bluuebunny/crossref_metadata_2025 huggingface dataset:
P0838HYPERPROLACTINEMIA IN CKD PATIENTS AND ITS ASSOCIATION WITH STRENGHT, SEXUAL DYSFUNCTION ANS QUALITY OF LIFE
Authors: Teichman Pedro do Valle , Zanotto de Oliveira Gabrielle , Sallaberry Echeverria Silveira Samile , Angarita Jaime Carlos Alberto , Lopes De Castro Mariana , Bauer Andrea Carla
Published: June 2020

Background and Aims

Hyperprolactinemia is a hormonal disorder associated with many diseases, including chronic kidney disease (CKD). Some studies have shown that serum prolactin (PRL) levels increase as CKD progresses, due to decreased renal clearance and increased production. This prolactin retention leads to inhibition of gonadotropic hormone production, and testosterone deficiency in male patients with CKD. Thus, this study aimed to evaluate PRL levels in male patients with different stages of CKD and its association with clinical and laboratory characteristics, strength, sexual dysfunction, and quality of life.

Method

This is a transversal study conducted in a tertiary hospital in southern Brazil. Patients with CKD stage IV and V were included and divided into three groups: 1) stage IV; 2) non-dialysis-dependent stage V and; 3) dialysis-dependent stage V (VD). Patients with prescribed hormone therapy were excluded. PRL, creatinine, testosterone, estradiol, albumin, SHBG, LH, and FSH levels were measured. Free testosterone was estimated by the Vermeulen equation. Patients were also evaluated for strength and musculoskeletal function through the “handgrip strength” test. For evaluation of the quality of life and sexual dysfunction, validated questionnaires were applied: AMS (Aging Male's Symptoms Scale), ADAM (Androgen Deficiency in the Aging Male) and SF-36 Health.

Results

In this study, 164 patients were included (IV=75; V=41; VD=48). The mean age was 64 [55-71] years and BMI 26,9 [23,3-30,04] kg/m2. The dialysis-dependent group had higher prevalence of hyperprolactinemia (22,6% vs. 49% vs. 66%, p<0,001), higher PRL (13,4 vs. 19,43 vs. 26,13, p<0,001) and estradiol (25,6 vs. 24,4 vs. 30,5, p=0,041). PRL levels were positive correlated with CKD stage (rs=0,482, p<0,001) and creatinine (rs=0,467, p<0,001) and negative correlated with testosterone (rs=-0,286, p<0,001) and free testosterone levels (rs=-0,307, p<0,001). There was no difference in PRL levels between hemodialysis and peritoneal dialysis (p=1,000). Analyzes related to the association of PRL levels with strength, quality of life, and sexual dysfunction are still being analyzed.

Conclusion

Hyperprolactinemia is associated with the severity of CKD, with a higher prevalence in dialysis patients. The relation of PRL levels with strength, quality of life, and sexual dysfunction are being evaluated.
P0847HEPATIC ERYTHROPOIETIN SYNTHESIS IS ENHANCED IN HEMODIALYSIS PATIENTS WHO DO NOT REQUIRE ERYTHROPOIESIS-STIMULATING AGENTS
Authors: Hirayama Aki , Yanagawa Takamoto , Kaneko Yoko , Nagano Yumiko , Owada Shigeru , Ishizu Takashi
Published: June 2020

Background and Aims

Erythropoietin is synthesized in the liver during the fetal period and mainly in the kidney after birth. However, some patients with end-stage chronic kidney disease do not require the administration of erythropoiesis-stimulating agents (ESA) despite their damaged renal function. This study aimed to clarify the origin of extrarenal erythropoietin generation in these patients.

Method

The origin of erythropoietin was investigated by analyzing the erythropoietin glycation patterns based on the percentages of migrated isoforms (PMI). Sera of stable hemodialysis (HD) patients with (ESA group) or without (non-ESA group) ESA treatment and umbilical cord blood of newborns (UCB group), which contained erythropoietin of liver origin, were analyzed. The non-ESA group was determined as HD patients without ESA treatment for > 6 months. Informed consent was obtained from all included HD patients and from the parents or guardians of the newborns. This study was performed with permission from the institutional ethical committee and was registered as a clinical trial (no. R000033462 UMIN000029335).

Results

The mean duration of no ESA treatment in the non-ESA group was 29.2 months. There were no differences in major clinical parameters, including age and HD duration. The hemoglobin concentration in the ESA group was 107 ± 5 g/L (mean ± standard error), which was significantly lower than that in the non-ESA group (123 ± 4 g/L) (P = 0.025, unpaired Student’s t-test). The PMI values of the ESA, non-ESA, and UCB groups were 12.6 ± 11.4％, 61.2 ± 13.1%, and 65.0 ± 13.5％, respectively, and the PMI value of the ESA group was significantly lower than that of non-ESA or UCB group (one-way analysis of variance with Tukey-Kramer test), suggesting that the glycation pattern of erythropoietin in the non-ESA group was similar to that in the UCB group but different from that in the ESA group. No significant differences were found in the reticulocyte ratio, serum iron concentration, total iron binding capacity, and ferritin and transferrin saturation between the ESA and non-ESA groups.

Conclusion

These results suggest that patients in the non-ESA group had enhanced extrarenal erythropoietin synthesis and that their erythropoietin originated from the liver. Further analysis of the underlying mechanism may contribute to the development of internal extrarenal erythropoietin-stimulating therapy.
P0850SERUM OSTEOPROTEGERIN LEVELS ARE ASSOCIATED WITH AN INCREASED RISK OF DEVELOPING ANEMIA IN PATIENTS WITH NON DIALYSIS CHRONIC KIDNEY DISEASE
Authors: Nam Yooju , Lee Seonyeong , Kim Hyung Woo , Chang Jae Hyun , Yoo Tae-Hyun
Published: June 2020

Background and Aims

Osteoprotegerin (OPG), which is an osteoclastic inhibitory factor, have been shown associated with adverse renal outcomes and progression of vascular calcification in chronic kidney disease (CKD) patients. Anemia and CKD-bone mineral disorders (CKD-MBD) are also frequently observed in these patients. Since CKD-MBD and anemia might be closely linked, therefore, we further examined whether OPG level as a marker for bone turnover can predict the future development of anemia in a large-scale prospective cohort.

