Detecting Volemic, Cardiac, and Autonomic Responses From Hypervolemia to Normovolemia via Non-Invasive ClearSight Hemodynamic Monitoring During Hemodialysis: An Observational Investigation.

Background: Unstable hemodynamics are not uncommon during hemodialysis (HD), which involves a rapid volume depletion, taking the patient from hypervolemia toward euvolemia. Since uremic patients commonly have cardiovascular comorbidities, hemodynamic changes during HD may reflect interactions among the volemic, cardiac, and autonomic responses to gradual volume depletion during ultrafiltration. Accurate identification of inappropriate responses helps with precisely managing intradialytic hypotension. Recently, the non-invasive ClearSight was reported to be able to detect causes of intraoperative hypotension. In this prospective observational study, we aimed to determine whether ClearSight could be used to detect patterns in stroke volemic, cardiac, and vasoreactive responses during HD. Methods: ClearSight was used to monitor chronic stable patients receiving maintenance HD. Data of mean arterial blood pressure (MAP), heart rate (HR), stroke volume index (SVI), cardiac index (CI), and calculated systemic vascular resistance index (SVRI) were obtained and analyzed to examine patterns in volemic, cardiac, and vasoreactive changes from T0 (before HD) until T8 in 30-min intervals (total 4 h). Results: A total of 56 patients with a mean age of 60.5 years were recruited, of which 40 of them were men. The average ultrafiltration volume at T8 was 2.1 ± 0.8 L. The changes in MAP and HR from T0 to T8 were non-significant. SVI at T7 was significantly lower than that at T1, T2, and T3. CI at T4 to T8 was significantly lower than that at T0. SVRI was significantly higher at T3 to T8 than at T0. Pearson's correlation coefficients between SVI and CI and between SVRI and MAP were positive at all time points. The correlation coefficients between SVRI and SVI and between CI and SVRI were significant and negative for all time points. Conclusion: ClearSight was able to detect patterns in hypervolemia during HD and was well tolerated for 4 h. CI decreased significantly after T4, with slightly decreased SVI. Ultrafiltration volume was not correlated with changes in SVI or CI. The vascular tone increased significantly, and this counteracted the reduced cardiac output after T4. With simultaneous monitoring on SVI, CI, and SVRI during HD, therefore, hypotension could be detected and managed by reducing the filtration rate or administering inotrope or vasopressors. Trial Registration: clinicaltrials.gov, ID: NCT03901794.

Long-term safety and efficacy of ferric citrate in phosphate-lowering and iron-repletion effects among patients with on hemodialysis: A multicenter, open-label, Phase IV trial.

BACKGROUND: We explored the long-term safety and efficacy of ferric citrate in hemodialysis patients in Taiwan, and further evaluated the iron repletion effect and change of iron parameters by different baseline groups. METHODS: This was a 12-month, Phase IV, multicenter, open-label study. The initial dose of ferric citrate was administered by patients' clinical condition and further adjusted to maintain serum phosphorus at 3.5-5.5 mg/dL. The primary endpoint was to assess the safety profiles of ferric citrate. The secondary endpoints were to evaluate the efficacy by the time-course changes and the number of subjects who achieved the target range of serum phosphorus. RESULTS: A total of 202 patients were enrolled. No apparent or unexpected safety concerns were observed. The most common treatment-emergent adverse events were gastrointestinal-related with discolored feces (41.6%). Serum phosphorus was well controlled, with a mean dose of 3.35±1.49 g/day, ranging from 1.5 to 6.0 g/day. Iron parameters were significantly improved. The change from baseline of ferritin and TSAT were 227.17 ng/mL and 7.53%, respectively (p-trend<0.001), and the increase started to slow down after 3-6 months of treatment. In addition, the increase trend was found only in patients with lower baseline level of ferritin (≤500 ng/mL) and TSAT (<30%). CONCLUSIONS: Ferric citrate is an effective phosphate binder with favorable safety profile in ESRD patients. The iron-repletion by ferric citrate is effective, and the increase is limited in patients with a higher baseline. In addition to controlling hyperphosphatemia, ferric citrate also shows additional benefits in the treatment of renal anemia. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT03256838; 12/04/2017.

Associations between urinary cysteine-rich protein 61 excretion and kidney function decline in outpatients with chronic kidney disease: a prospective cohort study in Taiwan.

