Nephrology referral slows the progression of chronic kidney disease, especially among patients with anaemia, diabetes mellitus, or hypoalbuminemia: A single-centre, retrospective cohort study.

BACKGROUND: The Kidney Disease Improving Global Outcomes guidelines recommend nephrology referral for patients with chronic kidney disease (CKD) stages 4 to 5, significant proteinuria and persistent microscopic haematuria. However, the recommendations are opinion-based and which patients with CKD benefit more from nephrology referral has not been elucidated. METHODS: In this retrospective cohort study, patients referred to our nephrology outpatient clinic from April 2017 to March 2019 were included. We excluded patients considered to have an acute decline in kidney function (annual decline in estimated glomerular filtration rate [eGFR] >10 mL/min/1.73 m2). The slopes of eGFR before and after nephrology referral were estimated and compared by linear mixed effects models. Interaction between time and referral status (before or after referral) was assessed and effect modifications by the presence of diabetes, proteinuria (defined by urine dipstick protein 2+ or more), urine occult blood, hypoalbuminemia (defined by albumin levels less than 3.5 g/dL) and anaemia (defined by haemoglobin levels less than 11.0 g/dL) were evaluated. RESULTS: The eGFR slope significantly improved from -2.05 (-2.39 to -1.72) to -0.96 (-1.36 to -0.56) mL/min/1.73 m2/year after nephrology referral (p < .001). The improvement in eGFR slope was more prominent among those with diabetes mellitus, anaemia, and hypoalbuminemia (all p-values for three-way interaction <.001 after adjustment for covariates). Further adjustments for time-dependent haemoglobin levels, the use of erythropoiesis-stimulating agents, iron supplementation, anti-hypertensives and anti-diabetic medications did not change the significance of the interactions. CONCLUSIONS: Nephrology referral slows CKD progression, especially among those with hypoalbuminemia, diabetes or anaemia. Patients with hypoalbuminemia, diabetes or anaemia might benefit more from specialized care and lifestyle modifications by nephrologists. The inclusion of anaemia and hypoalbuminemia in nephrology referral criteria should be considered.

Epidemiology and predictors of hyponatremia in a contemporary cohort of patients with malignancy: a retrospective cohort study.

Background: Hyponatremia is associated with worse outcomes among patients with malignancy. However, contemporary cohort data on epidemiology and risk factors are lacking. Methods: In this single-centre, retrospective cohort study, patients who received intravenous antineoplastic agents from 2018 to 2020 at Nagoya City University Hospital were enrolled. Associations of demographics, antineoplastic agents, types of malignancy and concomitant medications with hyponatremia, defined as serum sodium concentration ≤130 mmol/l, were analysed by mixed-effects logistic regression and the machine learning-based LightGBM model artificial intelligence technology. Results: Among 2644 patients, 657 (24.8%) developed at least one episode of hyponatremia. Approximately 80% of hyponatremia was due to sodium wasting from the kidneys. Variables associated with hyponatremia both by mixed-effects logistic regression and the LightGBM model were older age, hypoalbuminemia and higher estimated glomerular filtration rate. Among antineoplastic agents, cisplatin {odds ratio [OR] 1.52 [95% confidence interval (CI) 1.18-1.96]}, pembrolizumab [OR 1.42 (95% CI 1.02-1.97)] and bortezomib [OR 3.04 (95% CI 1.96-4.71)] were associated with hyponatremia and these variables also had a positive impact on predicted hyponatremia in the LightGBM model. Conclusions: Hyponatremia was common among patients with malignancy. In addition to older age and poor nutritional status, novel antineoplastic agents, including immune checkpoint inhibitors and bortezomib, should be recognized as risk factors for hyponatremia.

Sodium-glucose cotransporter 2 inhibitors and anemia among diabetes patients in real clinical practice.

