Association between adrenal function and dialysis vintage in hemodialysis patients.

INTRODUCTION: Adrenal insufficiency in hemodialysis patients is commonly encountered in clinical practice. However, its association with end-stage renal disease is unclear. We investigated the relationship between adrenal function and relevant clinical parameters, focusing on dialysis vintage. METHODS: Altogether, 100 maintenance hemodialysis patients were enrolled (age: 69.8 ± 11.8 years, dialysis vintage: 9.4 ± 9.2 years). Basal serum cortisol levels were measured and their associations with relevant clinical parameters were investigated. Subsequently, hormone stimulation tests were performed to assess adrenal function. RESULTS: Basal serum cortisol significantly decreased with an increase in dialysis vintage (< 10 years, 11.9 ± 3.7 µg/dL; 10-19 years, 10.9 ± 2.9 µg/dL; ≥ 20 years, 9.7 ± 3.8 µg/dL). Basal cortisol was negatively correlated with dry weight, ß2-microglobulin, creatinine, and lymphocyte count and positively correlated with brachial-ankle pulse wave velocity. Significant negative correlations were observed between basal cortisol and dialysis vintage after adjusting for confounding variables in the multivariate analysis. Standard adrenocorticotropic hormone (ACTH) and corticotropin-releasing hormone (CRH) stimulation tests were performed in 17 patients. Seven patients were diagnosed with adrenal insufficiency and all of them had a long dialysis vintage (≥ 10 years). According to the rapid ACTH test, cortisol responses were significantly decreased in patients with long dialysis vintage compared to those with short dialysis vintage (< 10 years). Similar findings were observed in ten patients without adrenal insufficiency. The CRH loading test showed similar tendencies, although the differences were not statistically significant. CONCLUSIONS: Adrenal function decreased with an increase in dialysis vintage. Long-term dialysis patients might be susceptible to adrenal insufficiency.

Assessment of the accuracy of an intermittent-scanning continuous glucose monitoring device in patients with type 2 diabetes mellitus undergoing hemodialysis (AIDT2H) study.

FreeStyle Libre has been approved for use in patients undergoing hemodialysis (HD) in Japan, unlike Europe and the United States; however, evidence regarding its accuracy in such patients is sparse. Forty-one participants with type 2 diabetes undergoing HD were recruited. The overall mean absolute relative difference and mean absolute difference were 23.4% and 33.9 mg/dL, respectively. Sensor glucose levels and capillary glucose levels were significantly correlated (r = 0.858, P < .01), although the sensor glucose levels were significantly lower than the capillary glucose levels. The accuracy of FreeStyle Libre in patients undergoing HD became deteriorated with the days of usage. The percentage of sensor results in Zones A and B in the consensus error grid analysis and in the Clarke error grid analysis were 99.7% and 99.0%, respectively. Its insufficient accuracy necessitates adjunct usage of FreeStyle Libre with self-monitoring of blood glucose in patients undergoing HD.

Eradication therapy for Helicobacter pylori infection improves nutrition status in Japanese hemodialysis patients: a pilot study.

Plasma ghrelin level is influenced by Helicobacter pylori (H. pylori) status and the severity of gastric mucosal atrophy, and the ghrelin level is associated with nutrition status in hemodialysis patients. Here, we investigated the efficacy of H. pylori eradication therapy in improving nutrition status in relation to the ghrelin level in H. pylori-positive hemodialysis patients. Of H. pylori-positive patients receiving hemodialysis at 8 dialysis center, 21 patients underwent gastroduodenoscopy for evaluation of the severity of gastric atrophy, and nutrition markers and plasma ghrelin levels before and 1 year after H. pylori eradication therapy were evaluated. Serum cholinesterase level was significantly increased after H. pylori eradication compared with the level before eradication (303.2 ± 76.0 vs 287.3 ± 68.1 IU/L, p = 0.029). In particular, cholesterol (before, 196.6 ± 23.2 mg/dl; after, 206.1 ± 25.9 mg/dl, p = 0.042) and cholinesterase levels (before, 296.9 ± 70.8 IU/L; after, 316.4 ± 73.8 IU/L, p = 0.049) increased more strongly in patients with mild-moderate atrophy than those with severe atrophy, irrespective of improvement of plasma acyl-ghrelin and desacyl-ghrelin levels after eradication therapy. In conclusion, H. pylori eradication may improve nutrition status by increasing serum cholinesterase and cholesterol levels in hemodialysis patients, especially those with mild and moderate gastric mucosal atrophy.

