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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.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.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, β2-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.Adrenal function decreased with an increase in dialysis vintage. Long-term dialysis patients might be susceptible to adrenal insufficiency.

Background Adrenal insufficiency causes abnormal subjective symptoms such as general fatigue, signs such as hypotension, and abnormalities such as hypoglycemia and leads to poor prognosis. However, all these are also observed in hemodialysis (HD) patients without adrenal insufficiency. The morphology of the adrenal glands in HD patients with adrenal insufficiency is unclear. Therefore, this study was performed to clarify the characteristics of adrenal insufficiency in HD patients. Methods Seventeen HD patients who had abnormal subjective symptoms and test results indicating adrenal insufficiency and whose serum cortisol levels were less than 18 μg/dL were recruited. Results Seven HD patients were diagnosed with adrenal insufficiency. No significant differences were found about abnormal subjective symptoms and images between patients with and without adrenal insufficiency. The levels of serum cortisol and serum cholinesterase were significantly lower in patients with adrenal insufficiency than in those without adrenal insufficiency. A plasma cortisol level of 8.45 μg/dL showed the highest sensitivity and specificity in the receiver operating characteristic curve. The serum cortisol levels were significantly and negatively associated with the plasma ferritin levels in patients with adrenal insufficiency. Multiple linear regression analyses revealed that the serum cortisol levels showed a significant negative association with the plasma ferritin levels after adjustments. Conclusions It is difficult to infer adrenal insufficiency in HD patients by subjective symptoms and images of the adrenal glands. Adrenal insufficiency correlates with nutritional and inflammatory status, and the levels of serum cholinesterase and plasma ferritin might reflect their corresponding status.

Preeclampsia and superimposed preeclampsia usually develop after 20 weeks of gestation. We report a case of a 35-year-old Japanese woman who developed hypertensive disorders of pregnancy (HDP) before 20 weeks of gestation. She presented with hypertension and proteinuria at 9 and 11 weeks of gestation, respectively, and developed nephrotic syndrome at 17 weeks of gestation. She did not have definite hypertension or urinary abnormalities before pregnancy. The patient was serologically positive for the antinuclear antibody. However, the complement levels were normal and anti-phospholipid antibody was not detected. A renal biopsy performed at 18 weeks of gestation showed diffuse endotheliosis and tip lesions of secondary focal segmental glomerulosclerosis but no hypertensive changes of the arterioles. Although electron microscopic examination showed electron-dense deposits in the subendothelial lesions, they were considered nonspecific plasma exudation by mass spectrometry. An abortion was performed at 20 weeks gestation because the patient’s congestive symptoms due to nephrotic syndrome had worsened and marked fetal growth restriction was observed. After delivery, the patient’s symptoms resolved immediately without any additional treatment; however, continuous antihypertensive medication was required. Finally, the patient was diagnosed with HDP based on the renal biopsy findings and her clinical course after delivery. Compared to previous reports, this case describes the earliest onset of HDP. Thus, HDP should be considered as a differential diagnosis in pregnant women with hypertension or proteinuria presenting with symptoms before 20 weeks of gestation.

Acute kidney injury (AKI) contributes to the development of acute lung injury (ALI) via proinflammatory responses. We hypothesized that activation of a nicotinic acetylcholine receptor (nAChR), which exerts cholinergic anti-inflammatory effects on macrophages, could reduce ALI after AKI. We aimed to determine whether nAChR agonists could reduce ALI after AKI and which macrophages in the lung or spleen contribute to the improvement of ALI by nAChR agonists. We induced AKI in male mice by unilateral ischemia-reperfusion injury (IRI) with contralateral nephrectomy and administered nAChR agonists in three experimental settings

Objective The intrarenal renin-angiotensin system (RAS) is activated in chronic kidney disease (CKD) patients and is not suppressed at night in CKD patients showing nocturnal hypertension, contributing to renal damage. Furthermore, changes in RAS inhibitor administration from morning to evening, namely chronotherapy, ameliorates renal damage at night. We attempted to clarify whether or not chronotherapy ameliorates renal damage by suppressing the intrarenal RAS activity. Methods We recruited 34 CKD patients with RAS inhibitors in the morning. We conducted ambulatory blood pressure (BP) monitoring and urine collection and evaluated urinary albumin (Alb) and angiotensinogen (AGT), which are surrogate markers for intrarenal RAS activity during the day and at night, respectively. The same experiments were conducted after changing the administration time. The ratio of values associated with morning versus evening dosing was defined as the morning to evening (M/E) ratio. Results The M/E ratio of urinary Alb had a significant and positive relationship with that of urinary AGT during the day and at night in all CKD patients. However, no significant relationships were found between the M/E ratios of urinary Alb and AGT using multiple linear regression analyses. Conversely, there was a significant and positive relationship between the M/E ratios of urinary Alb and AGT at night but not during the day in CKD patients whose estimated glomerular filtration rate was 0.90, even after adjustment. Conclusion This study indicated that chronotherapy with RAS inhibitors improved the renal damage via intrarenal RAS suppression, especially in CKD patients with an impaired renal function and nocturnal hypertension.

