Exploring molecular targets in diabetic kidney disease.

Diabetic kidney disease is the leading cause of end-stage kidney disease, and it remains a major challenge. Many factors, such as glomerular hyperfiltration, oxidative stress, inflammation, hypoxia, and epigenetics, are associated with the progression of diabetic kidney disease; however, the whole mechanism is not yet completely understood. No specific treatment for diabetic kidney disease has been established, so new approaches are being explored extensively. Sodium-glucose cotransporter 2 inhibitors have shown renoprotective effects in several human clinical trials. Glucagon-like peptide 1 receptor agonists and mineralocorticoid receptor antagonists have been reported to be effective in diabetic kidney disease, and novel therapeutic candidates are also being examined. In the TSUBAKI trial, a nuclear factor erythroid 2-related factor 2 activator, bardoxolone methyl, improved the glomerular filtration rate of diabetic kidney disease patients. Similarly, new agents that act in the oxidative stress and inflammation pathways are of major interest, such as pentoxifylline, apoptosis signal-regulating kinase-1 inhibitors, C-C chemokine receptor 2 inhibitors, and Janus kinase-1/2 inhibitors. Endothelin-1 receptor A antagonists and soluble guanylate cyclase stimulators are also expected to affect renal hemodynamics. Some preclinical studies suggest that hypoxia-inducible factor prolyl hydroxylase inhibitors, which influence multiple inflammations and oxidative stress pathways, reduce albuminuria in diabetic kidney disease. Advanced glycation end-product inhibitors and treatments related to epigenetics have also shown promise as potential diabetic kidney disease treatments in preclinical studies. The discovery of new targets could provide new therapeutic options for overcoming diabetic kidney disease.

[Renal anemia and hypoxia-inducible factor prolyl hydroxylase inhibitor].

Anemia is a significant complication of chronic kidney disease (CKD), caused by erythropoietin deficiency and reduced iron availability. Erythropoiesis-stimulating agents have been used with iron supplementation to treat anemia; however, they are associated with some problems. Hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) is a promising new class of oral therapy for the treatment of anemia associated with CKD. HIF-PHI inhibits HIF-prolyl hydroxylase enzymes and results in the HIF-α accumulation, which leads to increased expression of HIF-responsive genes, including erythropoietin and vascular endothelial growth factor (VEGF). HIF stimulates endogenous erythropoietin production and also reduces circulating hepcidin concentrations, resulting in improved anemia. Many clinical trials demonstrate that HIF-PHI improves anemia in patients with CKD and on dialysis. In addition to treating anemia, HIF-PHI may have multiple potential effects. Several animal experiments show that HIF-PHI protects against ischemic kidney damage that progresses to CKD and also improves metabolic disorders and ameliorates cardiovascular complications. In contrast, malignant tumor and retinopathy should be carefully evaluated due to theoretical concerns that HIF stabilization may result in increased VEGF protein expression. Some adverse events such as shunt occlusion reported in large clinical trials also need attention and warrant further investigations.

IL-6-producing Renal Cell Carcinoma Causing Renal and Endocrine Paraneoplastic Syndromes.

An 83-year-old man with stable chronic kidney disease (CKD) exhibited a sudden increase in urinary N-acetyl-ß-D-glucosaminidase and protein excretion, suggesting aggravated kidney damage. Simultaneously, he lost diabetic control, requiring up to 54 units of insulin daily. A detailed examination revealed the presence of renal cell carcinoma, which was surgically resected and confirmed to be interleukin-6-positive by immunohistochemistry. Postoperatively, his uni-nephrectomy necessitated hemodialysis, but the patient's insulin resistance was ameliorated; no medication was required to control diabetes, suggesting that the tumor had caused the insulin resistance. This report describes a case of a tumor secreting interleukin-6, which affects both the control of diabetes and CKD progression.

Atypical cause of intractable diarrhea in a hemodialysis patient, masked by Clostridium difficile-associated diarrhea and ischemic colitis: a case report.

BACKGROUND: Patients with end-stage kidney disease (ESKD) most commonly complain of gastrointestinal symptoms, such as diarrhea. Diarrhea negatively affects patient quality of life and has miscellaneous etiologies, such as Clostridium difficile-associated diarrhea (CDAD) and ischemic colitis. However, it is sometimes extremely difficult to determine the true etiology given the comorbidities and complications the patients have. A rare cause of diarrhea is ulcerative colitis (UC), which commonly affects the rectum and proximal colon in a continuous fashion. UC with rectal sparing or segmental distribution, although atypical, sometimes leads to misdiagnosis. Herein, we present a case of UC in a patient on hemodialysis with intractable diarrhea; we initially considered that the diarrhea was caused by CDAD and ischemic colitis. CASE PRESENTATION: A 69-year-old man with a history of hypertension, bilateral thalamic hemorrhage, and decreased kidney function was admitted to our hospital because of congestive heart failure. Volume control was impossible due to renal dysfunction and he was started on hemodialysis. Thereafter, he received various antibiotics for bacterial infections. Simultaneously, he experienced continuous watery, and sometimes bloody, diarrhea, which was diagnosed as CDAD owing to a positive stool test for Clostridium difficile toxins. Antibiotic treatment for CDAD did not result in symptom relief. Subsequently, we performed colon biopsy via colonoscopy, and the pathology showed virtually no inflammation with rectal sparing and segmental distributions. These findings favored the presence of ischemic colitis due to arteriosclerosis and ESKD rather than infections. He died of cardiac arrest before the diarrhea was alleviated. Finally, UC was revealed on autopsy as the main cause of the uncontrollable diarrhea. CONCLUSIONS: Patients with ESKD have a greater risk of developing CDAD and ischemic colitis, which have clinical features that sometimes overlap with those of UC, as in the present case. This case emphasizes the importance of correctly diagnosing the etiology of intractable diarrhea and the fact that other diarrhea etiologies can obscure the existence of inflammatory bowel disease, which should be considered and treated properly when patients on hemodialysis present with intractable diarrhea.