Masahiro Eriguchi

Long-term outcomes of idiopathic membranous nephropathy in Japanese patients treated with low-dose cyclophosphamide and prednisolone

BACKGROUND Treatment with cyclophosphamide and steroids for idiopathic membranous nephropathy (IMN) is effective in Caucasian patients, but the cumulative cyclophosphamide dosage exceeds 10 g and includes steroid pulse therapy. Adverse effects and difficulties with repeating treatment are major limitations. We studied the long-term outcomes of low-dose cyclophosphamide and prednisolone therapy in Japanese patients, who were thought to have relatively benign IMN compared with Caucasian patients. METHODS This is a prospective cohort study of 103 consecutive Japanese patients with IMN and nephrotic syndrome. Patients were treated with cyclophosphamide (50 mg/day for the first 3 months and 25 mg/day for the next 3 months) and prednisolone (30 mg/day for the first week and the dosage was gradually tapered to withdraw by 2 years). Additional therapies were allowed for initial treatment failure or relapse. RESULTS With a mean observation period of 8.5 years, 90 patients (87.4%) achieved proteinuria of <1 g/day and 78 (75.7%) achieved complete remission. A total of 27 patients did not respond to initial treatment and 30 patients had relapses after remission. Of these patients, 39 received additional therapies. At the last observation, 12 patients had developed renal insufficiency (S-Cr >1.5 mg/dL) but only 2 patients had reached renal death. Multivariate analysis revealed that the duration without remission was the strongest risk factor for renal prognosis. There were 14 deaths, and 8 patients developed cancers during the observation period. CONCLUSION Treating nephrotic IMN in Japanese patients with low-dose cyclophosphamide and prednisolone is beneficial for long-term renal prognosis with relatively few adverse effects.

Cardiorenal syndrome in chronic kidney disease

Purpose of reviewThe purpose of this study is to review current perspectives regarding the pathogenesis of cardiorenal syndrome (CRS) in chronic kidney disease (CKD), and current treatment guidelines for this condition. Recent findingsThe pathophysiological mechanisms underlying the development of CRS in CKD include neurohumoral, haemodynamic and CKD-related mechanisms. Recent evidence suggests that sympathetic nerve activity plays a role in CRS, but the SYMPLICITY HTN-3 trial failed to show a reduction of blood pressure after catheter-based renal denervation in patients with resistant hypertension. Kidney injury in patients with heart failure was previously considered to result from arterial underfilling due to low cardiac output, but the role of renal venous hypertension in this process has also recently been investigated. It would be useful to develop a reliable treatment option for CRS due to haemodynamic mechanism other than volume control using diuretics. Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone that has recently been identified as a CKD-related factor affecting CRS. FGF23 treatment has both advantages and disadvantages in terms of CRS progression. SummaryMultiple disorders underlie the development of CRS. Current treatment options include renin–angiotensin system blockade and volume control, but remain limited. A multidisciplinary approach is required to prevent CRS, including renal sympathetic denervation, treatment of renal venous hypertension and FGF23 treatment.

Renal denervation has blood pressure–independent protective effects on kidney and heart in a rat model of chronic kidney disease

We elucidate the underlying mechanisms of bidirectional cardiorenal interaction, focusing on the sympathetic nerve driving disruption of the local renin-angiotensin system (RAS). A rat model of N(ω)-nitro-L-arginine methyl ester (L-NAME; a nitric oxide synthase inhibitor) administration was used to induce damage in the heart and kidney, similar to cardiorenal syndrome. L-NAME induced sympathetic nerve-RAS overactivity and cardiorenal injury accompanied by local RAS elevations. These were suppressed by bilateral renal denervation, but not by hydralazine treatment, despite the blood pressure being kept the same between the two groups. Although L-NAME induced angiotensinogen (AGT) protein augmentation in both organs, AGT mRNA decreased in the kidney and increased in the heart in a contradictory manner. Immunostaining for AGT suggested that renal denervation suppressed AGT onsite generation from activated resident macrophages of the heart and circulating AGT excretion from glomeruli of the kidney. We also examined rats treated with L-NAME plus unilateral denervation to confirm direct sympathetic regulation of intrarenal RAS. The levels of urinary AGT and renal angiotensin II content and the degrees of renal injury from denervated kidneys were less than those from contralateral innervated kidneys within the same rats. Thus, renal denervation has blood pressure-independent beneficial effects associated with local RAS inhibition.

