Blood Hemoglobin Concentrations and the Incidence of Lower Extremity Peripheral Arterial Disease in Patients Undergoing Hemodialysis: 10-Year Outcomes of the Q-Cohort Study.

BACKGROUND: Lower extremity peripheral arterial disease is a potentially lethal cardiovascular complication in patients undergoing hemodialysis. Anemia is a risk factor for cardiovascular disease among the hemodialysis population. However, whether blood hemoglobin concentration is associated with the risk of peripheral arterial disease progression in this population remains undetermined. METHODS AND RESULTS: This is an extension of a 4-year multicenter, prospective, observational cohort study to 10 years. A total of 3504 Japanese patients undergoing maintenance hemodialysis were recruited between 2006 and 2007. The primary exposure was blood hemoglobin concentration at baseline. The main outcome was the first-ever incidence of major adverse limb events (MALE), composed of endovascular treatment, bypass surgery, and amputation. Multivariable-adjusted Cox proportional hazards model, Fine-Gray subdistribution hazards model, restricted cubic spline analysis, and restricted mean survival time analysis were used to determine the association of blood hemoglobin concentration with the incidence of MALE. During a median follow-up of 8.0 years, 257 patients experienced MALE. A Cox proportional hazards model showed that the risk of MALE in patients with blood hemoglobin concentrations <10.0 g/dL was significantly higher than in patients with concentrations of 11.0 to 11.9 g/dL, even after adjusting for confounding factors. In contrast, elevated hemoglobin concentration (≥12.0 g/dL) was not significantly associated with increased risk of MALE. Similar associations were observed when the Fine-Gray subdistribution regression model was used by setting all-cause mortality as the competing risk. CONCLUSIONS: A low blood hemoglobin concentration is an independent risk factor for peripheral arterial disease progression in patients undergoing maintenance hemodialysis.

Disturbance in the potential cardiovascular-bone-skeletal muscle axis and morbidity and mortality in patients undergoing haemodialysis: the Q-Cohort Study.

Background: Disturbances in the cardiovascular system, bone and skeletal muscle are independent risk factors for death among patients receiving haemodialysis (HD). However, the combined impact of disorders of these three organs on morbidity and mortality is unclear in the HD population. Methods: A total of 3031 Japanese patients on maintenance HD were prospectively followed. The outcomes were all-cause mortality, major adverse cardiovascular events (MACE) and bone fracture. Patients were divided into four groups (G1-G4) according to the baseline number of diseased organs represented as histories of cardiovascular disease and bone fractures and the presence of low skeletal muscle mass as follows: G1, no organ; G2, one organ; G3, two organs; G4, three organs. Multivariable-adjusted survival models were used to analyse associations between the number of diseased organs and outcomes. Results: During a 4-year follow-up, 499 deaths, 540 MACE and 140 bone fractures occurred. In the Cox proportional hazards model, the risk for all-cause mortality was significantly higher in G2, G3 and G4 than in G1 as the reference {hazard ratio: G2, 2.16 [95% confidence interval (CI) 1.65-2.84], G3, 3.10 [95% CI 2.27-4.23] and G4, 3.11 [95% CI 1.89-5.14]}. Similarly, the risks for developing MACE and bone fractures were significantly elevated as the number of organ disorders increased. Conclusions: Multiple disorders of the cardiovascular-bone-skeletal muscle axis are strong predictors of morbidity and mortality in patients undergoing HD.

A simple score for malnutrition-inflammation complex syndrome (MICS) is associated with the risk of mortality in Japanese patients undergoing maintenance hemodialysis.

INTRODUCTION: Malnutrition-inflammation complex syndrome (MICS) is highly prevalent in patients undergoing hemodialysis. We determined the prognostic value of the Simple MICS score, calculated using a combination of age, body mass index, and serum concentrations of albumin, creatinine, and C-reactive protein. METHODS: We retrospectively recruited 218 Japanese patients undergoing maintenance hemodialysis. The primary outcome was all-cause mortality, and the main exposure was the Simple MICS score. Cox proportional hazard regression analysis and logistic regression analysis were used to characterize the relationship between the Simple MICS score and mortality. RESULTS: During a median 4.4-year follow-up period, 56 patients died. Multivariable-adjusted models showed that a higher Simple MICS score was associated with higher risks of mortality. The predictability for all-cause mortality of the Simple MICS score was significantly better than conventional nutrition-related indices. CONCLUSION: The Simple MICS score can be used to stratify mortality risk in patients undergoing maintenance hemodialysis.