Gender Differences in Plasma Ghrelin Levels in Hemodialysis Patients.

Ghrelin is an orexigenic hormone mainly secreted by the stomach, and it decreases according to the severity of gastric atrophy. Ghrelin has multiple favorable functions, including protein anabolism enhancement, anti-inflammatory activity, and cardiovascular protection, and is associated with survival in hemodialysis (HD) patients. Although the plasma level and role of ghrelin may be different depending on gender, they have not been completely assessed in HD patients. We enrolled 80 (male/female: 51/29) maintenance HD patients. An upper gastrointestinal endoscopic examination was performed for all patients to determine the severity of gastric mucosal atrophy and Helicobacter pylori infection. We measured plasma acyl and desacyl ghrelin levels and assessed the association between ghrelin levels and relevant clinical parameters, including nutrition, inflammation, atherosclerosis, and bone metabolism, by gender. Both acyl and desacyl ghrelin levels in female HD patients were significantly higher than those in male HD patients. When stratified by gastric mucosal atrophy, these gender differences were observed only in patients without gastric atrophy. In female patients, acyl ghrelin level was negatively correlated with age. In male patients, both acyl and desacyl ghrelin levels were positively correlated with bone mineral density. Multiple regression analysis showed significant positive correlations between both ghrelin levels and female gender after adjusting for confounding factors. Plasma ghrelin levels were higher in female HD patients than in male HD patients. The gender difference was more evident in patients without gastric atrophy.

Correction to: Impaired endogenous nighttime melatonin secretion relates to intrarenal renin-angiotensin system activation and renal damage in patients with chronic kidney disease.

In the original publication, an error occurred in Table 4 (B), under Nighttime group. The value of "Nighttime Log U-AGT/Cr" for model 3 (under R = 0.68) was incorrectly published as 0.11. The correct value should read as -0.31.

A Rare Case of Lupus Nephritis Presenting as Thrombotic Microangiopathy with Diffuse Pseudotubulization Possibly Caused by Atypical Hemolytic Uremic Syndrome.

A 31-year-old woman was admitted to our hospital for thrombotic microangiopathy (TMA). She was diagnosed with systemic lupus erythematosus (SLE) and class V lupus nephritis. She had no aggravated SLE activity, Shiga toxin positivity, ADAMTS13 abnormality, or other causes of secondary TMA. Plasma exchange partially improved TMA, and eculizumab was introduced for suspected atypical hemolytic uremic syndrome (aHUS), as eculizumab was effective in suppressing the TMA activity. A kidney biopsy revealed diffusely organized crescents (pseudotubulization) with glomerular and arteriolar endothelial injury and subepithelial immune deposits. Thus, this was a rare case of lupus nephritis presenting as TMA with pseudotubulization possibly caused by aHUS.

Efficacy of Reduced Dosage of Amoxicillin in an Eradication Therapy for Helicobacter pylori Infection in Patients on Hemodialysis: A Randomized Controlled Trial.

BACKGROUND: An optimum Helicobacter pylori-eradication regimen for hemodialysis patients is yet to be established because of different pharmacokinetics of amoxicillin involved between hemodialysis patients and healthy subjects. We investigated to establish appropriate doses of amoxicillin for H. pylori infection eradication in hemodialysis patients. METHODS: Of 409 hemodialysis patients screened for H. pylori infection, 37 H. pylori-positive patients were randomized to different 1-week eradication regimens: esomeprazole 20 mg twice a day (b.i.d.) and clarithromycin 200 mg b.i.d., plus amoxicillin at either 750 mg b.i.d. (group A; conventional) or 250 mg b.i.d. (group B; experimental). Sixty-three patients with normal renal function received the conventional regimen (group C). Successful eradication was confirmed by urea breath testing. RESULTS: Eradication rates of group B (reduced amoxicillin-regimen) were 84.2% in intention-to-treat analysis and 88.9% in per-protocol analysis, which were similar with group A (77.8 and 77.8%) and group C (74.6 and 81.0%). However, the incidence of adverse events in group A was significantly higher than that in group C (22.2 vs. 5.1%, p = 0.027). CONCLUSIONS: In H. pylori-positive hemodialysis patients, amoxicillin at 250 mg b.i.d. may be an appropriate scheme for eradication with equivalent effects to the conventional therapy and safety effects for adverse events.