OBJECTIVES: To examine whether urinary excretion of cysteine-rich protein 61 (Cyr61), an acknowledged proinflammatory factor in kidney pathologies, increases in chronic kidney disease (CKD) and is associated with subsequent rapid kidney function decline. DESIGN: An observational cohort study. SETTING: In the nephrology outpatient clinics of a tertiary hospital in Taiwan. PARTICIPANTS: We enrolled 138 adult CKD outpatients (n=12, 32, 18, 18, 29 and 29 in stages 1, 2, 3a, 3b, 4 and 5 CKD, respectively) between February and October 2014 and followed them for 1 year. Their mean age was 60.46±13.16 years, and 51 (37%) of them were women. PRIMARY OUTCOME MEASURES: Urinary Cyr61 levels were measured by ELISA. Rapid kidney function decline was defined as an estimated glomerular filtration rate (eGFR) decline rate ≥ 4 mL/min/1.73 m2/year or developing end-stage renal disease during subsequent 3-month or 1-year follow-up period. Models were adjusted for demographic and clinical variables. RESULTS: The urine Cyr61-to-creatinine ratio (UCyr61CR) increased significantly in patients with stage 4 or 5 CKD. Multivariable linear regression analysis showed that log(UCyr61CR) was positively correlated with log(urine protein-to-creatinine ratio) (p<0.001) but negatively correlated with baseline eGFR (p<0.001) and hypertension (p=0.007). Complete serum creatinine data during the follow-up were available for 112 patients (81.2%). Among them, multivariable logistic regression identified log(UCyr61CR) was independently associated with rapid kidney function decline (adjusted OR 2.29, 95% CI 1.27 to 4.15) during the subsequent 3 months. UCyr61CR improved the discriminative performance of clinical models to predict 3-month rapid kidney function decline. In contrast, log(UCyr61CR) was not associated with rapid eGFR decline during the entire 1-year follow-up. CONCLUSIONS: Elevated urinary Cyr61 excretion is associated with rapid short-term kidney function deterioration in patients with CKD. Measuring urinary Cyr61 excretion is clinically valuable for monitoring disease trajectory and may guide treatment planning.

Alternative Complement Pathway Is Activated and Associated with Galactose-Deficient IgA1 Antibody in IgA Nephropathy Patients.

Background: Galactose-deficient IgA1 (Gd-IgA1) and alternative complement pathway activation are considered to be involved in the pathogenesis of IgA nephropathy (IgAN). Nevertheless, the relationships between alternative pathway activation and disease activity or Gd-IgA1 level remains unclear. Methods: Ninety-eight biopsy-diagnosed IgAN, twenty-five primary focal segmental sclerosis (FSGS) patients and forty-two healthy individuals were recruited in this study. Among them, fifty IgAN patients received immunosuppression. Follow-up blood samples at 1 and 3~6 months after immunosuppression were collected. Plasma levels of complement C5a, factor Ba and Gd-IgA1 were measured and analyzed. Immunostaining for complement was performed in twenty-five IgAN and FSGS patients. Results: At baseline, IgAN patients had higher levels of plasma C5a, factor Ba and Gd-IgA1 than control subjects. Gd-IgA1 levels positively correlated with plasma C5a and factor Ba. In addition, levels of factor Ba and Gd-IgA1 were positively associated with proteinuria and negatively associated with renal function. Immunostaining revealed positive staining for factor Bb and C3c in glomeruli in IgAN patients, but not in FSGS patients. At baseline, patients receiving immunosuppression had more severe proteinuria and higher factor Ba. After 6 months, eGFR declined and proteinuria persisted in patients without immunosuppression. In contrast, patients who received immunosuppression exhibited decreased plasma levels of C5a, factor Ba, and Gd-IgA1 as early as 1 month after treatment. Proteinuria decreased and renal function also remained stable 6 months after immunosuppression. Conclusions: Our results indicate a close relationship between alternative complement pathway activation, Gd-IgA1 concentration and clinical severity of IgAN. Level of complement factor B may be a potential marker for disease activity and therapeutic target in IgAN patients.

Extracorporeal Life Support Enhances the Forward Pressure Wave to Cause a Mismatch between Cardiac Oxygen Demand and Supply.