Background Low birth weight (LBW) is associated with end-stage kidney disease and hypertension and is considered to be a surrogate marker of low nephron number. Low nephron number is hypothesized to contribute to glomerular hyperfiltration that may cause kidney injury; however, this is not yet proven. Until now, the hyperfiltration in LBW patients has not been shown directly yet. Case presentation A 23-years-old female was referred with the persistent proteinuria and decreased renal function (estimated glomerular filtration rate by cystatin C (eGFRcys); 41.86 ml/min). She was a premature baby with low birth weight (704 g, 24 gestational weeks). Renal biopsy demonstrated focal segmental glomerulosclerosis (FSGS) of the perihilar variant with expanded glomerular diameter. We calculated the single-nephron estimated glomerular filtration rate (SN-eGFR) that was higher than that of the same age group in the healthy living kidney donors and speculated that glomerular hyperfiltration is a pathophysiological cause of FSGS. Conclusion This is the first case of SN-eGFR measurement in a patient with LBW. The increased SN-eGFR in this case provides an important insight into the pathophysiological mechanisms of LBW for its progression to kidney disease.

Atypical anti-glomerular basement membrane (GBM) nephritis is a rare variant of the classical anti-GBM antibody disease. Patients present with an undetectable anti-GBM antibody but show linear glomerular basement membrane staining for immunoglobulin. We present a 69-year-old man who underwent a living-donor kidney transplant. The aetiology of the renal failure was a focal segmental glomerulonephritis-like lesion resistant to immunosuppressive therapy. A renal graft biopsy revealed diffuse endocapillary hypercellularity, and mild mesangiolysis with linear GBM staining for IgG. The patient was diagnosed with atypical anti-GBM nephritis since the patient tested negative for circulating anti-GBM antibodies. Treatment involved intravenous methylprednisolone, plasma exchange, and rituximab administration. Protocol graft biopsy performed 1 year after the renal transplant showed a focal segmental glomerulonephritis-like lesion possibly progressing from endocapillary hypercellularity and mesangiolysis. These findings were similar to his native kidney biopsy findings. Although classical recurrent anti-GBM nephritis is rare when a renal transplant is performed after decreased disease activity, this case was considered as a case of recurrent atypical anti-GBM nephritis after renal transplant.

Excessive salt intake causes hypertension and heart diseases. B-type natriuretic peptide (BNP) is a surrogate marker of heart disease, and a slightly elevated BNP level is associated with a poor prognosis. Our previous cross-sectional study demonstrated that plasma BNP has a significant positive association with daily salt intake in the general population. However, the relationship between changes in salt intake and changes in plasma BNP remains unknown. We recruited 3051 participants without hypertension or electrocardiogram abnormalities who underwent annual health check-ups for two consecutive years. Clinical parameters, including plasma BNP, were obtained, and daily salt intake was evaluated using urinary samples. Annual changes in these parameters were calculated. The median plasma BNP level was 12.9 pg/mL, and the daily salt intake was 8.73 ± 1.89 g. The annual changes in plasma BNP and daily salt intake were 4.79 ± 36.38% and 2.01 ± 21.80%, respectively. Participants in the highest quartile of annual changes in daily salt intake showed the largest annual changes in plasma BNP. Annual changes in plasma BNP indicated a significant positive association with daily salt intake. Moreover, multiple linear regression analyses revealed that annual changes in plasma BNP showed a significant positive association with daily salt intake after adjustments. Our study showed a significant positive relationship between annual changes in plasma BNP and annual changes in daily salt intake. The suppression of plasma BNP is therefore induced by salt intake restriction. The monitoring of plasma BNP while reducing salt intake may therefore prevent heart diseases and lead to improved prognoses in the general population without heart diseases.

Membranous nephropathy (MN) is the leading cause of nephrotic syndrome in adults. We previously reported that the prevalence of phospholipase A2 receptor (PLA2R)- and thrombospondin type 1 domain containing 7A (THSD7A)-associated MN patients in Japan is 52.7% and 9.1%, respectively. In addition to PLA2R and THSD7A, we assessed the presence of newly discovered target antigens, neural epidermal growth factor-like 1 (NELL-1), semaphorin 3B (SEMA3B), and exostosin 1/exostosin 2 (Ext1/Ext2), in renal specimens from patients with primary and secondary MN by immunohistochemistry. We found enhanced glomerular staining of PLA2R, THSD7A, NELL-1, and Ext1/Ext2 in 53.6%, 8.7%, 1.5%, and 13.0% of the renal samples, respectively, in patients with primary MN. None of the patient specimens showed enhanced staining of SEMA3B. Enhanced glomerular staining of PLA2R, NELL-1, and Ext1/Ext2 was detected in 5.7%, 8.6%, and 22.9% of the patients with secondary MN, respectively. Based on our findings, we recommend the assessment of PLA2R, THSD7A and NELL-1 in addition to clinical information and IgG4 staining to differentiate between primary and secondary MN. This would aid in distinguishing secondary MN patients from primary MN patients who coincidentally have some secondary characteristics.

