Association between plasma aldosterone concentration and intraglomerular hemodynamics in primary aldosteronism.

BACKGROUND/AIMS: In primary aldosteronism (PA), aldosterone could affect glomerular hemodynamics by elevating renal vascular resistance and glomerular capillary pressure. However, the relationship between plasma aldosterone concentrations (PAC) and glomerular hemodynamics including efferent arteriolar resistance (Re), afferent arteriolar resistance (Ra) in humans is still unclear. The aim of this study was to investigate the relationships of PAC with intraglomerular hemodynamic parameters in patients with PA. METHODS: An observational study of glomerular hemodynamics was performed using simultaneous measurements of plasma clearance of para-aminohippurate and inulin (Cin; glomerular filtration rate (GFR)) in 17 patients with PA. Kidney function was evaluated by Cin, estimated GFR based on serum creatine (eGFRcre) and serum cystatin C (eGFRcys) and creatine clearance (Ccr). Intraglomerular hemodynamic parameters, including Re, Ra, and intraglomerular hydrostatic pressure (Pglo) were calculated using Gomez's formulae. RESULTS: In the 17 PA cases, PAC was significantly correlated with Cin (rho=0.752, p=0.001) and eGFRcys (rho=0.567, p=0.018), but was not correlated witheGFRcreand Ccr. PAC was also significantly correlated with Pglo, Re, and urinary protein/day (rho=0.775, p=0.0004, rho=0.625, p=0.009, and rho=0.625, p=0.007, respectively). Multivariable regression analysis showed that PAC was significantly associated with Cin and Re. In comparing aldosterone producing adenoma (APA) and non-APA cases, Cin was significantly elevated in APA (p=0.037), whereas eGFRcre, eGFRcys, and Ccr were not. Re tended to be higher in APA (p=0.064). CONCLUSIONS: These results suggest high aldosterone cause glomerular hyperfiltration by constricting Re. Cin, but not eGFRcre and Ccr, may be useful for evaluating kidney function in PA.

Improvement in the mobility of a patient with fibroblast growth factor 23-related hypophosphatemic osteomalacia and decompensated liver cirrhosis in response to burosumab: a case report.

Acquired fibroblast growth factor (FGF) 23-related hypophosphatemic osteomalacia is characterized clinically by muscle weakness, bone pain, and fractures. Its biochemical features include hypophosphatemia, caused by renal phosphate wasting, and inappropriately normal or low 1,25-dihydroxy-vitamin D levels. Recently, burosumab, a fully human monoclonal antibody targeting FGF23, was approved for the treatment of FGF23-related hypophosphatemic rickets and osteomalacia. We report the case of a 75-year-old Japanese woman with decompensated liver cirrhosis and hepatic encephalopathy, caused by primary biliary cholangitis, who complained of back pain and limited mobility resulting from multiple vertebral fractures. She was not receiving iron infusion therapy and denied alcohol consumption. The patient exhibited hypophosphatemia with a low tubular maximum reabsorption of phosphate per unit glomerular filtration rate (TmP/GFR) and a high circulating concentration of FGF23. Conventional therapy with alfacalcidol and oral phosphate slightly improved her serum phosphate concentration and back pain, but she experienced a hip fracture, causing her to become wheelchair-dependent. Burosumab was initiated 8 weeks after the hip fracture, which increased her serum phosphate concentration and TmP/GFR. Her mobility gradually improved, such that she could walk without a cane after 16 weeks of treatment. Her lumbar bone mineral density increased after 48 weeks. Hepatic encephalopathy developed once before the initiation of treatment and twice after the initiation of the therapy, but her liver function was preserved. This is the first study to report the efficacy and safety of burosumab treatment for FGF23-related hypophosphatemic osteomalacia with decompensated liver cirrhosis.

Bexarotene-induced central hypothyroidism assessed by TRH stimulation test in cutaneous T-cell lymphoma patients.