Extracorporeal life support (ECLS) is a world-famous life-saving method. Until now, changes in arterial wave properties due to ECLS have remained unexamined. In this study, we determined the effects of ECLS on arterial wave properties and ventricular/arterial coupling in male Wistar rats with the measured aortic pressure alone. Ascending aortic pressure signals were measured before ECLS and at 30, 60, and 90 min after weaned off. The aortic pressure signal then calculated by fourth-order derivative to obtain an assumed triangular flow wave. The ratio of mean systolic pressure to mean diastolic pressure (Pms/Pmd), a parameter for evaluating the matching condition between myocardial oxygen demand and supply, was significantly higher after ECLS. The magnitude of forward pressure (|Pf|) augmented by ECLS prevailed over the backward pressure (|Pb|), leading to a decline in wave reflection factor. Pms/Pmd was positively linearly correlated with |Pf| (Pms/Pmd = 0.9177 + 0.0078 × |Pf|, r = 0.8677; P < 0.0001). These findings suggest that |Pf| was a predominant factor responsible for the mismatch between the myocardial oxygen demand and supply in rats after ECLS phase of experiment.

Quantification of cardiac pumping mechanics in rats by using the elastance-resistance model based solely on the measured left ventricular pressure and cardiac output.

The cardiac pumping mechanics can be characterized by both the maximal systolic elastance (Emax) and theoretical maximum flow (Qmax), which are generated using an elastance-resistance model. The signals required to fit the elastance-resistance model are the simultaneously recorded left ventricular (LV) pressure and aortic flow (Qm), followed by the isovolumic LV pressure. In this study, we evaluated a single-beat estimation technique for determining the Emax and Qmax by using the elastance-resistance model based solely on the measured LV pressure and cardiac output. The isovolumic LV pressure was estimated from the measured LV pressure by using a non-linear least-squares approximation technique. The measured Qm was approximated by an unknown triangular flow (Qtri), which was generated by using a fourth-order derivative of the LV pressure. The Qtri scale was calibrated using the cardiac output. Values of EmaxtriQ and QmaxtriQ obtained using Qtri were compared with those of EmaxmQ and QmaxmQ obtained from the measured Qm. Healthy rats and rats with chronic kidney disease or diabetes mellitus were examined. We found that the LV Emax and Qmax can be approximately calculated using the assumed Qtri, and they strongly correlated with the corresponding values derived from Qm (P < 0.0001; n = 78): EmaxtriQ = 51.9133 + 0.8992 × EmaxmQ (r2 = 0.8257; P < 0.0001); QmaxtriQ = 2.4053 + 0.9767 × QmaxmQ (r2 = 0.7798; P < 0.0001). Our findings suggest that the proposed technique can be a useful tool for determining Emax and Qmax by using a single LV pressure pulse together with cardiac output.

The relationship of anti-phospholipase A2 receptor antibody and C5a complement with disease activity and short-term outcome in idiopathic membranous nephropathy.

BACKGROUND: The binding of anti-phospholipase A2 receptor (anti-PLA2R) antibody to podocyte and complement activation is the mechanisms of idiopathic membranous nephropathy (IMN). C5a, a complement activation end product, is a strong inflammatory cell stimulator and can influence the behavior of T cells and dendritic cells. This study examined the etiology-disease relationship and significance of auto-antibody and C5a with short-term remission. METHOD: Plasma anti-PLA2R antibody and C5a were measured with the blood samples that were collected when patients were admitted for renal biopsy. The deposition of IgA, IgG, IgM, C1q and C3c in glomerulus was graded according to immunofluorescence staining. The relationship of anti-PLA2R antibody with C5a, glomerular immunoglobulin and complement deposition was examined. Antibody and C5a levels as predictors of short-term remission were also examined. RESULTS: In 72 IMN patients, 50 patients had positive plasma anti-PLA2R antibody. The antibody had positive correlation to proteinuria. Patients with high grade IgG or C3c, but not IgA/IgM/C1q, deposition had higher anti-PLA2R antibody titers. C5a was increased in IMN patients, but had no correlation with anti-PLA2R antibody or proteinuria. The analysis revealed that C5a, not initial anti-PLA2R antibody, was a predictor associated with 12-month remission in patients receiving immunosuppression with multivariate-adjusted OR 0.74 (95% CI, 0.58-0.94, P = 0.01). CONCLUSION: This study provides indirect evidences of etiology-disease relationship of anti-PLA2R antibody in IMN patients. The role of C5a, a predictor of remission, in the disease course of MN and the influences on inflammatory cells in MN patients is worth to be clarified.

