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The prognosis of lupus nephritis (LN) has improved following the introduction of effective immunosuppressive therapy and progress in supportive care. This study examined recent renal and patient prognosis for adults with LN in Japan.We conducted a nationwide retrospective cohort study of LN patients who received a renal biopsy between 2007 and 2012 that were registered in the Japan Renal Biopsy Registry. Of 623 registered adults with LN from 25 institutions and their affiliated or community hospitals, 489 were eligible for this study.The median age at renal biopsy was 39 years, and 82.2% of patients were female. Renal biopsies were performed in 348 patients with new-onset LN, 106 with relapse LN, and 35 with refractory LN. The distribution of ISN/RPS 2003 Classes was as follows: I 1.6%; II 5.3%; III (± V) 27.0%; IV (± V) 47.0%; V 18.4%; VI 0.6%. During the median observation period of 63.8 months, 36 patients (7.3%) reached a doubling of serum creatinine or end-stage kidney disease (ESKD), and 28 patients (5.7%) died. The 5 year renal and patient survival rates were 93.9% and 94.7%, respectively. Multivariate analysis revealed body mass index (BMI) and estimated glomerular filtration rate (eGFR) were independent risk factors for a doubling of serum creatinine in ESKD. Age and eGFR were independent risk factors for death.Recent prognosis for adults with LN are relatively good in Japan. Risk factors for impaired renal function are BMI and eGFR at renal biopsy, while age and eGFR are risk factors for death.

Objective: In our recent study, non-Gaussianity of heart rate variability (λ25s), an indicator of sympathetic nerve activity, did not change during two-day treatment with the angiotensin II type 1 receptor blocker (ARB) azilsartan. Coadministration of calcium channel blockers (CCBs) might affect the study results. Methods: In this subanalysis, 20 patients with chronic kidney disease (14 men; age 61±15 years) were divided into three groups: patients with coadministration of L-type CCB, patients without coadministration of CCB, and patients with coadministration of sympathoinhibitory (L/T- or L/T/N-type) CCB. λ25s was calculated separately in daytime and nighttime. Results: Daytime λ25s at baseline was higher in patients with L-type CCB coadministration (0.62±0.18, n = 5) compared with those without CCB (0.49±0.13, n = 11) and those with sympathoinhibitory CCB (0.46±0.06, n = 4). The relationship between the changes in daytime λ25s and systolic blood pressure was positive in patients with L-type CCB coadministration, whereas the relationship was inverse in the other two groups. A larger decrease in daytime λ25s was shown in patients with L-type CCB coadministration compared with those in the other two groups. Conclusions: CCBs, as well as diuretics, are recommended as second-line antihypertensive agents. Our results suggested that ARBs can overwhelm the activation of sympathetic nerve activity stimulated by coadministration of L-type CCBs.

Objective: Although percutaneous transluminal angioplasty is an effective therapy against vascular access failure in hemodialysis patients, recurrent stenosis imposes enormous burden for hemodialysis patients. A nitinol scoring element–equipped helical balloon catheter (AngioSculpt®) has been altered the landscape for treating several vascular diseases. It is not, however, fully elucidated whether AngioSculpt for advanced vascular access stenosis, difficult to expand by conventional balloons, successfully provides bailout angioplasty. Here, we report our cases whose intradialytic venous pressure significantly improved after percutaneous transluminal angioplasty without any serious adverse complications using AngioSculpt. Patients and Methods: Among patients undergoing hemodialysis in Masuko Memorial Hospital, 16 cases with resistant and recurrent vascular access stenosis underwent AngioSculpt (diameter 6 mm, total length 4 cm) angioplasty. We simultaneously measured the average venous pressures during hemodialysis before and after percutaneous transluminal angioplasty. Results: The average outflow vessel stenosis rate was 73.0 ± 11.3% before AngioSculpt intervention. Fully enlarged vessels were observed by expanding vessels at maximum pressure of 14 atm in all cases without any complications including vascular ruptures. Their intradialytic venous pressures decreased from 181.8 ± 39.2 mmHg to 150.5 ± 39.3 mmHg ( p Conclusion: AngioSculpt may provide a promising option for treating hemodialysis patients with severely advanced vascular access stenosis, who would otherwise need repeated vascular access surgeries and/or conventional percutaneous transluminal angioplasties.