Objective Urinary angiotensinogen (AGT) is a surrogate marker for intrarenal renin-angiotensin system (RAS) activity that plays an important role in the development of renal damage. Urinary AGT levels are determined by the filtration of plasma AGT through the damaged glomeruli and production of AGT in the proximal tubules. However, the relative merits of the filtration and production of urinary AGT levels in chronic kidney diseases (CKD) have not been clarified. Therefore, we investigated them in CKD patients. Methods We recruited 41 biopsy-proven patients diagnosed with IgA nephropathy (IgAN) in 31, membranous nephropathy (MN) in 5, and tubulointerstitial nephritis (TIN) in 5. The patients taking RAS blockers were excluded. Results The urinary albumin levels in MN patients were significantly higher and those in TIN patients significantly lower than in IgAN patients, and the urinary AGT levels in the MN and TIN patients were significantly higher than those in IgAN patients. Conversely, the urinary AGT-to-urinary albumin (urinary AGT/Alb) ratios were the same for IgAN and MN patients, and those of TIN patients were significantly higher than those of IgAN and MN patients. A multiple linear regression analysis revealed that the urinary AGT/Alb ratios had a significant positive association with IgAN and TIN after adjustments (β=0.75, and p

Objective Salt loading induces renal damage independently of blood pressure (BP) elevation via reactive oxygen species and sympathetic activity. Melatonin, a hormone that regulates the circadian rhythm, has multiple functions, including anti-oxidant effects and the inhibition of sympathetic activity. We have shown that impaired melatonin secretion is associated with renal damage in chronic kidney disease (CKD) patients. However, the associations between salt loading, melatonin secretion, and urinary albumin and protein have not been clarified. Methods We recruited 32 CKD patients, conducted 24-hour ambulatory BP monitoring and collected daytime and nighttime urine while the patients were consuming a standard salt (10 g/day) or low salt (6 g/day) diet. The excretion levels of albumin, protein and 6-sulfatoxymelatonin (aMT6s), a metabolite of melatonin, in daytime and nighttime urine were investigated in patients consuming standard salt and low salt diets. Results The urinary aMT6s levels in daytime and nighttime of the patients consuming standard salt and low salt diets did not differ to a statistically significant extent. However, the urinary aMT6s levels in patients consuming a standard salt diet-but not patients consuming a low salt diet-were significantly and negatively correlated with the daytime and nighttime urinary albumin and protein levels. Contrarily, no significant correlations were found between the urinary aMT6s levels and the BP levels, renal function, and plasma angiotensin II levels in patients consuming either a standard salt or low salt diet. A multiple regression analysis adjusted for age, sex, and body mass index revealed that the urinary albumin and protein levels were significantly and negatively associated with the urinary aMT6s levels in patients consuming a standard salt diet, but not in patients consuming a low salt diet. Conclusion Salt loading aggravates the relationship between melatonin secretion and albuminuria or proteinuria.

Objective The intrarenal renin-angiotensin system (RAS) is activated in clinical settings, such as chronic kidney disease (CKD), as well as in CKD animal models, and kidney transplant donors have a greater risk of end-stage renal disease than healthy controls. However, whether or not the intrarenal RAS is activated immediately after kidney donation in kidney transplant donors is unclear, and the mechanism underlying intrarenal RAS activation is unknown. Methods We investigated 10 kidney transplant donors (4 men and 6 women, 58.6±9.0 years of age). Their blood pressure (BP), estimated glomerular filtration rate (eGFR), plasma angiotensinogen (AGT) and plasma angiotensin II (AngII) levels (which reflect circulating RAS activation), urinary albumin excretion, and urinary AGT excretion (which reflects intrarenal RAS activation) were evaluated before kidney donation (-1.2±0.40 days) and after kidney donation (7.5±1.7 days). Results The renal function after kidney donation was significantly lower than before donation. There were no significant differences in the BP during 24-h ambulatory BP monitoring, plasma AngII levels, or urinary albumin excretion after kidney donation. In contrast, the levels of plasma AGT and urinary AGT excretion were significantly increased after kidney donation. The urinary AGT excretion after kidney donation did not show a significant relationship with the systolic BP, plasma AGT, plasma AngII, or urinary albumin excretion. In addition, the percentage change in urinary AGT excretion after kidney donation was not associated with the percentage change in other clinical parameters. Conclusion The intrarenal RAS is activated in kidney transplant donors immediately after kidney donation, independent of the systemic BP and filtration of increased plasma AGT, due to augmented inflammation.