Method

Among 2,238 patients with non-dialysis CKD enrolled in the KoreaN cohort study for Outcome in patients With Chronic Kidney Disease (KNOW-CKD), 2,086 patients who measured hemoglobin, hepcidin, iron profiles and OPG level were included in the analysis. Anemia was defined as a hemoglobin level of < 13.0 g/dL and 12.0 g/dL for male and female, respectively.

Results

The mean age was 53.6 ± 12.2 years and 1,270 (60.9%) patients were males. At baseline, anemia was found in 941 (45.1%) patients. Log transformed OPG levels significantly correlated with FGF23 levels, but inversely with iron profiles and hemoglobin levels at baseline. A multivariate logistic regression model showed that log OPG level was independently associated with the prevalence of anemia (odds ratio [OR], 2.22; 95% confidence interval [CI], 1.41-3.48, P=0.001). Among 1110 patients without baseline anemia, 258 (25.3%) patients developed anemia during a median follow-up duration of 34.6 (interquartile range, 23-48) months. In the fully adjusted multivariable Cox models, risk of developing anemia was significantly higher in the fourth (hazard ratio [HR], 1.99; 95% CI, 1.08-3.67; P =0.028) than in the first OPG quartile. Similar association was observed in a model when OPG was treated as a continuous variable.

Conclusion

We showed that high serum OPG levels are associated with an increased risk of developing anemia in patients with non-dialysis CKD.
P0855ASSOCIATIONS BETWEEN A COMPREHENSIVE PANEL OF BIOMARKERS WITH ESA HYPORESPONSIVENESS: ROLE OF IMMUNE DYSFUNCTION IN THE PATHOPHYSIOLOGY OF CKD ANEMIA
Authors: Batalha Guilherme , Eugênia Canziani Maria , Guedes Murilo , Almeida Ana Clara , Moreno-Amaral Andrea N , Barra Ana Beatriz , Cuvello Américo , Poli De Figueiredo Carlos Eduardo , Pecoits-Filho Roberto
Published: June 2020

Background and Aims

An inadequate response to the treatment of anemia with erythropoiesis-stimulating agents (ESAs) in patients with chronic kidney disease is a challenging and common clinical condition previously associated with signs of inflammation and episodic clinical events. The associations between different immune response pathways and ESA hyporesponsiveness remain poorly understood. Here we describe the associations between a comprehensive panel of inflammatory biomarkers and ESA resistance in a group of stable HD patients.

Method

This is post-hoc analysis of the baseline evaluation of patients enrolled in the HDFIT, a randomized controlled trial. A panel comprising a more general (CRP), innate (IL-1β and IL-6), adaptive (IFNγ, IFNα2) biomarkers of immune response, and also a specific vascular inflammation (MCP-1) biomarkers were simultaneously measured with the same serum sample through turbidimetry and Milliplexï£¨ Human Cytokine Magnetic Bead Panel - EMD Milipore Corporation, USA. Multivariable analysis was used to assess the association of their concentrations with the erythropoietin resistance index (ERI), defined as the weekly ESA dose divided by hemoglobin level.

Results

A total of 155 patients were included in this analysis (mean age 52 ± 6; 70% male; 32% with diabetes; mean hemoglobin 11.7 ± 1.5; median ESA dose/week 8000 IU IQR: 4000-12.000). Patients in the highest ERI tercile were mostly female, younger, more diabetic and with slightly higher proportion of iron prescription compared to those in the lowest tercile of ERI. The multivariable models adjusted for age, sex, diabetes and vascular access demonstrated that higher serum levels of IL-1β and IFN-γ were associated with higher ESA resistance, while there were no detectable associations of serum levels of IL-6 or CRP and ERI.

Conclusion

Among the biomarkers included in this comprehensive panel of biomarkers representing the multilevel nature of immune dysfunction in CKD, we observed associations between higher concentrations of innate (IL-1β) and adaptive (IFN) immune response and ESA hyporesponsiveness. Our results support the role of immune dysfunction in the pathophysiology of CKD anemia.
P0856LOW BONE MASS IS SIGNIFICANTLY ASSOCIATED WITH AN INCREASED RISK OF ANEMIA IN PATIENTS WITH CKD
Authors: Lee Seonyeong , Nam Yooju , Kim Hyung Woo , Chang Jae Hyun , Yoo Tae-Hyun
Published: June 2020

Background and Aims

Hypoxia has been considered to be a risk factor for osteoporosis. Several studies have reported on the close associations between the anemia and an increased risk of bone loss. However, the relationship between hemoglobin levels and bone mineral density(BMD) has not been established in chronic kidney disease (CKD) patients. Therefore, the aim of this study is to investigate the relationship between BMD and anemia in a non-dialysis CKD cohort.

Method

Among 2,238 patients with non-dialysis CKD enrolled in the KoreaN cohort study for Outcome in patients With Chronic Kidney Disease (KNOW-CKD), 2,115 patients who measured hemoglobin(Hb) and BMD were included in the analysis. We defined anemia as hemoglobin(Hb) levels of < 13.0 g/dL and 12.0 g/dL for males and females, respectively. The primary endpoint was the onset of a 15% decline in Hemoglobin during follow-up.

Results

The mean age was 53.6 ± 12.2 years and 1,292(61.1%) patients were males. The BMD score was positively correlated with hemoglobin levels (β, 0.658; 95% CI, 0.215-1.101; P 0.004). In the multivariable logistic regression model, the prevalence of anemia was significantly higher in the osteoporosis group than that in the normal BMD group (odds ratio [OR], 1.59; 95% confidence interval [CI], 1.03-2.46, P=0.038). Among 1010 patients without data of following hemoglobin levels, 396 (19.7%) patients developed 15% decline in hemoglobin level during a median follow-up duration of 36 (interquartile range, 10-60) months. In the fully adjusted multivariable Cox models, risk of developing the 15% decline of hemoglobin was significantly higher in the osteoporosis group (HR, 1.45; 95% CI, 1.03-2.05; P= 0.035) as compared to normal BMD group.