Simplified geriatric nutritional risk index for assessing nutritional status and stratifying mortality risk in patients receiving maintenance hemodialysis.

INTRODUCTION: The geriatric nutritional risk index (GNRI) is a widely used tool for nutritional assessment in patients receiving hemodialysis. The simplification of the GNRI calculation would be more useful for easier screening of malnutrition and for providing an intuitive stratification of mortality risk. METHODS: We retrospectively evaluated 218 Japanese patients receiving maintenance hemodialysis at two hemodialysis centers. The primary outcome was all-cause mortality. The main exposure was a simplified GNRI (sGNRI) calculated as follows: sGNRI = serum albumin (g/dL) + 0.1 × body mass index (kg/m2 ). RESULTS: During the median 4.4-year follow-up, 56 patients died. Multivariable-adjusted Cox proportional hazard risk models showed that patients with a lower sGNRI showed a significantly increased mortality risk. No significant difference was observed between the original GNRI and sGNRI regarding mortality predictability. CONCLUSION: sGNRI is as useful as the original GNRI for screening for malnutrition and stratifying hemodialysis patients at increased mortality risk.

Association between prevalence of laxative use and history of bone fractures and cardiovascular diseases in patients with chronic kidney disease: the Fukuoka Kidney disease Registry (FKR) study.

BACKGROUND: Constipation is a common complication in patients with chronic kidney disease (CKD) and is involved in the pathogenesis of dysbiosis and progression of CKD. However, little is known about its association with disorders of the bone-cardiovascular axis in patients with CKD. METHODS: We performed a cross-sectional analysis of 3878 patients with CKD using the baseline dataset of the Fukuoka Kidney disease Registry study, as a multicenter, prospective cohort study of pre-dialysis CKD patients. The main exposure of interest was constipation defined as use of at least one type of laxative. The main outcomes were the histories of bone fractures and cardiovascular diseases (CVDs) as manifestations of disorders of the bone-cardiovascular axis. RESULTS: The prevalences of laxative use and histories of bone fractures and CVDs increased as kidney function declined. Among the 3878 patients, 532 (13.7%) patients used laxatives, 235 (6.1%) patients had prior bone fractures, and 1001 (25.8%) patients had prior CVDs. Histories of bone fractures and CVDs were significantly more prevalent among laxative users (P < 0.05). Multivariable-adjusted logistic regression analysis revealed that patients with laxatives had a significantly higher odds ratios for histories of bone fractures and CVDs than those without laxatives [adjusted odds ratios (95% confidence intervals) 1.67 (1.20-2.31) and 1.70 (1.30-2.22), respectively, P < 0.05]. CONCLUSIONS: These results suggest that constipation indicated by laxative use is associated with increased prevalences of historical bone fractures and CVDs in pre-dialysis patients with CKD.

Malnutrition-Inflammation Complex Syndrome and Bone Fractures and Cardiovascular Disease Events in Patients Undergoing Hemodialysis: The Q-Cohort Study.