Bexarotene-induced central hypothyroidism (CH), for which levothyroxine (LT4) replacement is recommended, has been shown to be caused by pituitary but not hypothalamic disorder experimentally, though the underlying mechanism in humans remains unclear. Here, the pathophysiology of bexarotene-induced CH was examined using a TRH stimulation test in cutaneous T-cell lymphoma (CTCL) patients. In this retrospective longitudinal observational study, serum TSH and free T4 (F-T4) levels were measured in 10 euthyroid patients with CTCL during 24 weeks of bexarotene treatment. TRH stimulation testing was performed following CH diagnosis, with LT4 replacement dosage adjusted to maintain F-T4 at the pre-treatment level. After one week of bexarotene administration, all 10 patients developed CH, based on combined findings of low or low-normal F-T4 with low or normal TSH levels. TSH peak response after a stimulation test at one week was reached at 30 minutes. However, that was <4 µIU/mL in all patients, indicating a blunted though not exaggerated and delayed TSH response. In eight who continued bexarotene for 24 weeks, median LT4 replacement dosage was 125 (range, 75-150) µg/day. TSH level at 30 as well as 15, 60, 90, and 120 minutes after TRH stimulation was significantly correlated with LT4 replacement dosage (ρ = -0.913, p = 0.002), whereas TSH and F-T4 basal levels at one week were not. These results suggest that pituitary hypothyroidism is responsible for bexarotene-induced CH, while TSH levels after TRH stimulation precisely reflect residual pituitary-thyroid function in patients receiving bexarotene.

Plasma Xanthine Oxidoreductase Activity Associated with Glycemic Control in Patients with Pre-Dialysis Chronic Kidney Disease.

INTRODUCTION: Xanthine oxidoreductase (XOR) activity plays an important role as a pivotal source of reactive oxygen species, which is associated with cardiovascular disease (CVD) events. Patients with CKD have increased risk of CVD events. In the present study, factors associated with plasma XOR activity in pre-dialysis CKD patients were investigated. METHODS: In this cross-sectional study, plasma XOR activity in 118 pre-dialysis CKD patients (age 68 [57-75] years; 64 males, 26 with diabetes mellitus [DM]) was determined using a newly established highly sensitive assay based on (13C2,15N2) xanthine and liquid chromatography/triple quadrupole mass spectrometry. RESULTS: Plasma glucose, hemoglobin A1c, and estimated glomerular filtration (eGFR) were significantly and positively correlated with plasma logarithmically transformed XOR (ln-XOR) activity. In multiple regression analyses, eGFR and hemoglobin A1c or plasma glucose were significantly, independently, and positively associated with plasma ln-XOR activity after adjusting for several confounders. Plasma XOR activity was significantly higher in CKD patients with (n = 26) than in those without (n = 92) DM (62.7 [32.3-122] vs. 25.7 [13.4-45.8] pmol/h/mL, p < 0.001). A total of 38 patients were taking uric acid-lowering drugs. Multiple regression analysis of CKD patients not administered uric acid-lowering drugs (n = 80) showed no significant association between eGFR and plasma ln-XOR activity. In contrast, association between glycemic control and plasma ln-XOR activity was significant even in CKD patients without uric acid-lowering drug treatment. CONCLUSIONS: These results indicate the importance of glycemic control in CKD patients in regard to decreased XOR, possibly leading to a decrease in CVD events.

Effects of burosumab on osteocalcin and bone mineral density in patient with 15-year history of nonremission tumor-induced osteomalacia initially treated with conventional therapy: Case report.

