Effect of Nonsupplemented Low-Protein Diet on the Initiation of Renal Replacement Therapy in Stage 4 and 5 Chronic Kidney Disease: A Retrospective Multicenter Cohort Study in Japan.

OBJECTIVE: In subjects with chronic kidney disease (CKD), the effect of low-protein diet (LPD) is expected to alleviate uremic symptoms. However, whether LPD is effective in preventing loss of kidney function is controversial. The aim of this study was to evaluate the association between LPD and renal outcomes. METHODS: We conducted a multicenter cohort study of 325 patients who suffered CKD stage 4 and 5 with eGFR ≥10 mL/min/1.73 m,2 between January 2008 and December 2014. The primary diseases of the patients were chronic glomerulonephritis (47.7%), nephrosclerosis (16.9%), diabetic nephropathy (26.2%), and others (9.2%). The patients were divided into four groups, based on the mean protein intake (PI)/day, group 1 (n = 76): PI < 0.5 g/kg ideal body weight/day, group 2 (n = 56): 0.5 ≤ PI < 0.6 g/kg/day, group 3 (n = 110): 0.6 ≤ PI < 0.8 g/kg/day, group 4 (n = 83): PI ≥ 0.8 g/kg/day. Dietary supplementation with essential amino acids and ketoanalogues was not used. The outcome measure was occurrence of renal replacement therapy (RRT) (hemodialysis, peritoneal dialysis, renal transplantation (excluding preemptive transplantation)) and all-cause mortality until December 2018. Cox regression models were used to examine whether LPD was associated with the risk of outcomes. RESULTS: During a mean follow-up of 4.1 ± 2.2 years. Thirty-three patients (10.2%) died of all causes, 163 patients (50.2%) needed to start RRT, and 6 patients (1.8%) received a renal transplant. LPD therapy of 0.5 g/kg/day or less was significantly related to a lower risk of RRT and all-cause mortality [Hazard ratio = 0.656; 95% confidence interval, 0.438 to 0.984, P = .042]. CONCLUSIONS: These results suggest that non-supplemented LPD therapy of 0.5 g/kg/day or less may prolong the initiation of RRT in stage 4 and 5 CKD patients.

[A case of nephrotic syndrome during TS-1 therapy after resection of rectal cancer and liver metastasis].

We report a case of a 63-year-old Japanese man who developed nephrotic syndrome during long-term TS-1 therapy, and was successfully treated with prednisolone (PSL). At 59 years of age, he underwent low anterior resection for rectal cancer, and resection of the lateral segment of the liver for metastasis, and cholecystectomy. He received chemotherapy with intravenous infusion of fluorouracil (5-FU) 500 mg, levofolinate calcium 350 mg, and hepatic arterial infusion of 5-FU 250 mg. After 6 cycles of 5-FU therapy, TS-1 therapy was started orally at 100 mg/day for 14 days followed by 7 days of rest. Edema appeared after 2 years. Urinary protein excretion was 6.38 g/day and hematuria was observed. His serum creatinine, total protein and albumin were 0.9 mg/dL, 4.9 g/dL and 2.6 g/dL, respectively. These data pointed to nephrotic syndrome. The renal pathology revealed segmental endocapillary proliferative lesions. Postinfectious glomerulonephritis, lupus nephritis and atypical IgA nephropathy were raised for differential diagnosis based on the pathology results. However, drug-induced nephrotic syndrome was suspected from the clinical course and laboratory findings. Discontinuation of TS-1 therapy decreased urinary protein, but increased the level of serum creatinine to 1.5 mg/dL. Seven months later, steroid therapy was started at PSL 60 mg/day. Proteinuria decreased further, and the dose of PSL was tapered and stopped 22 months later. Hypofunction of the kidney persisted with serum creatinine of 1.5 mg/dL, however, urinary protein disappeared. At the onset of nephrotic syndrome, cholestatic type liver injury was observed. During steroid therapy, liver dysfunction worsened, but almost recovered with tapering of the steroid. Another case reported in the literature with the renal pathological diagnosis of nephrotic syndrome associated with TS-1 was a case of thrombotic microangiopathy (TMA). In our case, the pathologic finding was different. Furthermore steroid therapy succeeded in achieving complete remission of the nephrotic syndrome.

The human growth hormone gene contains a silencer embedded within an Alu repeat in the 3'-flanking region.

Alu family sequences are middle repetitive short interspersed elements (SINEs) dispersed throughout vertebrate genomes that can modulate gene transcription. The human (h) GH locus contains 44 complete and four partial Alu elements. An Sx Alu repeat lies in close proximity to the hGH-1 and hGH-2 genes in the 3'-flanking region. Deletion of the Sx Alu repeat in reporter constructs containing hGH-1 3'-flanking sequences increased reporter activity in transfected pituitary GC cells, suggesting this region contained a repressor element. Analysis of multiple deletion fragments from the 3'-flanking region of the hGH-1 gene revealed a strong orientation- and position-independent silencing activity mapping between nucleotides 2158 and 2572 encompassing the Sx Alu repeat. Refined mapping revealed that the silencer was a complex element comprising four discrete entities, including a core repressor domain (CRD), an antisilencer domain (ASE) that contains elements mediating the orientation-independent silencer activity, and two domains flanking the CRD/ASE that modulate silencer activity in a CRD-dependent manner. The upstream modulator domain is also required for orientation-independent silencer function. EMSA with DNA fragments representing all of the silencer domains yielded a complex pattern of DNA-protein interactions indicating that numerous GC cell nuclear proteins bind specifically to the CRD, ASE, and modulator domains. The silencer is GH promoter dependent and, in turn, its presence decreases the rate of promoter-associated histone acetylation resulting in a significant decrease of RNA polymerase II recruitment to the promoter. The silencer may provide for complex regulatory control of hGH gene expression in pituitary cells.