Multicenter randomized controlled trial of intensive uric acid lowering therapy for CKD patients with hyperuricemia: TARGET-UA.

BACKGROUND: We investigate whether Intensive uric acid (UA)-lowering therapy (ULT) provides increased renal protection compared with standard therapy in chronic kidney disease (CKD) patients. METHODS: This was a multicenter randomized controlled trial. Only CKD patients with hyperuricemia were included in this study. The participants were randomly assigned to either the Intensive therapy group (target serum UA level ≥ 4.0 mg/dL and < 5.0 mg/dL) or the standard therapy group (serum UA level ≥ 6.0 mg/dL and < 7.0 mg/dL). ULT was performed using topiroxostat, a non-purine-type selective xanthine oxidase inhibitor. The primary endpoint was change in the logarithmic value of urine albumin to the creatinine ratio (ACR) between baseline and week 52 of the treatment. RESULTS: Three hundred fifty-two patients were included in the full analysis set. In the Standard therapy group, mean serum UA was 8.23 mg/dL at baseline and 6.13 mg/dL at 52 weeks. In the Intensive therapy group, mean serum UA was 8.15 mg/dL at baseline and 5.25 mg/dL at 52 weeks. There was no significant difference in changes in log ACR at 52 weeks between the Intensive therapy and the Standard therapy groups. CONCLUSION: This study did not reveal the benefit of Intensive ULT to improve albuminuria levels. (UMIN000026741 and jRCTs051180146).

Successful treatment of nephrotic syndrome induced by lambda light chain deposition disease using lenalidomide: A case report and review of the literature
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BACKGROUND: Light chain deposition disease (LCDD) is a monoclonal immunoglobulin deposition disease (MIDD) that is characterized by the deposition of monoclonal light chains in multiple organs, including the kidney. It is a rare disorder caused by an underlying monoclonal plasma cell dyscrasia. LCDD with renal involvement causes proteinuria, which sometimes can lead to nephrotic syndrome. The monoclonal light chains are mostly in the κ form. Treatment of LCDD is the same as that for multiple myeloma (MM); however, some conventional anticancer drugs show substantial toxicity and therefore cannot be administered to older patients or those with renal impairment. CASE PRESENTATION: An 80-year-old woman was referred to our department with severe nephrotic syndrome (13.6 g/gCr) and anemia. A renal biopsy showed mesangial proliferation and mesangial matrix expansion, and immunohistochemistry showed positive staining for λ chains along the glomerular basement membrane, but was negative for κ chains or amyloid deposition. A bone marrow biopsy revealed 64% plasma cells. Immunoglobulin G (IgG)-λ type M protein was detected, and the levels of free λ chain was significantly increased. We concluded that her nephrotic syndrome was caused by LCDD, which resulted from IgG-λ MM. The induction of a BCD (bortezomib, cyclophosphamide, and dexamethasone) treatment regimen did not lead to a hematological response or decrease in proteinuria. The administration of combination therapy of lenalidomide and prednisolone led to the successful reduction of proteinuria and hematuria. CONCLUSIONS: We presented a very rare case report describing the successful treatment of LCDD (λ chain)-induced nephrotic syndrome with lenalidomide.
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Efficacy of mizoribine and prednisolone combination therapy in adult patients with IgA vasculitis.

Immunoglobulin (Ig)A vasculitis (IgAV), formerly known as Henoch-Schönlein purpura, is one of the most common vasculitis caused by an IgA-mediated immune complex. It occurs most frequently in childhood and less commonly in adulthood. As for the treatment of IgAV in adults, there are few studies dealing with the administration and efficacy of intravenous pulse steroid therapy or combination therapy using prednisolone (PSL) and immunosuppressive drugs. Mizoribine (MZB) is a newly developed immunosuppressive drug with few adverse effects; however, there are currently few studies using MZB in adult patients with IgAV. In this study, we evaluated the efficacy of MZB combined with a course of PSL in adult patients with IgAV. Five patients with adult onset IgAV were enrolled in the study. All patients received oral PSL (initial dose 30-50 mg/day), and MZB was administered orally at a single morning dose of 150 mg. We investigated the clinical manifestations and prognosis of these patients receiving the combination therapy of MZB and PSL retrospectively. All patients showed complete or partial remission of proteinuria and microscopic hematuria with the combination therapy of MZB and PSL. Furthermore, no significant adverse effects were observed. Although this study had an uncontrolled small group, our results indicate that the combination of MZB with PSL could be a possible new treatment for adult patients with IgAV.