Natural Course of Helicobacter pylori Infection in Japanese Hemodialysis Patients.

INTRODUCTION: Helicobacter pylori (H. pylori) infection is one of the major risk factors for gastrointestinal morbidity in hemodialysis patients. Primary end point is to investigate H. pylori infection rate in hemodialysis patients. As secondary end point, we clarified whether pepsinogen (PG) level was related with H. pylori infection status in hemodialysis patients. METHODS: Serum levels of PG I, II, and anti-H. pylori IgG antibody were assessed in 500 Japanese hemodialysis patients. RESULTS: H. pylori infection rate was 15.0% (75/500; 95% CI 12.0-18.4). The duration of hemodialysis in H. pylori-positives was 4.6 ± 3.8 years, which was significantly shorter than in H. pylori-negatives (7.3 ± 6.9, p = 0.001). PG I levels positively correlated with the PG II level and PG I/II ratio (|R| = 0.661, p < 0.001, and |R| = 0.544, p <0.001, respectively). Using a cutoff value of 7.75, the sensitivity and specificity of PG I/II ratio for predicting H. pylori-negatives were 86.3 and 87.8%, respectively (area under the curve 0.930). CONCLUSIONS: In hemodialysis patients, infection rate with H. pylori was <20%, with lower rates in patients receiving hemodialysis for longer terms. A PG I/II ratio with a cutoff value of 7.75 may be useful for screening for H. pylori status.

Membranous Nephropathy with an Enhanced Granular Expression of Thrombospondin Type-1 Domain-containing 7A in a Pregnant Woman.

A 30-year-old woman with proteinuria first noted at 26 weeks of gestation was admitted to undergo further evaluation. A renal biopsy revealed membranous nephropathy (MN). There was no evidence of any secondary MN. Prednisolone was initiated 6 months after delivery. Four months later, her urine protein became negative. Enhanced granular staining for thrombospondin type-1 domain-containing 7A (THSD7A) in the glomeruli was retrospectively detected in a biopsy specimen. A literature review revealed that 60% of cases of THSD7A-related MN occurred in women of childbearing age. Therefore, THSD7A-related MN should be considered in female patients presenting with idiopathic MN in childbearing age.

Severity of Gastric Mucosal Atrophy Is the Major Determinant of Plasma Ghrelin Level in Hemodialysis Patients.

BACKGROUND: Ghrelin, an orexigenic hormone, has multiple favorable functions including protein anabolism enhancement, anti-inflammatory actions, and cardiovascular protection. A low plasma ghrelin level is associated with increased mortality in patients treated with hemodialysis (HD). However, it is unclear whether the plasma ghrelin level in HD patients correlates with the severity of gastric mucosal atrophy and Helicobacter pylori status. METHODS: Seventy-eight maintenance HD patients and 51 non-dialysis patients with chronic kidney disease were evaluated for severity of gastric mucosal atrophy by gastroduodenoscopy and for H. pylori status using an anti-H. pylori-antibody and rapid urease test. Plasma acyl and des-acyl ghrelin levels were measured and their associations with relevant clinical parameters were investigated. RESULTS: Des-acyl ghrelin level in HD patients was significantly higher than that in patients with kidney function preserved. Although acyl and des-acyl ghrelin levels were similar between current H. pylori positive and negative HD patients, both levels decreased significantly with the progress of endoscopic gastric mucosal atrophy in HD patients. Serum pepsinogen (PG) I level and PG I/II ratio decreased significantly according to the severity of atrophy in HD patients and positively significantly correlated with both ghrelin levels. Multiple regression analysis showed significant positive correlations between acyl ghrelin and PG I levels (ß = 0.738, p < 0.001) and significant negative correlations between ghrelin and age, albumin, and creatinine levels. CONCLUSIONS: Gastric atrophy is the major determinant of ghrelin level in HD patients. Management practices, such as H. pylori eradication, before advanced atrophy may be required to prevent the decrease of ghrelin levels and improve the prognosis of HD patients.

Serum Creatinine Modifies Associations between Body Mass Index and Mortality and Morbidity in Prevalent Hemodialysis Patients.

