Iwao Ohno

SERUM URIC ACID AND RENAL PROGNOSIS IN PATIENTS WITH IGA NEPHROPATHY

Background/Aims: This study was designed to elucidate the clinical significance of serum uric acid (SUA) and the relationship between hyperuricemia and renal prognosis in IgA nepropathy. Methods: The correlation between SUA and other clinical parameters were examined in 748 IgA nephropathy patients (432 males and 316 females). Among these patients, 226 (144 males and 82 females) who were followed for more than 5 years were examined for the relationship between hyperuricemia and renal prognosis. Results: In IgA nephropathy, SUA correlated negatively with creatinine clearance (Ccr), and positively with urinary protein and tubulointerstitial damage. SUA was higher in patients with hypertension or diffuse proliferative glomerulonephritis. Hyperuricemia was a risk factor for renal prognosis, both in terms of serum creatinine (p = 0.0025) and Ccr (p = 0.0057). In 56 patients with normal Ccr at renal biopsy, the change of Ccr after more than 8 years was –22.3 ± 20.8% in 13 patients with hyperuricemia, compared with +2.6 ± 39.4% in 43 patients without hyperuricemia (p = 0.0238). Hyperuricemia was related independently to deterioration of Ccr (p = 0.0461). Conclusion: Hyperuricemia in IgA nephropathy is derived from both glomerular and tubulointerstitial damage, and correlated with hypertension. Hyperuricemia is a risk factor for renal prognosis in IgA nephropathy.

PK/PD and safety of a single dose of TMX-67 (febuxostat) in subjects with mild and moderate renal impairment.

A single oral dose of 20 mg febuxostat was administered to subjects with normal, mild or moderate impairment in renal function. There was less than a 2‐fold difference in AUC of plasma unchanged febuxostat among the renal function groups, and changes in plasma urate levels from pre‐dose levels were not significant. A total of five adverse events were reported with all mild in severity. The results indicate that renal impairment will have little clinical impact on the pharmacokinetics (PK), pharmacodynamics (PD) and safety of the study drug.

Safety, efficacy and renal effect of febuxostat in patients with moderate-to-severe kidney dysfunction.

Hyperuricemia (HU) is common in patients with chronic kidney disease (CKD), and accumulating evidence suggests it has a pathogenic role in the progression of the disease. However, a major challenge in treating patients with HU is the adverse effects caused by urate-lowering drugs used to treat CKD. Because of these untoward effects, doses need to be reduced, which leads to suboptimal efficacy. Febuxostat has been shown to be highly efficacious in reducing serum uric acid (sUA) and is well tolerated in patients with mild kidney dysfunction. However, its safety and efficacy have not been well studied in more advanced cases of CKD. We studied the safety and efficacy of escalating doses of febuxostat over a 24-week period in 70 patients with CKD stages 3b, 4 and 5, and we also observed the changes in blood pressure, estimated glomerular filtration rate (eGFR) and proteinuria following the reduction of sUA. Drug-related adverse events (AEs) occurred in only 5 out of 70 patients. All but one of the events were mild, and all five patients fully recovered. By 24 weeks, the reduction of sUA levels was >40% in CKD stage 3b and >50% in CKD stages 4 and 5. More than 70% of patients achieved target sUA levels of 6 mg dl−1 or less. Multivariate analysis showed that a greater reduction in sUA with febuxostat was associated with an increase in eGFR and a tendency toward decreased proteinuria. Febuxostat was safe and efficacious in the treatment of CKD stages 3b–5.

Relationship Between Hyperuricemia and Chronic Kidney Disease

Because approximately 70% of uric acid is excreted from the kidney, hyperuricemia occurs when renal function deteriorates. Until now, it has not been clear if the hyperuricemia seen in such renal diseases plays a role in the progression of renal disease. However, recent clinical studies show that the serum uric acid value is closely associated with hypertension in hyperuricemic patients (cross-sectional study), and also with the onset of hypertension (longitudinal study). Furthermore, one interesting report shows that treatment of hyperuricemia with allopurinol lowers blood pressure in juvenile essential hypertension patients with hyperuricemia. In addition, it is well known that hyperuricemia is closely associated with chronic kidney disease (CKD), is a risk factor for renal insufficiency in general populations, and is a poor prognostic factor of renal function in patients who also have IgA nephropathy. On the other hand, in intervention studies on hyperuricemia, the treatment of hyperuricemia with allopurinol in CKD has resulted in a fall in blood pressure and inhibition of the progression of renal damage. Conversely, the cessation of allopurinol treatment in CKD was followed by a rise in blood pressure and the development of renal damage. Furthermore, the rise of blood pressure and development of renal damage following cessation of allopurinol treatment are only seen in patients not receiving angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB). This suggests that the renin angiotensin (RA) system plays an important role in the development of hypertension and renal damage from hyperuricemia.