Successful treatment of highly advanced immunoglobulin G4-related kidney disease presenting renal mass-like regions with end-stage kidney failure: a case study.

BACKGROUND: Immunoglobulin G4-related kidney disease characterized by immunoglobulin G4-positive plasma cell-rich tubulointerstitial nephritis has distinctive serological and radiological findings. Renal prognosis is good because of a good response to glucocorticoids. Here we report a case of successful treatment of highly advanced immunoglobulin G4-related kidney disease presenting renal mass-like regions with end-stage kidney failure. CASE PRESENTATION: A 59-year-old Japanese man was referred to our hospital because of uremia with a creatinine level of 12.36 mg/dL. Urinalysis revealed mild proteinuria and hyperß2microglobulinuria, and blood tests showed hyperglobulinemia with an IgG level of 3243 mg/dL and an IgG4 level of 621 mg/dL. Non-contrast computed tomography revealed renal mass-like regions. Based on the findings, immunoglobulin G4-related kidney disease was suspected, however, further radiological examination showed unexpected results. Ga-67 scintigraphy showed no kidney uptake. T2-weighted magnetic resonance imaging revealed high-intensity signals which corresponded to mass-like regions and multiple patchy low-intensity signals in kidney cortex. Finally, the patient was diagnosed with immunoglobulin G4-related kidney disease by renal pathology of severe immunoglobulin G4-positive plasma cell-rich tubulointerstitial nephritis and characteristic fibrosis. He received 50 mg oral prednisolone, which was tapered with a subsequent decrease of serum creatinine and IgG4 levels. One year after initiation of treatment, he achieved normalization of serum IgG4 level and proteinuria, and remained off dialysis with a creatinine level of 3.50 mg/dL. After treatment with steroids, repeat imaging suggested bilateral severe focal atrophy. However, mass-like regions did not show atrophic change although renal atrophy was evident in patchy low-intensity lesions on T2-weighted magnetic resonance imaging. These findings suggest that multiple patchy low-intensity signals and high-intensity mass-like regions were mildly atrophic lesions of immunoglobulin G4-related kidney disease due to severe fibrosis and normal parts of kidney, respectively. CONCLUSIONS: In immunoglobulin G4-related kidney disease with severe kidney failure, radiological findings should be carefully examined. In addition, renal prognosis may be good despite highly advanced tubulointerstitial nephritis and fibrosis.

Induction of vascular insulin resistance and endothelin-1 expression and acceleration of atherosclerosis by the overexpression of protein kinase C-ß isoform in the endothelium.

RATIONALE: Loss of insulin action in the endothelium can cause endothelial dysfunction and atherosclerosis. Hyperglycemia and elevated fatty acids induced by diabetes mellitus can activate protein kinase C-ß isoforms and selectively inhibit insulin signaling via phosphatidylinositol 3-kinase/Akt pathway to inhibit the activation of endothelial nitric oxide synthase and metabolic actions. OBJECTIVE: To demonstrate that overexpressing protein kinase C-ß2 isoform in endothelial cells can cause selective insulin resistance and exacerbate atherosclerosis in the aorta. METHODS AND RESULTS: Protein kinase C-ß2 isoform was overexpressed in endothelial cells using a promoter of vascular endothelial cell cadherin. These mice were cross-bred with apoE-/- mice [Tg (Prkcb)apoE-/-]. On a Western diet, Tg(Prkcb)apoE-/- and apoE-/- mice did not differ in systemic insulin sensitivity, glucose tolerance, plasma lipid, or blood pressure. Insulin action in endothelial cells and femoral artery from Tg(Prkcb)apoE-/- mice was impaired by ≈40% with respect to Akt/endothelial nitric oxide synthase activation, and leukocyte-endothelial cell binding increased in cultured lung endothelial cells from Tg(Prkcb)apoE-/- mice compared with that from apoE-/- mice. Basal and angiotensin-stimulated big endothelin-1 levels were elevated in Tg(Prkcb)apoE-/- mice compared with apoE-/- mice. The severity of atherosclerosis in the aorta from Tg(Prkcb)apoE-/- mice increased by ≈70% as measured by en face fat staining and plaque content of the number of smooth muscle cells, macrophages, and extracellular matrix. CONCLUSIONS: Specific protein kinase C-ß2 activation in the endothelial cells caused dysfunction and accelerated atherosclerosis because of loss of insulin-stimulated Akt/endothelial nitric oxide synthase activation and angiotensin-induced increases in endothelin-1 expression.