AIMS/INTRODUCTION: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) were reported to increase hemoglobin levels in short-term clinical trials. Whether it is also true in real clinical practice is unknown. MATERIALS AND METHODS: This is a retrospective cohort study. Inclusion criterion was diabetes patients who visited our outpatient clinic from January 2019 to August 2020. Exposure of interest was the use of SGLT2i. Outcomes were hemoglobin levels. For the cross-sectional analyses, non-linear regression models were fitted with restricted cubic splines to investigate the association between hemoglobin levels and estimated glomerular filtration rate (eGFR) for users and non-users of SGLT2i. For the case-control study, cases (anemia defined as hemoglobin <120 g/L for men, <110 g/L for women or the use of erythropoiesis stimulating agents) and controls were matched by age, sex and eGFR. RESULTS: Among 2,063 diabetes patients, 723 were taking SGLT2i. In the cross-sectional analyses, hemoglobin levels were higher among SGLT2i users compared with non-users at eGFR >15 mL/min/1.73 m2 . For the case-control study, 197 cases and controls were matched. Conditional logistic regression showed that the use of SGLT2i was associated with significantly lower prevalence of anemia (odd ratio 0.35, 95% confidence interval 0.21-0.58). Adjusted mean differences in hemoglobin levels between users and propensity score-matched non-users of SGLT2i were 7.0 g/L (95% confidence interval 3.0-10.0 g/L) at 6 months. Among SGLT2i users, the odds of an increase in 6-month hemoglobin were similar across eGFR categories, except for eGFR <15 mL/min/1.73 m2 . CONCLUSIONS: The use of SGLT2i was associated with higher hemoglobin levels and lower prevalence of anemia in real clinical practice.

A Patient with Fulminant Myasthenia Gravis Is Seropositive for Both AChR and LRP4 Antibodies, Complicated by Autoimmune Polyglandular Syndrome Type 3.

This article describes the first reported case of myasthenia gravis (MG) seropositive for both acetylcholine receptor antibody and low-density lipoprotein receptor-related protein 4 antibody, complicated by autoimmune polyglandular syndrome (APS) type 3. The patient exhibited myasthenic weakness restricted to the ocular muscles and ptosis. Severe clinical deterioration ensued with predominant bulbar symptoms. MG rapidly worsened, the patient was intubated, and agranulocytosis due to thiamazole was also present, so it was necessary to perform thyroidectomy with tracheostomy and thymectomy in two phases. Both the double-seropositive MG and the APS were involved in the patient's rapid deterioration.

Circadian rhythm of urinary potassium excretion during treatment with an angiotensin receptor blocker.

INTRODUCTION: We have reported that the circadian rhythm of urinary potassium excretion (U(K)V) is determined by the rhythm of urinary sodium excretion (U(Na)V) in patients with chronic kidney disease (CKD). We also reported that treatment with an angiotensin receptor blocker (ARB) increased the U(Na)V during the daytime, and restored the non-dipper blood pressure (BP) rhythm into a dipper pattern. However, the circadian rhythm of U(K)V during ARB treatment has not been reported. MATERIALS AND METHODS: Circadian rhythms of U(Na)V and U(K)V were examined in 44 patients with CKD undergoing treatment with ARB. RESULTS: Whole-day U(Na)V was not altered by ARB whereas whole-day U(K)V decreased. Even during the ARB treatment, the significant relationship persisted between the night/day ratios of U(Na)V and U(K)V (r=0.56, p<0.0001). Whole-day U(K)V/U(Na)V ratio (p=0.0007) and trans-tubular potassium concentration gradient (p=0.002) were attenuated but their night/day ratios remained unchanged. The change in the night/day U(K)V ratio correlated directly with the change in night/day U(Na)V ratio (F=20.4) rather than with the changes in aldosterone, BP or creatinine clearance. CONCLUSIONS: The circadian rhythm of U(K)V was determined by the rhythm of UNaV even during ARB treatment. Changes in the circadian U(K)V rhythm were not determined by aldosterone but by U(Na)V.

Angiotensin receptor blockers regulate the synchronization of circadian rhythms in heart rate and blood pressure.