Rationale & Objective: Malnutrition-inflammation complex syndrome (MICS) is common in patients receiving hemodialysis and increases the risks of morbidity and mortality. However, few studies have examined the overall impact of MICS on disorders of the bone-cardiovascular axis. Study Design: Prospective, multicenter, observational cohort study. Setting & Participants: A total of 3,030 patients receiving maintenance hemodialysis registered in the Q-Cohort Study. Predictors: A newly developed score for MICS composed of elements chosen from 8 baseline parameters related to nutrition and inflammation by bootstrap resampling, multivariable-adjusted Cox proportional hazard risk analysis for all-cause mortality, and the risk prediction rule. ß-coefficients of each element analyzed in the multivariable-adjusted model were used for the creation of the MICS score. Outcomes: Bone fractures, cardiovascular disease events, and the composite outcome of bone fractures and cardiovascular disease events. Analytical Approach: Cox proportional hazard regression and Fine-Gray proportional subdistribution hazards regression. Results: During a median follow-up of 4 years, 140 patients developed bone fractures and 539 developed cardiovascular disease events. Age; serum levels of creatinine, albumin, and C-reactive protein; and body mass index were selected for the creation of the MICS score. The median (IQR) MICS score was 196 (181-212). The multivariable-adjusted Cox proportional hazard risk model and the competing risk model showed that a higher MICS score was incrementally associated with elevated risks of bone fractures, cardiovascular disease events, and the composite outcome; hazard risks (95% CIs) of fractures, cardiovascular disease events, and the composite outcome for each 10-point increase in the MICS score were 1.18 (1.01-1.38), 1.16 (1.07-1.26), and 1.15 (1.07-1.24), respectively. Limitations: One-time measurement of the parameters used for the creation of the MICS score. Conclusions: Malnutrition and inflammation represented by the MICS score were associated with increased risks of bone-cardiovascular axis disorders in patients receiving maintenance hemodialysis.

Protective Roles of Xenotropic and Polytropic Retrovirus Receptor 1 (XPR1) in Uremic Vascular Calcification.

Cellular phosphate transporters play critical roles in the pathogenesis of vascular calcification (VC) in chronic kidney disease (CKD). However, the mechanistic link between VC and xenotropic and polytropic receptor 1 (XPR1), a newly identified phosphate exporter, remains unknown. We developed a new mouse model with rapidly progressive uremic VC in C57BL/6 mice and examined the roles of XPR1. The combination of surgical heminephrectomy and 8 weeks of feeding a customized warfarin and adenine-based diet induced extensive aortic VC in almost all mice. The XPR1 mRNA level in the aorta of CKD mice was significantly lower than those in control mice as early as week 2, when there was no apparent VC, which progressively declined thereafter. Dietary phosphate restriction increased XPR1 mRNA expression in the aorta but reduced aortic VC in CKD mice. In cultured vascular smooth muscle cells (VSMCs), a calcifying medium supplemented with high phosphate and calcium did not affect XPR1 mRNA expression. The XPR1 mRNA expression in cultured VCMCs was also unaffected by administration of indoxyl sulfate or calcitriol deficiency but was decreased by 1-34 parathyroid hormone or fibroblast growth factor 23 supplementation. Furthermore, XPR1 deletion in the cultured VSMCs exacerbated calcification of the extracellular matrix as well as the osteogenic phenotypic switch under the condition of calcifying medium. Our data suggest that XPR1 plays protective roles in the pathogenesis of VC and its decrease in the aorta may contribute to the progression of VC in CKD.

Association of the nutritional risk index for Japanese hemodialysis patients with long-term mortality: The Q-Cohort Study.

BACKGROUND: Protein-energy wasting (PEW) is a risk factor for mortality in patients undergoing hemodialysis. Recently, a nutritional risk index for Japanese hemodialysis patients (NRI-JH) has been proposed as a surrogate index of PEW. However, no study has determined the association of the NRI-JH with long-term mortality in patients undergoing hemodialysis. Furthermore, the validity of the NRI-JH has not been confirmed. METHODS: In total, 3046 patients undergoing hemodialysis and registered in the Q-Cohort Study were followed up for 10 years. The NRI-JH was calculated on the basis of body mass index and serum levels of albumin, total cholesterol, and creatinine. The patients were divided into four groups according to the NRI-JH scores: 0-3 (G1, n = 1343), 4-7 (G2, n = 1136), 8-10 (G3, n = 321), and 11-13 (G4, n = 246). We examined the association between the NRI-JH and the 4-year and 10-year risks of all-cause, cardiovascular, and infection-related deaths using the Cox proportional hazards model. RESULTS: During the follow-up period, 647 patients died during the first 4 years, and 1503 patients died within 10 years. The 4-year prognosis was analyzed and compared with the lowest NRI-JH score group. Multivariable-adjusted hazard ratios (95% confidence intervals) for all-cause death were 1.93 (1.57-2.38), 2.68 (2.05-3.50), and 3.16 (2.40-4.16) in the G2, G3, and G4 groups, respectively. Similarly, a higher NRI-JH score was associated with an increased risk of cardiovascular and infection-related deaths. CONCLUSION: A higher NRI-JH score was associated with an increased risk of long-term mortality in patients undergoing maintenance hemodialysis. TRIAL REGISTRATION: The study protocol was registered in the University Hospital Medical Information Network (UMIN) clinical trial registry (UMIN ID: 000000556).

