Expression pattern of Runt-related transcription factor (RUNX) family members and the role of RUNX1 during kidney development.

Runt-related transcription factor (RUNX) family members play critical roles in the development of multiple organs. Mammalian RUNX family members, consisting of RUNX1, RUNX2, and RUNX3, have distinct tissue-specific expression and function. In this study, we examined the spatiotemporal expression patterns of RUNX family members in developing kidneys and analyzed the role of RUNX1 during kidney development. In the developing mouse kidney, RUNX1 protein was strongly expressed in the ureteric bud (UB) tip and weakly expressed in the distal segment of the renal vesicle (RV), comma-shaped body (CSB), and S-shaped body (SSB). In contrast, RUNX2 protein was restricted to the stroma, and RUNX3 protein was only expressed in immune cells. We also analyzed the expression of RUNX family members in the cynomolgus monkey kidney. We found that expression patterns of RUNX2 and RUNX3 were conserved between rodents and primates, whereas RUNX1 was only expressed in the UB tip, not in the RV, CSB, or SSB of cynomolgus monkeys, suggesting a species differences. We further evaluated the roles of RUNX1 using two different conditional knockout mice: Runx1f/f:HoxB7-Cre and Runx1f/f:R26-CreERT2 and found no abnormalities in the kidney. Our findings showed that RUNX1, which is mainly expressed in the UB tip, is not essential for kidney development.

Aging-Related Kidney Diseases.

Clinical Background: Older age has been associated with higher prevalence and progression of chronic kidney disease (CKD). The presence of CKD leads to an increased risk of end-stage renal disease, cardiovascular diseases, and death. Epidemiology: Progressive aging of the population is accompanied by an increase in the prevalence of CKD worldwide. The high prevalence of CKD in the aged population would result in a considerably greater social burden. Challenges: Structural and functional changes are often observed in the aged kidney. The main pathological feature of the aged kidney is nephrosclerosis such as arteriosclerosis, glomerulosclerosis, tubular atrophy, and interstitial fibrosis. As a consequence of renal aging, the nephron number decreases. A lower nephron number approximately parallels with the decline in glomerular filtration rate (GFR), and GFR declines with aging. Recent studies have highlighted several pathological mechanisms involved in renal aging, that can serve as targets for intervention. Decreased renal oxygen levels, mitochondrial dysfunction, and inflammation drive renal fibrosis, one of the hallmarks of renal aging. Prevention and Treatment: Novel therapeutic approaches that target these functional changes are now being developed to prevent an aging-associated inevitable loss of renal function. For example, calorie restriction, Sirtuin 1 activator and peroxisome proliferator-activated receptor-γ agonists have the potential to ameliorate renal deterioration. This chapter provides an overview of the aged kidney and summarizes the current knowledge on therapeutic strategies to attenuate renal aging.

Myofibroblasts acquire retinoic acid-producing ability during fibroblast-to-myofibroblast transition following kidney injury.

Tubular injury and interstitial fibrosis are the hallmarks of chronic kidney disease. While recent studies have verified that proximal tubular injury triggers interstitial fibrosis, the impact of fibrosis on tubular injury and regeneration remains poorly understood. We generated a novel mouse model expressing diphtheria toxin receptor on renal fibroblasts to allow for the selective disruption of renal fibroblast function. Administration of diphtheria toxin induced upregulation of the tubular injury marker Ngal and caused tubular proliferation in healthy kidneys, whereas administration of diphtheria toxin attenuated tubular regeneration in fibrotic kidneys. Microarray analysis revealed down-regulation of the retinol biosynthesis pathway in diphtheria toxin-treated kidneys. Healthy proximal tubules expressed retinaldehyde dehydrogenase 2 (RALDH2), a rate-limiting enzyme in retinoic acid biosynthesis. After injury, proximal tubules lost RALDH2 expression, whereas renal fibroblasts acquired strong expression of RALDH2 during the transition to myofibroblasts in several models of kidney injury. The retinoic acid receptor (RAR) RARγ was expressed in proximal tubules both with and without injury, and αB-crystallin, the product of an RAR target gene, was strongly expressed in proximal tubules after injury. Furthermore, BMS493, an inverse agonist of RARs, significantly attenuated tubular proliferation in vitro. In human biopsy tissue from patients with IgA nephropathy, detection of RALDH2 in the interstitium correlated with older age and lower kidney function. These results suggest a role of retinoic acid signaling and cross-talk between fibroblasts and tubular epithelial cells during tubular injury and regeneration, and may suggest a beneficial effect of fibrosis in the early response to injury.

Onco-nephrology: current concepts and future perspectives.