We have revealed that even in humans, activated intrarenal renin–angiotensin–aldosterone system (RAAS) enhances tubular sodium reabsorption to facilitate salt sensitivity and nondipper rhythm of blood pressure (BP), and that angiotensin receptor blocker (ARB) could increase daytime urinary sodium excretion rate (U N a V) to produce lower sodium balance and restore nondipper rhythm. However, the sympathetic nervous system and intrarenal dopaminergic system can also contribute to renal sodium handling. A total of 20 patients with chronic kidney disease (61 ± 15 years) underwent 24‐h ambulatory BP monitoring before and during two‐day treatment with ARB, azilsartan. Urinary angiotensinogen excretion rate (U AGT V, μ g/gCre) was measured as intrarenal RAAS; urinary dopamine excretion rate (U DA V, pg/gCre) as intrarenal dopaminergic system; heart rate variabilities (HRV, calculated from 24‐h Holter‐ECG) of non‐Gaussianity index λ 25s as sympathetic nerve activity; and power of high‐frequency (HF) component or deceleration capacity (DC) as parasympathetic nerve activity. At baseline, glomerular filtration rate correlated inversely with U AGT V ( r = −0.47, P = 0.04) and positively with U DA V ( r = 0.58, P = 0.009). HF was a determinant of night/day BP ratio ( β = −0.50, F = 5.8), rather than DC or λ 25s . During the acute phase of ARB treatment, a lower steady sodium balance was not achieved. Increase in daytime U N a V preceded restoration of BP rhythm, accompanied by decreased U AGT V ( r = −0.88, P = 0.05) and increased U DA V ( r = 0.87, P = 0.05), but with no changes in HRVs. Diminished sodium excretion can cause nondipper BP rhythm. This was attributable to intrarenal RAAS and dopaminergic system and impaired parasympathetic nerve activity. During the acute phase of ARB treatment, cooperative effects of ARB and intrarenal dopaminergic system exert natriuresis to restore circadian BP rhythm.

Introduction: We have reported that the circadian rhythm of urinary potassium excretion (U K V) is determined by the rhythm of urinary sodium excretion (U Na V) in patients with chronic kidney disease (CKD). We also reported that treatment with an angiotensin receptor blocker (ARB) increased the U Na V during the daytime, and restored the non-dipper blood pressure (BP) rhythm into a dipper pattern. However, the circadian rhythm of U K V during ARB treatment has not been reported. Materials and methods: Circadian rhythms of U Na V and U K V were examined in 44 patients with CKD undergoing treatment with ARB. Results: Whole-day U Na V was not altered by ARB whereas whole-day U K V decreased. Even during the ARB treatment, the significant relationship persisted between the night/day ratios of U Na V and U K V ( r =0.56, p

Introduction:Increased sympathetic nerve activity has been suggested in patients with chronic kidney disease (CKD). Pathologic sympathetic activity can alter heart rate variability (HRV), and the altered HRV has prognostic importance, so that reducing sympathetic activity may be an important strategy. Novel nonlinear HRVs, including deceleration capacity (DC), have greater predictive power for mortality. We have recently proposed an increase in a non-Gaussianity index of HRV, λ25s, which indicates the probability of volcanic heart rate deviations of departure from each standard deviation level, as a marker of sympathetic cardiac overdrive. L/T-type calcium channel blocker (L/T-CCB), azelnidipine, decreases sympathetic nerve activity in experimental and clinical studies.Methods:In 43 hypertensive patients with CKD under treatment with an angiotensin receptor blocker (ARB), we investigated whether 8-week add-on L/T-CCB treatment could restore HRV.Results:Means of all normal-to-normal intervals over 24 h ( p25s( p=0.001) decreased regardless of gender, age, renal function or blood pressure, while no significant changes were observed in the other HRVs.Conclusions:Reduction of λ25sis useful to assess the effect of sympathoinhibitory treatment. Further studies are needed to investigate if the restoration of HRV is directly associated with the improvement of prognosis in patients with CKD.

Recently, we found that an angiotensin II receptor blocker (ARB) restored the circadian rhythm of the blood pressure (BP) from a nondipper to a dipper pattern, similar to that achieved with sodium intake restriction and diuretics (Fukuda M, Yamanaka T, Mizuno M, Motokawa M, Shirasawa Y, Miyagi S, Nishio T, Yoshida A, Kimura G. J Hypertens 26: 583–588, 2008). ARB enhanced natriuresis during the day, while BP was markedly lower during the night, resulting in the dipper pattern. In the present study, we examined whether the suppression of tubular sodium reabsorption, similar to the action of diuretics, was the mechanism by which ARB normalized the circadian BP rhythm. BP and glomerulotubular balance were compared in 41 patients with chronic kidney disease before and during ARB treatment with olmesartan once a day in the morning for 8 wk. ARB increased natriuresis (sodium excretion rate; UNaV) during the day (4.5 ± 2.2 to 5.5 ± 2.1 mmol/h, P = 0.002), while it had no effect during the night (4.3 ± 2.0 to 3.8 ± 1.6 mmol/h, P = 0.1). The night/day ratios of both BP and UNaV were decreased. The decrease in the night/day ratio of BP correlated with the increase in the daytime UNaV ( r = 0.42, P = 0.006). Throughout the whole day, the glomerular filtration rate ( P = 0.0006) and tubular sodium reabsorption ( P = 0.0005) were both reduced significantly by ARB, although UNaV remained constant (107 ± 45 vs. 118 ± 36 mmol/day, P = 0.07). These findings indicate that the suppression of tubular sodium reabsorption, showing a resemblance to the action of diuretics, is the primary mechanism by which ARB can shift the circadian BP rhythm into a dipper pattern.

