 guidelines, although 10 to 11 g/dL was optimal for long‐term prognosis if the Hb level prior to the hemodialysis session in an HD patient had been established at the target level, it has been reported that, based on data accumulated on Japanese PD and ND patients, in patients without serious cardiovascular disease, higher levels have a cardiac or renal function protective effect, without any safety issues. Accordingly, the guidelines establish a target Hb level in PD and ND patients of 11 g/dL or more, and recommend 13 g/dL as the criterion for dose reduction/withdrawal. However, with the results of, for example, the CHOIR (Correction of Hemoglobin and Outcomes in Renal Insufficiency) study in mind, the guidelines establish an upper limit of 12 g/dL for patients with serious cardiovascular disease or patients for whom the attending physician determines high Hb levels would not be appropriate.
Chapter 3 discusses the criteria for iron supplementation. The guidelines establish reference levels for iron supplementation in Japan that are lower than those established in the Western guidelines. This is because of concerns about long‐term toxicity if the results of short‐term studies conducted by Western manufacturers, in which an ESA cost‐savings effect has been positioned as a primary endpoint, are too readily accepted. In other words, if the serum ferritin is <100 ng/mL and the transferrin saturation rate (TSAT) is <20%, then the criteria for iron supplementation will be met; if only one of these criteria is met, then iron supplementation should be considered unnecessary.
Although there is a dearth of supporting evidence for these criteria, there are patients that have been surviving on hemodialysis in Japan for more than 40 years, and since there are approximately 20 000 patients who have been receiving hemodialysis for more than 20 years, which is a situation that is different from that in many other countries. As there are concerns about adverse reactions due to the overuse of iron preparations as well, we therefore adopted the expert opinion that evidence obtained from studies in which an ESA cost‐savings effect had been positioned as the primary endpoint should not be accepted unquestioningly.
In Chapter 4, which discusses ESA dosing regimens, and Chapter 5, which discusses poor response to ESAs, we gave priority to the usual doses that are listed in the package inserts of the ESAs that can be used in Japan. However, if the maximum dose of darbepoetin alfa that can currently be used in HD and PD patients were to be used, then the majority of poor responders would be rescued.
Blood transfusions are discussed in Chapter 6. Blood transfusions are attributed to the difficulty of managing renal anemia not only in HD patients, but also in end‐stage ND patients who respond poorly to ESAs. It is believed that the number of patients requiring transfusions could be reduced further if there were novel long‐acting ESAs that could be used for ND patients.
Chapter 7 discusses adverse reactions to ESA therapy. Of particular concern is the emergence and exacerbation of hypertension associated with rapid hematopoiesis due to ESA therapy.
The treatment of renal anemia in pediatric CKD patients is discussed in Chapter 8; it is fundamentally the same as that in adults.
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