Miho Hida

Inhibition of the Accumulation of Uremic Toxins in the Blood and Their Precursors in the Feces after Oral Administration of Lebenin®, a Lactic Acid Bacteria Preparation, to Uremic Patients Undergoing Hemodialysis

The plasma levels of phenol, p-cresol, and indican are markedly increased in uremic patients, and cannot be efficiently reduced by hemodialysis. Such uremic toxins, which are produced in the intestine as bacterial putrefactive metabolites, accumulate to a great degree in the feces of hemodialysis patients. Oral administration of Lebenin, a preparation consisting of antibiotic-resistant lactic acid bacteria, reduced the levels of fecal putrefactive metabolites to levels comparable with those of healthy subjects. Moreover, the plasma level of indican also significantly decreased in these Lebenin-treated patients. An analysis of the fecal microflora revealed that a disturbed composition of the microflora characterized by an overgrowth of aerobic bacteria is restored to normal by oral administration of Lebenin in hemodialysis patients. These results thus demonstrate that oral administration of lactic acid bacteria in uremic patients is effective in reducing the levels of uremic toxins, especially that of indican, in the blood by inhibiting bacterial production by means of correcting the intestinal microflora.

Metastatic patterns of prostatic cancer: Correlation between sites and number of organs involved

Prostatic cancer in 1885 autopsy cases was classified according to the number of organs involved in metastasis, and a comparison was made concerning the frequency of metastasis to the various organs. The frequencies of metastasis to the lungs and para‐aortic lymph nodes were low in cases with single‐organ involvement (4.6% and 2.3%, respectively), but increased rectilinearly in accordance with the number of organs involved and became high in cases with metastasis to three or more organs (49.1% and 21.8% in total, respectively). On the other hand, the frequencies of local extension to the bladder and invasion of the pelvic lymph nodes were high even in cases with single‐organ involvement (34.5% and 9.2%, respectively) and were not significantly changed regardless of the number of organs involved. No significant correlation was seen between pelvic and para‐aortic lymph node involvement. In cases with single‐organ involvement, metastasis to the lumbar spine occurred frequently, but those to the ribs, sternum, and ilium occurred less frequently. There may be multiple metastases in cases with metastases to the para‐aortic lymph nodes, sternum, and ilium. The number of metastatically involved organs is useful in analyzing the mode of metastasis.

Clinical Evidence of Peroxynitrite Formation in Chronic Renal Failure Patients with Septic Shock

The production of both nitric oxide (NO) and superoxide increases in septic shock. The cogeneration of these molecules is known to yield peroxynitrite, which preferentially nitrates tyrosine residues of protein and non-protein origins. We present evidence of peroxynitrite production in septic shock by measuring plasma nitrotyrosine. The nitrotyrosine was measured by an HPLC C-18 reverse-phase column and ultraviolet detector in chronic renal failure patients with or without septic shock, and in healthy volunteers. Plasma nitrite + nitrate (NOx) was also measured to evaluate NO production. Nitrotyrosine was selected as an index for production of peroxynitrite because the direct measurement of peroxynitrite in vivo is difficult. Patients with renal failure were selected in order to minimize nitrotyrosine excretion through the kidney. Plasma nitrotyrosine levels were not detectable in volunteers, 28.0 +/- 12.3 microM (1.6 +/- 1.1% of total tyrosine) in renal failure patients without septic shock, and 118.2 +/- 22.0 microM (5.5 +/- 1.2% of total tyrosine) in patients with septic shock. NOx levels were also higher in patients with septic shock than in patients without septic shock (173.9 +/- 104.7 vs. 75.6 +/- 19.1 microM). Although renal failure itself increases plasma concentrations of both molecules, the higher levels in patients with septic shock suggest that peroxynitrite is generated and the nitration of tyrosine residues is increased in this disease.

Prognosis of parathyroid function after successful percutaneous ethanol injection therapy guided by color doppler flow mapping in chronic dialysis patients