Some cardiovascular disorders disturb circadian variation of endothelial function. We investigated whether deterioration of renal function alters circadian variation of endothelial function in patients with hypertension. Endothelial function was assessed by the peak forearm blood flow (FBF) response to reactive hyperemia, and 24-hour ambulatory blood pressure monitoring was performed in 25 patients with essential hypertension (61 ± 17 years). Relationships among renal function, 24-hour blood pressure, and endothelial function were analyzed. The ratio of nighttime to daytime mean arterial pressure was inversely correlated with estimated glomerular filtration rate (eGFR) ( r = −0.43, P = .03). The FBF response to reactive hyperemia examined at 21:00, but not at 6:30 or 11:30, was significantly correlated with eGFR ( r = 0.44, P = .03). Furthermore, the ratio of FBF response measured at 21:00 to that measured at 6:30 was independently correlated with eGFR (β = 0.47, P = .02). Renal dysfunction is associated with the derangement of circadian variation of both endothelial function and blood pressure. Nocturnal blood pressure is elevated, and evening endothelial function deteriorates in parallel with a decline in renal function in hypertensive patients.

In healthy subjects, blood pressure (BP) drops by 10-20% during the night. Conversely, in patients with the salt-sensitive type of hypertension or chronic kidney disease, nighttime BP does not fall, resulting in an atypical pattern of circadian BP rhythm that does not dip. This pattern is referred to as the 'non-dipper' pattern. Loss of renal functional reserve, due to either reduced ultrafiltration capacity or enhanced tubular sodium reabsorption, induces the salt-sensitive type of hypertension. When salt intake is excessive in patients with salt-sensitive hypertension, the defect in sodium excretory capability becomes evident, resulting in elevated BP during the night. This nocturnal hypertension compensates for diminished natriuresis during the daytime and enhances pressure natriuresis during the night. Nocturnal hypertension and the non-dipper pattern of circadian BP rhythm cause cardiovascular events. When excess salt intake is loaded in patients who are in a salt-sensitive state, glomerular capillary pressure is also elevated, resulting in glomerular sclerosis and eventual renal failure. In this way, salt sensitivity and excess salt intake contribute to both cardiovascular and renal damage at the same time. We propose that salt sensitivity of BP and excess salt intake have important roles in the genesis of the cardiorenal connection. Salt sensitivity and circadian rhythm of BP are the keys to understanding the connections between cardiovascular and renal complications.

We have postulated that the diminished renal capacity to excrete sodium causes nocturnal blood pressure (BP) elevation, which enhances pressure natriuresis in compensation for impaired daytime natriuresis. If such a mechanism holds, high BP during sleep at night may continue until excess sodium is sufficiently excreted into urine. This study examined whether the duration, defined as “dipping time,” until nocturnal mean arterial pressure began to fall to cr ; ρ=−0.61; P P P cr (mean arterial pressure: r =−0.58, P r =−0.69, P cr (mL/min), hazard ratios of nocturnal BP dip adjusted for age, gender, and body mass index were 0.37 (95% CI: 0.17 to 0.79; P =0.01) for the second tertile (C cr : 50 to 90) and 0.20 (95% CI: 0.08 to 0.55; P =0.002) for the third tertile (C cr : 5 to 41) compared with the first tertile (C cr : 91 to 164). These findings demonstrate that patients with renal dysfunction require a longer duration until BP falls during the night. The prolonged duration until BP dip during sleep seems an essential component of the nondipper pattern of the circadian BP rhythm.

We have shown that as renal function deteriorated, night-time fall in both blood pressure and urinary sodium excretion were diminished. We have also reported that sodium intake restriction and diuretics both normalized circadian blood pressure rhythm from nondipper to dipper patterns. In this study, we investigated whether an angiotensin II receptor blocker, olmesartan, could restore night-time blood pressure fall.Twenty patients with chronic kidney disease (13 men, seven women; mean age 44.8 +/- 18.1 years; BMI 22.9 +/- 3.5 kg/m2) were studied. At baseline and 8 weeks after the treatment with olmesartan medoxomil (10-40 mg/day), 24-h blood pressure monitoring and urinary sampling for both daytime (0600-2100 h) and night-time (2100-0600 h) were repeated to compare the circadian rhythms of blood pressure and urinary sodium excretion.The 24-h mean arterial pressure was lowered by olmesartan, while urinary sodium excretion remained unchanged. On the other hand, daytime urinary sodium excretion was increased from 4.8 +/- 2.2 to 5.7 +/- 2.1 mmol/h, while night-time urinary sodium excretion tended to be reduced from 3.9 +/- 1.7 to 3.4 +/- 1.6 mmol/h. Night/day ratios of mean arterial pressure (0.98 +/- 0.1 to 0.91 +/- 0.08; P = 0.01) and urinary sodium excretion (0.93 +/- 0.5 to 0.68 +/- 0.4; P = 0.0006) were both decreased. Olmesartan enhanced night-time falls more in mean arterial pressure (r = 0.77; r2 = 0.59; P0.0001) and urinary sodium excretion (r = 0.59; r2 = 0.34; P = 0.007), especially in patients whose baseline night-time falls were more diminished.These findings demonstrated that olmesartan could restore night-time blood pressure fall, as seen with diuretics and sodium restriction, possibly by enhancing daytime sodium excretion. Since nocturnal blood pressure is a strong predictor of cardiovascular events, olmesartan could relieve cardiorenal load through normalization of circadian blood pressure rhythm besides having powerful ability to block the renin-angiotensin system.