BACKGROUND: High body mass index (BMI) is paradoxically associated with better outcomes in hemodialysis (HD) patients. This study aimed to examine whether serum creatinine (Cr), a marker of muscle mass, could modify the association between BMI, and mortality and morbidity in prevalent HD patients. METHODS: A retrospective study was conducted using a nationwide database from the registry of the Japanese Society for Dialysis Therapy. A total of 119,099 patients were selected (age: 65±12 years; median time on HD: 5.6 years; male: 62%), and we examined the association of basal BMI with mortality and morbidity after a 1-year period. Patients were stratified either by BMI into 4 groups or by serum Cr levels into 3 tertiles. Odds ratio (OR) [95% confidence interval] was calculated by multivariate logistic regression analysis. RESULTS: Higher BMI did not predict a higher 1-year total mortality. However, when we stratified the patients by serum Cr levels, the risk of cardiac death became significantly higher in obese patients with the lowest Cr levels, in both males (OR 2.82 [1.51-5.27], p<0.01) and females (OR 2.00 [1.03-3.90], p<0.05). The risk of new cerebral infarction was also higher in obese male patients within the lowest Cr tertile. In contrast, there was a significantly lower risk of cardiac, cerebrovascular, and infection-related death in non-obese patients with higher levels of Cr. Higher serum Cr was also related to a lower risk of cardiovascular events and hip fracture in non-obese HD patients. CONCLUSIONS: The obesity paradox was found to be present in HD patients only when obesity was defined by BMI. Decreased serum Cr levels were found to be positively associated with clinical poor outcomes in all BMI groups. Thus, irrespective of BMI, the evaluation of serum Cr levels is important to predict mortality and morbidity in patients receiving regular HD.

Impaired endogenous nighttime melatonin secretion relates to intrarenal renin-angiotensin system activation and renal damage in patients with chronic kidney disease.

BACKGROUND: Activation of the intrarenal renin-angiotensin system (RAS) plays a critical role in the pathophysiology of chronic kidney disease (CKD) and hypertension. The circadian rhythm of intrarenal RAS activation leads to renal damage and hypertension, which are associated with diurnal blood pressure (BP) variation. The activation of intrarenal RAS following reactive oxygen species (ROS) activation, sympathetic hyperactivity and nitric oxide (NO) inhibition leads to the development of renal damage. Melatonin is a hormone regulating the circadian rhythm, and has multiple functions such as anti-oxidant and anti-adrenergic effects and enhancement of NO bioavailability. Nocturnal melatonin concentrations are lower in CKD patients. However, it is not known if impaired endogenous melatonin secretion is related to BP, intrarenal RAS, or renal damage in CKD patients. METHODS: We recruited 53 CKD patients and conducted 24-h ambulatory BP monitoring. urine was collected during the daytime and nighttime. We investigated the relationship among the melatonin metabolite urinary 6-sulphatoxymelatonin (U-aMT6s), BP, renal function, urinary angiotensinogen (U-AGT), and urinary albumin (U-Alb). RESULTS: Patients' U-aMT6s levels were significantly and negatively correlated with clinical parameters such as renal function, systolic BP, U-AGT, and U-Alb, during both day and night. Multiple regression analyses for U-aMT6s levels were performed using age, gender, renal function, and each parameter (BPs, U-AGT or U-Alb), at daytime and nighttime. U-aMT6s levels were significantly associated with U-AGT (ß = -0.31, p = 0.044) and U-Alb (ß = -0.25, p = 0.025) only at night. CONCLUSION: Impaired nighttime melatonin secretion may be associated with nighttime intrarenal RAS activation and renal damage in CKD patients.

Augmented circadian rhythm of the intrarenal renin-angiotensin systems in anti-thymocyte serum nephritis rats.

We report that disturbance to the circadian rhythm of urinary angiotensinogen (AGT) excretion may lead to renal damage, hypertension and diurnal blood pressure (BP) variations. We aim to clarify the circadian rhythm of the intrarenal renin-angiotensin system (RAS) and its contribution to renal damage, hypertension and BP variations, and to evaluate whether the administration of RAS blockers influences the circadian rhythms of intrarenal RAS components. Anti-thymocyte serum (ATS) nephritis rats were used as a chronic progressive glomerulonephritis model (group A) and compared with control rats (group C). Other rats with ATS nephritis received olmesartan medoxomil (an angiotensin II (AngII) type 1 receptor (AT1R) blocker; group AO) or hydralazine (a vasodilator; group AH). The levels of intrarenal RAS components were evaluated every 6 h. The expression levels of intrarenal AGT, AngII and AT1R were increased in group A and peaked at the same time as BP and urinary protein excretion during the rest phase. The amplitude of the circadian fluctuation of these proteins was more increased in group A than in group C. The circadian fluctuation of these proteins was reduced in groups AO and AH. However, renal function, proteinuria and augmentation of intrarenal RAS components were reduced only in group AO. Intrarenal RAS components, such as AGT, AngII and AT1R proteins, were increased and the amplitude of the oscillations of these proteins was augmented in ATS nephritis rats. Interestingly, renal damage may be linked to the activation of the intrarenal RAS independent of the amplitude of its oscillations and BP.