Associations Between Surrogates of Skeletal Muscle Mass and History of Bone Fracture in Patients with Chronic Kidney Disease: The Fukuoka Kidney disease Registry (FKR) Study.

Patients with chronic kidney disease (CKD) are at increased risks of both sarcopenia and fragility fractures. However, information on the association between skeletal muscle mass (SMM) and the risk of bone fractures in patients with CKD is lacking. We performed a cross-sectional analysis of 4146 patients with CKD using the baseline dataset of the Fukuoka Kidney disease Registry Study, as a multicenter, prospective cohort study of pre-dialysis CKD patients. The main measure was estimated SMM (eSMM) calculated using an equation validated by bioelectrical impedance analysis with two independent datasets of 100 and 81 CKD patients. The main outcome was historical bone fractures. The associations between sex-specific quartiles (Q1-Q4) of eSMM and fracture history were assessed by logistic regression analyses. The prevalence of a history of fractures increased and eSMM decreased with progressive CKD stages. Among the 4146 patients, 249 had prior bone fractures, including 111 patients in Q1 (lowest quartile), 65 in Q2, 46 in Q3, and 27 in Q4 (highest quartile). A multivariable-adjusted model revealed that patients in Q1 had a significantly higher odds ratio (95% confidence interval) for bone fracture history than those in Q4 (reference): Q1, 2.77 (1.32-5.80); Q2, 1.95 (1.05-3.65); and Q3, 1.57 (0.90-2.75) (P-value for trend < 0.001). Similar associations were obtained when other skeletal muscle surrogates were applied: serum creatinine to serum cystatin C and daily urinary creatinine excretion. These results suggest that a lower eSMM is associated with an increased prevalence of historical bone fractures in pre-dialysis CKD patients.

Association of normalized protein catabolic rate (nPCR) with the risk of bone fracture in patients undergoing maintenance hemodialysis: The Q-Cohort Study.

BACKGROUND & AIMS: Normalized protein catabolic rate (nPCR) is used as a surrogate for daily dietary protein intake and nutritional status in patients receiving maintenance hemodialysis. It remains uncertain whether the nPCR level is associated with the incidence of bone fracture. METHODS: A total of 2869 hemodialysis patients registered in the Q-Cohort Study, a multicenter, prospective, observational study, were followed up for 4 years. The primary outcome was bone fracture at any site. The main exposure was the nPCR level at baseline. Patients were assigned to four groups based on their baseline nPCR levels (G1: <0.85, G2: 0.85≤, <0.95, G3: 0.95≤, <1.05 [reference], G4: ≥1.05 g/kg/day). We examined the relationship between the nPCR levels and the risk for bone fracture using Cox proportional hazards models. RESULTS: During the follow-up period, 136 patients experienced bone fracture at any site. In the multivariable analyses, the risk for bone fracture was significantly higher in the lowest (G1) and highest (G4) nPCR groups than the reference (G3) group (hazard ratio [95% confidence intervals]: G1, 1.93 [1.04-3.58]; G2, 1.27 [0.67-2.40]; G3 1.00 (reference); G4, 2.21 [1.25-3.92]). The association remained almost unchanged, even when patients were divided into sex-specific nPCR quartiles, when analysis was limited to patients with a dialysis vintage ≥2 years, assumed to have lost residual kidney function, or when a competing risk model was applied. CONCLUSIONS: Our results suggest that both lower and higher nPCR levels are associated with an increased risk for bone fracture in hemodialysis patients.

