Koshiro Fukiyama

Impact of the initial levels of laboratory variables on survival in chronic dialysis patients

Besides the age at start of dialysis and the presence of diabetes mellitus, serum albumin has been shown to be a significant predictor of survival in prevalent dialysis patients. However, this was not evaluated in incipient dialysis patients. The initial biochemical variables were retrieved for a large dialysis population (N = 1,982) who were started on chronic dialysis in Okinawa, Japan from 1971 to 1990. Biochemical data that included blood urea nitrogen, serum creatinine, serum electrolytes (sodium, potassium, calcium, and phosphate), total cholesterol, triglyceride, total protein, serum albumin, and hematocrit obtained just before the first dialysis session were available for 1,491 (75.2%) patients. Six hundred sixty-four (43.2%) patients died by the end of 1993. Cox proportional analysis adjusted for sex, age, year of start of dialysis, presence of diabetes mellitus, and the laboratory variables was performed to examine the significance of the initial biochemical data on survival. The risk ratio was 0.577 (P = 0.0025) in serum albumin, 1.291 (P = 0.0138) in serum potassium, and 0.966 (P = 0.0202) in serum sodium. The study results support the notion that nutritional status is important for survival in chronic dialysis patients. Causes of hypoalbuminemia, hyperkalemia, and hyponatremia should be evaluated carefully at initiation of dialysis.

Evidence for Increased Cancer Deaths in Chronic Dialysis Patients

We analyzed longitudinal data on the cancer mortality rate in chronic dialysis patients and in the general population in Okinawa, Japan. In the general population from 1980 to 1990, the mortality rate has been stable at approximately 1.300 males and 0.897 females per thousand persons year, the male to female ratio being 1.45. In the period from 1971 to 1990, we found 91 (4.6%) patients with cancer in a group of 1,982 (824 females and 1,158 males) chronic dialysis patients; forty-nine of the 91 patient (53.8%) died by April 1, 1991. Using the standard mortality rate in the general population, which was obtained for each sex and age class (0 to 34 years, 35 to 44 years, 45 to 54 years, 55 to 64 years, and > or = 65 years), we calculated the relative risk of death from cancer in dialysis patients. The risk ratio in dialysis patients was significantly increased, being 2.48 (P < 0.05) for males and 3.99 (P < 0.05) for females. The mean (+/- SEM) age at the time of death from cancer in the dialysis group was 60.1 +/- 2.0 years in the males and 60.1 +/- 2.1 years in the females; the males were 6.3 years younger than the general population and the females were 9.3 years younger. The proportion of patients with colon cancer (both sexes) and cancer of the uterus and breast (females) was higher in the dialysis patients than in the general population.

An Epidemiologic Analysis of End-stage Lupus Nephritis

We analyzed 566 patients (515 females and 51 males) with systemic lupus erythematosus who were treated in Okinawa, Japan, from 1972 to 1991 and followed until April 1993. One hundred four patients (95 females and 9 males) died, and 51 were considered to have end-stage lupus nephritis. The annual incidence and prevalence, per million population in each sex, were increased from 16.0 and 66.0 in 1972 to 46.7 and 683.9 in 1991 in the female patients, and from 4.2 and 8.3 in 1973 to 8.3 and 70.0 in 1991 in the male patients, respectively. Cox proportional hazard analysis was done to determine the effects of several covariates on patients and renal survival. The patients survival rate improved, as the hazard ratio (HR) was decreased to 0.69 (year of diagnosis, 1982 to 1986) and to 0.48 (year of diagnosis, 1987 to 1991) when the HR in patients diagnosed before 1981 was taken as 1.00. Similarly, we examined renal survival by using the Cox proportional model. For this analysis, the date of start of dialysis therapy was regarded as the time of renal death. Male patients had significantly poor renal survival; the HR was 3.64 (95% confidence interval, 1.89 to 6.98) when the HR in the females was taken as 1.00. However, age at diagnosis and year of diagnosis did not significantly affect renal survival. The cumulated incidence of end-stage lupus nephritis from the time of diagnosis of systemic lupus erythematosus was 3.1% at 5 years, 9.4% at 10 years, 15.5% at 15 years, and 21.0% at 20 years.(ABSTRACT TRUNCATED AT 250 WORDS)

BRAIN ANGIOTENSIN AND CIRCULATORY CONTROL

1. Components of the renin‐angiotensin system (RAS) are found in the brain; both outside and inside the blood‐brain barrier.