Quantification of contractile mechanics in the rat heart from ventricular pressure alone.

To quantitate the contractile mechanics of the heart, the ventricle is considered an elastic chamber with known end-systolic elastance (Ees ). Ees can be calculated from a single pressure-ejected volume curve, which requires simultaneous records of left ventricular (LV) pressure and the aortic flow (Qm). In clinical settings, it is helpful to evaluate patients' cardiac contractile status by using a minimally invasive approach to physiological signal monitoring, wherever possible, such as by using LV pressure alone. In this study, we evaluated a method for determining Ees on the basis of the measured LV pressure and an assumed aortic flow with a triangular wave shape (Qtri). Qtri was derived using a fourth-order derivative of the LV pressure to approximate its corresponding Qm. Values of EestriQ obtained using Qtri were compared with those of EesmQ obtained from the measured Qm. Healthy rats (NC; n = 28) and rats with type 1 diabetes (DM; n = 26) and chronic kidney disease (CKD; n = 20) were examined. The cardiodynamic conditions in both the DM and CKD groups were characterized by a decline in EesmQ and EestriQ. A significant regression line for Ees was observed (P < 0.0001): EestriQ = 2.6214 + 1.0209 × EesmQ (r2 = 0.9870; n = 74). Our finding indicates that the systolic pumping mechanics of the heart can be derived from a single LV pressure recording together with the assumed Qtri.

Defects in Vascular Mechanics Due to Aging in Rats: Studies on Arterial Wave Properties from a Single Aortic Pressure Pulse.

Changes in vascular mechanics due to aging include elevated vascular impedance, diminished aorta distensibility, and an accelerated return of pulse wave reflection, which may increase the systolic workload on the heart. Classically, the accurate measurement of vascular mechanics requires the simultaneous recording of aortic pressure and flow signals. In practice, it is feasible to estimate arterial wave properties in terms of wave transit time (τw) and wave reflection index (RI) by using aortic pressure signal alone. In this study, we determined the τ w and magnitudes of the forward (∣Pf ∣) and backward (∣Pb ∣) pressure waves in Long-Evans male rats aged 4 (n = 14), 6 (n = 17), 12 (n = 17), and 18 (n = 24) months, based on the measured aortic pressure and an assumed triangular flow (Qtri). The pulsatile pressure wave was the only signal recorded in the ascending aorta by using a high-fidelity pressure sensor. The base of the unknown Qtri was constructed using a duration, which equals to the ejection time. The timing at the peak of the triangle was derived using the fourth-order derivative of the aortic pressure waveform. In the 18-month-old rats, the ratio of τ w to left ventricular ejection time (LVET) decreased, indicating a decline in the distensibility of the aorta. The increased ∣Pb ∣ associated with unaltered ∣Pf ∣ enhanced the RI in the older rats. The augmentation index (AI) also increased significantly with age. A significant negative correlation between the AI and τ w /LVET was observed: AI = -0.7424 - 0.9026 × (τ w /LVET) (r = 0.4901; P < 0.0001). By contrast, RI was positively linearly correlated with the AI as follows: AI = -0.4844 + 2.3634 × RI (r = 0.8423; P < 0.0001). Both the decreased τ w /LVET and increased RI suggested that the aging process may increase the AI, thereby increasing the systolic hydraulic load on the heart. The novelty of the study is that Qtri is constructed using the measured aortic pressure wave to approximate its corresponding flow signal, and that calibration of Qtri is not essential in the analysis.

Renin-Angiotensin System Inhibitor is Associated with Lower Risk of Ensuing Chronic Kidney Disease after Functional Recovery from Acute Kidney Injury.

