Propagermanium administration for patients with type 2 diabetes and nephropathy: A randomized pilot trial.

AIMS: We assessed the potential efficacy and safety of propagermanium (PG), an organic compound that inhibits the C-C chemokine receptor type 2, administration in patients with type 2 diabetes and nephropathy. Furthermore, we assessed the feasibility of future studies. MATERIALS AND METHODS: We recruited patients from nine medical institutions in Japan for this randomized, open-label, parallel two-arm pilot trial. Inclusion criteria were diagnosis of type 2 diabetes, age 30-75 years, dipstick proteinuria of ≥1+ or urinary albumin-to-creatinine ratio (UACR) of ≥30 mg/g and estimated glomerular filtration rate of ≥30 mL/min/1.73 m2. Patients were randomly assigned (1:2) using a minimization algorithm to either continuing usual care or concomitant administration of 30 mg PG per day for 12 months. The primary outcome was the change in UACR from baseline to 12 months. We also collected safety information for all patients who received at least one dose of PG. RESULTS: We enrolled 29 patients, 10 were assigned to continue usual care and 19 to receive PG. Changes in UACR by PG in addition to the usual care were 25.0% (95% CI -20.4%, 96.5%, P = .33). No severe adverse events or renal events were observed during the study. CONCLUSION: Although the treatment with PG was generally well tolerated, the dosage of 30 mg/d for 12 months did not reduce albuminuria when used in addition to usual care in patients with type 2 diabetes and nephropathy. Efficacy of PG should be verified in future definitive trials.

[A review of urinary examination--what medical practice expects now and what urinary examinations have to provide in the future].

Urinary examination can be performed frequently because of its non-invasive nature. To take advantage of this advantage, it is important to inform clinicians about the following: not only analytical results of chemical as well as morphological components but also easy-to-understand factors that are comprehensively analyzed, causing these components to emerge in urine. Here we review issues with the guidelines for hematuria diagnosis and management guidelines for chronic kidney disease. We report issues with the standard urinary erythrocyte count to define hematuria, the significance of urinary albumin test strips in the prevention of CKD or CVD development, and information on the morphologies of urinary erythrocytes.

[Pitfalls in measuring urinary proteins: age-related changes in urinary creatinine excretion that affect the urine protein/creatinine ratio].

Knowing the amount of protein excreted in the urine is important in determining the severity and activity of renal diseases. In general, screening tests have been carried out using the urine dipstick. However, there are limitations in determining the amount of urinary protein excretion using qualitative tests for protein in spot urine samples due to the concentration and dilution of urine. Therefore, when using spot urine samples, it is helpful to calculate the urine protein/creatinine ratio (P/C) by simultaneous measurement of urinary creatinine for determining daily protein excretion. We examined P/C measurements using the dipstick method in 22,718 subjects who visited our hospital for health examinations. The results showed positive rates for qualitative urinary protein (1 + and more) of 4.2% for males and 2.7% for females. Also positive rates for P/C (150 mg/g.cre and more) were found of 7.7% for males and 10.2% for females. The results showed a reversal of positive rates for males and females compared with the results of qualitative urinary protein. In addition, P/C showed a higher positive rate in 70 years old or older both for males and females. The distribution of urinary creatinine levels simultaneously measured by dipstick method showed that the percentage of diluted urine with urinary creatinine level less than 50 mg/dL was 6.8% for males and 18.3% for females overall. Females showed a higher rate and the percentage tended to increase with age both for males and females. From these results, it was suggested that changes in urinary creatinine excretion with age that affect the P/C ratio are large. We then measured the albumin excretion rate in the 24-hour urine as well as examined the correlation between the urinary creatinine concentration and albumin index with regard to age and sex in 1,280 diabetic patients. The results showed that daily urinary creatinine excretion overall in males, overall in females, in males over 80 years old and in females over 80 years old were 1.063 +/- 0.428 g/day (mean +/- S.D.), 0.714 +/- 0.270 g/day, 0.666 +/- 0.201 g/day, and 0.531 +/- 0.017 g/day, respectively, which showed large variations. From these results, creatinine correction, in which uniformity of daily urinary creatinine excretion is the principle, is useful for assessment of short-term fluctuations in the individuals. However, it is indicated that there is a problem when used for screening, from young people to the elderly.

Matrix metalloproteinase-2 (MMP-2) and membrane-type 1 MMP (MT1-MMP) affect the remodeling of glomerulosclerosis in diabetic OLETF rats.

BACKGROUND: We reported previously that diabetic glomerular nodular-like lesions were formed during the reconstruction process of mesangiolysis. However, the precise mechanism has yet to be elucidated. Here, we investigated the roles of matrix metalloproteinase (MMP)-2, which is activated from proMMP-2 by membrane-type (MT)-MMP in the sclerotic and endothelial cell injury process of a type II diabetic model, Otsuka Long-Evans Tokushima Fatty (OLETF) rats. METHODS: Monocrotaline (MCT) or saline only was injected three times every 4 weeks in 36-week-old OLETF rats and control Long-Evans Tokushima Otsuka rats. Glomerular expression and enzymatic activity of MMP-2 and MT1-MMP were assessed by immunohistochemistry, gelatin zymography of cultured glomerular supernatants, in situ enzymatic detection and reverse transcription-polymerase chain reaction. RESULTS: Mesangial matrix increased in OLETF rats. In addition, mesangiolysis and nodular-like mesangial expansion were observed only in MCT-injected endothelial injured OLETF rats. MMP-2 and MT1-MMP proteins increased in the expanded mesangial lesions in OLETF rats. Gelatin zymography revealed an increase in 62-kDa activated MMP-2 in the culture supernatants of isolated glomeruli from OLETF rats. In situ enzymatic activity of MMP in the mesangial areas was also detected in 50-week-old MCT-injected OLETF rats. CONCLUSION: These results suggest that MMP-2 and MT1-MMP are produced and activated in glomeruli through the progression of diabetic nephropathy and may have some effect on the remodeling of the glomerular matrix in diabetic nephropathy.

The beneficial effects of lymphocytapheresis for treatment of nephrotic syndrome.

A considerable permeability factor (or factors) derived from circulating T cells has a crucial role in proteinuria of nephrotic syndrome (NS). We attempted to remove pathogenic T cells through lymphocytapheresis (LCAP) in 6 patients with primary NS, 2 patients with minimal change nephrotic syndrome (MCNS), 2 patients with focal segmental glomerulosclerosis (FSGS), 1 patient with membranous nephropathy (MN), and 1 patient with MN and FSGS using Cellsorba (Asahi Medical Co., Osaka, Japan). LCAP was performed 2 times in 2 consecutive weeks and was followed with corticosteroid therapy with or without cyclosporine A in 5 patients. Two patients with MCNS, 1 with FSGS, and 1 with MN and FSGS showed a dramatic decrease of proteinuria (-30% and -94%) in their urine protein/creatinine ratio. Three out of 4 patients had a complete or partial remission (proteinuria <1g/day) within 8 weeks following immunosuppressive therapy. During the LCAP, T cells, especially activated T cells, decreased significantly in the response group. The other 2 patients, 1 with FSGS and 1 with MN, however, had no response to LCAP and following immunosuppressive therapy or low-density lipoprotein apheresis and suffered from end-stage renal failure or death by pneumonia. These results suggested that LCAP might have a beneficial effect on the treatment of NS, especially MCNS and in some patients with FSGS, despite varying responses to LCAP and concomitant immunosuppressive therapy.