Melatonin is a hormone produced by the pineal gland, predominantly at night, and plays a pivotal role in regulating the circadian rhythm as well as a variety of biological functions, including anti-inflammation, anti-oxidation, inhibition of sympathetic nerve activity, and preservation of endothelial cell function. The intrarenal renin-angiotensin system (RAS) is one of the most important contributors in the pathophysiology of chronic kidney disease (CKD) and hypertension, independent of the circulating RAS, due to sodium reabsorption and inflammation and fibrosis in the kidney. However, the relationship between melatonin secretion and intrarenal RAS activation has remained unknown. It has been recently shown that impaired nighttime melatonin secretion is associated with nighttime urinary angiotensinogen excretion, a surrogate marker of intrarenal RAS activation and renal damage in patients with CKD. Moreover, it has also been indicated that melatonin administered exogenously exercises antioxidant effects that ameliorate intrarenal RAS activation and renal injury in chronic progressive CKD animal models. As a result, the new roles of melatonin in suppressing RAS in the kidney via amelioration of reactive oxygen species have been clarified. Therefore, we review the relationship between melatonin and intrarenal RAS activation and indicate the possibility of a new strategy to suppress CKD, which is a risk factor for cardiovascular and end-stage renal diseases.

Excessive salt intake causes hypertension and cardiovascular diseases (CVDs). B-type natriuretic peptide (BNP) is synthesized and released from the ventricle, and is a surrogate marker reflecting various CVDs. Moreover, when a slight BNP elevation is shown, it leads to a poor prognosis in the general population. However, the relationship between salt intake and BNP levels in the general population remains unclear, especially in those without hypertension and heart diseases. In this study, we recruited 1404 participants without hypertension and electrocardiogram abnormalities, who received regular annual health check-ups in Japan. Plasma BNP levels were measured, and daily salt intake levels were evaluated using urinary samples. In addition, some clinical parameters were obtained, and the data were cross-sectionally analyzed. The median of plasma BNP levels was 10.50 pg/mL, and daily salt intake was 8.50 ± 1.85 g. When dividing participants into quartiles according to daily salt intake, those with the highest daily salt intake revealed the highest plasma BNP levels. Plasma BNP levels were significantly and positively associated with daily salt intake. Moreover, multiple linear regression analyses revealed that plasma BNP levels showed a significant positive association with daily salt intake levels after adjustments. Plasma BNP levels were significantly and positively associated with daily salt intake after adjustment in the general population. Plasma BNP levels may be a surrogate marker reflecting salt-induced heart diseases.

Objective The intrarenal renin-angiotensin system (RAS) is activated in patients with chronic kidney disease (CKD), and urinary angiotensinogen (AGT) levels, a surrogate marker of the intrarenal RAS activation, are associated with blood pressure (BP) and urinary albumin excretion. In addition, it has been shown that changes in urinary AGT levels correlate with annual changes in the estimated glomerular filtration rate (eGFR) in patients with type 2 diabetes and that elevated levels of urinary AGT in type 2 diabetic patients with albuminuria are a high-risk factor for worsening renal and cardiovascular complications. However, whether or not baseline urinary AGT levels predict deterioration of the kidney function in all patients with CKD is unclear. Methods We recruited 62 patients with CKD whose eGFR was >15 mL/min/1.73 m2. We performed 24-hour ambulatory BP monitoring at 30-min intervals and daily urinary collection to examine the urinary AGT levels and albumin excretion and measured the levels of plasma angiotensin II (Ang II), a surrogate marker of circulating RAS. In addition, annual changes in the eGFR were followed up for 3.4±1.5 years. Results Annual changes in the eGFR were significantly and negatively associated with urinary AGT levels (r=-0.31, p=0.015) as well as the age, systolic BP, and urinary albumin levels. In contrast, annual changes in the eGFR were not correlated with plasma Ang II levels. Furthermore, when dividing patients into quartiles according to urinary AGT levels, patients with the highest urinary AGT levels showed a progressive decline in the eGFR. Conclusion These results suggest that elevated baseline urinary AGT levels can predict renal dysfunction in patients with CKD.