Acute kidney injury (AKI) is an independent risk factor for ensuing chronic kidney disease (CKD). Animal studies have demonstrated that renin-angiotensin system (RAS) inhibitor can reduce ensuing CKD after functional recovery from AKI. Here we study the association between ensuing CKD and use of RAS inhibitor including angiotensin converting enzyme inhibitor or angiotensin II type 1a receptor blocker starting after renal functional recovery in our prospectively collected observational AKI cohort. Adult patients who had cardiac surgery-associated AKI (CSA-AKI) are studied. Patients with CKD, unrecovered AKI, and use of RAS inhibitor before surgery are excluded. Among 587 eligible patients, 94 patients are users of RAS inhibitor which is started and continued after complete renal recovery during median follow-up period of 2.99 years. The users of RAS inhibitor show significantly lower rate of ensuing CKD (users vs. non-users, 26.6% vs. 42.2%) and longer median CKD-free survival time (users vs. non-users, 1079 days vs. 520 days). Multivariate Cox regression analyses further demonstrate that use of RAS inhibitor is independently associated with lower risk of ensuing CKD (hazard ratio = 0.46, P < 0.001). We conclude that use of RAS inhibitor in CSA-AKI patients after renal functional recovery is associated with lower risk of ensuing CKD development.

Determining arterial wave transit time from a single aortic pressure pulse in rats: vascular impulse response analysis.

Arterial wave transit time (τw) in the lower body circulation is an effective biomarker of cardiovascular risk that substantially affects systolic workload imposed on the heart. This study evaluated a method for determining τw from the vascular impulse response on the basis of the measured aortic pressure and an assumed triangular flow (Qtri). The base of the unknown Qtri was constructed with a duration set equal to ejection time. The timing of the peak triangle was derived using a fourth-order derivative of the pressure waveform. Values of τws obtained using Qtri were compared with those obtained from the measure aortic flow wave (Qm). Healthy rats (n = 27), rats with chronic kidney disease (CKD; n = 22), and rats with type 1 (n = 22) or type 2 (n = 11) diabetes were analyzed. The cardiovascular conditions in the CKD rats and both diabetic groups were characterized by a decrease in τws. The following significant relation was observed (P < 0.0001): τwtriQ = -1.5709 + 1.0604 × τwmQ (r2 = 0.9641). Our finding indicates that aortic impulse response can be an effective method for the estimation of arterial τw by using a single pressure recording together with the assumed Qtri.

Losartan reduces ensuing chronic kidney disease and mortality after acute kidney injury.

Acute kidney injury (AKI) is an important risk factor for incident chronic kidney disease (CKD). Clinical studies disclose that ensuing CKD progresses after functional recovery from AKI, but the underlying mechanisms remain illusive. Using a murine model representing AKI-CKD continuum, we show angiotensin II type 1a (AT1a) receptor signaling as one of the underlying mechanisms. Male adult CD-1 mice presented severe AKI with 20% mortality within 2 weeks after right nephrectomy and left renal ischemia-reperfusion injury. Despite functional recovery, focal tubular atrophy, interstitial cell infiltration and fibrosis, upregulation of genes encoding angiotensinogen and AT1a receptor were shown in kidneys 4 weeks after AKI. Thereafter mice manifested increase of blood pressure, albuminuria and azotemia progressively. Drinking water with or without losartan or hydralazine was administered to mice from 4 weeks after AKI. Increase of mortality, blood pressure, albuminuria, azotemia and kidney fibrosis was noted in mice with vehicle administration during the 5-month experimental period. On the contrary, these parameters in mice with losartan administration were reduced to the levels shown in control group. Hydralazine did not provide similar beneficial effect though blood pressure was controlled. These findings demonstrate that losartan can reduce ensuing CKD and mortality after functional recovery from AKI.

Repeated cycles of high-dose intravenous immunoglobulin and plasmapheresis for treatment of late antibody-mediated rejection of renal transplants.

BACKGROUND/PURPOSE: Intravenous immunoglobulin (IVIG) plays a central role in the treatment of antibody-mediated rejection (AMR) of renal allografts, but the treatment outcomes for late AMR (>6 months after transplantation) are poor. METHODS: We performed a retrospective study to assess the response patterns of IVIG-based (2 g/kg) desensitization for late AMR. Patients who received desensitization after the pathological diagnosis of late AMR positive for complement component C4d were grouped as the Desensitized Group and compared to a historical Control Group with complement component C4d positivity in retrospective stainings. RESULTS: The 10-year graft survival of the Desensitized Group (73.9%, n = 35) was significantly better than that of the historical Control Group (35.0%, n = 40) without desensitization. In the Desensitized Group, a subgroup of patients (D2 Subgroup, n = 11), who responded to desensitization initially but deteriorated later, was identified to benefit from repeated cycles of desensitization at 31.1 ± 20.9 months. Patients receiving only one cycle of desensitization were further grouped into D1-good (n = 10) and D1-poor (n = 14) based on their long-term renal function. The D2 Subgroup patients did not exhibit significant improvements in renal function compared to the D1-poor patients, until 30 months after IVIG-based desensitization, suggesting desensitization therapy has a working window of approximately 24 months. CONCLUSION: Repeated cycles of IVIG-based desensitization help stabilize long-term renal function in patients with persistent AMR.