Conclusion

This study showed that low bone mass density was independently related with anemia and hemoglobin levels in patients with non-dialysis CKD. Our findings suggest that preserve bone mass be important to maintain the levels of hemoglobin with CKD patients.
P0859ACTIVATE ENDOGENOUS HYDROXYMETHYLATION TO RESTORE ERYTHROPOIETIN PRODUCTION IN FIBROTIC KIDNEYS
Authors: LUO AN JIE , LIN SHUEI-LIONG
Published: June 2020

Background and Aims

Our previous studies have shown that DNA methyltransferases (Dnmt) and Epo hypermethylation are upregulated in myofibroblasts in fibrotic murine kidneys. Demethylation leads to redifferentiation of myofibroblasts into pericytes. Furthermore, nontoxic doses of 5-azacytidine can restore EPO production and ameliorate anemia in mice with kidney fibrosis. Physiologic hydroxymethylation in zygotes is mediated by the 10 − 11 translocation enzymes (Tet1, Tet2, and Tet3).

Method

The mouse model of unilateral ureteral obstruction (UUO)-induced kidney fibrosis has been found to display enhanced Tet1 and Tet3 mRNA expression at day 7 and marked increase with the disease progression.

Results

According to the results, Tet expression significantly increased in fibrotic kidney. To study the effect of myofibroblast-specific Tet3 knockout in murine models of renal fibrosis. Tet3F/F mice were generated by a targeting vector with floxed region contains exons 8-9 of Tet3, which included the coding region for the conserved Fe2+-binding motif of dioxygenase. Gli1CreERT2/+;Tet3F/F mice were used to induce knockout of Tet3 in pericytes and myofibroblasts after tamoxifen administration. Tet3F/F mice were used as the control. Oral gavage of tamoxifen 8 mg/day for 3 days was used to activate Cre recombinase in Gli1+ pericytes and myofibroblasts in adult mice (6-8 week). After two-week washout period, mice were subjected to UUO for 7 or 14 days. The body weight, plasma creatinine and BUN levels showed no significant differences between groups in mice after induction and also UUO surgery. Plasma levels of BUN and creatinine were maintained within the normal range by normally functioning contralateral kidneys after UUO surgery. In UUO kidneys, knockout of Tet3 decreased renal α-SMA and Col1a1 expression. But plasma hematocrit and renal Epo mRNA level were not different between groups. In addition to Gli1CreERT2/+ mice we also used Pdgfrb-rtTATg;LC1Tg mice to breed with Tet3F/F mice for inducible knockout of Tet3. The plasma creatinine, BUN, and hematocrit were no different between groups after UUO surgery again.

Conclusion

Overall, these findings suggested increased Tet3 in myofibroblasts may play an important role in myofibroblast activation and fibrosis. Further studies need to explore the mechanisms.
P0862DAPRODUSTAT INTERACTION WITH PHOSPHATE BINDERS HAS MINIMAL IMPACT ON HEMOGLOBIN VALUES IN HEMODIALYSIS POPULATION
Authors: Cizman Borut , Meadowcroft Amy , Biswas Nandita , Sprys Michael , Cobitz Alexander
Published: June 2020

Background and Aims

Daprodustat is a novel hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) currently in phase 3 development for the treatment of anemia of chronic kidney disease (CKD). Phosphate binders (PB) are widely prescribed for hemodialysis (HD) patients to control for hyperphosphatemia. The coadministration of PB and HIF-PHI may potentially impact hemoglobin values thus requiring time between PB administration and HIF-PHI. The purpose of this analysis was to determine whether daprodustat interaction with PB has an impact on hemoglobin (Hgb) values in the HD population.

Method

GSK PHI113633 study (NCT01977482) included 216 subjects on maintenance HD previously treated with rhEPO. This study included daprodustat dose-ranging for the first 4 weeks, followed by a Hgb correction/maintenance phase for the next 20 weeks; daprodustat was dosed daily without regard to the timing of PB administration. The control group received placebo for 4 weeks, followed by rhEPO for the next 20 weeks as previously reported (Clin Kidney J 2019;12(1):139-148). Target Hgb range was 10.0-11.5 g/dL from Week 4 through Week 24. Baseline PB use was a prespecified study subgroup of interest. The difference in mean Hgb values at Week 24 between treatment groups was summarized overall and by subgroup. Comparisons were performed for the Week 24 Hgb (post hoc), as well as the final dose of daprodustat, for those receiving/not receiving PB.

Results

The majority of HD subjects in this 24-week safety and efficacy study received PB at baseline; 136 of 177 (77%) of subjects on daprodustat and 33 of 39 (85%) of subjects on control were taking PBs, with comparable phosphate control at baseline [mean (±SD) phosphate: daprodustat 1.76 mmol/L (0.56); control 1.67 mmol/L (0.44)].

No meaningful difference in Hgb change from baseline (CFB) at Week 24 was noted between daprodustat and rhEPO groups (Table 1).

Conclusion

These results suggest that daprodustat can be taken without regard to the timing of PB administration. Results of the large, phase 3 dialysis study of daprodustat will be important to definitively confirm these initial observations.
P0867ANEMIA AND IRON DEFICIENCY IN NON-DIALYISIS CHRONIC KIDNEY DISEASE: A LINK WITH ADVERSE OUTOCOMES?
Authors: Fernandes Sara , Falcao Luis , Fernandes Adriana Paixão , Donato Beatriz , Costa Ana Cortesão , Raimundo Mário , Teixeira Catarina , Silva Sónia , Macedo Ana , Almeida Edgar
Published: June 2020

Background and Aims

Anemia is a major complication of Chronic Kidney Disease (CKD). There are few large observational studies analyzing the association between anemia and significant clinical outcomes in non-dialysis dependent CKD (ND-CKD) patients. Our aim was to evaluate the prevalence of anemia and iron deficiency and their association with mortality, cardiovascular events, need for renal replacement therapy and hospitalizations in an outpatient ND-CKD population.