Guidelines on the use of iodinated contrast media in patients with kidney disease 2012: digest version

Open image in new window What is the definition of CIN? Answer: CIN is defined as an increase in serum creatinine (SCr) levels by ≥0.5 mg/dL or ≥25 % from baseline within 72 h after a contrast radiography using iodinated contrast media. Open image in new window Because the risk for developing CIN increases as kidney function decreases, it is important to evaluate kidney function on the basis of the latest SCr levels prior to contrast radiography. According to the classification of the severity of CKD, which is based on the cause, GFR, and presence and severity of albuminuria (Table 1) [1], patients with a GFR of <60 mL/min/1.73 m2 (G3a–G5) are considered to have CKD in this guideline. In another words, CKD is also diagnosed in patients with a GFR of ≥60 mL/min/1.73 m2 and albuminuria, in the present guidelines only patients with a GFR of <60 mL/min/1.73 m2 are defined as having CKD. Table 1 Classification of severity of CKD (2012) Open image in new window Risks of ESKD requiring dialysis or transplantation, and risks for cardiovascular diseases such as stroke, myocardial infarction, and heart failure are coded with colors ranging from green (lowest), yellow, orange and red (highest) CKD chronic kidney disease, Cr creatinine, ESKD end-stage kidney disease, GFR glomerular filtration rate Adapted from KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Inter Suppl. 2013;3:19–62 [1], with permission from Nature Publishing Group., modified for Japanese patients The following formula is used to calculate estimated GFR (eGFR). Open image in new window CIN is a form of acute kidney injury (AKI) that occurs after exposure to iodinated contrast media, and is diagnosed on the basis of reducing kidney function after contrast radiography when other causes such as cholesterol embolism are ruled out. AKI due to CIN is generally reversible. Usually, SCr levels increase to a peak 3–5 days after onset, and return to normal in 7–14 days. However, kidney injury may worsen to the point that hemodialysis is required in some patients. The criteria for the diagnosis of CIN used in clinical research of this condition vary among studies. The minimum increment of SCr levels that defined CIN included 0.5 mg/dL, 1.0 mg/dL, and 25 % or 50 % from baseline, and the duration of monitoring for CIN included 24 h, 48 h, 72 h, 4 days, and 7 days after contrast radiography. The most commonly used criteria for CIN in clinical research is an increase in SCr levels by ≥0.5 mg/dL or ≥25 % from baseline within 72 h after contrast radiography. However, physicians in the clinical setting should not wait for 72 h, and should start close monitoring of SCr levels from an early stage when CIN is suspected. The incidence of CIN, and clinical characteristics such as patients’ baseline kidney function, vary depending on the criteria used for diagnosis. Standardized diagnostic criteria are necessary to promote clinical research of this condition and develop preventive procedures. Open image in new window Open image in new window

A Case of Renal Amyloidosis Associated with Hepatic Adenoma: The Pathogenetic Role of Tumor Necrosis Factor-α

We report a case of a 35-year-old man with secondary amyloidosis chiefly involving the kidney and heart. The patient showed severe proteinuria and ischemic heart damage and had hepatic adenoma at the age of 33. Biopsy specimens from the kidney, heart, stomach and rectum showed extensive deposition of amyloid. After the surgical resection of a 300-gram hepatic adenoma, highly elevated c-reactive protein (CRP) levels decreased and the serum amyloid A (SAA) level was completely normalized. Normal liver cells were immunostained with rabbit anti-SAA antibody, but the cells in adenoma tissue and kidney were not. Electron microscopic examination revealed extracellular deposition of amyloid fibrils in the hepatic adenoma and kidney tissue. The concentration of tumor necrosis factor-alpha (TNF-alpha) (312 pg/mg tissue protein) was 7-fold higher in adenoma tissue than in normal liver tissue. Moreover, SAA (2.8 ng/mg tissue protein) was 2-fold higher in normal liver tissue than in adenoma tissue. Since TNF-alpha has been known to induce SAA production in target cells, the present results suggest that the hepatic adenoma produced TNF-alpha, which then caused mainly secondary amyloidosis in the kidney and heart. Currently, 2 years after surgical resection, urinary excretion of protein has been markedly reduced (from 3.5 to 0.8 g/day) and renal and cardiac functions are normal without specific medical treatment.