Excess fibroblast growth factor 23 (FGF23) causes hypophosphatemic osteomalacia, which is associated with impaired bone matrix mineralization. Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by over-secretion of FGF23 from a tumor. Burosumab, a fully human monoclonal antibody with activities against FGF23, was initially approved in Japan before the rest of the world for treatment of FGF23-associated hypophosphatemic osteomalacia by TIO. We report here a patient with a 15-year history of non-remission TIO initially treated with conventional therapy who was then switched to burosumab treatment. Persistent hypophosphatemia and a relative low level of osteocalcin (bone Gla protein, BGP) compared with bone alkaline phosphatase (BAP) level, indicating poor matrix mineralization, developed during long-term conventional therapy. Repeated surgical and stereotactic body radiation treatments did not result in complete resection of the causable tumor, and bone mineral density (BMD) gradually decreased. Ultimately, burosumab treatment was administered and the serum Pi concentration immediately normalized, while both BGP and BMD also showed a good response. This is first known case report of the detailed efficacy of burosumab for nonremission TIO as an alternative to conventional therapy.

Association of higher arterial ketone body ratio (acetoacetate/ß-hydroxybutyrate) with relevant nutritional marker in hemodialysis patients.

BACKGROUND: An association of higher levels of ß-hydroxybutyrate (ß-HB) in serum with greater mortality in hemodialysis (HD) patients has been reported. This study examined the significance of arterial ketone body ratio (AcAc/ß-HB), a relevant marker of energy state, in HD patients. METHODS: The levels of arterial AcAc and ß-HB, and AcAc/ß-HB ratio were determined in 49 HD patients just before undergoing an HD session. Additionally, changes in those levels during the session were examined to investigate their associations with clinical nutritional markers. RESULTS: Arterial ß-HB, but not AcAc, was significantly higher at the baseline in 25 patients with type 2 diabetes mellitus (T2DM) as compared to 24 non-DM patients, with a significant reduction in arterial AcAc/ß-HB ratio seen in those with DM. Although the arterial AcAc/ß-HB ratio before the HD session was significantly higher in the non-DM group, it did not differ significantly after the session between the groups, indicating a faster rate of ß-HB disappearance from circulation in non-DM HD patients during the interdialytic period. Multiple regression analysis, which included age, gender, presence/absence of DM, log HD duration, log ß-HB, and log AcAc/ß-HB ratio as independent variables, revealed an independent and significant association of log AcAc/ ß-HB ratio, but not log ß-HB, with serum albumin and uric acid. CONCLUSION: We found that a decreased AcAc/ß-HB ratio resulting from increased ß-HB, but not increased ß-HB itself, was a significant factor independently associated with decreased levels of serum albumin and uric acid, known to be related to higher mortality in HD patients. Furthermore, it is possible that higher mortality in DM HD patients can be explained by reduced arterial AcAc/ß-HB ratio.

Effects of denosumab as compared with parathyroidectomy regarding calcium, renal, and bone involvement in osteoporotic patients with primary hyperparathyroidism.

PURPOSE: To evaluate the effects of denosumab (Dmb) on calcium, renal, and bone involvement in osteoporotic patients with primary hyperparathyroidism (PHPT) and compare with those who underwent a parathyroidectomy (PTX) procedure. METHODS: This retrospective, longitudinal study included patients treated with Dmb (60 mg) once every 6 months (n = 19) and those who successfully underwent a PTX procedure (n = 19) corrected calcium (cCa), eGFR, bone mineral density (BMD) in the lumbar spine (LS), total hip (TH), and femoral neck (FN) and LS-trabecular bone score (TBS) changes at 1 year after beginning Dmb or undergoing PTX were measured. RESULTS: Dmb group had older age, and showed milder disease activity and lower eGFR as compared with PTX group. In PTX group, cCa and eGFR were significantly decreased following surgery, while those were stable in Dmb group. There were significant increases in LS, TH, and FN-BMD in both Dmb (LS: 6.0 ± 0.8%, TH: 3.7 ± 1.0%, FN: 4.3 ± 1.5%) and PTX (LS: 11.2 ± 1.5%, TH: 7.5 ± 1.5%, FN: 7.9 ± 2.1%) groups. In Dmb group, LS-TBS was significantly improved by 3.0 ± 1.0%, while TBS change in PTX group approached significance (2.8 ± 1.5%). Percent change in TH-BMD was significantly correlated with baseline tartrate-resistant acid phosphatase-5b (TRACP-5b) in both groups. CONCLUSIONS: Dmb treatment not only increased BMD, dependent on bone turnover status, the same as PTX, but also improved LS-TBS. In addition, it did not decrease the level of eGFR, whereas PTX did. These results suggest that Dmb treatment help in the clinical management of osteoporotic patients with PHPT who do not undergo surgery as alternative to PTX.