Tirzepatide Reduces Fat Mass and Provides Good Glycaemic Control in Type 2 Diabetes Patients Undergoing Haemodialysis: A Single-Centre Retrospective Study.

OBJECTIVE: Tirzepatide is an injectable peptide approved by the US Food and Drug Administration for the treatment of Type 2 diabetes (T2DM). Its weight-loss effect primarily targets fat reduction; however, such effect on patients with chronic kidney disease (CKD) undergoing haemodialysis (HD) has not been reported. METHODS: Nine patients with CKD undergoing HD received weekly tirzepatide doses (2.5-7.5 mg) once a week. Evaluations encompassed tirzepatide's impact on dry weight (DW) and body composition assessed at baseline and study conclusion using bioelectrical impedance analysis. This longitudinal study included nine patients, with a median age of 53 years and median HD duration of 4 years. RESULTS: Tirzepatide treatment significantly decreased glycated albumin compared with the value at baseline (22.7 ± 5.4 vs. 18.3 ± 2.5%, p = 0.028, respectively). Significant reductions were observed in DW (-1.0 kg, p = 0.024) and body mass index (-0.6 kg/m2, p = 0.050) following tirzepatide administration. Total fat mass was also reduced, but not significantly (- 2.51% from baseline, p = 0.214). In contrast, skeletal muscle mass was not decreased (-1.02% from baseline, p = 0.722). No serious side effects other than nausea were observed during the study period. CONCLUSION: Tirzepatide effectively provides good glycaemic control in T2DM patients undergoing HD, decreasing DW by reducing body fat mass without increasing frailty risk.

Safety and Efficacy of Dotinurad on Uric Acid in Patients With Chronic Kidney Disease With Estimated Glomerular Filtration Rate Below 25 mL/Min/1.73 m².

Introduction Dotinurad is being developed as a selective uric acid reabsorption inhibitor. However, its effect on lowering serum uric acid (UA) levels in chronic kidney disease (CKD) patients with severe renal dysfunction is unknown. Therefore, the purpose of this study was to determine the effect of dotinurad on renal function in CKD patients with an estimated glomerular filtration rate (eGFR) below 25 mL/min/1.73 m2. Methods Seven patients with CKD who received dotinurad 0.5 mg to 4 mg per day were studied retrospectively. Changes in UA, eGFR, and urine protein-to-creatinine ratio (UPCR) were analyzed. The observation period was 10.9±2.1 months. Results Serum UA levels were decreased and maintained with dotinurad administration. Nevertheless, there were no improvements noted in renal function. Additionally, no serious adverse effects were identified in any of the patients throughout the observation period. Conclusion Although the sample size in this study was small, our findings demonstrate the efficacy of dotinurad in individuals with advanced CKD who have an eGFR lower than 25 mL/min/1.73 m2.

Efficacy and Safety of Vildagliptin for Type 2 Diabetes in Patients With Diabetic Kidney Disease.

BACKGROUND/AIM: Vildagliptin is one of the dipeptidyl peptidase-4 (DPP-4) inhibitors that have been shown to improve hyperglycemia in clinical trials among patients with type 2 diabetes. However, few studies have examined the efficacy of vildagliptin in patients with diabetic kidney disease (DKD). PATIENTS AND METHODS: Eight patients with DKD received oral vildagliptin 50-100 mg/day. The duration of diabetes was 6.7±5.9 years and observation period was 23.6±9.8 months. Changes in fasting blood glucose, and hemoglobin A1c (HbA1c), estimated glomerular filtration rate (eGFR), and urine protein-to-creatinine ratio (UPCR) were studied before and after the administration of vildagliptin. RESULTS: Vildagliptin treatment significantly decreased fasting blood glucose and HbA1c, compared to baseline (132±56 mg/dl, p=0.036, 6.0±0.3, p=0.041, respectively). UPCR tended to be decreased, albeit without statistical significance. However, eGFR was decreased after the administration of vildagliptin. No significant adverse effects were observed in all patients during the study. CONCLUSION: Although the sample size was limited and the observation period was brief, vildagliptin was found to be an effective and reasonably well-tolerated treatment for patients with DKD.

Effect of finerenone on nephrotic syndrome in patients with diabetic kidney disease.