Relationship between ghrelin, Helicobacter pylori and gastric mucosal atrophy in hemodialysis patients.

AIM: To investigate the relationship between plasma ghrelin level, Helicobacter pylori (H. pylori) infection status and the severity of atrophy in hemodialysis patients. METHODS: One hundred eights patients who received hemodialysis and 13 non-hemodialysis H. pylori-negative controls underwent gastroduodenoscopy to evaluate the severity of gastric atrophy. Serum levels of pepsinogen (PG) were measured as serum markers of gastric atrophy. H. pylori infection was evaluated by anti-H. pylori IgG antibody, rapid urease test and culture test. We classified H. pylori infection status as non-infection, present infection and past infection. In addition, plasma acyl-ghrelin and desacyl-ghrelin levels were measured by enzyme-linked immunosorbent assay. RESULTS: Infection rate of H. pylori was 45.4% (49/108). Acyl-ghrelin level in the non-infection group (39.4 ± 23.0 fmol/mL) was significantly higher than in the past (23.4 ± 19.9 fmol/mL, P = 0.005) and present infection groups (19.5 ± 14.0 fmol/mL, P < 0.001). Furthermore, desacyl-ghrelin level in the non-infection group (353.2 ± 190.2 fmol/mL) was significantly higher than those in the past (234.9 ± 137.5 fmol/mL, P = 0.008) and present infection groups (211.8 ± 124.2 fmol/mL, P < 0.001). Acyl-ghrelin was positively correlated with the PG I level and PG I/II ratio (|R| = 0.484, P < 0.001 and |R| = 0.403, P < 0.001, respectively). Both ghrelins were significantly decreased in accordance with the progress of endoscopic atrophy (both P < 0.001) and acyl-ghrelin was significantly lower in patients with mild, moderate and severe atrophy (24.5 ± 23.1 fmol/mL, 20.2 ± 14.9 fmol/mL and 18.3 ± 11.8 fmol/mL) than in those with non-atrophy (39.4 ± 22.2 fmol/mL, P = 0.039, P = 0.002 and P < 0.001, respectively). CONCLUSION: In hemodialysis patients, plasma ghrelin level was associated with the endoscopic and serological severity of atrophy related to H. pylori infection.

Tubulointerstitial Nephritis Caused by Peritubular Capillaritis Accompanied by Cryoglobulinemia.

A 73-year-old man with fever, renal insufficiency, and purpura was referred to our hospital to be evaluated for renal insufficiency. Renal biopsy revealed acute and chronic tubulointerstitial nephritis with no laboratory findings of sarcoidosis or connective tissue disease. Low C4 levels and elevation of rheumatoid factors suggested cryoglobulinemia, which was confirmed with quantitative analysis. CD34 staining of kidney tissue revealed peritubular capillaritis. Antineutrophil cytoplasmic antibodies were negative. The etiology of peritubular capillaritis was not clear in our patient; however, it might be associated with cryoglobulinemia because we cannot find any other diseases that could have induced the peritubular capillaritis.

Hyperuricaemia is associated with renal damage independently of hypertension and intrarenal renin-angiotensin system activation, as well as their circadian rhythms.

