Tirzepatide and prevention of chronic kidney disease

Chronic kidney disease; Diabetes mellitus; ObesityMalaltia renal crònica; Diabetis mellitus; ObesitatEnfermedad renal crónica; Diabetes mellitus; ObesidadTirzepatide is a twincretin recently approved to improve glycemic control in type 2 diabetes mellitus (T2DM). More specifically, tirzepatide is an agonist of both the glucose-dependent insulinotropic polypeptide (GIP) and the glucagon-like peptide-1 (GLP1) receptors. In recent clinical trials in persons with obesity or overweight with associated conditions, tirzepatide decreased body weight and other cardiorenal risk factors (blood pressure, low-density lipoprotein cholesterol, glycated hemoglobin and albuminuria). Moreover, in a post hoc analysis of the SURPASS-4 randomized clinical trial, tirzepatide decreased albuminuria and total estimated glomerular filtration rate (eGFR) slopes and nearly halved the risk of a pre-specified composite kidney endpoint (eGFR decline ≥40%, renal death, kidney failure or new-onset macroalbuminuria) in participants with T2DM and high cardiovascular risk when compared with insulin glargine. Similar to other kidney-protective drugs, tirzepatide, alone or combined with sodium-glucose co-transporter 2 inhibitors, caused an early dip in eGFR. Moreover, tirzepatide also decreased eGFR slopes in participants with eGFR >60 mL/min/1.73 m2 or with normoalbuminuria. We now review the potential kidney health implications of tirzepatide, addressing its structure and function, relationship to current GLP1 receptor agonists, impact of recent results for the treatment and prevention of kidney disease, and expectations for the future.FIS/Fondos FEDER (PI18/01366, PI19/00588, PI19/00815, PI20/00744, DTS18/00032, ERA-PerMed-JTC2018 KIDNEY AT390 TACK AC18/00064 and PERSTIGAN AC18/00071, ISCIII-RETIC REDinREN RD016/0009), Sociedad Española de Nefrología, Sociedad Madrileña de Nefrología (SOMANE), FRIAT, Comunidad de Madrid en Biomedicina (B2017/BMD-3686 and CIFRA2-CM). Instituto de Salud Carlos III (ISCIII) RICORS program (RICORS2040-395 , RD21/0005/0001) and SPACKDc PMP21/00109, FEDER funds funded by European Union—Next Generation EU’, Mecanismo para la Recuperación y la Resiliencia (MRR) and RD16/0009

MYH9-related disease : it does exist, may be more frequent than you think and requires specific therapy

Altres ajuts: Sources of support: FIS/Fondos FEDER (REDinREN RD016/0009), Sociedad Española de Nefrología, FRIAT, Comunidad de Madrid en Biomedicina B2017/BMD-3686 CIFRA2-CM. Salary support: ISCIII Rio Hortega to M.V.P.-G.In this issue of ckj, Tabibzadeh et al. report one of the largest series of patients with MYH9 mutations and kidney disease. The cardinal manifestation of MYH9-related disease is thrombocytopenia with giant platelets. The population frequency of pathogenic MYH9 mutations may be at least 1 in 20 000. The literature abounds in misdiagnosed cases treated for idiopathic thrombocytopenic purpura with immune suppressants and even splenectomy. Additional manifestations include neurosensorial deafness and proteinuric and hematuric progressive kidney disease (at some point, it was called Alport syndrome with macrothrombocytopenia), leucocyte inclusions, cataracts and liver enzyme abnormalities, resulting in different names for different manifestation combinations (MATINS, May-Hegglin anomaly, Fechtner, Epstein and Sebastian syndromes, and deafness AD 17). The penetrance and severity of kidney disease are very variable, which may obscure the autosomal dominant inheritance. A correct diagnosis will both preclude unnecessary and potentially dangerous therapeutic interventions and allow genetic counselling and adequate treatment. Morphological erythrocyte, granulocyte and platelet abnormalities may allow the future development of high-throughput screening techniques adapted to clinical peripheral blood flow cytometers

Epigenetic modifiers as potential therapeutic targets in diabetic kidney disease

Diabetic kidney disease is one of the fastest growing causes of death worldwide. Epigenetic regulators control gene expression and are potential therapeutic targets. There is functional interventional evidence for a role of DNA methylation and the histone post-translational modifications—histone methylation, acetylation and crotonylation—in the pathogenesis of kidney disease, including diabetic kidney disease. Readers of epigenetic marks, such as bromodomain and extra terminal (BET) proteins, are also therapeutic targets. Thus, the BD2 selective BET inhibitor apabetalone was the first epigenetic regulator to undergo phase-3 clinical trials in diabetic kidney disease with an endpoint of kidney function. The direct therapeutic modulation of epigenetic features is possible through pharmacological modulators of the specific enzymes involved and through the therapeutic use of the required substrates. Of further interest is the characterization of potential indirect effects of nephroprotective drugs on epigenetic regulation. Thus, SGLT2 inhibitors increase the circulating and tissue levels of β-hydroxybutyrate, a molecule that generates a specific histone modification, β-hydroxybutyrylation, which has been associated with the beneficial health effects of fasting. To what extent this impact on epigenetic regulation may underlie or contribute to the so-far unclear molecular mechanisms of cardio-and nephroprotection offered by SGLT2 inhibitors merits further in-depth studies.This research was funded by FIS/FEDER funds (PI15/00298, CP14/00133, PI16/01900, PI18/01386, PI18/0133, PI19/00588, PI19/00815, DTS18/00032, ERA-PerMed-JTC2018 (KIDNEY ATTACK AC18/00064 and PERSTIGAN AC18/00071), ISCIII-RETIC REDinREN RD016/0009), Sociedad Española de Nefrología, FRIAT, Comunidad de Madrid en Biomedicina B2017/BMD- 3686 CIFRA2-CM. Salary support: ISCIII Miguel Servet to ABS and MDS-N, ISCIII Sara Borrell to JM-MM, REDinREN RD016/0009 to MF-B, and MICIU to JG-M

MYH9-related disease : it does exist, may be more frequent than you think and requires specific therapy

Altres ajuts: Sources of support: FIS/Fondos FEDER (REDinREN RD016/0009), Sociedad Española de Nefrología, FRIAT, Comunidad de Madrid en Biomedicina B2017/BMD-3686 CIFRA2-CM. Salary support: ISCIII Rio Hortega to M.V.P.-G.In this issue of ckj, Tabibzadeh et al. report one of the largest series of patients with MYH9 mutations and kidney disease. The cardinal manifestation of MYH9-related disease is thrombocytopenia with giant platelets. The population frequency of pathogenic MYH9 mutations may be at least 1 in 20 000. The literature abounds in misdiagnosed cases treated for idiopathic thrombocytopenic purpura with immune suppressants and even splenectomy. Additional manifestations include neurosensorial deafness and proteinuric and hematuric progressive kidney disease (at some point, it was called Alport syndrome with macrothrombocytopenia), leucocyte inclusions, cataracts and liver enzyme abnormalities, resulting in different names for different manifestation combinations (MATINS, May-Hegglin anomaly, Fechtner, Epstein and Sebastian syndromes, and deafness AD 17). The penetrance and severity of kidney disease are very variable, which may obscure the autosomal dominant inheritance. A correct diagnosis will both preclude unnecessary and potentially dangerous therapeutic interventions and allow genetic counselling and adequate treatment. Morphological erythrocyte, granulocyte and platelet abnormalities may allow the future development of high-throughput screening techniques adapted to clinical peripheral blood flow cytometers