Introduction: Diabetic kidney disease (DKD) is an important complication of diabetes as it results in end-stage renal disease; hence, several drugs have been developed for its treatment. However, even with treatment with renin-angiotensin system inhibitors and sodium-glucose cotransporter-2 inhibitors, the residual risk of DKD remains. While this risk is an issue, the renoprotective effects of finerenone, a novel non-steroidal mineralocorticoid receptor antagonist, are becoming evident. High proteinuria increases the risk of cardiovascular death as well as renal failure. Hence, it is especially important to address cases of urine protein to nephrotic levels in DKD, however, no previous studies have assessed the safety and efficacy of finerenone in patients with DKD and nephrotic syndrome. Therefore, this study aimed to assess whether finerenone has a renoprotective effect in advanced DKD complicated by nephrotic syndrome. Methods: Nine patients with DKD and nephrotic syndrome who received 10-20 mg/day of finerenone were retrospectively analyzed. The average observation period was 9.7 ± 3.4 months. Patients with serum potassium levels greater than 5.0 mEq/L at the start of finelenone were excluded. Changes in urinary protein levels, estimated glomerular filtration rate (eGFR), and serum potassium levels were studied before and after finerenone administration. Results: The mean changes in the urinary protein creatinine ratio (UPCR) at baseline were 6.6 ± 2.0. After finerenone treatment, the mean UPCR decreased to -0.6 ± 3.9; however, this change was not statistically significant.The eGFR decline slope also tended to decrease with finerenone treatment (before vs. after: 3.1 ± 4.9 vs. -1.7 ± 3.2 mL/min/1.73 m2. Furthermore, finerenone did not increase serum potassium levels. Conclusions: Patients treated with finerenone showed decreased UPCR; hence, it is suggested that finerenone may be effective in treating nephrotic syndrome in patients with DKD. These findings may be applicable to real-world clinical settings. Nonetheless, it is important to note that this study was a retrospective analysis of a single-center cohort and had a limited sample size, highlighting the need for additional large-scale investigations.

Effects of Oral Semaglutide on Renal Function in Diabetic Kidney Disease: A Short-term Clinical Study.

BACKGROUND/AIM: In the SUSTAIN-6 trial, semaglutide reduced the risk of worsening nephropathy in patients with type 2 diabetes. The objective of this retrospective study was to elucidate the effect and safety of oral semaglutide (Rybelsus®) in patients with diabetic kidney disease (DKD). PATIENTS AND METHODS: Six patients with DKD received 3 mg/day semaglutide orally. The observation period was 9.0±5.0 months. Changes in estimated glomerular filtration rate (eGFR), urinary protein, fasting blood glucose, and hemoglobin A1c were studied from 6 months before the administration of oral semaglutide until 6 months after administration. RESULTS: The change in eGFR over the 6 months prior to semaglutide administration was -1.2±1.6 ml/min/1.73 m2, showing a trend for a decrease; although not statistically significant, the change at 6 months after oral semaglutide initiation showed improved eGFR (1-50.7±1.8 ml/min/1.73 m2). Proteinuria was not reduced after treatment with oral semaglutide. No significant adverse effects (including retinopathy) were observed in any patient during the study. CONCLUSION: Despite the small sample size and short observation period, oral semaglutide was found to be a relatively well-tolerated drug for patients with DKD.

Effect of Sacubitril/Valsartan on Patients Having Heart Failure With Preserved Left Ventricular Ejection Fraction Undergoing Hemodialysis: A Long-term Observational Study.

BACKGROUND/AIM: Sacubitril/valsartan (SV), a novel pharmacological class of angiotensin receptor neprilysin inhibitors, is effective in treating heart failure (HF) by inhibiting the degradation of natriuretic peptides and the renin-angiotensin-aldosterone system. However, no studies have observed the long-term effects of SV on patients with HF and preserved left ventricular ejection fraction (LVEF) undergoing hemodialysis (HD) over a long period. PATIENTS AND METHODS: This single-center retrospective study of 21 months duration involved consecutive patients with HF and preserved LVEF undergoing HD, who received 50-200 mg/day. All patients were followed up regularly, and clinical, biochemical, and echocardiographic parameters were recorded at baseline and during follow-up. The efficacy and safety of SV were also analyzed. RESULTS: This longitudinal study included nine patients, with a median age of 76 years. The median HD duration was 7 years. At baseline, the mean brain natriuretic peptide (BNP) was 133±73.6 pg/ml and that of LVEF was 66%±9%. After SV therapy, the systolic blood pressure, diastolic blood pressure, and heart rate decreased, albeit without statistical significance. BNP levels, LVEF, left atrial anteroposterior dimension, and left ventricular mass index did not change, compared to baseline values. No adverse effects were observed in any of the patients. CONCLUSION: SV tended to decrease blood pressure and heart rate in patients with HF and preserved LVEF undergoing HD but did not alter cardiac function assessments, such as BNP or echocardiography.