Background. Nocturnal polyuria has been well known in renal insufficiency. Recently, we found that as renal function deteriorated in chronic kidney disease (CKD), natriuresis was enhanced during the night with nocturnal blood pressure elevation. In the present study, we investigated whether nocturnal polyuria in CKD was due to the inability to concentrate urine, as previously proposed, or based on osmotic diuresis mainly by natriuresis. Methods. In 27 CKD patients, circadian rhythms of urinary sodium, potassium, urea and osmolar excretion rates (UNaV, UKV, UureaV, UosmV) as well as of urinary volume (V) and free-water clearance ðC H2O Þ were estimated during both daytime (6:00 to 21:00) and nighttime (21:00 to 6:00). Then, the night/day ratios of these parameters were analysed in relation to creatinine clearance (Ccr) as a marker of glomerular filtration rate. Results. Ccr had significantly negative relationships with night/day ratios of V (R ¼� 0.69; P < 0.0001), UosmV (R ¼� 0.54; P ¼ 0.004) and UNaV (R ¼� 0.63; P ¼ 0.0005), but no correlation with night/day ratios of CH2O (R ¼� 0.33; P ¼ 0.1), UKV (R ¼� 0.29; P ¼ 0.1) or UureaV (R ¼� 0.31; P ¼ 0.1). Linear and multiple regression analysis identified nocturnal natriuresis rather than urea excretion as an independent determinant of nocturia. Conclusion. As renal function deteriorated, nocturnal polyuria was seen, being consistent with classical recognition. Furthermore, this increase in nocturnal urine volume seemed related to osmotic diuresis mainly by natriuresis rather than to water diuresis or urea excretion.

We recently illustrated a close relationship between glomerular filtration rate and circadian rhythm of blood pressure (BP) in patients with chronic kidney disease. However, it remains undetermined from such cross-sectional findings which occurs first, the loss of kidney function or the lack of nocturnal BP fall. In the present study, we examined whether circadian rhythm of BP is affected by unilateral nephrectomy for kidney donation to clarify this important issue. Fifteen healthy subjects (4 men, 11 women; aged 33 to 65 years; mean age 55 +/- 2 years) who underwent unilateral nephrectomy for kidney donation were studied. Ambulatory BP was monitored for 24 h, while serum and urinary samples were collected to estimate creatinine clearance before and on the 8th day after nephrectomy. Then, changes in the night/day ratios of mean arterial BP were analyzed in relation to the decrease in 24-h creatinine clearance as a marker of glomerular filtration rate by nephrectomy. Creatinine clearance was reduced by 29% in average from 84 +/- 6 to 60 +/- 4 ml/min by nephrectomy, while 24-h mean arterial BP values were 91 +/- 3 and 94 +/- 4 mmHg (p=0.08) before and after nephrectomy. Although mean BP (daytime, nighttime or night/day ratio) was not altered significantly by nephrectomy, the decrease in creatinine clearance was positively correlated with the increase in the night/ day ratio of mean BP (r=0.61, p=0.017). The decrease in creatinine clearance was not correlated with changes in either 24-h, daytime or nighttime mean BP. Our results suggest that unilateral nephrectomy disturbs the circadian rhythm of BP as a function of renal dysfunction without affecting absolute levels of BP. Non-dipping of BP seems the consequence of the loss of renal function, rather than the cause.