Spironolactone ameliorates arterial medial calcification in uremic rats: the role of mineralocorticoid receptor signaling in vascular calcification

Vascular calcification (VC) is a critical complication in patients with chronic kidney disease (CKD). The effects of spironolactone (SPL), a mineralocorticoid receptor (MR) antagonist, on VC have not been fully investigated in CKD. The present in vivo study determined the protective effects of SPL on VC in CKD rats. Rats were divided into a control group and four groups of rats with adenine-induced CKD. Three groups were treated with 0, 50, and 100 mg·kg(-1)·day(-1) SPL for 8 wk, and one group was treated with 100 mg·kg(-1)·day(-1) SPL for the last 2 wk of the 8-wk treatment period. After 8 wk, CKD rats developed azotemia and hyperphosphatemia, with increases in the expression of serum and glucocorticoid-regulated kinase-1 and sodium-phosphate cotransporter, in inflammation and oxidative stress level, in osteogenic signaling and apoptosis, and in aortic calcification, compared with control rats. SPL dose dependently decreased these changes in the aortas, concomitant with improvements in renal inflammation, tubulointerstitial nephritis, and kidney function. SPL neither lowered blood pressure level nor induced hyperkalemia. Treatment of CKD rats for the last 2 wk with 100 mg·kg(-1)·day(-1) SPL attenuated VC compared with CKD rats with the same degree of kidney function and hyperphosphatemia. In conclusion, SPL dose dependently inhibits the progression of VC by suppressing MR signaling, local inflammation, osteogenic transition, and apoptosis in the aortas of CKD rats.

Improvement in spatial memory dysfunction by telmisartan through reduction of brain angiotensin II and oxidative stress in experimental uremic mice.

AIMS We previously reported that chronic uremia induces spatial working memory dysfunction in mice, and that it is attributed to cerebral oxidative stress. The source of oxidative stress was considered to be uremic toxins, but this remains unclear. In the present study, we examined whether the brain renin-angiotensin system was activated in the CKD mouse model, and whether it contributed to cognitive impairment. MAIN METHODS CKD was induced in 8-week-old male mice by 5/6 nephrectomy. Mice were divided into four groups: control mice administered tap water (Cont-V), control mice treated with 0.5mg/kg/day telmisartan, an angiotensin II (AII) receptor blocker, for 8 weeks (Cont-T), CKD mice administered tap water (CKD-V), and CKD mice treated with 0.5 mg/kg/day telmisartan for 8 weeks (CKD-T). After the treatment period, a radial arm water maze (RAWM) test was performed, and angiotensin II (AII) concentrations and markers of oxidative stress were measured in the brains of mice. KEY FINDINGS Errors in the RAWM test were more frequent in the CKD-V group than in the Cont-V group. In addition, errors in the CKD-T group were comparable to control mice. Tissue brain AII concentrations were greater in the CKD-V group compared with the other groups. Oxidative DNA damage and lipid peroxidation in the brain were also greater in the CKD-V group compared with the other groups. SIGNIFICANCE Our results suggest that brain AII levels were exaggerated in CKD mice, and that this contributes to cognitive impairment through oxidative stress.

The clinical utility of serum tartrate‐resistant acid phosphatase 5b in the assessment of bone resorption in patients on peritoneal dialysis

Serum tartrate‐resistant acid phosphatase 5b (TRACP5b) is a bone resorption marker used in the assessment of bone metabolic status. The present study was designed to determine the clinical characteristics and utility of measuring serum TRACP5b levels in peritoneal dialysis (PD) patients.

Relationship Between Residual Renal Function and Serum Fibroblast Growth Factor 23 in Patients on Peritoneal Dialysis

Fibroblast growth factor 23 (FGF23) levels in dialysis patients are influenced by various factors, including phosphorus load. However, the clinical parameters that determine serum FGF23 levels in patients on peritoneal dialysis (PD) remain unclear. The aim of the present study was to examine the effects of clinical factors, on serum FGF23 levels, with an emphasis on residual renal function (RRF). This cross‐sectional study included 56 outpatients undergoing PD therapy. Urine volume ≥100 mL/day or renal creatinine (Cr) clearance was used as a surrogate marker for RRF. Clinical characteristics were compared between patients with and without RRF. Linear regression analysis was conducted with serum FGF23 level as the dependent variable and renal Cr clearance as the main independent variable. The median and interquartile range of serum FGF23 levels were 5970 (1451–11 688) pg/mL. Patients with RRF showed higher urinary and total phosphate eliminations, and lower serum FGF23 and phosphate levels than patients without RRF. Multivariate linear regression analysis showed that the renal Cr clearance and serum phosphate and dialysis history were negatively associated with serum FGF23 levels, even after adjusting for potential confounders including peritoneal Cr clearance. Further, the predictabilities of serum FGF23 were comparable among renal Cr clearance, Kt/V for urea, and renal phosphate clearance. RRF determined by renal Cr clearance or residual urine volume is an independent negative determinant of serum FGF23 levels in PD patients.