Method

A patient-level, retrospective, cohort analysis of all adult ND-CKD patients evaluated in an outpatient nephrology clinic between January 2012 to December 2017 with at least one year follow up. Anemia (defined according to the WHO definition - Hemoglobin [Hb] < 13.0 g/dL in men and 12.0g/dL in women), absolute iron deficiency (ferritin < 100 ng/mL), other demographic and clinical data (CKD staging and etiology, comorbidities) were assessed at the first visit through individual consultation of electronic medical records.

Results

During the 6-year period, 3008 patients were identified (mean age 70.9±14.1 years; 54.5% male; 91.7% white) with a mean follow-up of 3.3±2.0 years. The most frequent cardiovascular comorbidities were arterial hypertension (81.9%), obesity (58%), diabetes mellitus (57.9%) and dyslipidemia (43.9%). The mean Hb was 11.8 ±1.9 g/dL. Anemia was present in 49.9 % of patients, with similar distribution between genders (50.4% in men vs 49.6% in women) and more frequent in white patients (92% vs 8% p= 0.019). Anemia prevalence increased across CKD stages - 12.9%, 25.9%, 57.2%, 72.7% and 86.4% for stages 1 to 5, respectively (p<0,001 for the trend). Anemia was associated with cardiovascular comorbidities, such as diabetes (52% vs 32%, p<0.001), hypertension (86.7% vs 77.7%, p<0.001), obesity (65.5% vs 60.8 %, p=0.012) and dyslipidemia (46% vs 41.2%, p=0.01). Among patients with ferritin levels available (1638), 41.7% had absolute iron deficiency. Anemia was associated with increased mortality (74% vs 26%, p <0,001) and hospitalization (61,8% vs 38.2%, p <0.001). In multivariate logistic regression analysis, anemia (OR 1,923; 95%IC 1,362-2.716; p<0,001) and absolute iron deficiency (OR 0.531 95% IC 0.348-0.809; p=0.003) emerged as independent predictors of death. Cardiovascular events were more prevalent in the group of patients with Hb levels 10-12 g/dL (4.1 vs2.3% 2p=0.006).

Conclusion

As expected, anemia prevalence increases across CKD stages and, as well as absolute iron deficiency, is independently associated with adverse clinical outcomes in ND-CKD patients, including death. Future studies should be developed to investigate if correction of these factors improves adverse outcomes.
P0889TO WHAT EXTENT CAN WE ACHIEVE MINERAL BONE METABOLISM TREATMENT TARGETS AS SUGGESTED BY UPDATED 2017 KDIGO GUIDELINES IN PATIENTS WITH PREDIALYSIS CHRONIC KIDNEY DISEASE
Authors: Dincer Mevlut Tamer , Özcan Şeyda Gül , Alagoz Selma , Karaca Cebrail , Gulcicek Sibel , Trabulus Sinan , Pekpak Meltem , Seyahi Nurhan
Published: June 2020

Background and Aims

The mineral bone disorder is an essential problem in chronic kidney disease (CKD). It is an independent modifiable risk factor for renal damage progression and CKD related mortality. Therefore, it is important to treat chronic kidney disease mineral bone disorder (CKD-MBD) according to international guidelines. Data on the management of mineral bone disorders in predialysis patients is scarce. We aimed to investigate the proportion of CKD-MBD patients reaching targets suggested by the updated 2017 KDIGO guidelines.

Method

We performed a multicenter cross-sectional study. We recruited consecutive adult (>18 years of age) CKD 3-5 patients who were on regular nephrology outpatient clinic follow up. Patients who have GFR loss over 30% in the last six months, patients with malignancy, and decreased life expectancy due to severe comorbid disease and patients on renal replacement therapy were excluded. Data were collected in two-time points: one during the recruitment (second data point) and one, three to six months prior to the current visit (first data point). Persistent laboratory abnormalities were defined by out of normal range values in both time points. Therapeutic inertia was calculated for hyperphosphatemia. It was defined as a lack of using phosphate binders despite hyperphosphatemia.

Results

We examined a total of 213 patients for 3 different nephrology outpatient clinics. Of these patients, 49.5 % were male, with a mean age of 64,9 ± 12,0 years. 51.7 % of the patients were diabetic, 78 % were hypertensive, and 20.1 % had a history of coronary artery disease. Laboratory values related to MBD are shown in Table 1. KDIGO guideline targets were not reached in 14.8%, 18.4%, 59.0%, 71.0% patients regarding Ca, P, PTH, and vitamin D in the first visit. The targets were not reached in 15.0%, 19,2%, 61,2%, 81% patients regarding Ca, P, PTH, and vitamin D in the second visit. Persistence of out of target values were observed in 5.8%, 9.9%, 49.2% and 65.4% of the patients for Ca,P, PTH and Vitamin D respectively. The prevalence of therapeutic inertia for hyperphosphatemia was 34,4 % in the second visit

Conclusion

Regarding KDIGO guidelines, MBD is not optimally managed in predialysis CKD patients. Clinicians should have an active attitude regarding the correction of MBD even at the earlier stages of CKD.
P0896TRABECULAR BONE SCORE PREDICTS OSTEOPOROTIC FRACTURE IN CHRONIC KIDNEY DISEASE PATIENTS
Authors: Bae Eunjin , Lee Tae Won , Jang Ha Nee , Cho Hyun Seop , Kim Hyun-Jung , Chang Se-Ho , Park Dong Jun
Published: June 2020

Background and Aims

Chronic kidney disease and mineral bone disease (CKD-MBD) is a common complication of CKD and this is associated with higher risk of fracture, morbidity and mortality. Current guidelines recommend measurement of bone mineral density (BMD) in CKD patients. However, the focus is only on bone turnover and bone density, and there is no guideline for trabecular bone score (TBS) for trabecular bone microarchitecture in CKD patients. We aim to evaluate the role of TBS in predicting osteoporotic fracture in CKD patients

Method

We retrospectively enrolled 125 patients with CKD between 2016 and March 2019. Lumbar spine TBS was extracted from dual-energy X-ray absorptiometry, and we categorized the TBS into three groups as lowest (≥ 1.31), moderate (1.31-1.23), and highest risk group (≤ 1.23). The logistic regression analysis was used to assess osteoporotic fracture risk.