Nocturnal blood pressure is elevated with natriuresis and proteinuria as renal function deteriorates in nephropathy. Background We reported that patients with sodium sensitive type of hypertension exhibited the lack of nocturnal fall in blood pressure with enhanced natriuresis during night. Sodium sensitivity is caused by diminished glomerular filtration capability and/or augmented tubular reabsorption of sodium, and seems tightly linked with glomerular capillary hypertension. In the present study, we investigated the relationship between glomerular filtration rate and circadian rhythms of these parameters in patients with glomerulopathy. Methods Twenty six patients (15 men and 11 women; aged 17 to 72 years; mean age 47 ± 3 years), whose diagnosis was confirmed as glomerulopathy with renal biopsy, were studied during hospitalization. Ambulatory blood pressure for 24 hours was monitored, while urinary samples were collected for both daytime (6:00 a.m. to 9:00 p.m.) and nighttime (9:00 p.m. to 6:00 a.m.) to estimate circadian rhythms of urinary sodium and protein excretion rates (U Na V, U pro V). Then night/day ratios of mean arterial blood pressure (MAP), U Na V, and U pro V were analyzed in relation to 24-hour creatinine clearance as a marker of glomerular filtration rate. Results Serum creatinine and creatinine clearance were 1.1 ± 0.1 mg/dL and 89 ± 7 mL/min/1.73m2. There were significant day-night differences in MAP (96 ± 2 mm Hg vs. 92 ± 2 mm Hg; P = 0.006), U Na V (6.7 ± 0.9 mmol/hour vs. 3.6 ± 0.3mmol/hour; P = 0.003), and U pro V (161 ± 27 mg/hour vs. 128 ± 28 mg/hour; P = 0.02). Creatinine clearance had significantly negative relationships with night/day ratios of MAP ( r =-0.49; P = 0.01), U Na V ( r =-0.43; P = 0.03,) and U pro V ( r =-0.41; P = 0.04). In addition, night/day ratio of MAP had significantly positive relationships with night/day ratios of U Na V ( r = 0.49; P = 0.01) and U pro V ( r = 0.45; P = 0.02). Conclusion Our results show that as renal function deteriorates in glomerulopathy the nocturnal dip in blood pressure is lost, resulting in enhanced urinary sodium and protein excretions during night. These findings are compatible with our proposal that impaired natriuresis during daytime makes nocturnal blood pressure elevated to compensate for diminished natriuresis by pressure natriuresis. We speculate that nocturnal glomerular capillary hypertension contributes, at least in part, to enhanced urinary sodium and protein excretions during night.

Background Although genome-wide association studies (GWASs) have implicated several genes in the predisposition to chronic kidney disease (CKD) in Caucasian or African American populations, the genes that confer susceptibility to CKD in Asian populations remain to be identified definitively. We performed a GWAS to identify genetic variants that confer susceptibility to CKD in Japanese individuals. Methods 3851 Japanese individuals from three independent subject panels were examined. Subject panels A, B, and C comprised 252, 910, and 190 individuals with CKD and 249, 838, and 1412 controls, respectively. A GWAS for CKD was performed in subject panel A. Results Five single nucleotide polymorphisms (SNPs) at chromosome 3q28, ALPK1 , FAM78B , and UMODL1 were significantly (false discovery rate

Objective The sympathetic nervous system plays an important role in blood pressure regulation even in the early stages of chronic kidney disease (CKD). Methods To understand the role of the sympathetic system, we examined the relationship between day/night ratios of both heart rate (HR) and mean arterial pressure (MAP) as well as HR variability (HRV, SD) before and during an 8-week treatment with the angiotensin II receptor blocker (ARB), olmesartan, in 45 patients with CKD. Results The day/night HR ratio strongly correlated with the day/night MAP ratio before and during ARB treatment. The ratio of [day/night HR ratio] over [day/night MAP ratio] was increased as renal function deteriorated at baseline (r = -0.31, P = 0.04), and it was attenuated (1.10 ± 0.10 to 1.06 ± 0.10; P = 0.04) and became independent of renal function during ARB treatment (r = -0.04, P = 0.8). ARB increased both the day/night HR ratio (1.17 ± 0.09 to 1.21 ± 0.13; P = 0.04) and HRV (10.6 ± 2.9 to 11.7 ± 4.2; P = 0.04), which were lower when baseline renal function deteriorated. Conclusion The present study indicates that there exists a close correlation in circadian rhythms between HR and MAP in CKD. Synchronization between the two rhythms was progressively lost as renal function deteriorated, and ARB partly restored the synchronization. These findings suggest that the sympathetic nervous system is activated as renal function deteriorates, and ARB may suppress its activation.

Objective: Angiotensin receptor blockers (ARBs) produce a lower sodium (Na) balance, and the natriuretic effect is enhanced under Na deprivation, despite falls in blood pressure (BP) and glomerular filtration rate (GFR). Methods: The effect of additional hydrochlorothiazide (HCTZ; 12.5 mg/day) to ARB treatment (valsartan; 80 mg/day) on glomerulotubular Na balance was evaluated in 23 patients with chronic kidney disease. Results: Add-on HCTZ decreased GFR, tubular Na load, and tubular Na reabsorption (tNa), although 24-hour urinary Na excretion (UNaV) remained constant. Daily urinary angiotensinogen excretion (UAGTV, 152±10→82±17 μg/g Cre) reduced ( p=0.02). Changes in tubular Na load ( r2=0.26) and tNa ( r2=0.25) correlated with baseline 24-hour UAGTV. Changes in filtered Na load correlated with changes in nighttime systolic BP ( r2=0.17), but not with changes in daytime systolic BP. The change in the tNa to filtered Na load ratio was influenced by the change in daytime UNaV (β=−0.67, F=16.8), rather than the change in nighttime UNaV. Conclusions: Lower Na balance was produced by add-on HCTZ to ARB treatment without an increase of intra-renal renin-angiotensin system activity, leading to restoration of nocturnal hypertension. A further study is needed to demonstrate that the reduction of UAGTV by additional diuretics to ARBs prevents the progression of nephropathy or cardiovascular events.