Circadian fluctuation disorder of the intrarenal renin-angiotensin system (RAS) causes that of blood pressure (BP) and renal damage. In renal damage with an impaired glomerular filtration barrier, liver-derived angiotensinogen (AGT) filtered through damaged glomeruli regulates intrarenal RAS activity. Furthermore, glomerular permeability is more strongly affected by glomerular hypertension than by systemic hypertension. Thus, we aimed to clarify whether the circadian rhythm of intrarenal RAS activity is influenced by AGT filtered through damaged glomeruli due to glomerular capillary pressure. Rats with adriamycin nephropathy and an impaired glomerular filtration barrier were compared with control rats. In adriamycin nephropathy rats, olmesartan medoxomil (an angiotensin II type 1 receptor blocker) or hydralazine (a vasodilator) was administered, and the levels of intrarenal RAS components in the active and rest phases were evaluated. Moreover, the diameter ratio of afferent to efferent arterioles (A/E ratio), an indicator of glomerular capillary pressure, and the glomerular sieving coefficient (GSC) based on multiphoton microscopy in vivo imaging, which reflects glomerular permeability, were determined. Mild renal dysfunction was induced, and the systemic BP increased, resulting in increased A/E ratios in the adriamycin nephropathy rats compared with the control rats. Fluctuations in intrarenal RAS activity occurred in parallel with circadian fluctuations in glomerular capillary pressure, which disappeared with olmesartan treatment and were maintained with hydralazine treatment. Furthermore, the GSCs for AGT also showed similar changes. In conclusion, intrarenal RAS activity is influenced by the filtration of liver-derived AGT from damaged glomeruli due to circadian fluctuation disorder of the glomerular capillary pressure.

Introduction Patients without detectable serum antiglomerular basement membrane (GBM) antibodies but with GBM staining for immunoglobulins (Ig), absence of a crescentic phenotype, mild renal insufficiency, and absence of pulmonary hemorrhage have atypical anti-GBM diseases. We report the case of a 64-year-old man with slowly progressive glomerulonephritis. Case history A 64-year-old Peruvian man presented with persistent microscopic hematuria, proteinuria of 2.1 g/g creatinine (Cr), serum Cr 1.00 mg/dL, and C-reactive protein 0.80 mg/dL. Renal biopsy revealed necrotizing glomerulonephritis with 39% cellular crescent formation and diffuse segmental endocapillary proliferation. He had linear staining of monoclonal IgG1-κ in the capillary walls but no detectable serum anti-GBM antibodies. Because renal dysfunction was slowly progressing, steroid monotherapy was initiated, and serum Cr level decreased from 1.48 to 1.13 mg/dL. However, serum Cr increased again to 1.35 mg/dL owing to active glomerular damage with crescent formation and endocapillary proliferation, confirmed by the second renal biopsy at 9 months after therapy. Renal function improved after cyclophosphamide therapy. Conclusion We described an atypical variant of anti-GBM disease due to monoclonal IgG1-κ. Unlike usual atypical anti-GBM disease cases, we observed crescent formation in our patient. Further investigations are needed to identify the cause of nondetectable serum anti-GBM antibodies and to describe the causal relationships between clinicopathological features and the pattern of IgG subclass and light chain in atypical anti-GBM disease.

Objective The mechanisms underlying the intrarenal renin-angiotensin system (RAS) activation depend on the conditions of kidney diseases. In angiotensin II (AngII) infusion models, the circulating AngII is filtered into the renal tubular lumens, activating intrarenal RAS. However, in the chronic kidney disease (CKD) models, plasma angiotensinogen (AGT) is filtered into the tubular lumens because of glomerular injury, activating intrarenal RAS. The intrarenal dopamine system activation reduces intrarenal AGT expression and suppresses the intrarenal RAS activity in AngII infusion models. However, the relationship between the intrarenal dopamine system and intrarenal RAS has not been elucidated. Therefore, this study was conducted to determine that relationship in CKD patients. Methods We recruited 46 CKD patients (age: 51.1±20.0 years; 16 men; causes of CKD: chronic glomerulonephritis, 34; diabetic nephropathy, 2; nephrosclerosis, 4; and others, 6) not undergoing dialysis or taking RAS blockers. The urinary dopamine (U-DOPA) level, an indicator of intrarenal dopamine activity, and the urinary AGT (U-AGT) level, a surrogate marker of intrarenal RAS activity, were measured. Results As the CKD stages progressed, the U-DOPA levels decreased while the U-AGT levels increased. The U-DOPA levels were significantly and negatively correlated with the U-AGT levels but significantly and positively correlated with the estimated glomerular filtration rate (eGFR). A multiple regression analysis revealed that the U-DOPA levels were associated with the U-AGT levels after adjusting for age, sex, body mass index, and blood pressure (β=-0.38, p=0.045). However, no correlation was observed when eGFR was also adjusted (β=-0.17, p=0.29). Conclusion The negative correlation between the intrarenal dopamine system and intrarenal RAS in CKD patients may be affected by the renal function.

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.