Significance of urinary C-megalin excretion in vitamin D metabolism in pre-dialysis CKD patients.

Serum 1,25(OH)2D and 24,25(OH)2D are decreased in CKD. Megalin in proximal tubular epithelial cells reabsorbs glomerular-filtered 25(OH)D-DBP complex to convert 25(OH)D to 1,25(OH)2D and 24,25(OH)2D. Urinary C-megalin excretion is increased via exocytosis from injured nephrons overloaded with megalin-mediated protein metabolism. This study investigated the significance of urinary C-megalin excretion in vitamin D metabolism in 153 pre-dialysis CKD patients. Urinary C-megalin was positively associated with urinary protein, ß2MG and α1MG, and exhibited negative correlations with serum 25(OH)D, 1,25(OH)2D and 24,25(OH)2D. Multiple regression analysis showed that urinary C-megalin had a significantly negative association with 25(OH)D. Serum 1,25(OH)2D and 24,25(OH)2D, as well as 1,25(OH)2D/25(OH)D and 24,25(OH)2D/25(OH)D ratios, showed positive correlations with eGFR. Additionally, wholePTH was positively associated with 1,25(OH)2D/25(OH)D and 1,25(OH)2D/24,25(OH)2D, while FGF23 was positively associated with 24,25(OH)2D/25(OH)D and negatively with 1,25(OH)2D/24,25(OH)2D. Urinary C-megalin emerged as an independent factor positively associated with 1,25(OH)2D/25(OH)D and 1,25(OH)2D/24,25(OH)2D. Although 1,25(OH)2D and 24,25(OH)2D are decreased in CKD patient serum, our findings suggest that PTH and FGF23 retain their effects to regulate vitamin D metabolism even in the kidneys of these patients, while production of 1,25(OH)2D and 24,25(OH)2D from 25(OH)D is restricted due to either impairment of megalin-mediated reabsorption of the 25(OH)D-DBP complex or reduced renal mass.

Improvement of glycemic control by treatment for insomnia with suvorexant in type 2 diabetes mellitus.

INTRODUCTION: Acute and chronic insomnia can exacerbate type 2 diabetes mellitus (T2DM). We investigated suvorexant (an anti-insomnia drug that targets the orexin system) effects on sleep architecture and glucose metabolism in T2DM patients with insomnia. MATERIALS AND METHODS: This 7 day open-label, single-arm, intervention trial included 18 subjects with T2DM and insomnia. After 1 day acclimatization, daily glucose levels, sleep architecture, and autonomic nervous function were evaluated by continuous glucose monitoring (CGM), single-channel electroencephalography, and accelerometry, respectively. RESULTS: Suvorexant treatment for 3 days significantly increased total sleep time and sleep efficiency, with partial suppression of sympathetic nerve activity. CGM-measured 24 h mean glucose level decreased significantly from 157.7 ±â€¯22.9 to 152.3 ±â€¯17.8 mg/dL, especially in the early glucose surge after the midnight nadir (from 28.3 ±â€¯15.0 to 18.2 ±â€¯9.9 mg/dL), and until supper with a significant improvement in homeostasis model assessment of insulin resistance from 4.0 ±â€¯2.8 to 2.9 ±â€¯1.6, respectively. CONCLUSIONS: Suvorexant treatment for insomnia of subjects with T2DM significantly improved CGM-measured daily glycemic control, which was associated with changes in sympathomimetic tone and/or improved insulin sensitivity. The amelioration of insomnia may therefore be a target for improving glycemic control in T2DM patients with insomnia.