Epidemiologic Analysis of Diabetic Patients on Chronic Dialysis

We retrospectively surveyed all of the available medical records of 404 (191 females and 213 males) chronic dialysis patients, of whom 16 (4%) had insulin-dependent diabetes mellitus (IDDM) and 388 (96%) non-insulin-dependent diabetes mellitus (NIDDM). The patients were among 2,214 dialysis patients in Okinawa, Japan, of whom 443 were diabetic. The patients entered a large population-based dialysis registry. The mean duration from the diagnosis of diabetes mellitus (DM) to dialysis was 181.6 months in the IDDM patients and 150.4 months in the NIDDM patients. The NIDDM patients were classified into four subgroups according to their status when DM was first suspected. The duration from the diagnosis of DM until the onset of dialysis treatment was significantly shorter than in any other subgroup or in the IDDM subgroup with major vascular disease (131.9 months). Otherwise, the course of renal disease in NIDDM patients was similar to that in IDDM individuals. Most of our dialysis patients with DM had NIDDM. In most of the NIDDM patients, the diagnosis had been delayed for several years for unknown reason. However, if diagnosed early, NIDDM shows a clinical time course until dialysis similar to that of IDDM. Whether NIDDM patients contract chronic renal disease at an equal incidence to that of IDDM patients and the fraction of all diabetic patients accepted for chronic dialysis remain to be determined.

Short-term effects of angiotensin II blockade on renal blood flow and sympathetic activity in awake rats.

To investigate the effects of an angiotensin II type 1 receptor antagonist (CV-11974) on renal blood flow and renal sympathetic nerve activity compared with a calcium antagonist (nicardipine), we measured both parameters in conscious spontaneously hypertensive rats aged 13 to 15 weeks. One to 2 days after surgery, CV-11974 (n = 9) and nicardipine (n = 8) were intravenously administered to decrease arterial pressure in a similar time course and degree of hypotension. CV-11974 increased renal blood flow by 23 +/- 4% at the maximal fall in mean arterial pressure (-32 +/- 1 mm Hg), and renal nerve activity increased by 70 +/- 7%. The maximal increase in renal blood flow (+27 +/- 4%) was observed when mean pressure was reduced by approximately 20 mm Hg. The maximal reduction of renal vascular resistance (-33 +/- 3%) correlated significantly with pretreatment levels of plasma renin concentration (r = -.792). In contrast, nicardipine produced a progressive reduction of renal blood flow and marked increases in heart rate and renal nerve activity. Increases in heart rate and nerve activity were greater than those with CV-11974 treatment (P < .001). At the maximal fall in mean pressure (-32 +/- 1 mm Hg), renal blood flow decreased by 23 +/- 4%, which was significantly correlated with percent changes in renal nerve activity (+150 +/- 11%, r = -.744). Renal denervation in another set of rats (n = 6) improved renal blood flow and renal vascular resistance responses to nicardipine.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of Meal Ingestion and Active Standing on Blood Pressure in Patients ≥60 Years of Age

Postprandial hypotension and orthostatic hypotension occur often in elderly patients. In the present study, we examined hemodynamic and humoral responses to meal ingestion and active standing in 20 patients > or = 60 years of age who were free of apparent autonomic and cardiac dysfunction. For a time-control study, water was given instead of a meal to 19 of the 20 patients. After the meal ingestion, there was a fall in systolic blood pressure (BP) in 6 patients of > 20 mm Hg, whereas the fall in systolic BP during the control study was not > 20 mm Hg in any patient. The low-frequency power of the systolic BP wave, an index of peripheral sympathetic activity, was significantly increased only in the patients without postprandial hypotension. The postprandial changes in systolic BP were correlated with the changes in the low-frequency power of the systolic BP wave (r = 0.61; p < 0.01), but they were not correlated with the changes in plasma norepinephrine, insulin, cardiac output, or parameters obtained by the spectral analysis of the RR interval. The systolic BPs in the upright position were comparable after the meal and the water ingestion. Thus, the effects of meal ingestion and upright position on BP are not additive. Dysfunction of peripheral sympathetic control of vascular tone may contribute to the postprandial hypotension in elderly patients.

