Association Between Kidney Function Decline and Baseline TNFR Levels or Change Ratio in TNFR by Febuxostat Chiefly in Non-diabetic CKD Patients With Asymptomatic Hyperuricemia.

Background: The levels of circulating tumor necrosis factor receptor (TNFR) 1 and 2 help predict the future decline of estimated glomerular filtration rate (eGFR) chiefly in patients with diabetes. It has been recently reported that the change ratio in TNFR1 by SGLT2 inhibitor treatment is also related with future GFR decline in patients with diabetes. The aims of this study are to investigate the association between baseline TNFR levels and early change in TNFR levels by the non-purine selective xanthine oxidase inhibitor, febuxostat, and future eGFR decline chiefly in chronic kidney disease (CKD) patients without diabetes. Methods: We conducted a post-hoc analysis of the FEATHER study on patients with asymptomatic hyperuricemia and CKD stage 3, who were randomly assigned febuxostat 40 mg/day or matched placebo. This analysis included 426 patients in whom baseline stored samples were available. Serum TNFR levels at baseline were measured using enzyme-linked immunosorbent assay. Those levels were also measured using 12-week stored samples from 197 randomly selected patients. Results: Compared with placebo, short-term febuxostat treatment significantly decreased the median percent change from baseline in serum uric acid (-45.05, 95% CI -48.90 to -41.24 mg/dL), TNFR1 (1.10, 95% CI-2.25 to 4.40), and TNFR2 (1.66, 95% CI -1.72 to 4.93), but not TNFR levels. Over a median follow-up of 105 weeks, 30 patients (7.0%) experienced 30% eGFR decline from baseline. In the Cox multivariate model, high levels of baseline TNFR predicted a 30% eGFR decline, even after adjusting for age, sex, systolic blood pressure, high sensitivity C-reactive protein, uric acid, and presence or absence of febuxostat treatment and diabetes, in addition to baseline albumin to creatinine ratio and eGFR. Conclusion: Early change in circulating TNFR levels failed to predict future eGFR decline; however, regardless of febuxostat treatment, the elevated baseline level of TNFR was a strong predictor of 30% eGFR decline even in chiefly non-diabetic CKD patients with asymptomatic hyperuricemia.

Reduction of proteinuria by therapeutic intervention improves the renal outcome of elderly patients with IgA nephropathy.

BACKGROUND: The number of elderly patients with IgA nephropathy (IgAN) is increasing in parallel with the increased longevity in the general population. However, information is limited regarding the characteristics of such patients. METHODS: IgAN patients who were ≥60 years of age at diagnosis were retrospectively analyzed. The clinicopathological features at biopsy, therapies during the follow-up period, renal outcomes and extrarenal complications were evaluated. RESULTS: The characteristics of a total of 87 patients were as follows (mean values): 65 years of age, an eGFR of 47 mL/min/1.73 m2, and urinary protein excretion (UPE) of 1.9 g/day. In the initial 1-year follow-up period, UPE decreased from 2.4 to 0.4 g/day in patients treated with corticosteroids and 1.4 to 0.8 g/day in patients treated with conservative therapies, including renin-angiotensin system blockade. During the observation period, 26 % of the patients who received corticosteroids and 38 % of the patients treated with conservative therapies showed a ≥30 % decrease in their eGFR or reached end-stage renal disease. In the analysis of all patients, UPE at 1 year after the diagnosis was identified to be an independent predictor of the subsequent loss of renal function. However, neither corticosteroid therapy nor conservative therapies was identified to be an independent valuable. There was no significant difference in the incidence of the extrarenal complications between patients treated with corticosteroids and those with conservative therapies. CONCLUSION: In elderly IgAN patients, the reduction of proteinuria by therapeutic interventions may lead to better renal outcomes without causing severe extrarenal complications.

Gout and hyperuricemia in Japan: perspectives for international research on purines and pyrimidines in man.

One of the best-known disorders in purine metabolism is accumulation of uric acid leading to gout. Gout is a lifestyle disease, which was nicely illustrated in the joint symposium of the Japanese Society of Gout and Nucleic Acid Metabolism and of the Purine and Pyrimidine Society held in February 2011 in Tokyo, Japan. The westernization of the Japanese diet led to an increase in hyperuricemia in Japanese, which subsequently boosted research in this field, as illustrated in this symposium. As a consequence, Japanese nucleotide research also expanded, leading to the development of not only new drugs for treatment of gout, but also for other diseases such as cancer, viral infections, and cardiovascular diseases. The research on inborn errors led to the identification of various genetic polymorphisms affecting drug metabolism, revealing differences between Asians and non-Asians. Such genetic differences may also affect the enzymatic properties of an enzyme or a transporter, necessitating specific inhibitors. This knowledge will help to introduce personalization of treatment. In this symposium, the interaction between various specialties formed an excellent basis for translational research between these specialties but also from the bench to the clinic.

A case of slowly progressive scleroderma kidney.