Association of serum phosphate concentration with the incidence of intervention for peripheral artery disease in patients undergoing hemodialysis: 10-year outcomes of the Q-Cohort Study.

BACKGROUND AND AIMS: Peripheral artery disease (PAD) is mainly caused by atherosclerosis and is a critical cardiovascular complication in patients undergoing hemodialysis. Although hyperphosphatemia is a risk factor for cardiovascular events, whether serum phosphate concentration is associated with PAD remains unclear. This study was performed to clarify the relationship between serum phosphate concentration and the risk of intervention for PAD in patients undergoing hemodialysis. METHODS: In total, 3505 patients undergoing hemodialysis registered in the Q-Cohort Study were followed up for 10 years. The primary outcome was the incidence of major adverse limb events (MALE) as a surrogate endpoint of intervention for PAD. The patients were divided into quartiles according to the baseline serum phosphate concentration: Q1 (n = 886), <4.2 mg/dL; Q2 (n = 837), 4.2-4.8 mg/dL; Q3 (n = 909), 4.9-5.6 mg/dL; and Q4 (n = 873), ≥5.7 mg/dL. A multivariable-adjusted Cox proportional hazards risk model was employed to examine the association between the serum phosphate concentration and the risk of MALE. RESULTS: During a median follow-up period of 8.2 years, 257 patients required intervention with MALE. The Cox proportional hazards risk model showed that the risk of MALE in Q4 was significantly higher than that in Q1 (hazard ratio, 1.81; 95% confidence interval, 1.25-2.63). Every 1-mg/dL increase in serum phosphate concentration was also significantly associated with the increased incidence of MALE (hazard ratio, 1.24; 95% confidence interval, 1.10-1.39). CONCLUSIONS: An elevated serum phosphate concentration was associated with an increased risk of MALE in patients undergoing hemodialysis.

Association Between Plasma Intact Parathyroid Hormone Levels and the Prevalence of Atrial Fibrillation in Patients With Chronic Kidney Disease　- The Fukuoka Kidney Disease Registry Study.

BACKGROUND: Parathyroid hormone (PTH) has been associated with cardiovascular disorders; however, it is unknown whether plasma PTH concentrations are associated with atrial fibrillation (AF) in patients with chronic kidney disease (CKD).Methods and Results:The present cross-sectional study analyzed baseline data of 3,384 patients registered in the Fukuoka Kidney Disease Registry Study, a Japanese multicenter prospective cohort study of patients with non-dialysis-dependent CKD. The outcome was prevalence of AF, and the main risk factor was plasma intact PTH concentration. Associations between plasma intact PTH concentration quartiles (Q1-Q4, from lowest to highest) and the presence of AF were analyzed using logistic regression. In all, 185 patients had AF; 22, 34, 59, and 70 patients were in Q1, Q2, Q3, and Q4 of PTH concentrations, respectively. The prevalence of AF increased incrementally with increases in plasma intact PTH. In the logistic regression model, patients with higher plasma intact PTH concentrations (Q2-Q4) had higher adjusted odds ratios (95% confidence intervals) for the prevalence of AF relative to the reference group (Q1), namely 1.33 (0.76-2.34), 1.82 ([1.06-3.13), and 1.99 (1.08-3.64), respectively (P=0.016). CONCLUSIONS: Higher plasma intact PTH concentrations were significantly and incrementally associated with an increased prevalence of AF in non-dialysis-dependent CKD patients.

Increased Risk of Infection-Related and All-Cause Death in Hypercalcemic Patients Receiving Hemodialysis: The Q-Cohort Study.