Modulation of baroreflex function by angiotensin II endogenous to the caudal ventrolateral medulla

Neurons in the ventrolateral medulla (VLM) mainly determine the tonic sympathetic activity. The caudal VLM (CVLM) relays baroreflex signals to the rostral VLM. We have reported that endogenous angiotensin II (ANG II) contributes to the ongoing activity of the VLM neurons. In the present study, we examined if ANG II endogenous to the CVLM modulates the baroreflex function in anesthetized normotensive Sprague-Dawley rats. Changes in renal sympathetic nerve activity (RSNA) in response to changes in mean arterial pressure (MAP) induced by i.v. infusion of phenylephrine and nitroglycerin were recorded before and after bilateral microinjection of [Sar1, Thr8]-ANG II, an ANG II antagonist, into the CVLM. The ANG II antagonist injection into the CVLM significantly increased MAP and RSNA by 17.6 +/- 8.0 mmHg (mean +/- S.D.) and 36.3 +/- 18.1%, respectively. It also significantly increased the baroreflex sensitivity (BS) from -0.49 +/- 0.38 to -0.74 +/- 0.37%/mmHg during nitroglycerin infusion. In contrast, the BS examined by phenylephrine infusion was not altered by the pretreatment with ANG II antagonist. Injection of artificial CSF affected neither the baseline values of MAP and RSNA nor the BS. These results suggest that ANG II endogenous to the CVLM exert a modulating role in baroreflex control of RSNA.

Seasonal Variation in the Incidence of End-Stage Renal Disease

The effect of ambient temperature (AMT) on the incidence of end-stage renal disease (ESRD) was examined in Okinawa, Japan, where there is a distinct seasonal variation in monthly AMT but constant intradiurnal temperature change throughout a year. Arbitral continuous and cyclic functions were examined using Fourier analysis and calculation of the cross-correlation coefficient. The calendar month of the start of chronic dialysis was regarded as the time of onset of ESRD. A total of 1,982 patients, 824 females and 1,158 males, was registered with ESRD between 1971 and 1990. The normalized monthly number of new ESRD patients, divided by days of each month, was smallest in August, n = 4.06, and largest in January, n = 6.45, and this pattern was well reproduced by the Fourier synthesized value. The cross-correlation coefficient showed that monthly mean AMT and the normalized number of ESRD patients correlated best with 6 months lag time. Taken together, our results showed that there was strong correlation between the normalized number of ESRD patients and AMT. Uremic symptoms leading to initiate dialysis, such as congestive heart failure, may be aggravated in lower AMT. We speculated a role of an inverse relation between AMT and the sympathetic nerve function. The public health implications of these findings warrant their further investigation.

Effect of renal diseases and comorbid conditions on survival in chronic dialysis patients

International and geographical differences in the survival rates of chronic dialysis patients can be explained by differences in primary renal disease, in the acceptance rate of elderly patients, and in predialysis comorbid conditions. Several studies have shown the effects of these factors on survival. However, in most studies, a large number of patients may leave for renal transplantation or transfer to other centers, so that precise analysis becomes impossible. Although the number of patients in our registry is not so large (n = 1,982), we have few such problems and were able to examine the effects of the above-mentioned factors on patient survival using the Cox proportional hazard model. Hazard ratios (HR) and 95% confidence intervals were 0.739 and 0.366-1.491 in patients with polycystic kidney disease (n = 38), 2.669 and 1.513-4.708 in patients with systemic lupus erythematosus (n = 39), 1.245 and 0.935-1.660 in patients with nephrosclerosis (n = 122), 1.815 and 1.447-2.229 in patients with diabetes mellitus (n = 374), and 1.595 and 1.201-2.117, respectively, in patients with other renal diseases (n = 146) when the HR in patients with chronic glomerulonephritis (n = 1,263) was taken as 1.00. HR and 95% confidence intervals were 1.222 and 1.016-1.470 in patients with one comorbid condition (n = 217) and 1.494 and 1.033-2.160, respectively, in patients with two comorbid conditions (n = 24) when the HR of patients with no predialysis comorbid conditions (n = 1,741) was taken as 1.00. Our data demonstrate the effects of renal diseases and number of predialysis comorbid conditions on the survival in chronic dialysis patients.(ABSTRACT TRUNCATED AT 250 WORDS)