Results

Of 125 patients, mean age was 65.9 ± 14.2 years, 49.6% were on dialysis, 11.2% was highest risk group by TBS. Patients with highest risk group by TBS were significantly older, had lower height, weight, serum 25-OH vitamin D, serum sodium level, BMD T-score (lumbar spine, femur neck and total hip) than lower risk group. TBS significantly correlated with BMD T-score (lumbar spine, femur neck and total hip), height, weight and serum creatinine level (P <0.001). Osteoporotic fracture was identified in 20 (16.0%) patients. In univariate analyses, old age, women, lower weight, TBS tertile group, lower potassium level were significantly associated with osteoporotic fracture. In multivariate analyses, only highest risk group by TBS was significantly associated with increased osteoporotic fracture risk after adjustment for demographic, comorbid, medication use, and previous fracture.

Conclusion

Lumbar spine TBS significantly correlated with BMD T-score and predicts osteoporotic fractures in patients with CKD.
P0902DAILY TERIPARATIDE TREATMENT AND PHARMACOKINETICS IN HEMODIALYSIS PATIENTS WITH LOW BONE MASS
Authors: Hiramatsu Rikako
Published: June 2020

Background and Aims

Daily 20µg teriparatide (PTH1-34) is an osteoanabolic agent approved for use treating osteoporosis. However, there are few reports about concerning use of this agent in hemodialysis patients.

Method

We conducted an observational study, single centre study on 5 patients with low bone mineral density (BMD) and low iPTH levels defied as iPTH below 60 pg/mL, who were treated with recombinant human PTH1-34; teriparatide 20 µg 3 times per week between January 2012 and January 2015. All patients were 20 years of age or older, had undergone regular hemodialysis treatment and were without skeletal malignancies and bone metastasis. Low BMD in this study was defined either as BMD T-score -2.5 at the lumbar spine (LS) or /and femoral neck (FN) and distal one –third radius (RS) analyzed by dual-energy X-ray absorptiometry (DXA), or BMD T-score of -2.5 to -1.0 with history of fragility fractures. We analyzed the biochemical data including bone metabolic makers (intact amino-terminal propeptide of type I collagen (iP1NP), bone alkaline phosphatase (BAP), and tartrate-resistant acid phosphatase-5b (TRACP-5b) at baseline, and after 3, 6, and 12 months of teriparatide treatment. BMD at LS and FN were evaluated at 6months of treatment.

Results

Data from five patients (mean age: 69.2±7.4years; mean hemodialysis time: 23.2±6.2years) were reviewed. Laboratory data at baseline were iPTH: 34.2±24.2 pg/mL, BAP: 13.0±4.9 µg/L, iP1NP: 45.3±14.3 ng/mL, TRACP-5b: 350±201 mU/dL, corrected Ca (cCa): 9.7±0.3 mg/dL, and P:4.1±0.7 mg/dL. Baseline BMD T-score at LS and FN were -2.8±1.7 and -3.0±0.6, respectively. During a 12 month- teriparatide treatment, mean cCa levels significantly decreased from 9.7±0.3 to 9.1±0.2 mg/dL at 3 months (P < 0.05) and returned to 9.5±0.4 mg/dL at 12 months. As for bone metabolic markers, BAP and iP1NP significantly increased from baseline by 31.3±12.9 (P < 0.05) and 47.4±14.5% (P < 0.05) at 6 months of teriparatide treatment, while TRACP-5b significantly decreased by 10.5±2.5% at 3 months, which did not reach a statistical significance. BMD changes from baseline at LS and FN were 2.1±2.5% and 1.2±1.5% at 6 months of treatment with a significant change at LS.

Pharmacokinetics of Teriparatide The time-course of changes in plasma teriparatide acetate concentration was evaluated in one patient who had undergone parathyroidectomy 20 years before enrollment in this study and her serum endogenous iPTH level was undetectable at baseline. After teriparatide injection, serum teriparatide acetate levels peaked at 30 minutes at 157.2 pg/mL, and then rapidly decreased to undetectable levels at 240 minutes.

Conclusion

We report that teriparatide improved LS and FN BMD in hemodialysis patients with low iPTH. Pharmacokinetics showed this agent might not accumulate in dialysis patients and can be used safely. Adequate Ca supplementation might be needed to adjust serum Ca levels.
P0910CLINICAL-LABORATORY AND CYTOMORPHOLOGICAL CHARACTERISTICS OF HYPERPARATHYROIDISM IN PATIENTS WITH CRONIC KIDNEY DISEASE
Authors: Ivanova Maria , Vetchinnikova Olga , Zakharova Natalia
Published: June 2020

Background and Aims

Secondary hyperparathyroidism (HPT) is a serious complication of chronic kidney disease (CKD), which decrease the medical and social rehabilitation of patients, increases cardiovascular morbidity and mortality. The aim of the study is analysis the clinical and laboratory manifestations of secondary HPT and cytomorphological signs of parathyroid glands (PG) tissue in patients with CKD.

Method

51 patients (age 24-66 years) with CKD G5D (on hemodialysis – 30 patients and peritoneal dialysis – 21 patients) and HPT were examined. Clinical and laboratory examination included determination of laboratory parameters of mineral and bone metabolism, an ultrasound study of the PG, a fine needle aspiration biopsy of the visualized lesions in the projection of the PG, and light microscopy of the material obtained (х400). The method of logical-semantic analysis (program “Consilium”) is used.

Results

All patients had severe HPT with high turnover bone disease: bone pain and deformity, increase of serum PTH to 2200±817 pg/ml, calcium and phosphorus of blood, respectively 2.4±0.2 and 2.2±0.4 mmol/l, alkaline phosphatase activity 489±205 u/l (norm 30-117), a decrease in bone mineral density according to dual energy X-ray absorptiometry in the distal forearm – 100% patients, proximal femur and lumbar spine – 50% patient. An ultrasound procedure visualized from two to four enlarged PG with a diameter of more than 1 cm and a heterogeneous ultrasound structure. A large number of epithelial elements were determined in the puncture material of the PG tissue, multicellular clusters of major dark parathyrocytes in combination with groups of major light parathyrocytes, the presence of pronounced intercellular contacts and the absence of macrophages and fat cells (fig).