Non-mercaptalbumin, Oxidized Form of Serum Albumin, Significantly Associated with Renal Function and Anemia in Chronic Kidney Disease Patients.

Oxidative stress plays a major role in development of cardiovascular disease in patients with chronic kidney disease (CKD). Human mercaptalbumin (HMA), a reduced form of serum albumin, and non-mercaptalbumin (HNA), an oxidized form of serum albumin, are known as indicators for evaluating oxidative stress in systemic circulation, including end-stage renal disease cases. We investigated factors associated with fraction of HNA [f(HNA)] in 112 pre-dialysis CKD patients (63.6 ± 14.0 years old; 59 males, 53 females) using a newly established anion-exchange column packed with hydrophilic polyvinyl alcohol gel as well as high performance liquid chromatography. Mean f(HNA) in our CKD patients was 30.0 ± 6.1%, higher than that previously reported for healthy subjects. In multiple regression analysis, age (ß = 0.200, p = 0.014), eGFR (ß = -0.238, p = 0.009), hemoglobin (ß = -0.346, p < 0.001), and ferritin (ß = 0.200, p = 0.019) were significantly and independently associated with f(HNA) (R2 = 0.356, p < 0.001). In addition, factors related to CKD-mineral and bone disorder (CKD-MBD), including intact-PTH (ß = 0.218, p = 0.049) and 1,25-dihydroxyvitamin D (1,25(OH)2D) (ß = -0.178, p = 0.040), were significantly and independently associated with serum f(HNA) (R2 = 0.339, p < 0.001), whereas fibroblast growth factor-23 was not. These findings indicate the importance of management of hemoglobin and ferritin levels, as well as appropriate control of CKD-MBD factors for a better redox state of serum albumin in CKD patients.

Urinary Iron Excretion is Associated with Urinary Full-Length Megalin and Renal Oxidative Stress in Chronic Kidney Disease.

BACKGROUND/AIMS: Megalin mediates the uptake of glomerular-filtered iron in the proximal tubules. Urinary full length megalin (C-megalin) excretion has been found to be increased in association with megalin-mediated metabolic load to the endo-lysosomal system in proximal tubular epithelial cells (PTECs) of residual nephrons. In the present study, we investigated the association between urinary iron and C-megalin in chronic kidney disease (CKD) patients, and the possible harmful effect of iron in renal tubules. METHODS: Urinary levels of iron and C-megalin were measured in 63 CKD patients using automatic absorption spectrometry and a recently-established sandwich ELISA, respectively. RESULTS: Although both urinary C-megalin and urinary total protein levels were correlated with urinary iron (C-megalin: ρ = 0.574, p <0.001; total protein: ρ = 0.500, p <0.001, respectively), urinary C-megalin alone emerged as an independent factor positively associated with urinary iron (ß = 0.520, p <0.001) (R2 = 0.75, p <0.001). Furthermore, urinary iron was significantly and positively associated with urinary 8-hydroxydeoxyguanosine, an oxidative stress marker, while no association with other markers of renal tubular injury, i.e., ß2-microglobulin and N-acetyl-ß-D-glucosaminidase, was noted. CONCLUSIONS: Our findings suggest that renal iron handling may be associated with megalin-mediated endo-lysosomal metabolic load in PTECs of residual nephrons and oxidative stress in renal tubules.

Positive association of plasma leptin with sleep quality in obese type 2 diabetes patients.