Impaired renal sodium excretion causes sodium retention, which prevents the nocturnal dip in blood pressure (BP); thus, high BP persists until excess sodium is excreted. The authors defined "dipping time" (DT) as the duration until the nocturnal BP falls below 90% of the daytime average. Diuretic (e.g., hydrochlorothiazide [HCTZ]) and angiotensin receptor blocker (ARB) are able to eliminate sodium retention and restore the non-dipper BP rhythm. Reanalysis of two previous studies demonstrate that HCTZ and ARB shortened the DT. Shortening DT correlated directly with the increase in daytime urinary sodium excretion (Study 2). DT can be used as a preliminary indicator of sodium retention.

AIMS We previously reported in patients with chronic kidney disease (CKD) that the circadian rhythms of blood pressure (BP) and urinary sodium excretion were both impaired into non-dipper pattern as renal function deteriorated. However, the circadian rhythm of urinary potassium excretion has not been studied in relation to renal dysfunction. METHODS BP and urinary excretion rates of sodium (UNaV) and potassium (UKV) were evaluated for daytime and nighttime to estimate their circadian rhythms in 83 subjects with CKD. RESULTS As renal function deteriorated, night/day ratios of UNaV and UKV were both increased. Night/day ratio of UKV was positively correlated with night/day ratio of UNaV (r = 0.60, p < 0.0001). Multiple regression analysis (R2 = 0.37, p < 0.0001) revealed that night/day ratio of UKV was determined independently by the night/day ratio of UNaV (r = -0.55, p < 0.0001), rather than renal function or night/day ratio of BP. CONCLUSIONS Circadian rhythm of natriuresis was regulated by renal function and night/day ratio of BP. On the other hand, the circadian rhythm of urinary potassium excretion was primarily determined by neither renal function nor BP, but was correlated with that of urinary sodium excretion.

We have shown that as renal function deteriorates, the circadian blood pressure (BP) rhythm shifts to a nondipper pattern and the duration until nocturnal BP decline [dipping time (DT)] is prolonged. We investigated whether or not morning hypertension (BP 2 h after awakening135/85 mmHg) in chronic kidney disease (CKD) was sustained type with a prolonged DT.Twenty-four-hour BP was monitored in 104 patients with CKD. Fifty-one of 104 participants (group A) did not exhibit morning hypertension. The patients with morning hypertension (group B, n=53) were classified into three groups: group C (n=23), participants who exhibited morning hypertension but did not meet the criteria for the surge or sustained type; group D (n=29), the sustained type (with no night-time BP readings120/70 mmHg); and group E (n=1), the surge type (systolic BP rises25 mmHg after awakening).The night/day BP ratio and DT were compared among groups A, C, and D because there was only one participant in group E. Night/day ratio of BP and DT were both significantly higher in group D compared with groups A and C. The prevalence of nondippers tended to be higher in group D compared with the other groups (A, 65%; C, 57%; D, 86%, P=0.09). Creatinine clearance was significantly lower in group D compared with groups A and C.Sustained elevation of night-time BP until the early morning and high night/day ratio of BP may contribute to the high frequency of morning hypertension, which is generally the sustained rather than the surge type in CKD.

Although recent genetic studies suggested that several genetic variants increase the risk for chronic kidney disease (CKD), the genes that underlie genetic susceptibility to this condition remain to be identified definitively. We showed that the C→T polymorphism (rs6929846) of BTN2A1 and A→G polymorphism (rs2569512) of ILF3 were significantly associated with myocardial infarction in Japanese individuals by a genome-wide association study. The purpose of the present study was to examine a possible association of these polymorphisms (rs6929846, rs2569512) with CKD in Japanese individuals.A total of 7542 Japanese individuals from two independent populations were examined: Subject panel A comprised 971 individuals with CKD (estimated glomerular filtration rate (eGFR)60 mL/min 1.73 m(-2)) ) and 2269 controls (eGFR ≥60 mL/min 1.73 m(-2) ); and subject panel B comprised 1318 individuals with CKD and 2984 controls.The χ(2) test revealed that rs6929846 of BTN2A1, but not rs2569512 of ILF3, was significantly related to the prevalence of CKD both in subject panels A (P = 0.0383) and B (P = 0.0477). Multivariable logistic regression analysis with adjustment for covariates revealed that the C→T polymorphism (rs6929846) of BTN2A1 was significantly associated with the prevalence of CKD in subject panels A (P = 0.0422; recessive model; odds ratio, 2.36) and B (P = 0.0386; dominant model; odds ratio, 1.21) with the T allele representing a risk for this condition.Our results suggest that BTN2A1 may be a susceptibility gene for CKD in Japanese individuals.

Summary The activity and gene expression of ornithine decarboxylase (ODC, an indicator of tumour promotion) were induced by the phorbol ester tumour promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA), in mouse skin. In the present study, the effect of colchicine, a microtu-bule-disrupting agent, on ODC activity and its gene expression were investigated. On administration of colchicine (100 μg) intraperitoneally 1·5 h before TPA treatment, ODC activity and ODC mRNA levels stimulated by TPA were suppressed to about 52 and 64%, respectively. These results suggest the involvement of a microtubule or colchicine-sensitive substrate in the signal transduction system for gene expression.