Conclusion

Severe HPT in patients with CKD is characterized by an increase in PG by more than 1 cm with a heterogeneous ultrasound structure and pronounced proliferative activity in the parenchyma of glands tissue.
P0915PROTEIN ENERGY WASTING IS ASSOCIATED WITH A DECLINE IN MUSCLE PROTEIN SYNTHESIS IN CKD PATIENTS
Authors: Saio Michela , Sofia Antonella , Russo Rodolfo , Cipriani Leda , Garibotto Giacomo , Verzola Daniela
Published: June 2020

Background and Aims

Skeletal muscle is a highly adaptive tissue, however even small imbalances between protein synthesis and degradation can lead to substantial protein loss. Althought proteolysis plays a major role in the development of cachexia in CKD (chronic kidney disease), the responses of muscle protein metabolism to malnutrition had not been completely elucidated.

We evaluated retrospectively the results of kinetic studies of protein turnover estimated by the forearm perfusion method associated with H2phenylalanine kinetic, obtained in CKD patients and controls in the last 25 years.

Method

We analyzed 59 forearm H2phenylalanine kinetic studies obtained in 14 controls (C) (M 11, F 3) and 45 patients with CKD, of whom 15 (M 10, F 5) were on conservative treatment (CKD stage IV-V), 16 (M 14, F 2) under maintenance hemodialysis (HD), 14 (M 12, F 2) in peritoneal dialysis (DP); all subjects were on non-restricted protein/calorie (0.8-1.1 g/kg and 28-32 kcal/kg, respectively) diets. Ten (M 9, F 1) HD patients had Protein Energy Wasting. Acidosis was corrected in all patients (HCO3 24.2±1.9 mmol/L) and studies were performed in the post-absorptive overnight fasted state at rest.

Results

Overall, Muscle protein synthesis and degradation were similar (p=NS) in patients and controls. Protein net balance was reduced in patients with PD and those with CKD Stage IV-V (p <0.003 - p <0.014) indicating a reduced catabolic state and nitrogen conservation. However PEW HD patients showed reduced rates of protein synthesis and degradation (p <0.048 and p <0.04 respectively). In addition the efficiency of muscle protein turnover, a parameter expressing muscle's ability to reuse amino acids derived from degradation into protein synthesis, was significantly reduced in HD PEW patients vs. controls (55.5 vs. 61.2 %, p <0.018, respectively) and vs. not malnourished patients in conservative treatment (70.1 % p <0.0025) or in PD (74.6 % p <0.005).

Conclusion

In CKD patients, in absence of acidosis, muscle is able to increase the efficiency of protein metabolism for the maintenance of nitrogen balance. However, in PEW patients, combined alterations of protein synthesis and degradation proceed together to a reduced efficiency of amino acids recycled into protein synthesis and contribute to maintaining wasting. These data also suggest that calorie/protein requirements of CKD patients with PEW may be higher than currently theorized.
P0920THE METHIONINE RESTRICTION DIET ATTENUATES CHRONIC KIDNEY PROGRESSION IN MICE
Authors: Yang Jihyun , Min Hyeon-jin , Sun Bong Gyun , Son Young-Bin , Choi Eunho , Oh Se Won , Kim Myung-gyu , Jo Sang-Kyung , Cho Won-Yong
Published: June 2020

Background and Aims

The clinical usefulness of protein-restricted diets is known to slow the progression of obesity, fatty liver, aging and cancer. Protein-restricted diet in chronic kidney disease is known to alleviate the deterioration of the renal function. The purpose of this study is to confirm whether the reduction in new function can be improved when methionine restricted (MR) diet is supplied in the chronic kidney disease (CKD) animal model and to study the its renoprotection mechanism.

Method

We used four-week-old C57L/B6 to make a CKD model by administration 0.025% adenine chow mixed with R3 diet for four weeks for the control group. For the MR diet group, we supplied the mixture of 0.025% adenine with methionine/Choline Deficient Diet. We measured serum blood urea nitrogen (BUN), serum creatinine, gut permeability, stool short chain fatty acid (SCFA), kidney α-SMA and renal pathology. This study was approved by Korea University Institutional Animal Care and Use Committee (KOREA-2019-0047).

Results

The principal coordinates analysis of the microbiome showed the two groups have distinctive component features. The stool SCFA, especially butyrate was increased in the MR diet group. However, gut permeability using FITC-dextran showed no significant change. The kidney α-SMA and MT stain area showed that the MR diet could improve renal fibrosis. The kidney inflammation including neutrophil and macrophage infiltration was also improved in histology analysis. The macrophage phenotype was more favorable to M2 type. Serum BUN and creatinine were significantly attenuated in the MR diet group.

Conclusion

In conclusion, the MR diet has a reno-protective effect in adenine induced CKD. The MR diet increased butyrate production and decreased renal inflammation and fibrosis. These results shed light on the role of protein restriction diet for CKD management in the real world.
P0926ASSOCIATION OF HIGH-SENSITIVE C-REACTIVE PROTEIN WITH CARDIOVASCULAR EVENTS, MORTALITY, AND ADVERSE KIDNEY OUTCOMES IN KOREAN PATIENTS WITH CHRONIC KIDNEY DISEASE: RESULTS FROM KNOW-CKD
Authors: Lee Changhyun , Park Keun Hyung , Joo Young Su , Nam Ki Heon , Chang Tae-Ik , Kang Ea Wha , Lee Joongyub , Oh Yun Kyu , Jung Ji Yong , Ahn Curie , Lee Kyu-Beck , Park Jung Tak , Yoo Tae-Hyun , Kang Shin-Wook , Han Seung Hyeok
Published: June 2020

Background and Aims

High-sensitivity C-reactive protein (hs-CRP) level is lower in East Asians than in the Western people and its clinical significance needs to be further explored. We aimed to investigate whether hs-CRP could function as a biomarker in Korean CKD patients.

Method

We studied the association of hs-CRP with adverse clinical outcomes in 2,018 patients from the KoreaN cohort study for Outcome in patients With Chronic Kidney Disease (KNOW-CKD). The primary outcome was a composite of extended major cardiovascular events (MACE) or all-cause mortality. Extended MACE (eMACE) included non-fatal cardiovascular events, symptomatic arrhythmia, and cardiac death. The secondary endpoints were separate outcome of eMACE, all-cause death, and adverse kidney outcome. We also evaluated predictive ability of hs-CRP for the primary outcome.