Intrarenal renin-angiotensin system (RAS) activation plays an important role in the development of hypertension and renal damage. However, the association between daytime and night-time intrarenal RAS activation and renal structural damage in normotensive IgA nephropathy patients is unclear. We investigated the relationships between urinary angiotensinogen (U-AGT) excretion, which reflects intrarenal RAS activity, and renal structural damage (i.e., endocapillary and mesangial cell hypercellularity, arteriolar hyalinosis and arteriosclerosis levels, and global glomerulosclerosis and tubulointerstitial fibrosis percentages) in 27 normotensive IgA nephropathy patients (age 39.2 ± 13.6 years, 10 men and 17 women, estimated glomerular filtration rate (eGFR) 74.0 ± 17.3 ml/min/1.73 m2, urinary protein excretion 0.58 ± 0.50 g/day, and U-AGT excretion 64.9 ± 100.6 μg/day). The arteriosclerosis level had a significant positive association with the daytime and night-time U-AGT excretion levels. By contrast, the endocapillary and mesangial cell hypercellularity and arteriolar hyalinosis levels and global glomerulosclerosis and tubulointerstitial fibrosis percentages did not correlate with the daytime and night-time U-AGT excretion levels. The daytime and night-time U-AGT excretion levels were higher in patients with arteriosclerotic changes than in patients without these changes. Multiple linear regression analysis revealed that the arteriosclerosis levels had a significant positive association with the U-AGT excretion levels at night after adjusting for age, sex, body mass index, and the eGFR. However, when diastolic BP was added as an independent variable, the relationship between U-AGT excretion and arteriosclerosis at night disappeared. In normotensive IgA nephropathy patients, intrarenal RAS activation at night due to nocturnal hypertension may be associated with arteriosclerosis.

A 55-year-old woman presented with deafness, increased levels of myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody (ANCA), and renal insufficiency with proteinuria and hematuria. Renal biopsy revealed crescentic glomerulonephritis with the linear deposition of immunoglobulin G along the glomerular basement membrane (GBM) and peritubular capillaritis. The anti-GBM antibody levels on admission and 10 days after admission were 11.7 U/mL and 127 U/mL, respectively. These results indicated the sequential development of anti-GBM nephritis and MPO-ANCA-associated vasculitis. This report shows that anti-GBM nephritis may be caused by MPO-ANCA-associated vasculitis because of preceding otitis media, the sequential anti-GBM antibody titers, and the findings of peritubular capillaritis.

A higher heart rate is one of the risk factors for heart failure and cardiovascular disease. Activation of the intrarenal renin–angiotensin system (RAS) plays an important role in the development of hypertension and renal damage. However, the association between heart rate and intrarenal RAS activation is unclear. We investigated the relationship between heart rate and urinary angiotensinogen (U-AGT) excretion, a surrogate marker for intrarenal RAS activity, in ten subjects without chronic kidney disease (CKD) and 72 CKD patients who were not taking medications that influence heart rate and RAS blockers (age 50.0 ± 17.4 years, 27 men and 45 women, serum creatinine (sCr) 1.85 ± 2.71 mg/dL, blood pressure 120.5 ± 15.8/72.9 ± 10.1 mmHg, heart rate 67.3 ± 8.9 /min, urinary protein excretion 1.27 ± 2.63 g/day, and U-AGT excretion 747.4 ± 2714.6 µg/day). As heart rate is influenced by behavior and emotion, we divided it into daytime and nighttime. Heart rate had a significant positive association with sCr levels during daytime and nighttime in CKD patients but not in non-CKD subjects. Moreover, although heart rate was not associated with U-AGT excretion levels in non-CKD subjects, it was associated with U-AGT excretion levels during daytime (r = 0.23 and p = 0.047) and nighttime (r = 0.45 and p

Circulating renin–angiotensin system (RAS) activation is maintained after renal function has deteriorated. The activation of the intrarenal RAS plays a critical role in the pathophysiology of chronic kidney disease (CKD), independently of the circulating RAS. However, the activation of intrarenal RAS and the chymase-dependent pathway after initiation of dialysis has not been clarified. We recruited 19 CKD patients (10 without dialysis and 9 with dialysis) who underwent a heminephrectomy. Circulating RAS was investigated before nephrectomy. The levels of intrarenal RAS components and chymase-positive cells were investigated using radioimmunoassay or immunoblot analysis on samples collected from the removed kidney. Renal damage was evaluated by the extent of tubulointerstitial fibrosis. No significant differences in circulating RAS between nondialysis and dialysis patients were found. However, intrarenal angiotensin II (AngII) and the extent of tubulointerstitial fibrosis in dialysis patients were significantly increased when compared with nondialysis patients. Prorenin and angiotensin-converting enzyme (ACE) levels were dramatically decreased in accordance with renal dysfunction. On the other hand, chymase-positive cells and AngII type 1 receptor (AT1R) expression was significantly increased in dialysis patients when compared with nondialysis patients. In multiple linear regression analyses, there were significant positive and negative relationships between the extent of interstitial fibrosis and angiotensinogen (β=0.45, P=0.042) and prorenin levels (β=−0.85, P

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. 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). 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 (β = −0.31, p = 0.044) and U-Alb (β = −0.25, p = 0.025) only at night. Impaired nighttime melatonin secretion may be associated with nighttime intrarenal RAS activation and renal damage in CKD patients.