Glomerular VEGF resistance induced by PKCδ/SHP-1 activation and contribution to diabetic nephropathy.

This study characterizes the effect of glucose-induced activation of protein kinase Cδ (PKCδ) and Src homology-2 domain-containing phosphatase-1 (SHP-1) expression on vascular endothelial growth factor (VEGF) actions in glomerular podocytes in cultures and in glomeruli of diabetic rodents. Elevation of glucose levels induced PKCδ and p38 mitogen-activated protein kinase (p38 MAPK) to increase SHP-1 expression, increased podocyte apoptosis, and inhibited VEGF activation in podocytes and glomerular endothelial cells. The adverse effects of high glucose levels can be negated by molecular inhibitors of PKCδ, p38MAPK, and SHP-1 and only partially reduced by antioxidants and nuclear factor-κB (NF-κB) inhibitor. Increased PKCδ activation and SHP-1 expression correlated with loss of VEGF signaling and podocyte numbers in the glomeruli of diabetic rats and mice. In contrast, diabetic PKCδ-knockout (Prkcd(-/-)) mice did not exhibit activation of p38 MAPK and SHP-1 or inhibition of VEGF signaling in renal glomeruli. Functionally, diabetic Prkcd(-/-) mice had decreased expressions of TGFß, VEGF, and extracellular matrix and less albuminuria than diabetic Prkcd(+/+) mice. Hyperglycemia and diabetes can cause glomerular podocyte apoptosis and endothelial dysfunction partly due to increased PKCδ/p38 MAPK activation and the expression of SHP-1 to cause VEGF resistance, independent of NF-κB activation.

Enarodustat Treatment for Renal Anemia in Patients With Non-dialysis Chronic Kidney Disease.

BACKGROUND/AIM: Renal anemia is a major complication in patients with chronic kidney disease (CKD), leading to morbidity and mortality. Hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors (PHI), also called HIF stabilizers, increase endogenous erythropoietin production and are expected to be novel orally administrated agents for renal anemia in CKD. Enarodustat is being developed as an oral HIF-PHI. It was recently approved in Japan and clinical development is ongoing in the USA and South Korea. Therefore, there are only a few real-world data regarding treatment of renal anemia using enarodustat. This study evaluated the efficacy of enarodustat in patients with non-dialysis CKD. PATIENTS AND METHODS: Nine patients (78±11 years old, male=6, female=3) were enrolled in this study. Patients received enarodustat as first-line therapy or changed from erythropoiesis stimulating agents (2-6 mg). The observation period was 4.8±2.0 months. RESULTS: Levels of hemoglobin were effectively increased and maintained with enarodustat administration. C-reactive protein and serum ferritin were significantly decreased, but no change in renal function was observed. Furthermore, no serious adverse effects were recognized in all patients during the study. CONCLUSION: Enarodustat is an effective and relatively well-tolerated agent for the treatment of renal anemia in patients with non-dialysis CKD.

Safety and Efficacy of Imeglimin for Type 2 Diabetes in Patients Undergoing Dialysis.

BACKGROUND/AIM: Imeglimin is a novel small molecular tetrahydrotriazine that has been shown to improve hyperglycemia in clinical trials among patients with type 2 diabetes. Nevertheless, its pharmacokinetics in patients with renal dysfunction remain unclear. The objective of this study was to elucidate the safety and effects of imeglimin in patients with type 2 diabetes undergoing dialysis. PATIENTS AND METHODS: Six patients with type 2 diabetes undergoing hemodialysis (HD) or peritoneal dialysis (PD) received imeglimin 500 mg/day. The observation period was 3.3±2.3 months. RESULTS: Fasting blood glucose was significantly decreased, compared to baseline after imeglimin treatment (126.2±32.0 mg/dl, p=0.037, vs. baseline). Furthermore, levels of alanine aminotransferase were decreased (10.3±6.3 IU/l, p=0.006, vs. baseline). Glycated hemoglobin A1c and triglyceride tended to be decreased, albeit without statistical significance. Levels of total cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol, and aspartate aminotransferase were not changed compared to baseline values. CONCLUSION: Despite the small sample size, imeglimin was found to be an effective and relatively well-tolerated agent for the treatment of patients with type 2 diabetes undergoing both HD and PD. During the observation period, adverse events such as hypoglycemia, diarrhea, nausea, or vomiting were not recognized in any patient.