Selective percutaneous ethanol injection therapy (PEIT) of the parathyroid glands has been shown to be effective in chronic dialysis patients with severe secondary hyperparathyroidism. In this study, we examined whether it was possible to maintain parathyroid function within target range (intact parathyroid hormone [iPTH], 160 to 360 pg/mL) in the long term after successful destruction of hyperplastic tissue. PEIT was performed in 46 patients resistant to calcitriol pulse therapy, and all glands larger than 5 mm in diameter were destroyed by ethanol, guided by power Doppler flow mapping. Serum iPTH levels decreased from 633.3 +/- 359.9 to 226.3 +/- 204.7 pg/mL at 3 weeks and were maintained at 289.9 +/- 222.4 pg/mL at 1 year after PEIT. Total alkaline phosphatase activity decreased from 384.9 +/- 160.1 to 234.0 +/- 110.5 IU/L at 1 year after PEIT. In 19 patients, iPTH levels decreased into relative hypoparathyroidism (iPTH < 160 pg/mL) at 3 weeks after PEIT; however, they recovered at 1 year after PEIT (191.1 +/- 29.6 pg/mL). Parathyroid function was maintained within target range in 80.4% of the patients at 1 year after PEIT with appropriate medical therapy. Surgical parathyroidectomy was not required in any patient. Conversely, in eight other patients with recurrent hyperparathyroidism after subtotal parathyroidectomy, iPTH levels recovered in only 50% of the patients at 1 year after PEIT. Thus, destruction of hyperplastic tissue should be optimized in such patients. Recurrent nerve palsy was observed in only one patient, but was reversible. In conclusion, selective PEIT guided by color Doppler flow mapping is an effective and safe adjunct to medical therapy with a low risk for hypoparathyroidism.

Metastatic Processes and a Potential Indication of Treatment for Metastatic Lesions of Renal Adenocarcinoma

Renal adenocarcinoma findings from 307 autopsied cases with metastasis to 1 and 2 organs were investigated concerning the mode of metastasis. The lung was the most frequent site of metastasis to 1 organ, although the frequency was rather low (30 per cent), followed by bones (over-all), lymph nodes (over-all) and brain, and involving frequently the thoracic spine and retroperitoneal lymph nodes. In patients with metastases to 2 organs a significant correlation was found between the pulmonary-tracheal lymph nodes and those to the lungs. Potential indications for treatment of metastatic lesions were 1) lymphadenectomy and/or radiation therapy for the retroperitoneal and para-aortic lymph nodes and 2) resection of metastatic lesions in the lungs combined with lymphadenectomy and/or radiation therapy for the pulmonary-tracheal lymph nodes. In patients without lung metastasis lymphadenectomy and/or radiation therapy for the pulmonary-tracheal lymph nodes is not always necessary.

Urinary Tract Infection in Oliguric Patients with Chronic Renal Failure

We studied 182 patients with chronic renal failure by urinalysis and urine cultures. Of the patients 27 per cent had significant bacteriuria (more than 10(5) per ml.), 38 per cent had significant pyuria (more than 10 white blood cells per high power field), 19 per cent had urinary tract infection and 7 per cent had symptomatic urinary tract infection. All 12 patients with symptomatic urinary tract infection had significant bacteriuria and 11 had significant pyuria, while 1 had 5 to 10 white blood cells per high power field. Incidences of urinary tract infection differed depending on the primary renal disease (12, 13, 41 and 67 per cent for chronic glomerulonephritis, diabetic nephropathy, polycystic kidney and chronic pyelonephritis, respectively). Among the patients with chronic glomerulonephritis no significant differences were seen in frequencies of bacteriuria and urinary tract infection between male and female patients or between those who did and did not undergo hemodialysis. Also, no significant correlation was seen between bacteriuria and daily urine output but pyuria was significantly more frequent in oliguric patients or those on hemodialysis.

Survival advantage of lanthanum carbonate for hemodialysis patients with uncontrolled hyperphosphatemia

BACKGROUND Lanthanum carbonate is a non-calcium phosphate binder that is effective for the treatment of hyperphosphatemia. However, it is unknown whether treatment with lanthanum affects survival. METHODS We retrospectively collected data on maintenance hemodialysis patients at 22 facilities (n = 2292) beginning in December 2008, a time point immediately prior to the commercial availability of lanthanum in Japan. We compared 3-year all-cause mortality among patients who initiated lanthanum (n = 560) and those who were not treated with lanthanum during the study period (n = 560) matched by the propensity score of receiving lanthanum. Several sensitivity analyses were performed to test the robustness of the primary analysis. RESULTS After the market introduction of lanthanum, the percentage of patients receiving the binder increased gradually to 27%. In the propensity score-matched analysis, the mortality rate for the lanthanum group was not significantly lower than the non-lanthanum group [hazard ratio (HR), 0.71; 95% confidence interval (CI), 0.47-1.09). However, stratification by serum phosphorus disclosed significant survival benefit of lanthanum for patients with serum phosphorus >6.0 mg/dL (HR, 0.52; 95% CI, 0.28-0.95), but not in patients with serum phosphorus ≤6.0 mg/dL (HR, 1.00; 95% CI, 0.55-1.84). The survival benefit of lanthanum in patients with serum phosphorus >6.0 mg/dL was consistent across subgroups and robust in different analytical approaches. CONCLUSIONS Treatment with lanthanum was independently associated with a significant survival benefit in hemodialysis patients with inadequately controlled hyperphosphatemia. Further studies are required to confirm these findings.