AIM: Both hyperuricaemia and activation of the intrarenal renin-angiotensin system (RAS) play an important role in the development of hypertension and renal damage. However, it has not been clear whether hyperuricaemia is associated with renal damage due to hypertension or intrarenal RAS activation, as well as their circadian rhythms. METHODS: We recruited 43 chronic kidney disease (CKD) patients who did not receive RAS blockers and antihyperuricaemic drugs, and investigated the relationship among serum uric acid (sUA) levels, the circadian rhythm of urinary angiotensinogen (U-AGT) excretion levels, and the levels of albuminuria (U-ACR) and proteinuria (U-P/Cr). RESULTS: sUA levels were significantly associated with estimated glomerular filtration rate (eGFR) (P = 0.002), systolic blood pressure (SBP) (daytime, P = 0.031), and U-ACR (daytime, P = 0.006 and nighttime, P = 0.008) and U-P/Cr (daytime, P = 0.017 and nighttime, P = 0.013). However, there were no significant differences between sUA levels and SBP in nighttime and U-AGT excretion levels in both time periods. Multiple regression analyses for sUA levels were performed using age, sex, eGFR and each parameter (SBP, U-AGT/Cr, U-ACR or U-P/Cr). sUA levels were not associated with SBP or U-AGT/Cr in both time periods. sUA levels tended to correlate with U-P/Cr levels in nighttime, and were significantly associated with U-P/Cr in daytime (P = 0.026) and U-ACR in daytime (P = 0.017) and nighttime (P = 0.046). Moreover, no significant differences were found between sUA levels and night-to-day ratios of some parameters. CONCLUSION: These data suggest that hyperuricaemia is associated with renal damage, independently of hypertension and intrarenal RAS activation, as well as their circadian rhythms.

The level of urinary α1 microglobulin excretion is a useful marker of peritubular capillaritis in antineutrophil cytoplasmic antibody associated vasculitis.

BACKGROUND: Antineutrophil cytoplasmic antibody (ANCA) associated vasculitis affects small vessels in the kidney (i.e., arterioles, glomerular or peritubular capillaries, or venules). Although crescentic glomerulonephritis is a common histological finding, the incidence of peritubular capillaritis (PTC) or arteriolitis is unclear. Moreover, the laboratory data that reflect the degree of renal histological damage and distinguish between PTC and arteriolitis have not yet been clarified. METHODS: We investigated laboratory data and histological findings from 11 patients diagnosed with ANCA-associated vasculitis (2 men and 9 women, mean age 70.3 ± 3.3 years) whose renal biopsies were performed between 2009 and 2014. RESULTS: All patients were positive for myeloperoxidase (MPO)-ANCA. PTC or arteriolitis was detected in six patients (54.5 %), respectively. The only significant positive relationship between laboratory data and histological findings observed was that between levels of urinary α1 microglobulin (u-α1MG) excretion and the percentage of tubular atrophy and interstitial fibrosis (r = 0.67, p = 0.035). No significant differences in laboratory data were found between patients with or without arteriolitis. However, the levels of u-α1MG excretion were significantly higher in patients with PTC than in those without PTC (75.2 ± 19.5 vs. 15.0 ± 3.6 mg/dl, p = 0.035). CONCLUSION: PTC or arteriolitis occurs at a high rate independently of crescentic glomerulonephritis in ANCA-associated vasculitis patients. The levels of u-α1MG excretion reflect the degrees of tubular atrophy and interstitial fibrosis. Moreover, high levels of u-α1MG excretion suggest that PTC is more likely than arteriolitis in ANCA-associated vasculitis patients.

Role of intrarenal (pro)renin receptor in ischemic acute kidney injury in rats.

BACKGROUND: (Pro)renin receptor [(P)RR], a trans-membrane receptor for renin and prorenin, is involved in the local activation of renin-angiotensin system (RAS) in the kidney. However, it remains to be determined whether (P)RR plays a role in the development of ischemic acute kidney injury (AKI). METHODS: We examined the abundance of (P)RR, renin/prorenin, angiotensinogen (AGT), AT1 receptor (AT1R), phosphorylation of extracellular signal-regulated protein kinase 1/2 (ERK 1/2) and nuclear factor-κB (NF-κB) by Western blots at 6, 24 and 48 h, and at 7 days after 45-min ischemic injury in rats. Intrarenal angiotensin II (Ang II) levels were determined by radioimmunoassay. We then tested whether the beneficial effects of oral loading of saline solution (1.0 % NaCl) for 7 days prior to ischemic injury were associated with changes in RAS components and ERK 1/2 and NF-κB phosphorylation in the kidney. We also examined the effect of AT1R blocker, olmesartan, on ischemia-induced changes of (P)RR downstream such as AGT and phosphorylation of ERK 1/2. RESULTS: Renal ischemia increased the abundance of (P)RR protein at 24 h, and peaked at 48 h. (P)RR was mainly stained in the connecting tubules and collecting ducts in control rats, while ischemia increased its immunointensity in the damaged proximal tubules. Renal ischemia increased phosphorylation of ERK 1/2 and NF-κB proteins as early as at 6 h. There was a significant increase in AGT and Ang II levels at 24 and 48 h. Prior saline loading prevented the increase in serum creatinine at 48 h (5.36 ± 1.26 vs. 3.38 ± 1.74 mg/dL, p < 0.05), and suppressed the increases in renal (P)RR, AGT and Ang II contents. Saline drinking also significantly blocked the ischemia-induced increases in phosphorylation of ERK 1/2 and NF-κB. In contrast, although treatment with olmesartan (10 mg/kg/day) for 14 days suppressed an increase of intrarenal AGT, olmesartan did not alleviate ischemic AKI, along with no change of (P)RR and phosphorylated ERK 1/2. CONCLUSIONS: These findings suggest that increased (P)RR is associated with activation of RAS-independent downstream such as ERK 1/2 and NF-κB phosphorylation in the ischemic kidney.