Role of insulin signaling and its associated signaling in glomerulus for diabetic kidney disease.

The number of patients with diabetic kidney disease (DKD) has been rising significantly over the last several decades and is one of the most frequent causes of chronic kidney disease (CKD) in the United States. Hyperglycemia accelerates development of DKD, a direct result of increased intracellular glucose availability. Two large clinical studies, the Diabetes Control and Complications Trial in type 1 diabetes and the United Kingdom Prospective Diabetes Study in type 2 diabetes showed that intensive glycemic control delayed the onset and the progression of DKD. On the other hand, it is reported that glycemic control alone is not sufficient to control DKD progression. Recent data support that insulin signaling and its associated signaling contribute significantly to preserve glomerular function. However, little is known about the key regulators of insulin signaling in glomerular component cells. In this review, we summarize the novel knowledge regarding the reno-protective effects of insulin signaling or its associated signaling in glomerular constituent cells on DKD.

IgA nephropathy after COVID-19 vaccination and analysis of reported cases.

Background: Immunoglobin A nephropathy (IgAN) is one of the most common forms of chronic glomerulonephritis and has been shown to occur in association with vaccinations. While various vaccines against COVID-19 have become widely used, their side effects, especially on IgAN following COVID-19 vaccines are still unclear. In this report, we describe the clinical courses and histopathologic findings of a newly diagnosed case of IgAN after receiving the mRNA-1273 (Moderna) COVID-19 vaccination. Methods: This study presents a case of new-onset IgAN following mRNA-1273 COVID-19 (Moderna) vaccination. In addition, we review and analyze similar cases previously reported in the literature up to October 2022. Results: Of the 52 cases reviewed, including our own, the majority of patients were female, and 64% of patients had initial onset IgAN. The most common manifestation was gross hematuria (87%), other associated symptoms were fever (44%), myalgia (8%), arthralgia (4%), and edema (4%). Many of these cases occurred after receiving Pfizer products as the second vaccination. Oral corticosteroids were used to 16 cases, and steroid pulse therapy was used to treat 7 cases. Conclusion: While this is not a controlled study, it is important for physicians to consider the possibility that COVID-19 vaccines may provoke a flare of IgAN. Several therapeutic agents may be useful for treating COVID-19 vaccine-induced IgAN, although a specific mechanism or pathophysiological association cannot be confirmed without further research.

Current findings on the efficacy of incretin-based drugs for diabetic kidney disease: A narrative review.

Diabetic kidney disease (DKD) is the most common cause of chronic kidney disease (CKD), leading end-stage renal disease. Thus, DKD is one of the most important diabetic complications. Incretin-based therapeutic agents, such as glucagon-like peptide-1 (GLP-1) receptor agonizts and dipeptidyl peptidase-4 (DPP-4) inhibitors have been reported to elicit vasotropic actions, suggesting a potential for effecting reduction in DKD. Glucose-dependent insulinotropic polypeptide (GIP) is also classified as an incretin. However, the insulin action after GIP secretion is known to be drastically reduced in patients with type 2 diabetes. Therefore, GIP has been formally considered unsuitable as a treatment for type 2 diabetes in the past. This concept is changing as it has been reported that resistance to GIP can be reversed and its effect restored with improved glycemic control. The development of novel dual- or triple- receptor agonizts that can bind to the receptors, not only for GLP-1 but also to GIP and glucagon receptors, is intended to simultaneously address several metabolic pathways including protein, lipid, and carbohydrate metabolism. These led to the development of GIP receptor agonist-based drugs for type 2 diabetes. The possibility of combined GIP/GLP-1 receptor agonist was also explored. The novel dual GIP and GLP-1 receptor agonist tirzepatide has recently been launched (Mounjaro®, Lilly). We have revealed precise mechanisms of the renoprotective effect of GLP-1 receptor agonizts or DPP-4 inhibitors, while the long-term effect of tirzepatide will need to be determined and its potential effects on kidneys should be properly tested.