A Case of Pheochromocytoma of the Urinary Bladder in a Long-Term Hemodialysis Patient

The development is reported of a pheochromocytoma of the urinary bladder in a 33-year-old patient with systemic lupus erythematosus who had undergone long-term hemodialysis. A hypertensive episode followed by defecation was demonstrated by the monitoring of blood pressure with a portable automated sphygmomanometer without elevation of plasma catecholamines. The tumor was surgically removed and normalization of the patients blood pressure followed. Thus, monitoring of blood pressure for 24 h proved useful for the diagnosis of pheochromocytoma and, in particular, of paroxysmal hypertension.

Effect of Sairei-to on gentamicin nephrotoxicity in rats

The effect of Sairei-to, an oriental traditional medicine, against gentamicin nephrotoxicity was examined in gentamicin nephrotoxicity rat models. Gentamicin nephrotoxicity was induced by s. c. injection of gentamicin (100 mg/kg/day, for 3 days) in male Sprague-Dawley rats. Renal functions of two rat groups were compared, one eating rat chow containing 2.5% Sairei-to, the other eating normal rat chow. Sairei-to administration reduced the increase of urinary N-acetyl-β-D-glucosaminidase (NAG) and protein excretion, and decreased creatinine clearance induced by gentamicin. Gentamicin increased renal cortical malondialdehyde (MDA) concentration in normal diet group but not in the Sairei-to diet group. The renal cortical gentamicin concentration was not different between the two groups. In conclusion, Sairei-to shows reno-protective action against gentamicin nephrotoxicity, possibly through its anti-oxidant action.

Familial Juvenile Gouty Nephropathy: Exclusion of 16p12 from the Candidate Locus

Background/Aims: Familial juvenile gouty nephropathy (FJGN, MIM 162000) is an autosomal-dominant renal disease characterized by underexcretion-type hyperuricemia, gouty arthritis, and progressive renal disease at younger ages. We analyzed the localization of the responsible gene for FJGN concerning the chromosomal region of 16p12 using parametric linkage analysis in our FJGN. Methods: The affected members of this family were accompanied with polyuria due to nephrogenic diabetes insipidus and without hypertension. Fifteen samples were collected from 9 affected and 6 nonaffected members of the family. By using microsatellite markers mainly focused on the short arm of chromosome 16, two point and multipoint linkage analyses were carried out. Results: All of the 2-point logarithm of odds (LOD) scores were typically negative and all of the multipoint LOD scores were less than –3.0 in our FJGN family. Conclusion: The results suggested that the localization of the responsible gene to 16p12 can be excluded in our FJGN family. This finding means that the responsible gene for FJGN is not common.

A Turkish Case with Molybdenum Cofactor Deficiency

Molybdenum cofactor deficiency (MIM 252150) is a rare progressive neurodegenerative disorder with about 100 cases reported worldwide. We have identified a male with molybdenum cofactor deficiency and analyzed the molybdenum cofactor synthesis (MOCS)1 gene, MOCS2 gene, MOCS3 gene and GEPH gene. We homozygously identified the CGA insertion after A666 of the MOCS1 gene which produces arginine insertion at codon 222 of MOCS1A. The parents, his brother and his sister who did not have any symptoms were heterozygous for the same mutation. This region was highly conserved in various species. The N-terminal part of MOCS1 a protein is suggested to form the central core of the protein and be composed of an incomplete [(alpha/beta)6] triosephosphate isomerase (TIM) barrel with a lateral opening that is covered by the C-terminal part of the protein. The insertion is located in the loop connecting the fifth beta strand to the sixth alpha helices of the TIM barrel structure. This arginine insertion would induce the conformation change and the lack of the activity.