Increased plasma tetrahydrobiopterin in septic shock is a possible therapeutic target

Hemoperfusion with a column of polymyxin B immobilized on fibers (PMX) has been used to adsorb endotoxin in-patients with septic shock. PMX hemoperfusion (PMX-H) increases blood pressure (BP) too rapidly for the effect to be attributable to endotoxin removal. Since inducible NO synthase (iNOS) is known to be involved in the profound hypotension, we hypothesized that a decrease of tetrahydrobiopterin (BH(4)), an essential cofactor of iNOS, might account for the rapid effect of PMX-H on BP, if plasma BH(4) is increased concomitantly with NO in septic shock patients and if PMX can decrease BH(4). BH(4) was evaluated by measuring total biopterin, which can include derivatives of BH(4) by using high-performance liquid chromatography (HPLC). We confirmed that PMX fabric time dependently decreased total biopterin concentration in vitro. The plasma level of total biopterin in shock patients was indeed markedly elevated compared with that in volunteers (131.1+/-33.4 vs. 10.4+/-1.1 nM, n=5, P<0.01). Level of NO metabolites (NOx) were 173.9+/-104.7 versus 28.7+/-11.6 µM (P<0.01). In beagles, plasma total biopterin was 44.7+/-6.9 nM at baseline, reached 118+/-28.6 nM after lipopolysaccharide (LPS) injection, and fell to 70.2+/-15.8 nM after PMX-H. Plasma NOx concentration was increased from 15.2+/-4.2 to 41.0+/-7.5 µM by LPS treatment. BP was 130+/-11.3 mmHg at baseline, 82.2+/-8.3 mmHg at 14 h after LPS, and 115.2+/-16.0 mmHg after PMX-H. In rats, plasma total biopterin was 88.8+/-1.5 nM at baseline, 383.7+/-144.2 nM after LPS and 177.0+/-14.2 nM after PMX-H. Plasma NOx was also increased after LPS (from 34.6+/-4.4 to 1445.6+/-376.0 nM). The marked increase in total biopterin concomitantly with NOx in septic shock patients and its reduction by PMX-H in animal models of septic shock are consistent with our hypothesis, and appear to justify further research on BH(4) removal as a potential therapeutic target.

Intestinal bacteria-derived putrefactants in chronic renal failure

AbstractBackground. Phenols and indoles are fermentation products and putrefactants of intestinal bacterial origin. They present a problem in chronic renal failure and hemodialysis patients because they accumulate in the body as uremic toxins. Methods. A comparative study was performed in groups of patients with chronic renal failure (CRF) before the initiation of dialysis, hemodialysis patients (HD), and healthy adults to investigate changes in intestinal flora and to measure the blood levels of uremic toxins. Results. The level of Escherichia coli was significantly increased in the CRF and HD groups compared with the healthy controls (P= 0.02, controls vs CRF before dialysis; P= 0.0014, controls vs HD). Fecal concentrations of phenol and scatole were most highly elevated in the HD group, and the difference between the CRF and HD groups was significant (P= 0.02 for phenol; P= 0.01 for scatole). Serum concentrations of phenol, p-cresol, and indican were significantly elevated in the CRF group (P= 0.01; P= 0.008; and P < 0.0001 vs controls, respectively). For indican, a correlation was found between fecal and serum concentrations only in the HD group (correlation coefficient of 0.821; P= 0.04). In the CRF group, a correlation was obtained between the urine and serum concentrations of phenol and p-cresol (0.852, P= 0.01; 0.758, P= 0.02, respectively). A correlation was also found between the serum concentrations of indican and serum creatinine (SCr) (0.610; P= 0.004) and β2-microglobulin (β2-MG) (0.739; P= 0.005). Conclusions. An abnormal balance of intestinal bacterial flora and increased intestinal bacteria-derived putrefactants were observed in the CRF group. The increased concentration of toxins with renal sclerosing effects, such as indican, may contribute to further deterioration of renal function.

Age changes in metastatic patterns in renal adenocarcinoma

The metastatic pattern in primary renal adenocarcinoma with respect to age has been studied by analyzing the necropsy records of 1828 patients. Metastasis‐free cases were noticeably frequent in the patients over 70 years of age. The metastatic pattern varied with age and was classified grossly into four types according to the age‐associated change in frequency: (1) diminishing; (2) increasing; (3) peaked; and (4) invariable. The incidence of hematogenous metastases showed little or no relation to advancing age whereas dissemination, which was possibly lymphogenous, was found to diminish as the age advanced, the latter trend being especially conspicuous in patients with lymph nodes distant from the primary lesion. It has been inferred that organs displaying comparable tendencies of age‐associated change in frequency of metastasis may share the same route of dissemination.