Factors associated with serum fetuin-A concentrations after long-term use of different phosphate binders in hemodialysis patients.

BACKGROUND: Fetuin-A is known as a circulating inhibitor of vascular calcification. Factors associated with serum fetuin-A concentrations after long-term use of different phosphate binders in hemodialysis patients is still uncertain. METHODS: In the post-hoc study, we analyzed serum fetuin-A and biochemical factors (Ca, P, i-PTH, hsCRP, TG, LDL-C) in 50 hemodialysis patients, who completed a 48-week, open-Label, controlled randomized parallel-group study. 23 patients received sevelamer and 27 patients received calcium carbonate. RESULTS: After the 48-week treatment, the sevelamer group had less serum calcium increment, less iPTH decrement, more ALK-P increment, more hsCRP decrement and more LDL-C decrement. There was no significant difference in the serum fetuin-A decrement between two groups. Decreased serum fetuin-A levels were found after 48-week treatment in both groups: from 210.61 (104.73) to 153.85 (38.64) ug/dl, P = 0.003 in sevelamer group, from 203.95 (107.87) to 170.90 (58.02) ug/mL, P =0.002 in calcium group. The decrement in serum fetuin-A (Δfetuin-A) levels was associated with ΔCa (ρ = - 0.230, P = 0.040), ΔiPTH (ρ = 0.306, P = 0.031) and Δalbumin (ρ = 0.408, P = 0.003), not associated with sevelamer use, ΔP and ΔhsCRP. CONCLUSION: After long-term sevelamer or calcium carbonate treatment, both groups of maintenance HD patients had lower serum fetuin-A levels. Serum levels of increased calcium, decreased iPTH and decreased albumin were associated with the serum fetuin-A decrement.

Risk Factors for Development and Progression of Chronic Kidney Disease: A Systematic Review and Exploratory Meta-Analysis.

The risk factors influencing the natural course of chronic kidney disease (CKD) are complex and heterogeneous, and few systematic reviews to date have focused on this issue. The aim of the study is to identify the risk factors for disease development and progression in each stage of CKD. We conducted electronic literature searches of PubMed, MEDLINE, Scopus, and the Cochrane Library up to October 15, 2012, for observational studies evaluating the risk factors on the development or progression of CKD. Eligible studies should have collected repeated information that could evaluate changes in renal function. Extracted information from all the included studies was synthesized narratively. Quality assessments were performed using the Newcastle-Ottawa Scale. An exploratory random-effects meta-analysis was performed where feasible to pool effect sizes across studies for a specific risk factor in a specific outcome. We identified 38 cohort studies and 2 case-control studies from 40 articles, with a total of 318,898 participants from 14 countries. The follow-up duration ranged from 1.5 to 16 years. The majority of the included studies were of high quality. The baseline CKD stages of the included studies ranged from normal to later stages, and only 19 studies could be classified into a specific range of CKD stages during follow-up. Three risk factors from studies of the same baseline and follow-up CKD stages were eligible for the exploratory meta-analysis, including male sex, substantial proteinuria, and diabetes. The hazard ratios for the progression from CKD stages 3-5 to end-stage renal disease (ESRD) were 1.37 (95% confidence interval 1.17-1.62), 1.64 (1.01-2.66), and 1.16 (0.98-1.38) for male sex, substantial proteinuria, and diabetes, respectively. In conclusion, our analyses comprehensively summarize the initiating and perpetuating factors for CKD. Male sex and substantial proteinuria are significant perpetuating factors for the progression from late stage CKD to ESRD, and diabetes may play a minor role for the outcome of ESRD among patients with later stages of CKD.