OBJECTIVE: The sympathetic nervous system plays an important role in blood pressure regulation even in the early stages of chronic kidney disease (CKD). METHODS: To understand the role of the sympathetic system, we examined the relationship between day/night ratios of both heart rate (HR) and mean arterial pressure (MAP) as well as HR variability (HRV, SD) before and during an 8-week treatment with the angiotensin II receptor blocker (ARB), olmesartan, in 45 patients with CKD. RESULTS: The day/night HR ratio strongly correlated with the day/night MAP ratio before and during ARB treatment. The ratio of [day/night HR ratio] over [day/night MAP ratio] was increased as renal function deteriorated at baseline (r = -0.31, P = 0.04), and it was attenuated (1.10 ±â€Š0.10 to 1.06 ±â€Š0.10; P = 0.04) and became independent of renal function during ARB treatment (r = -0.04, P = 0.8). ARB increased both the day/night HR ratio (1.17 ±â€Š0.09 to 1.21 ±â€Š0.13; P = 0.04) and HRV (10.6 ±â€Š2.9 to 11.7 ±â€Š4.2; P = 0.04), which were lower when baseline renal function deteriorated. CONCLUSION: The present study indicates that there exists a close correlation in circadian rhythms between HR and MAP in CKD. Synchronization between the two rhythms was progressively lost as renal function deteriorated, and ARB partly restored the synchronization. These findings suggest that the sympathetic nervous system is activated as renal function deteriorates, and ARB may suppress its activation.

Circadian rhythm of urinary potassium excretion in patients with CKD.

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

Predictors of proteinuria reduction by monotherapy with an angiotensin receptor blocker, olmesartan.

INTRODUCTION: It is known that reduced glomerular filtration rate (GFR) is a crucial factor to limit the blood pressure lowering effect of antihypertensives. In the present study, we tested whether the effects of monotherapy with an angiotensin receptor blocker (ARB) to lower proteinuria could be restricted by reduced GFR. MATERIALS AND METHODS: Thirty-five renal patients who had albuminuria more than 30 mg/day, but did not have diabetic nephropathy or nephrotic syndrome, were studied before and during eight weeks of monotherapy with ARB, olmesartan. RESULTS: Blood pressure was lowered from 129 ± 18/79 ± 12 to 116 ± 18/72 ± 12 mmHg (p < 0.0001), while albuminuria was reduced from 614±630 to 343±472 mg/day (p < 0.0001). Albuminuria was inversely correlated with GFR both before and during treatment. Albuminuria reduction was enhanced as plasma renin activity (p = 0.047) and dose of olmesartan were increased (p = 0.04). Although the absolute reduction in proteinuria was not correlated with GFR (p = 0.56), the % reduction was significantly proportional with GFR (p = 0.027). Multiple regression analysis demonstrated that 64% of proteinuria reduction could be explained by baseline levels of albuminuria, GFR and renin activity. CONCLUSIONS: The reduction in proteinuria by olmesartan may be roughly predicted using baseline GFR and other parameters. These findings clarify that the effect of ARB on proteinuria reduction is restricted by reduced GFR.

Low birth weight and end-stage renal disease: demographic analysis by region in Japan.

UNLABELLED: BACKGROUND We have previously shown regional differences in the incidence of end-stage renal disease (ESRD)within Japan, which is ethnically homogenous, suggesting that non-genetic factors may contribute to the differences.We examined regional distribution in the incidence of low birth weight (LBW), a surrogate for low nephron number,in our search for an explanation. METHODS: Each year, the Ministry of Health, Labour and Welfare of Japan and the Japanese Society for Dialysis Therapy report the number of LBW babies and patients initiating maintenance dialysis in each prefecture of Japan,respectively. In this study, we calculated the annual incidences of LBW and ESRD in 11 regions of Japan over a 24-year period from 1984 to 2007. RESULTS: There were distinct regional differences in the annual incidences of both LBW and ESRD (p<0.0001).These regional distributions persisted despite consistent increases (p<0.0001) in incidences of both LBW and ESRD during the study period. Compared with the reference group consisting of 3 regions with the lowest LBW incidence, the odds ratios for ESRD (95% confidence interval) of the 5 regions with intermediate LBW incidence and the 3 regions with the highest LBW incidence are 1.09(1.05­1.14) and 1.29 (1.22­1.35), respectively. The annual incidence of LBW was positively correlated with annual incidence of ESRD in their regional distribution across 11 regions (r = 0.66, p = 0.03). CONCLUSIONS: The present study, relating regional distribution between LBW and ESRD dynamics in a nationwide population of Japan, revealed that the marked regional differences in the incidence of ESRD within Japan could be explained by a similar regional distribution in the incidence of LBW.

Morning hypertension in chronic kidney disease is sustained type, but not surge type.