Results

The median hs-CRP level was 0.60 mg/L (IQR 0.2-1.7), and the mean eGFR was 53.6 ml/min/1.73 m2. During the mean follow-up of 3.9 years, there were 125 (6.2%) eMACEs and 80 (4.0%) deaths. The primary composite outcome occurred more frequently in patients with higher hs-CRP level than in those with lower hs-CRP level. In multivariable Cox analysis after adjustment of confounders, there was a graded association of hs-CRP with the primary outcome. The HRs (95% CI) for hs-CRP of 1.0 to 2.99, and ≥ 3.0 mg/L were 1.37 (0.89-2.12) and 2.20 (1.36-3.56), compared with

hs-CRP of <1.0 mg/L. In analyses of secondary outcomes, this association was consistent for eMACE and all-cause death; however, hs-CRP was not associated with adverse kidney outcomes. Finally, prediction models failed to show improvement of predictive performance of hs-CRP compared to conventional factors.

Conclusion

In Korean CKD patients, serum hs-CRP level was low and significantly associated with higher risk of eMACEs and mortality. However, a low serum hs-CRP level was not predictive of adverse kidney outcome, and the predictive performance of hs-CRP was not strong.
P0929LOW PROTEIN DIET, BLOOD PRESSURE CONTROL AND NATRIURESIS IN PATIENTS WITH ADVANCED DIABETIC KIDNEY DISEASE AND HEAVY PROTEINURIA
Authors: Mihalache Andreea , Garneata Liliana , Mocanu Carmen-Antonia , Simionescu Tudor Petrisor , Mircescu Gabriel
Published: June 2020

Background and Aims

Recent data suggest the possibility to optimize blood pressure control by low protein diet (LPD) in patients with diabetic kidney disease (DKD). We aimed to assess the effects of a low protein diet (LPD) supplemented with keto-analogues on urinary sodium excretion and blood pressure control.

Method

Prospective, uni-center study with a total duration of 15 months.The study was conducted in a tertiary Nephrology Clinic and included a total of 92 diabetic patients with advanced CKD (eGFR < 30 mL/min) and heavy proteinuria (> 3 g/g creatininuria). Intervention consisted in a LPD (0.6 g/kg-day) supplemented with keto-analogues of essential amino acids with nutritional counselling and adjustment of antihypertensive therapy.

The primary efficacy parameter was proteinuria during intervention as compared to pre-enrolment. Blood pressure (BP), urinary sodium excretion, eGFR and blood glucose control were secondary end-points.

Results

Mean arterial pressure (MAP) decreased from baseline (Bs) to end of study (EOS) with -11 (-17 to -7) mmHg despite a reduction with 22% of patients needing antihypertensive medication. Independent predictors of a lower than median MAP (90mmHg) were a lower protein intake (HR 0.00 (0.00; 0.04; p=0.002), treatment with furosemide (HR 1.06 [1.06; 3.85]; p=0.03) but not with angiotensin-aldosterone system inhibitors (RAASi) [HR 0.17 (0.17; 0.90); p=0.03)] and was not influenced by natriuresis.

Natriuresis decreased from 130 (121-135) to 80 (71-86) mmol/day (p<0.0001). A lower than median natriuresis (100mmol/day) was directly related to proteinuria [HR 0.0003 (0.00; 0.004); p=<0.0001], eGFR [HR 0.0001 (0.00; 0.14); p=0.01] and to diuretic therapy [0.21 (0.05; 0.83); p=0.03] but not to protein intake.

Cardiovascular events were observed in 20% of patients and their occurrence was related to a lower MAP [0.97 (0.95; 0.99}; p=0.001]. No renal adverse were noted and the diet was nutritionally safe.

Conclusion

A low protein diet supplemented with ketoanalogues of essential amino acids on top of anti-hypertensive therapy (mostly loop diuretics) allows for a good control of blood pressure, unrelated to natriuresis in heavy proteinuric patients with advanced DKD.
P0930SERUM LEVELS OF OSTEOPROTEGERIN ARE ASSOCIATED WITH OBESITY IN CHRONIC KIDNEY DISEASE
Authors: Nam Yooju , Lee Seonyeong , Kim Hyung Woo , Chang Jae Hyun , Yoo Tae-Hyun
Published: June 2020

Background and Aims

Osteoprotegerin (OPG), which is an osteoclastic inhibitory factor, is associated with type 2 diabetes mellitus, severity of vascular calcification, coronary artery disease, and chronic kidney disease. Obesity is a risk factor for diabetes, and cardiovascular disease, however there are few studies about the relationship between OPG and obesity, especially in patients with CKD. This study aimed to investigate association between OPG level and obesity in a large-scale prospective cohort.

Method

Among 2,238 patients with non-dialysis CKD enrolled in the KoreaN cohort study for Outcome in patients With Chronic Kidney Disease (KNOW-CKD), 1,970 patients who measured body mass index (BMI), waist circumference (WC) and OPG level were included in the analysis. Obesity were defined as having a BMI >25 kg/m2 and WC > 90 cm in male, > 85 cm in female.

Results

The mean age was 53.6 ± 12.2 years and 1,196 (60.7%) patients were males. At baseline, obesity by BMI, WC, and composite of BMI and WC were found in 814 (41.3%), 208 (26.9%) and 1,137 (57.7%) patients. A multivariate logistic regression model showed that log transformed OPG level was independently associated with the prevalence of obesity by BMI, WC, composite of BMI and WC (odds ratio [OR], 0.33; 95% confidence interval [CI], 0.16-0.65, P<0.001 and OR, 0.37; 95% CI, 0.18-0.75, P=0.006, and OR, 0.33, 95% CI, 0.16-0.69, P=0.003, respectively). Among patients without baseline obesity, 207 (19.3%) patients developed obesity by BMI, 202 (21.7%) by WC, and 194 (23.3%) by composite of BMI and WC. In the fully adjusted multivariable Cox models, risks of developing obesity by BMI, WC and composite of BMI and WC were significantly higher with increased level of OPG (hazard ratio [HR], 0.59; 95% CI, 0.38-0.92; P=0.019, HR, 0.63; 95% CI, 0.41-0.98; P=0.001).