Although hypercalcemia is a risk factor for all-cause mortality in hemodialysis patients, it remains unknown whether hypercalcemia increases the risk of infection-related death. A total of 2869 hemodialysis patients registered in the Q-Cohort Study, a multicenter, prospective cohort study of hemodialysis patients, were analyzed. The predictor was albumin-corrected serum calcium level at baseline. The main outcome was infection-related death. Death risk were estimated by multivariable-adjusted Cox proportional hazard risk models and competing risk models. During the follow-up period of 4 years, 107 patients died of infection and 473 died of any cause. The patients were divided into four groups by the serum calcium level at baseline (G1, 5.7-8.9 mg/dL; G2, 9.0-9.4 mg/dL; G3, 9.5-9.9 mg/L; G4 10.0-16.5 mg/dL). In the multivariable-adjusted model, the incidence of infection-related death was significantly higher in the highest serum calcium group (G4) compared with the lowest serum calcium group (G1): hazard ratio [95% confidence interval], 2.34 [1.35-4.04], P = 0.002. Furthermore, higher serum calcium level was significantly associated with increased risk of all-cause death. In conclusion, our data suggest that a higher serum calcium level may be a risk factor for infection-related and all-cause death in hemodialysis patients.

Modified creatinine index and risk for long-term infection-related mortality in hemodialysis patients: ten-year outcomes of the Q-Cohort Study.

Modified creatinine (Cr) index, calculated by age, sex, pre-dialysis serum Cr concentration, and Kt/V for urea, is an indicator of skeletal muscle mass in hemodialysis (HD) patients. It remains unknown whether the modified Cr index predicts infection-related mortality in this population. We investigated the association between the modified Cr index and infection-related mortality. A total of 3046 patients registered in the Q-Cohort Study, a multicenter, observational study of HD patients, were analyzed. Associations between sex-specific quartiles (Q1-Q4) of the modified Cr index and the risk for infection-related mortality were analyzed by Cox proportional hazard model. During a median follow-up of 8.8 years, 387 patients died of infection. The estimated risk for infection-related mortality was significantly higher in the lower quartiles (Q1, Q2, and Q3) than in the highest quartile (Q4) as the reference group (hazard ratios and 95% confidence intervals [CI]: Q1, 2.89 [1.70-5.06], Q2, 2.76 [1.72-4.62], and Q3, 1.79 [1.12-2.99]). The hazard ratio (95% CI) for a 1 mg/kg/day decrease in the modified Cr index was 1.18 (1.09-1.27, P < 0.01) for infection-related mortality. In conclusion, a lower modified Cr index is associated with an increased risk for long-term infection-related mortality in the HD population.

Lower Serum Albumin Level Is Associated With an Increased Risk for Loss of Residual Kidney Function in Patients Receiving Peritoneal Dialysis.

Preserving residual kidney function (RKF) is important in the management of patients on peritoneal dialysis. However, few studies have examined the association between serum albumin level and the risk of RKF loss. We prospectively recruited 104 patients who began peritoneal dialysis treatment at our hospital between 2006 and 2016. The primary outcome was complete RKF loss, defined as urine volume < 100 mL/day. Serum albumin level at baseline was the main exposure. During a median observation period of 24 months, 33 patients developed RKF loss. A Cox proportional hazards model showed that hypoalbuminemia was associated with an increased risk of RKF, even after adjustments for potential confounding factors. Multivariable-adjusted linear regression analysis also showed that hypoalbuminemia was associated with greater rates of decline in 24-h urine volume and in renal Kt/V urea. Our findings suggest that hypoalbuminemia is associated with an increased risk of RKF loss in patients with peritoneal dialysis.

Short- and Long-term Effects of Dialysate Calcium Concentrations on Mineral and Bone Metabolism in Hemodialysis Patients: The K4 Study.