A case of posterior tongue lymphoma associated with adult T-cell leukemia (ATL) that occurred as a lesion in the lingual dorsal portion is reported in a 64-year-old woman. Initially, a diagnosis of Hodgkin's lymphoma was considered as no findings associated with ATL except lymphadenopathy and serum anti-ATLA antibodies were present. Combined radiotherapy and chemotherapy were administered with favorable results; however, 4 months later, Pneumocystis carinii pneumonia developed, and 2 months later, generalized lymphadenopathy and hypercalcemia evolved. At this time, a diagnosis of ATL was made. The patient died of renal dysfunction 6 months after the initial presentation. In suspected cases of ATL and malignant diseases of T-cell lineage, namely, malignant lymphoma and mycosis fungoides, the presence of HTLV-I infection should be confirmed by testing for anti-ATLA antibodies.

症例は40歳,女性.マグネシウムを含む市販の下剤を長期間大量服用し,高Mg血症と急性腎不全が発症した.水腎症や脱水が急性腎不全を発症させ高Mg血症を増悪させたと考えたが,甲状腺機能低下症が関与した可能性も示唆された.実験モデルでは甲状腺機能低下症が高Mg血症を惹起するという報告があるものの,臨床例での報告はなく,興味ある症例と考えられる.

The pathogenesis of antibody-mediated rejection has been investigated, but the precise mechanism of chronic glomerular rejection remains unclear. We have followed the clinicopathological course of a patient with pre-existing anti-donor antibody only detected by flow-cytometry crossmatch for over 3 years. Glomerular endothelial injuries and peculiar glomerular lesions were noted in biopsy specimen of postoperative year 3; however, both typical chronic vascular rejection lesions and peritubular capillary multilayered lesions were not revealed. We consider that the presence of weak anti-donor antibody leading early onset of acute humoral rejection played a role in the pathogenesis of early onset of chronic transplant glomerulopathy.

Background: Glomerular capillary injuries result in proteinuria, previously reported to be a risk factor for renal allograft dysfunction. According to the Banff 97 Working Classification of Renal Allograft Pathology, ‘double contours’ in glomerular capillary loops (GC-DC) were suggested to be most specific for chronic transplant glomerulopathy. Tenascin-C (TN), a component of extracellular matrix, is known to be overexpressed in various conditions. Methods: TN immunostaining was performed by the labeled streptavidin biotin method. The correlations between glomerular capillary TN (GC-TN) and proteinuria, and between GC-DC and GC-TN, were studied in 27 biopsies showing chronic allograft nephropathy (CAN) lesions. In 14 patients (serum creatinine Results: In CAN, GC-TN correlated with GC-DC. Proteinuria in patients with intense GC-TN tended to increase during 1 year after biopsy. In graft outcome analysis, GC-TN was significantly lower in stable grafts than in deteriorated ones. Furthermore, all 3 patients demonstrating weak GC-TN without GC-DC returned to dialysis. Conclusion: TN immunostaining is a sensitive method to detect glomerular capillary injury with a predictive value for renal allograft dysfunction.

Lysyl oxidase (LOX) initiates the crosslinking of the lysine-derived aldehyde and plays an essential role in maturation of collagen, for example in wound healing. Although the activity of this enzyme has been examined in various disorders, and a further intriguing aspect of the relationship between LOX and tumorigenesis has recently emerged, its gene expression pattern in tissues is still unknown. We examined LOX gene expression during wound healing in rat skin. In addition, type III collagen gene expression was studied to determine the formation of fibrils. The LOX mRNA level reached a peak by day 3 after injury, which was earlier than that of type III collagen, and continued at a high level until day 22. The type III collagen mRNA level began to rise from day 3 and had increased intensely by day 22. In situ hybridization revealed grains corresponding to LOX mRNA in the fibroblasts of the granulomatous tissue. These results suggest that LOX is produced before collagen synthesis in preparation for crosslinking in the early phase of wound healing.

Ultraviolet-B and PUVA share several biological events with phorbol ester tumor promoters. The effects of ultraviolet-B irradiation and topical PUVA treatment on ornithine decarboxylase activity, DNA synthesis, and protein kinase C activity, which are known to be induced or activated by phorbol ester tumor promoter, were investigated in hairless mouse skin. Ornithine decarboxylase activity was remarkably enhanced by ultraviolet-B and PUVA. Although PUVA did not affect DNA synthesis significantly, ultraviolet-B stimulated epidermal DNA synthesis approximately 5-fold over control values at 48 h. However, unexpectedly, neither cytosolic nor membrane-bound protein kinase C activity showed any change during the 2 h after either treatment. These results suggest that the protein kinase C system is not involved in the initial signal transduction system of ultraviolet-B or PUVA, unlike the case with phorbol ester tumor promoter.