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.

Objective Hypertension and diurnal blood pressure (BP) variation are widely accepted as risk factors for renal damage. However, the effects of unilateral nephrectomy on BP and its circadian rhythm have not yet been clarified in patients with a compromised renal function, including dialysis patients. Methods We investigated 22 unilateral nephrectomized patients (16 men and 6 women, age: 64.5±14.3 years). The function of the circulating renin-angiotensin system (RAS) (plasma renin activity and plasma angiotensin II) and 24-h ambulatory BP monitoring (ABPM) were evaluated before and after nephrectomy. Daytime and nighttime 24-h ABPM values were determined based on sleep and waking times. Results In non-dialysis patients, the estimated glomerular filtration rate after nephrectomy was significantly lower than that before (before, 62.4±23.2 mL/min/1.73 m2 vs. after, 43.7±16.8 mL/min/1.73 m2; p

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.

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.

Cutaneous and systemic plasmacytosis (CSP) is a rare lymphoproliferative disorder that mainly affects middle-aged Asian individuals. Although Castleman disease is often complicated with various renal involvements, glomerulonephritis associated with CSP, which is considered as a variant of Castleman disease, is rare. This report presents the case of a 41-year-old Japanese man with nephrotic syndrome associated with CSP. Renal biopsy findings showed focal segmental glomerulosclerosis (FSGS) and diffusely mild segmental mesangial proliferation. Plasma cell infiltration in the interstitium was not observed. Electron microscopic findings showed diffuse foot process effacement, localized involvement of subendothelial space widening with amorphous materials, and endothelial cell swelling. Lymph node biopsy findings denied Castleman disease. His skin regions and proteinuria were successfully treated with prednisolone and cyclosporine. The causal relationship between CSP and FSGS is unknown. However, increased serum levels of IL-6 and VEGF and decreased VEGF expression in the podocyte may contribute to renal lesions in patients with CSP. To our best knowledge, this is the first case of a patient with FSGS associated with CSP.

Activation of the intrarenal renin–angiotensin system (RAS) plays a critical role in the pathophysiology of chronic kidney disease (CKD) and hypertension. It has been reported that reactive oxygen species (ROS) are important components of intrarenal RAS activation. Melatonin is recognized as a powerful antioxidant, and we recently reported that impaired nighttime melatonin secretion correlates negatively with urinary angiotensinogen excretion, the surrogate marker of intrarenal RAS activity in patients with CKD. However, whether melatonin supplementation ameliorates the augmentation of intrarenal RAS in CKD has remained unknown. We aimed to clarify whether exogenous melatonin ameliorates intrarenal RAS activation via the reduction of ROS production. 5/6 Nephrectomized (Nx) rats were used as a chronic progressive CKD model and compared with sham-operated control rats. The Nx rats were divided into untreated Nx rats and melatonin-treated Nx rats. The levels of intrarenal RAS, ROS components, and renal injury were evaluated after 4 weeks of treatment. Compared with the control rats, the untreated Nx rats exhibited significant increases in intrarenal angiotensinogen, angiotensin II (AngII) type 1 receptors, and AngII, accompanied by elevated blood pressure, higher oxidative stress (8-hydroxy-2′-deoxyguanosine), lower antioxidant (superoxide dismutase) activity, and increased markers of interstitial fibrosis (α-smooth muscle actin, Snail, and type I collagen) in the remnant kidneys. Treatment with melatonin significantly reversed these abnormalities. Antioxidant treatment with melatonin was shown to ameliorate intrarenal RAS activation and renal injury in a 5/6 Nx rat model.

Background Thin basement membrane nephropathy (TBMN) is a relatively common disease. Patients typically present with isolated hematuria, which has a good renal prognosis. In contrast, glomerulocystic kidney disease (GCKD) is a rare disease, associated with slow progressive renal dysfunction. To our knowledge, co-occurring diagnosis of TBMN with GCKD has not been reported previously. Case presentation A 30-year old woman was admitted to our hospital for evaluation of hematuria and renal insufficiency. Upon examination, her urinary protein level was 40 mg/day and occult blood in her urine was 2+. The patient’s urinary dysmorphic red blood cell sediment was 30–49/high power field. In contrast, her serum creatinine levels increased from 0.57 mg/dl to 0.86 mg/dl during the previous 2-years, without special events. She suffered from far-sightedness and astigmatism beginning at birth; She had no family history of renal disease. Renal biopsy demonstrated cystic dilatation of the Bowman’s capsule and atrophy of the glomerular tuft. The glomerular basement membrane (GBM) was thin, with an average thickness of 191 nm. Next-generation sequencing was used to evaluate for mutations in COL4A3 and COL4A4, associated with TBMN, and UMOD, MUC1, and SEC61A1, associated with hereditary GCKD. No pathogenic mutations were identified. We thus diagnosed the patient with TBMN coexistent with sporadic GCKD. Conclusion We report the patient diagnosed with TBMN accompanied by sporadic GCKD, based on renal biopsy and genetic testing. Because it is possible that other diseases, such as GCKD, can coexist with TBMN, it is important to consider renal biopsy.