RATIONALE & OBJECTIVE: The short- and long-term impact of conversion of dialysate calcium concentration from either 2.5 or 3.0 mEq/L to 2.75 mEq/L on mineral and bone metabolism remains unknown in hemodialysis patients. STUDY DESIGN: Nonrandomized intervention study. SETTING & POPULATION: 12 hemodialysis patients treated at baseline with a 2.5-mEq/L dialysate calcium concentration and another 12 hemodialysis patients treated with a 3.0-mEq/L dialysate calcium concentration. INTERVENTION: Use of 2.75-mEq/L dialysate calcium concentration. OUTCOMES: Changes in intradialytic calcium and phosphate clearance and changes in predialysis and intradialytic serum and ionized mineral and biochemical parameters over the 24 weeks following dialysate calcium conversion. RESULTS: Conversion of dialysate calcium concentration from 2.5 to 2.75 mEq/L increased intradialytic calcium loading and serum total and ionized calcium levels, whereas conversion of dialysate calcium from 3.0 to 2.75 mEq/L decreased intradialytic calcium loading and serum total and ionized calcium levels. Dialysate calcium concentration conversion did not affect intradialytic serum parathyroid hormone level, intradialytic phosphate elimination, or predialysis serum calcium, phosphate, parathyroid hormone, and fibroblast growth factor 23 levels. Intradialytic calcium influx was determined by dialysate calcium concentration and predialysis serum calcium levels, whereas intradialytic phosphate elimination was determined by predialysis serum phosphate levels. LIMITATIONS: Small sample size and no control groups treated with 2.5- and 3.0-mEq/L dialysate calcium concentrations during the 24 weeks of the observation period. CONCLUSIONS: Conversion of dialysate calcium concentration from either 3.0 or 2.5 to 2.75 mEq/L results in expected changes in calcium loading based on predialysis calcium concentration. The dialysate calcium concentration should be personalized based on clinical factors. FUNDING: None. TRIAL REGISTRATION: University Hospital Medical Information Network, www.umin.ac.jp/english/, R000040105, UMIN000035184.

Adrenal crisis presented as acute onset of hypercalcemia and hyponatremia triggered by acute pyelonephritis in a patient with partial hypopituitarism and pre-dialysis chronic kidney disease.

A 57-year-old woman with pre-dialysis chronic kidney disease (CKD) was hospitalized because of fever and fatigue. On admission, increased inflammatory response and pyuria with bacteriuria were observed. Pyelonephritis was successfully treated with antibiotics, whereas her fatigue continued and she developed progressive hypercalcemia and hyponatremia; serum sodium level, 116 mEq/L and corrected serum calcium level, 13.4 mg/dL. Plasma concentrations of adrenocorticotropic hormone and cortisol and serum luteinizing hormone were under the detection level. Although the reaction of other anterior pituitary hormones and the serum antidiuretic hormone (ADH) was preserved, the response of serum luteinizing hormone to administration of luteinizing hormone releasing hormone was impaired. Magnetic resonance imaging showed no structural abnormality in the thalamus, hypothalamus, and pituitary gland. She was diagnosed with adrenal insufficiency caused by partial hypopituitarism in concomitant with pyelonephritis. After starting hydrocortisone replacement, serum levels of sodium and calcium were rapidly normalized. This case highlights the importance of adrenal insufficiency as a differential diagnosis of hypercalcemia in patients with pre-dialysis CKD, especially when hyponatremia was concomitantly observed. Besides, infection should be considered as an important trigger for the development of latent adrenal insufficiency since it could increase the physiological demand of corticosteroid in the body. Also, CKD may enhance the magnitude of hypercalcemia since CKD patients have decreased capacity to increase urinary calcium excretion.

Use of phosphate-binders and risk of infection-related and all-cause mortality in patients undergoing hemodialysis: The Q-Cohort Study.

The use of phosphate (P)-binders allows hemodialysis patients to take in more protein and thus may maintain a good nutritional status. Protein-energy-malnutrition increases the risk of infection-related death. The association between use of P-binders and the relative risks of infection-related death remains unknown in hemodialysis patients. A total of 2926 hemodialysis patients registered to the Q-Cohort Study was followed up for 4-years. The association between use of P-binders and the risks for infection-related and all-cause mortality were estimated by Cox proportional hazards risk model with multiple adjustments by conventional and propensity-score based approaches. During the follow-up period, 106 patients and 492 patients died of infection and any cause, respectively. Cox proportional hazards models with multivariable adjustments including nutritional confounders showed that the incidence of infection-related death was significantly lower in patients with P-binders use compared with those without (hazard ratio [95% confidence interval] for infection-related mortality 0.63 [0.40-0.99]). The results remained significant even after applying four different propensity score-based analyses. Notably, use of P-binders was associated with a lower risk of all-cause mortality. Further studies including randomized controlled clinical trials and observational studies analyzed by an instrumental variable model will provide more robust evidences for the associations observed in our study.