AIMS/INTRODUCTION: Poor sleep quality is associated with obesity and diabetes. The adipocyte-derived hormone, leptin, was recently shown to underlie the link between abnormal sleep and obesity. We aimed to investigate the association between leptin and sleep quality in type 2 diabetes patients. MATERIALS AND METHODS: In the present cross-sectional study, we studied 182 type 2 diabetes patients, among whom 113 were diagnosed with obesity (body mass index ≥25 kg/m2 ). Fasting plasma leptin levels were measured, and sleep architecture was assessed using single-channel electroencephalography. RESULTS: Using unadjusted analyses, the obese type 2 diabetes patients, but not their non-obese counterparts, showed a positive correlation between plasma leptin levels and a parameter for deep sleep assessed by delta power during the first sleep cycle. Multivariate analysis showed that plasma leptin levels were positively associated with delta power, but not with the total sleep time, after adjusting for potential confounders including age, body mass index and the apnea-hypopnea index, in the obesity group. However, neither delta power nor total sleep time was associated with leptin in the non-obesity group. CONCLUSIONS: Plasma leptin levels are independently associated with sleep quality in obese, but not in non-obese, type 2 diabetes patients. The present study indicates a favorable relationship between leptin and sleep quality in obese type 2 diabetes patients.

Development of hyperkalemia following treatment with dapagliflozin (DAPA) in a patient with type 2 diabetes after bilateral adrenalectomy.

Dapagliflozin (DAPA), a sodium-glucose co-transporter 2 (SGLT2) inhibitor, is known to have a beneficial diuretic effect, in addition to a glucose-lowering effect. Although SGLT2 inhibitor has been reported, the increase of hyperkalemia in patients treated with renin-angiotensin-aldosterone system (RAAS) inhibitors, their mechanism of action is unclear. We report the first case of a type 2 diabetes (T2DM) patient with potential mineralocorticoid deficiency who developed hyperkalemia after administration of DAPA. A 79-year-old woman underwent bilateral adrenalectomy for uncontrolled hypercortisolism due to an inoperable recurrence of Cushing's disease, and she was subsequently maintained on replacement therapy with glucocorticoid. She was diagnosed as having T2DM at 71 years of age and was treated with sitagliptin and miglitol. Since she presented with weight gain of about 5 kg over 6 months and her HbAlc level increased over 12%, 5 mg/day DAPA was added to her daily regimen. After the start of DAPA treatment, she developed hyperkalemia (6.5 mEq/L) with increased plasma renin activity of 53.1 ng/mL/h. She was diagnosed with aldosterone deficiency and started on fludrocortisone 0.1 mg daily, after which the hyperkalemia improved immediately. In this case, DAPA treatment could potentially increase the requirement for mineralocorticoid replacement, directly suggesting that the SGLT2 inhibition-induced natriuretic effect is accompanied by compensatory activation of the RAAS axis, which is essential to keep the serum potassium level within the normal range. Therefore, physicians should be careful about the development of hyperkalemia in patients when SGLT2 and RAAS inhibitors are used in combination.

A case of Adrenocoricotrophic hormone -independent bilateral adrenocortical macronodular hyperplasia concomitant with primary aldosteronism.

BACKGROUND: Adrenocoricotrophic hormone (ACTH) - independent bilateral adrenocortical macronodular hyperplasia (AIMAH) is a rare cause of Cushing's syndrome, and is characterized by bilateral adrenal hyperplasia. However, Primary aldosteronism (PA) is a relatively common adrenal disease. CASE PRESENTATION: A 56-year-old man who has been treated hypertension and diabetes mellitus was detected low plasma potassium level with an elevated level of plasma aldosterone concentration and bilateral adrenal swelling. Endocrinological examinations showed autonomous secretion of cortisol and aldosterone, with suppression of plasma ACTH level and renin activity. A selective adrenal venous sampling demonstrated that left adrenal gland was responsible for aldosterone hypersecretion. He was diagnosed preclinical Cushing's syndrome due to ACTH - independent bilateral adrenocortical macronodular hyperplasia (AIMAH) associated with aldosterone producing adenoma of the left adrenal gland. A laparoscopic left adrenalectomy was performed. CONCLUSION: The resected adrenal specimen histologically consisted with a diagnosis of AIMAH. Moreover, tiny cell clusters positive immunostaining for aldosterone synthase was revealed. This is a rare case of AIMAH accompanied by preclinical Cushing's syndrome and primary aldosteronism.