A rapidly progressive renal deterioration accompanied by acute-onset/uncontrolled hypertension characterizes scleroderma renal crisis (SRC), a life-threatening complication that occurs in patients with systemic sclerosis (SSc). To date, however, SSc with advanced renal failure has only rarely been reported in the absence of SRC. We report here an atypical case of diffuse cutaneous SSc where renal insufficiency progressed slowly to end-stage renal failure over a 14-year follow-up period after the diagnosis of SSc. In the renal biopsy, which was obtained at a relatively early stage of renal impairment, we found histological findings consistent with those of scleroderma kidneys. Unlike typical SRC, however, the larger renal arteries seemed to be unaffected. These histological findings were probably responsible for the "slowly progressive" renal impairment over the years without causing typical SRC.

Effect of fenofibrate on uric acid metabolism and urate transporter 1.

OBJECTIVE: To examine the effects of fenofibrate, an antilipotropic drug, on uric acid metabolism in healthy male subjects and on urate transporter 1 (URAT1). METHODS: Fenofibrate was administered to nine male volunteers at a dose of 300 mg (corresponding to 200 mg of micronized fenofibrate), and the metabolic parameters of uric acid were investigated for more than 12 hours. In addition, the effect of fenofibrate on URAT1-expressing cells was examined. RESULTS: After the administration of fenofibrate, the concentration of serum uric acid had significantly decreased from 5.8+/-0.4 mg/dL to 4.3+/-0.3 mg/dL at 10 h. Uric acid clearance and the fractional excretion of uric acid increased. Fenofibric acid, a fenofibrate metabolite, inhibited URAT1 to an extent similar to that observed with benzbromarone and losartan. CONCLUSION: Fenofibrate decreased serum uric acid levels by increasing its urinary excretion, most likely through the inhibition of URAT1 by fenofibric acid, its major metabolite.

[Measures against hyperuricemia].

It is suggested that hyperuricemia has a pathogenetical role in the onset and progression of hypertension and renal disease in both clinical studies and animal experiments. The treatment of hyperuricemia by allopurinol was reported to cause improvement of hypertension and renal function, and the withdrawal of allopurinol treatment was also reported to bring worsening of hypertension and acceleration of the rate of loss of renal function in the patients with chronic kidney disease (CKD). However, the necessity of treatment against hyperuricemia in CKD has to be warranted by large scale clinical experiments in the future.

[Usefulness of combination treatment using allopurinol and benzbromarone for gout and hyperuricemia accompanying renal dysfunction: kinetic analysis of oxypurinol].

A study was conducted to determine whether combination treatment using allopurinol and benzbromarone was more useful than single allopurinol treatment for the gout and hyperuricemia accompanying renal dysfunction. The subjects were 45 male patients who received urate-lowering treatment and showed a stable serum urate level. The patients were divided into four groups according to the urate-lowering treatment and creatinine clearance (Ccr) (A group: single treatment, normofunction, B group: single treatment, hypofunction, C group: combined treatment, normofunction, D group: combined treatment, hypofunction). There were no differences in serum urate levels among the four groups. Urate clearance (CUA)and daily urinary urate excretion (UUAV) showed significantly high values in the C group, but no difference was seen in the fractional excretion of urate (FEUA) among the four groups. The dosage of allopurinol in the D group was significantly lower than in the A and B groups. Serum oxypurinol concentration in the C group was lower than that in the B group. Oxypurinol clearance (C oxypurinol) in the C group was significantly high compared with the B and D groups. There was a close correlation between C oxypurinol, Ccr, and CUA, with an especially strong correlation between C oxypurinol and CUA. There were no differences in the serum concentration and clearance of xanthine and hypoxanthine among the four groups. Results of the study suggested that combination treatment using allopurinol and benzbromarone for the gout and hyperuricemia accompanying renal dysfunction is more useful, because a lower dose of allopurinol can be used and the serum oxypurinol concentration is reduced compared with single allopurinol treatment.

[Uricosuric agent].

Urate lowering treatment is indicated in patients with recurrent acute attacks, tophi, gouty arthropathy, radiographic changes of gout, multiple joint involvement, or associated uric acid nephrolithiasis. Uricosuric agents like benzbromarone and probenecid are very useful to treat hyperuricemia as well as allopurinol (xanthine oxidase inhibitor). Uricosuric agents act the urate lowering effect through blocking the URAT1, an urate transporter, in brush border of renal proximal tubular cells. In order to avoid the nephrotoxicity and urolithiasis due to increasing of urinary urate excretion by using uricosuric agents, the proper urinary tract management (enough urine volume and correction of aciduria) should be performed.

[Drug induced nephrotic syndrome].

This review summarizes drug induced nephrotic syndrome. Major drugs which induce drug related nephrotoxicity are antibiotics, NSAID, radiocontrast media, anticancer drug and antirheumatic drug. Drug induced nephropathy can show various forms of renal diseases. The nephropathy consists of acute tubular necrosis, acute tubulointerstitial nephritis, pre-renal type renal failure, obstructive renal failure, chronic tubulointerstitial nephritis and glomerular damage. Major drugs which induce nephrotic syndrome and glomerular damage are gold, penicillamine, bucillamine and NSAID. In the nephrotic syndrome due to these drugs, the major type of renal disease is the membranous glomerulonephritis and the nephropathy resolves completely when the drug is withdrawn; renal function does not deteriorate, and corticosteroids are unnecessary.