Conclusion

We showed that serum OPG levels are associated with obesity in patients with non-dialysis CKD.
P0936INJURY OF NEUTROPHILS DURING HAEMODIALYSIS AND ITS INVOLVEMENT FOR DEVELOPMENT OF CHRONIC MICROINFLAMMATION
Authors: Nakayama Masaaki , Miyazaki Mariko , Yamamoto Tae , Fukushi Taro
Published: June 2020

Background and Aims

Owing to the quality developments of membrane material and dislysis water, it is believed that the biocompatibility of haemodialysis (HD) system has been considerably improved. However, mortality and morbidities of dialysis patients have remained unacceptably high, which raises a question as to the biocompatibility improvement of current HD systems.

Method

Seventy-one patients on regular HD (male/female: 52/19, mean age: 63 years old, median HD duration: 19 months, HD session 3 times a week for 3 to 4 hours each by using high performance synthetic membrane) at Tohoku University Hospital were examined. Blood samples were obtained from all patients before and after the HD session, to measure followings; number of white blood cell fraction, and apotosis cells, plasma levels of following molecules; myeloperoxidase (MPO), pentraxin 3, angiogenin, lactoferrin, complement (C3a, C5a, C5b-9), and 17 cytokines. Apoptosis (positive for Annexin-V-FITC and negative for propidium iodide) was measured in 100,000 cells by flow cytometer, and plasma molecules were measured by ELISA kit.

Results

The main findings of this study were as follows (changes in the values after HD as compared to the pre HD); the significant decrease of leukocytes counts (neutrophil and lymphocyte), significant increases of apoptosis positive cells of leukocytes (neutrophiles and monocytes), significant increases of plasma MPO and pentraxin3 levels, significant decrease of angiogenin, and, no or only marginal changes in plasma pro-inflammatory cytokine levels and complement products. There was a significant positive correlation between the change in MPO and apoptosis before and after HD.

Conclusion

Bio-incompatibility of HD has remained a crucial issue even in the current systems. Among the several pathologies, process of neutrophile apoptosis accompanying MPO degranulation, may plays a central role for developing microinflammation. In this regard, change of plasma MPO could be a clinical marker for the biocompatibility of HD system. And in order to achieve better patients’ outcomes, innovative HD systems which fully improve biocompatibility are needed.
P0940CLINICAL ASSOCIATION BETWEEN SEVERE INFECTION AND HYPOZINCEMIA IN INCIDENT PATIENTS ON HEMODIALYSIS
Authors: Saka Yosuke , Kato Akihisa , Naruse Tomohiko
Published: June 2020

Background and Aims

Hypozincemia can arise in patients with advanced chronic kidney disease (CKD) due to low protein intake and urinary or dialytic loss. Several studies have confirmed an association between hypozincemia and infection. Because infections comprise a major complication in patients with advanced CKD, we investigated whether hypozincemia is associated with infection risk in incident patients on dialysis.

Method

We prospectively analyzed 380 consecutive patients aged 20 years old or more who started hemodialysis between January 2013 and December 2018. Six patients who were receiving zinc supplementation at the time of the study were excluded. Serum zinc values were obtained at the time of dialysis initiation. We followed up the remaining patients after enrollment. The endpoint was severe infection defined as infection-related death or bacteremia confirmed by the detection of microorganisms in two sets of culture bottles. The patients were equally divided into groups with low, middle or high serum zinc concentrations. Data were analyzed using Kaplan-Meier curves and Cox hazards models. The local ethics committee approved this research. Informed consent was obtained from each individual participant included in the study.

Results

The rate of severe infection events over a follow-up of one year was the highest in the group with low zinc (p = 0.030). Cox hazards models adjusted for age, sex, diabetes mellitus, serum albumin and serum zinc, selected hypozincemia as an independent risk factor for severe infection events (HR, 10.76; 95% CI, 1.28–90.41; p = 0.029).

Conclusion

Hypozincemia is associated with risk of subsequent severe infection in incident patients on dialysis.
P0942HYPOXEMIA AND UREMIA INDUCE OXIDATIVE IMBALANCE IN ENDOTHELIAL CELLS
Authors: Moreno-Amaral Andrea N , Carvalho Silva Caroline , Andrade Gabriela Bohnen , Monteiro Julia , Grobe Nadja , Silva Pecoits Filho Roberto Flavio , Stinghen Andréa E M , Kotanko Peter
Published: June 2020

Background and Aims

Intradialytic hypoxemia is associated with oxidative stress, endothelial dysfunction, inflammation, higher erythropoietin requirements, and higher all-cause hospitalization and mortality in hemodialysis (HD) patients (Meyring-Wosten, et al., 2016). The aim of the present study was to further expand our insights into the hypoxia-uremia axis by investigating the oxidative balance in endothelial cells (EC) under hypoxic and uremic conditions.

Method

Human umbilical EC were incubated with DMEM medium supplemented with 10% of fetal bovine serum (FBS; control) or with sera obtained from healthy subjects (S-CON) or HD patients (S-HD, 1:10), respectively, for 40 minutes, 4 hours, and 24 hours under normoxic (21% O2) or hypoxic (5% O2) conditions (Culture Chamber ProOx, Biospherix). EC were analyzed by flow cytometer (BD Accuri™ C6 Plus) to assess a) intracellular production of reactive oxygen species (ROS, DCFH-DA probe, Abcam); b) reduced glutathione (GSH) content (ThiolTracker Violet probe, Thermo Fisher Scientific).

Results

S-HD increased intracellular ROS production at all time points compared to S-CON. Moreover, ROS production was higher under hypoxic conditions. ROS production declined after 24 hours. S-HD induced slightly higher GSH content when compared to S-CON in normoxia (Table 1).

Conclusion

In our in vitro experiments, hypoxia and uremia jointly favor EC oxidative imbalance. This effect is particularly pronounced after 4 hours. Translational studies are warranted to explore the clinical relevance of our findings.