Experience and Daily Burden of Patients with Chronic Kidney Disease Not Receiving Maintenance Dialysis or Renal Transplantation.

INTRODUCTION: Daily burden of patients with chronic kidney disease (CKD) who have not received maintenance dialysis or renal transplantation has not been well reported compared with patients receiving dialysis. We conducted a patient survey and an advisory board in Japan to investigate the experience and perception of CKD and its treatments from the patient's perspective. METHODS: An anonymous web survey (n = 342) was conducted in October and November 2020. Participants, who were recruited through multiple panels, aged 20 years or older, diagnosed with any stage of CKD, and who had neither received nor planned maintenance dialysis or renal transplantation were included. A questionnaire prepared under the medical advisor's guidance was used to collect the background information, burden of disease and treatments, and needs and expectations for future treatments. An advisory board with five patients nominated from a patient group was conducted in December 2020. Additional insights to interpret the results of the preceding survey were collected using pre-identified discussion topics. RESULTS: Establishing a diagnosis of CKD generally took a long time; approximately 20% of the patients waited more than 5 years before diagnosis. In daily life, patients were burdened with CKD-related symptoms (e.g., tinnitus, leg cramps) and behavioral restrictions, including diet. They also felt psychological burdens, such as concerns about possible future dialysis and/or renal transplantation, lack of awareness and understanding of disease among the other people in their lives, and financial burdens related to medical expenses. Furthermore, they felt a lack of communication in daily interactions with health care professionals and others around them, and they desired interaction with patients with CKD. CONCLUSION: Understanding the burdens and the thoughts of patients with CKD could inform discussions about the ways to improve communication with patients in daily practice, the role of the patient community, and new therapeutic options to address patients' expectations. TRIAL REGISTRATION: UMIN000042300.

Predictive significance of glomerular insulin receptor substrate-1 in patients with diabetic kidney disease.

Background: In rodents, glomerular expression of insulin receptor substrate 1 (IRS1) is decreased in diabetic kidney disease (DKD) and reduced associated functioning is involved in the development and progression of DKD. This study aimed to evaluate the significance of glomerular IRS1 expression in DKD patients, and investigated whether glomerular IRS1 expression can reflect renal pathology and predict renal outcomes. Methods: This study included 10 patients who underwent renal biopsy and were diagnosed with DKD or minor glomerular abnormality (MGA). IRS1-positive cells were determined based on renal biopsy and immunostaining, and the associations of the number of these cells with baseline and prognostic parameters were analyzed. Results: IRS1-positive cells were significantly decreased in DKD than in MGA. IRS1 positivity tended to be negatively correlated with global glomerulosclerosis and tubulointerstitial fibrosis. The rate of change in estimated glomerular filtration rate before and 12 months after renal biopsy was positively correlated to the number of IRS1-positive cells. Furthermore, a tendency towards negative correlation was observed between the number of glomerular IRS1-positive cells and the proteinuria. Conclusions: This study shows the glomerular IRS1-positive cell count was significantly decreased in DKD, and that the degree IRS1 positivity was partially correlated with renal pathology and function.

Multicentric IL-5-positive Castleman Disease With Nephrotic Syndrome Relapsed After Rituximab Treatment.

BACKGROUND/AIM: To date, no reports of interleukin (IL)-5-producing Castleman disease with nephrotic syndrome and moreover no reports of relapse after remission with rituximab treatment, have been published. CASE REPORT: A 67-year-old male presented to the Osaka Medical and Pharmaceutical University Hospital with a history of low-grade fever, papules, and nephrotic syndrome. Lymph nodes were palpated in the inguinal region. The patient showed anemia, eosinophilia, polyclonal hypergammaglobulinemia, and elevated interleukin (IL)-6 levels. Patient's serum IL-5 and IL-6 levels were measured using ELISA and immunohistochemical staining of lymph nodes was performed with antibodies specific to CD134. Histological examination confirmed diagnosis of a plasma cell variant of Castleman disease. After a total of four weekly doses of rituximab, urinary protein disappeared, and skin symptoms improved. However, one month after rituximab treatment, the skin rash worsened again, and eosinophils and IL-5 were elevated significantly. CONCLUSION: This is the first report of recurrent Castleman disease with direct evidence of increased serum IL-5. It may be reasonable to use rituximab, an anti-CD20 antibody for treating the disease, however, for IL-5-producing cases the effect of rituximab may be partial.