Onco-nephrology is a new and evolving subspecialized area in nephrology that deals with kidney diseases in cancer patients. As many newer cancer therapies emerge in the field of oncology, cancer patients are surviving longer than ever before. However, the benefits of the remarkable advances in cancer management have not been fully appreciated. Not only is cancer often associated with abnormalities that affect the kidney, but cancer therapy often leads to both acute and chronic kidney diseases. The development of cancer-associated kidney complications is associated with poor prognosis, whereas prompt recognition and treatment initiation are associated with improved outcomes in this population. Therefore, both nephrologists and oncologists should be familiar with the diagnosis and management of cancer-associated kidney complications. Another unique aspect of onco-nephrology is that significant improvements in predialysis and dialysis care in recent years have led to prolonged survival and a higher incidence of patients with chronic kidney disease suffering from cancer. Therefore, research is urgently needed to establish treatment for patients with chronic kidney disease. This update addresses the pathophysiology and treatment of various cancer-associated kidney complications, and highlights cancer treatment for patients with chronic kidney disease.

Nephrotic range proteinuria as a strong risk factor for rapid renal function decline during pre-dialysis phase in type 2 diabetic patients with severely impaired renal function.

BACKGROUND: Proteinuria is an established risk factor for progression of renal disease, including diabetic nephropathy. The predictive power of proteinuria, especially nephrotic range proteinuria, for progressive renal deterioration has been well demonstrated in diabetic patients with normal to relatively preserved renal function. However, little is known about the relationship between severity of proteinuria and renal outcome in pre-dialysis diabetic patients with severely impaired renal function. METHODS: 125 incident dialysis patients with type 2 diabetes were identified. This study was aimed at retrospectively evaluating the impact of nephrotic range proteinuria (urinary protein-creatinine ratio above 3.5 g/gCr) on renal function decline during the 3 months just prior to dialysis initiation. RESULTS: In total, 103 patients (82.4 %) had nephrotic range proteinuria. The median rate of decline in estimated glomerular filtration rate (eGFR) in this study population was 0.98 (interquartile range 0.51-1.46) ml/min/1.73 m(2) per month. Compared to patients without nephrotic range proteinuria, patients with nephrotic range proteinuria showed significantly faster renal function decline (0.46 [0.24-1.25] versus 1.07 [0.64-1.54] ml/min/1.73 m(2) per month; p = 0.007). After adjusting for gender, age, systolic blood pressure, serum albumin, calcium-phosphorus product, hemoglobin A1c, and use of an angiotensin-converting enzyme inhibitor or an angiotensin II receptor blocker, patients with nephrotic range proteinuria showed a 3.89-fold (95 % CI 1.08-14.5) increased risk for rapid renal function decline defined as a decline in eGFR ≥0.5 ml/min/1.73 m(2) per month. CONCLUSION: Nephrotic range proteinuria is the predominant renal risk factor in type 2 diabetic patients with severely impaired renal function receiving pre-dialysis care.

Prognostic implications of anemia with or without chronic kidney disease in patients undergoing elective percutaneous coronary intervention.

BACKGROUND: Little is known about the prognostic implications of anemia in patients undergoing elective percutaneous coronary intervention (PCI), especially when they have coexisting chronic kidney disease (CKD). METHODS: We identified 7299 patients who underwent elective PCI from the CREDO-Kyoto registry cohort-2. The primary outcome was 3-year major adverse cardiac events (MACE); composite of all cause death, heart failure hospitalization, and myocardial infarction. RESULTS: In total, 1466 patients (20.0%) had mild anemia (hemoglobin=11.0-11.9 g/dL for women and 11.0-12.9 g/dL for men), and 740 patients (10.1%) had moderate-to-severe anemia (hemoglobin<11.0 g/dL both for women and for men). Compared to the no-anemia group, cumulative incidence of MACE was significantly higher in the mild and moderate-to-severe anemia groups (7.9%, 20.1%, and 34.2%, respectively). The adjusted hazard ratios of mild and moderate-to-severe anemia versus no-anemia for MACE were 1.77 (95% confidence interval: 1.47-2.15) and 2.53 (95% confidence interval: 2.03-3.14), respectively. In a subgroup analysis, significantly higher risk for MACE was consistently observed with mild and moderate-to-severe anemia both in patients with and without CKD. The risk for MACE showed an accretive increment with exacerbation in either the renal function or anemia (interaction p<0.001). CONCLUSIONS: Even mild anemia was associated with significantly worse 3-year clinical outcomes in patients who underwent elective PCI. Coexisting CKD additively increased the risk for MACE in these patients.

A case of Behçet's disease developing after poststreptococcal acute glomerulonephritis.

We report a case of a 73-year-old Japanese male patient who developed Behçet's disease (BD) after poststreptococcal acute glomerulonephritis. Three months after the initial presentation, acneiform eruption and oral and genital ulcers appeared. Treatment with oral prednisolone (20 mg/day) resulted in the remarkable disappearance of these symptoms. These findings support the hypothesis that Streptococcus pyogenes may be an etiologic factor of BD.