Summary Herpes simplex viral DNA was detected in biopsy specimens obtained from four patients with Kaposi's varicelliform eruption using an in situ hybridization technique with btotinylated complementary DNA probes. Herpes simplex viral DNA was consistently found almost exclusively in the nuclei of giant cells and balloon cells in vesicles during day 2, 5 and 7 of the disease. In the nuclei, the viral DNA staining pattern was granular or agglomerate. No positive staining was observed in the cytoplasm.

Ornithine decarboxylase (ODC), a rate-limiting enzyme of polyamine synthesis, is a well-established indicator of tumor promotion [7]. The mechanism of ODC induction has been intensively studied using Northern blot analysis, especially in 12-O-tetradecanoylphorbol-13-acetatetreated (TPA-treated) skin [4, 10]. Following ultraviolet (UV) irradiation, ODC activity is markedly induced in the skin [5]. We have previously demonstrated a UVinduced increase in ODC gene expression using Northern blotting of mRNAs extracted from the whole skin of the mouse [6]. In the present study, we examined the spatial distribution o fODC mRNA in UV-irradiated mouse skin using an in situ hybridization technique. Female Charles River CD-1 mice aged 7 to 10 weeks were used in all experiments. The dorsal skin of the mouse was shaved 3 to 4 days before the experiments. The dorsa of the mice were irradiated with 40 mJ/cm 2 UV using two fluorescent lamps [FL20SE-30, Toshiba, Japan: UV emission between 280 and 320 nm (peak, 305 nrn)]. The dorsal skin was excised 24 h after irradiation, fixed in 4% paraformaldehyde (PFA), embedded in OCT compound (Lab-Tek, Naperville, Ill., USA), frozen in liquid nitrogen and sectioned at 4 ~tm. The sections were processed for in situ hybridization using a modification of methods previously described [3, 8]. In brief, sections were treated with proteinase K, post-fixed in 4% PFA, acetylated in acetic anhydride and dehydrated in an ethanol series. The samples were pre-hybridized for 30 rain at 42~ in a solution containing 50% formamide, 0.6 M NaC1, 20% dextran sulfate, 200 ~tg/ml bovine serum albumin, 0.02% polyvinylpyrrolidone, 250 I, tg/ml yeast tRNA, 100 ~tg/ml salmon sperm DNA, 0.02% Ficoll

In order to gain insight into the origin of Warthin's tumor, 10 cases of Warthin's tumor were compared immunohistologically with macroscopically and microscopically normal areas of the same glands, using 6 types of functional markers; carcinoembryonic antigen, secretory component, lactoferrin, keratin, S-100 protein and glial fibrillary acidic protein. It was shown that in normal parotid glands, the cells of acini, the intercalated ducts, the striated ducts, and the excretory ducts, as well as myoepithelial cells differed from each other in intensity and distribution of reaction products with antisera against those markers. Although the differences were rather subtle, the results suggested that those markers could differentiate the cell types of the salivary glands. In Warthin's tumors with double-layered tumor epithelia, the staining characteristics of the luminal and basal epithelia differed from each other. Epithelial cells on the luminal side showed immunological characteristics similar to striated duct cells of the parotid gland, while those of the basal side had characteristics similar to those of basal cells of the excretory duct. It is therefore suggested that the epithelia of Warthin's tumor may show differentiation into 2 different cell types.

It has been pointed that adrenergic β-receptor is greatly concerned in the salivary secretion of amylase, which is one of the main digestive enzymes (1). It has also been noticed that the repeated administrations of isoprenaline which has a strong affinity to β-receptor for catecholamines show a marked enlargement of the salivary glands (2-11). On the other hand, it has been also demonstrated that dibenamine, one of the potent α-adrenergic blocking agents, and guanethidine, an antiadrenergic agent, show a gradual atrophy in the salivary gland after the chronic administration (11, 12). Although there are many reports concerning the enlargement of the submaxillary glands treated with isoprenaline, little has been known whether this enlargement is due to the β-action of isoprenaline and whether it produces an enzymatic alterations in the enlarged salivary glands. The present study deals with the effects of β-adrenergic blocking agent on the development of the enlargement induced by the chronic administration of isoprenaline in rat submaxillary glands from the histological, histochemical, biochemical and pharmacological points of view.

Five cases of apocrine hidrocystoma are reported. One is multiple and the others are solitary lesions. There are more than 60 cases reported in the Japanese literature. Apocrine hidrocystomas usually occur as a solitary lesion. Only two cases of multiple apocrine hidrocystoma have been described so far in Japan. We reviewed the literature and discussed the clinicopathologic nature of this tumor. Apocrine hidrocystomas are usually composed of a cystic cavity lined by columnar epithelium, showing apocrine type secretion. Peripheral to this, myoepithelial cells are usually seen; however, they were absent from all of the present cases. Change in hue of the tumor is another characteristic feature. About half of the reported Japanese cases exhibited distinctive coloration, variously light brown, red-brown, or bluish. In contrast, non-Japanese cases tended to have darker coloration.