Disturbed circadian rhythm of the intrarenal renin-angiotensin system: relevant to nocturnal hypertension and renal damage.

BACKGROUND: The intrarenal renin-angiotensin system (RAS) plays an important role in the development of hypertension and renal damage. Disruption of diurnal blood pressure (BP) variation is an additional risk factor for renal damage. However, little is known regarding whether intrarenal RAS circadian rhythm exists or if it influences the disruption of diurnal BP and renal damage. METHODS: We investigated the circadian rhythm of urinary angiotensinogen (U-AGT) that reflects intrarenal RAS activity in 14 individuals without chronic kidney disease (CKD) and 36 CKD patients classified according to circadian BP rhythms. RESULTS: BP values were higher during the daytime than during the nighttime in both individuals without CKD and CKD patients. U-AGT levels were not different between the daytime and nighttime in individuals without CKD, but were significantly higher in the daytime in CKD patients (log U-AGT/creatinine: daytime, 2.39 ± 0.99; nighttime, 2.24 ± 1.06; p = 0.001). Furthermore, in CKD patients showing a riser pattern of circadian BP, U-AGT levels did not decrease during the nighttime compared with those in the daytime (log U-AGT/creatinine: daytime, 2.51 ± 0.65; nighttime, 2.52 ± 0.71; p = 0.78). Circadian fluctuation of albuminuria and proteinuria occurred parallel to that of the U-AGT levels. U-AGT levels were significantly and positively correlated with the levels of BP and circadian fluctuation of U-AGT was correlated with diurnal BP changes. CONCLUSION: These data suggest that the circadian rhythm of intrarenal RAS activation may lead to renal damage and hypertension, which are associated with diurnal BP variation.

Clinical manifestation of hypercalcemia caused by adrenal insufficiency in hemodialysis patients: a case-series study.

OBJECTIVE: The goal of this study was to clarify the clinical manifestation of hypercalcemia due to hypoadrenalism in hemodialysis (HD) patients. METHODS: We retrospectively analyzed the clinical characteristics of five HD patients who had presented with hypercalcemia due to adrenal insufficiency (age: 69 ± 7 [58-75] years old, time on HD: 13 ± 11 [2-32] years). We conducted corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) stimulation tests. We also examined serum bone turnover markers before and after glucocorticoid replacement. RESULTS: All patients had critical illnesses at the onset of hypercalcemia. They had at least one symptom, such as eosinophilia, hypoglycemia, or fever. The prevalence of hypercalcemia due to adrenal insufficiency was 1.3% in maintenance HD patients on admission. The causes of adrenal insufficiency were isolated ACTH deficiency, pituitary apoplexy, pituitary atrophy, glucocorticoid withdrawal syndrome, and unilateral adrenalectomy. Serum calcium (Ca) levels corrected by serum albumin were maximally increased to 12.9 to 14.3 mg/dL in four anuric HD patients and mildly elevated to 10.4 mg/dL in a patient with residual diuresis. Their basal serum cortisol levels ranged from <1.0 to 15.4 µg/dL. Single CRH injections failed to increase serum cortisol in any of the patients. Glucocorticoid replacement acutely normalized serum Ca and decreased levels of carboxy-terminal telopeptide of type I collagen, a marker of bone resorption. CONCLUSION: Adrenal insufficiency could therefore be an occult cause of hypercalcemia in anuric HD patients who are critically ill.