Remitting seronegative symmetrical synovitis with pitting edema syndrome in a chronic hemodialysis patient.

A 75-year-old male who was undergoing chronic hemodialysis developed abrupt-onset pitting edema and pain in the dorsum of both hands and feet. Biochemical analysis disclosed increased C-reactive protein, and negative rheumatoid factor and antinuclear antibody. Radiological examination showed no bony erosion. Computed tomography and gallium scintigraphy revealed no active infection or neoplasms. The clinical diagnosis was remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome. The pitting edema and inflammatory response quickly subsided after low-dose prednisolone therapy. This case demonstrates that RS3PE syndrome could be a differential diagnosis in elderly patients undergoing dialysis who develop pitting edema and joint pain.

Vascular endothelial growth factor-C ameliorates renal interstitial fibrosis through lymphangiogenesis in mouse unilateral ureteral obstruction

Renal fibrosis is the final common pathway of chronic kidney diseases. Lymphatic vessel (LV) proliferation is found in human renal diseases and other fibrotic diseases, suggesting that lymphangiogenesis is associated with the progression or suppression of kidney diseases. However, the purpose of LV proliferation is not completely understood. We investigated the effect of vascular endothelial growth factor (VEGF)-C on lymphangiogenesis, inflammation, and fibrosis in the mouse kidney using the unilateral ureteral obstruction (UUO) model. In UUO mice, significant proliferation of LVs was accompanied by tubulointerstitial nephritis and fibrosis. We continuously administered recombinant human VEGF-C to UUO model mice using an osmotic pump (UUO+VEGF-C group). Lymphangiogenesis was significantly induced in the UUO+VEGF-C group compared with the vehicle group, despite similar numbers of capillaries in both groups. The number of infiltrating macrophages, and levels of inflammatory cytokines and transforming growth factor-β1 were reduced in the UUO+VEGF-C group compared with the vehicle group. Renal fibrosis was consequently attenuated in the UUO+VEGF-C group. In cultured lymphatic endothelial cells, administration of VEGF-C increased the activity and proliferation of lymphatic endothelial cells (LECs) and expression of adhesion molecules such as vascular cell adhesion molecule-1. These findings suggest that induction of lymphangiogenesis ameliorates inflammation and fibrosis in the renal interstitium. Enhancement of the VEGF-C signaling pathway in LECs may be a therapeutic strategy for renal fibrosis.

Assessment of urinary angiotensinogen as a marker of podocyte injury in proteinuric nephropathies

Urinary protein (UP) is widely used as a clinical marker for podocyte injury; however, not all proteinuric nephropathies fit this model. We previously described the elevation of urinary angiotensinogen (AGT) accompanied by AGT expression by injured podocytes in a nitric oxide inhibition rat model (Eriguchi M, Tsuruya K, Haruyama N, Yamada S, Tanaka S, Suehiro T, Noguchi H, Masutani K, Torisu K, Kitazono T. Kidney Int 87: 116-127, 2015). In this report, we performed the human and animal studies to examine the significance and origin of urinary AGT. In the human study, focal segmental glomerulosclerosis (FSGS) patients presented with higher levels of urinary AGT, corrected by UP, than minimal-change disease (MCD) patients. Furthermore, AGT was evident in podocin-negative glomerular segmental lesions. We also tested two different nephrotic models induced by puromycin aminonucleoside in Wistar rats. The urinary AGT/UP ratio and AGT protein and mRNA expression in sieved glomeruli from FSGS rats were significantly higher than in MCD rats. The presence of AGT at injured podocytes in FSGS rats was detected by immunohistochemistry and immunoelectron microscopy. Finally, we observed the renal tissue and urinary metabolism of exogenous injected human recombinant AGT (which is not cleaved by rodent renin) in FSGS and control rats. Significant amounts of human AGT were detected in the urine of FSGS rats, but not of control rats. Immunostaining for rat and human AGT identified that only rat AGT was detected in injured podocytes, and filtered human AGT was seen in superficial proximal tubules, but not in injured podocytes, suggesting AGT generation by injured podocytes. In conclusion, the urinary AGT/UP ratio represents a novel specific marker of podocyte injury.