OBJECTIVE: We have shown that as renal function deteriorates, the circadian blood pressure (BP) rhythm shifts to a nondipper pattern and the duration until nocturnal BP decline [dipping time (DT)] is prolonged. We investigated whether or not morning hypertension (BP 2 h after awakening >135/85 mmHg) in chronic kidney disease (CKD) was sustained type with a prolonged DT. MATERIALS AND METHODS: Twenty-four-hour BP was monitored in 104 patients with CKD. Fifty-one of 104 participants (group A) did not exhibit morning hypertension. The patients with morning hypertension (group B, n=53) were classified into three groups: group C (n=23), participants who exhibited morning hypertension but did not meet the criteria for the surge or sustained type; group D (n=29), the sustained type (with no night-time BP readings <120/70 mmHg); and group E (n=1), the surge type (systolic BP rises >25 mmHg after awakening). RESULTS: The night/day BP ratio and DT were compared among groups A, C, and D because there was only one participant in group E. Night/day ratio of BP and DT were both significantly higher in group D compared with groups A and C. The prevalence of nondippers tended to be higher in group D compared with the other groups (A, 65%; C, 57%; D, 86%, P=0.09). Creatinine clearance was significantly lower in group D compared with groups A and C. CONCLUSION: Sustained elevation of night-time BP until the early morning and high night/day ratio of BP may contribute to the high frequency of morning hypertension, which is generally the sustained rather than the surge type in CKD.

Is salt intake an independent risk factor of stroke mortality? Demographic analysis by regions in Japan.

We reported a remarkable regional difference within Japan in the incidence of end-stage renal disease. Regional differences were also well-known for salt intake, blood pressure (BP), and mortality from stroke, which remains one of the leading causes of death. Noting these regional differences, we examined mutual relationships among salt intake, BP, and stroke mortality in 12 regions of Japan. Data of salt intake, BP, and stroke mortality in 12 regions were collected from National Nutrition Survey (NNS-J), reanalysis of NNS-J, and Vital Statistics of National Population Dynamic Survey (Ministry of Health, Labor and Welfare), respectively. Significant regional differences were found in salt intake (P < .0001), mean arterial BP (P = .0001), and stroke mortality (P < .0001). Although annual changes in these parameters were also significant, their regional differences persisted. Salt intake had positive relationships with both mean arterial BP (r = 0.26, P = .0009) and stroke mortality (r = 0.26, P < .0001) across 12 regions, whereas mean arterial BP was not correlated with stroke mortality. Multiple regression analysis further identified salt intake as an independent factor to increase stroke mortality, but mean arterial BP was not a determinant. Compared with the four regions with lowest salt intake, odds ratios of stroke mortality adjusted by mean arterial BP were 1.04 (95% CI, 1.03-1.06) for the intermediate four regions and 1.25 (95% CI, 1.23-1.27) for the four regions with highest salt intake. These findings suggest that salt intake may have an adverse effect on stroke mortality independently of BP.

Angiotensin receptor blockers shift the circadian rhythm of blood pressure by suppressing tubular sodium reabsorption.

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

Geographic differences in the increasing ESRD rate have disappeared in Japan.

BACKGROUND: We previously showed that there are marked geographic differences in the incidence of end-stage renal disease (ESRD) within Japan. In addition, the use of renin-angiotensin system inhibitors was found to be inversely correlated with the increasing ESRD rate. It was recently demonstrated that the incidence of ESRD due to diabetic nephropathy is declining in both Europe and USA. Therefore, we investigated the increasing ESRD rate and its geographic difference in Japan. METHODS: Each year, the Japanese Society for Dialysis Therapy reports the numbers of patients initiating maintenance dialysis therapy in each prefecture of Japan. We used old (1984-1991) and recent (2001-2008) data to compare the increasing ESRD rate, which was estimated from the slope of the regression line of the annual incidence corrected for population, between the two periods in 11 regions of Japan. RESULTS: Increasing ESRD rate almost halved, from 11.1 ± 5.6 to 5.4 ± 0.7/million per year from the old to the recent period. Deceleration of the increasing ESRD rate from the old to the recent period was correlated with the incidence in the old period across 11 regions (r = 0.81, p < 0.003); i.e., the deceleration was greater in the regions where ESRD incidence had been higher. Whereas the increasing ESRD rate was significantly different among regions in the old period, this was not the case in the recent period, resulting in uniformity throughout Japan. CONCLUSIONS: The increasing ESRD rate is slowing in Japan, and its geographic differences, previously observed, have disappeared.