Abnormal blood pressure (BP) variability (BPV), occurring as beat-to-beat, 24 h, and day-to-day fluctuations, is related to target organ damage. However, the associations between abnormal BPV and renal structural changes have not been clearly investigated. We evaluated the day time and night time BP s.d. and average real variability (ARV), which reflected short-term BPV, the night time to day time (N/D) ratio of systolic BP (SBP), and the 7-day BPV, in 29 normotensive IgA nephropathy (IgAN) patients. We further compared the results with renal structural changes. The degree of arteriosclerosis was positively correlated with age, s.d. of night time SBP and the N/D ratio of SBP, and was negatively correlated with the estimated glomerular filtration rate (eGFR). The degree of arteriolar hyalinosis was positively correlated with age, night time SBP, s.d. of day time and night time SBP, day time and night time ARV, the N/D ratio of SBP and 7-day SBP, and was negatively correlated with the eGFR. A multiple linear regression analysis revealed that the level of arteriolar hyalinosis, but not arteriosclerosis, was associated with the s.d. of night time SBP (β=0.63, P

Activation of the intrarenal renin-angiotensin system (RAS) has a critical role in the pathophysiology of the circadian rhythm of blood pressure (BP) and renal injury, independent of circulating RAS. Although it is clear that the circulating RAS has a circadian rhythm, reports of a circadian rhythm in tissue-specific RAS are limited. Clinical studies evaluating intrarenal RAS activity by urinary angiotensinogen (AGT) levels have indicated that urinary AGT levels were equally low during both the daytime and nighttime in individuals without chronic kidney disease (CKD) and that urinary AGT levels were higher during the daytime than at nighttime in patients with CKD. Moreover, urinary AGT levels of the night-to-day (N/D) ratio of urinary AGT were positively correlated with the levels of N/D of urinary protein, albumin excretion and BP. In addition, animal studies have demonstrated that the expression of intrarenal RAS components, such as AGT, angiotensin II (AngII) and AngII type 1 receptor proteins, increased and peaked at the same time as BP and urinary protein excretion during the resting phase, and the amplitude of the oscillations of these proteins was augmented in a chronic progressive nephritis animal compared with a control. Thus, the circadian rhythm of intrarenal RAS activation may lead to renal damage and hypertension, which both are associated with diurnal variations in BP. It is possible that augmented glomerular permeability increases AGT excretion levels into the tubular lumen and that circadian fluctuation of glomerular permeability influences the circadian rhythm of the intrarenal RAS.

Background (Pro)renin receptor [(P)RR], a specific receptor for renin and prorenin, was identified as a member of the renin-angiotensin system (RAS). (P)RR is cleaved by furin, and soluble (P)RR [s(P)RR] is secreted into the extracellular space. Previous reports have indicated that plasma s(P)RR levels show a significant positive relationship with urinary protein levels, which represent renal damage. However, it is not fully known whether plasma s(P)RR reflects renal damage. Methods We recruited 25 patients who were admitted to our hospital to undergo heminephrectomy. Plasma s(P)RR levels were examined from blood samples drawn before nephrectomy. The extent of renal damage was evaluated by the levels of tubulointerstitial fibrosis. Immunohistochemical analysis of intrarenal (P)RR and cell surface markers (cluster of differentiation [CD]3, CD19, and CD68) was performed on samples taken from the removed kidney. Moreover, double staining of (P)RR and cell surface markers was also performed. Results There were significant positive relationships between plasma s(P)RR and tubulointerstitial fibrosis in all the patients and those not receiving RAS blocker therapy. Significant positive relationships were found between plasma s(P)RR levels and the extent of tubulointerstitial fibrosis after adjustment for age, sex, body weight, blood pressure, and plasma angiotensin II, in all the patients and those not receiving RAS blockers. Moreover, (P)RR expression was elevated in infiltrated mononuclear cells but not connecting tubules or collecting ducts and vessels. Infiltrated cells positive for (P)RR consisted of CD3 and CD68 but not CD19. Conclusions These data suggest that plasma s(P)RR levels may reflect (P)RR expression levels in infiltrated mononuclear cells, which can be a surrogate marker of renal damage.

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.

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.