DNA methyltransferase inhibition restores erythropoietin production in fibrotic murine kidneys.

Renal erythropoietin-producing cells (REPCs) remain in the kidneys of patients with chronic kidney disease, but these cells do not produce sufficient erythropoietin in response to hypoxic stimuli. Treatment with HIF stabilizers rescues erythropoietin production in these cells, but the mechanisms underlying the decreased response of REPCs in fibrotic kidneys to anemic stimulation remain elusive. Here, we show that fibroblast-like FOXD1+ progenitor-derived kidney pericytes, which are characterized by the expression of α1 type I collagen and PDGFRß, produce erythropoietin through HIF2α regulation but that production is repressed when these cells differentiate into myofibroblasts. DNA methyltransferases and erythropoietin hypermethylation are upregulated in myofibroblasts. Exposure of myofibroblasts to nanomolar concentrations of the demethylating agent 5-azacytidine increased basal expression and hypoxic induction of erythropoietin. Mechanistically, the profibrotic factor TGF-ß1 induced hypermethylation and repression of erythropoietin in pericytes; these effects were prevented by 5-azacytidine treatment. These findings shed light on the molecular mechanisms underlying erythropoietin repression in kidney myofibroblasts and demonstrate that clinically relevant, nontoxic doses of 5-azacytidine can restore erythropoietin production and ameliorate anemia in the setting of kidney fibrosis in mice.

Systolic aortic pressure-time area is a useful index describing arterial wave properties in rats with diabetes.

The accurate measurement of arterial wave properties in terms of arterial wave transit time (τw) and wave reflection factor (Rf) requires simultaneous records of aortic pressure and flow signals. However, in clinical practice, it will be helpful to describe the pulsatile ventricular afterload using less-invasive parameters if possible. We investigated the possibility of systolic aortic pressure-time area (PTAs), calculated from the measured aortic pressure alone, acting as systolic workload imposed on the rat diabetic heart. Arterial wave reflections were derived using the impulse response function of the filtered aortic input impedance spectra. The cardiovascular condition in the rats with either type 1 or type 2 diabetes was characterized by (1) an elevation in PTAs; and (2) an increase in Rf and decrease in τw. We found that an inverse linear correlation between PTAs and arterial τw reached significance (τw = 38.5462 - 0.0022 × PTAs; r = 0.7708, P < 0.0001). By contrast, as the PTAs increased, the reflection intensity increased: Rf = -0.5439 + 0.0002 × PTAs; r = 0.8701; P <0 .0001. All these findings suggested that as diabetes stiffened aortas, the augmented aortic PTAs might act as a useful index describing the diabetes-related deterioration in systolic ventricular workload.

Methylprednisolone Protects Cardiac Pumping Mechanics from Deteriorating in Lipopolysaccharide-Treated Rats.

It has been shown that a prolonged low-dose corticosteroid treatment attenuates the severity of inflammation and the intensity and duration of organ system failure. In the present study, we determined whether low-dose methylprednisolone (a synthetic glucocorticoid) can protect male Wistar rats against cardiac pumping defects caused by lipopolysaccharide-induced chronic inflammation. For the induction of chronic inflammation, a slow-release ALZET osmotic pump was subcutaneously implanted to infuse lipopolysaccharide (1 mg kg(-1) d(-1)) for 2 weeks. The lipopolysaccharide-challenged rats were treated on a daily basis with intraperitoneal injection of methylprednisolone (5 mg kg(-1) d(-1)) for 2 weeks. Under conditions of anesthesia and open chest, we recorded left ventricular (LV) pressure and ascending aortic flow signals to calculate the maximal systolic elastance (E max) and the theoretical maximum flow (Q max), using the elastance-resistance model. Physically, E max reflects the contractility of the myocardium as an intact heart, whereas Q max has an inverse relationship with the LV internal resistance. Compared with the sham rats, the cardiodynamic condition was characterized by a decline in E max associated with the increased Q max in the lipopolysaccharide-treated rats. Methylprednisolone therapy increased E max, which suggests that the drug may have protected the contractile status from deteriorating in the inflamed heart. By contrast, methylprednisolone therapy considerably reduced Q max, indicating that the drug may have normalized the LV internal resistance. In parallel, the benefits of methylprednisolone on the LV systolic pumping mechanics were associated with the reduced cardiac levels of negative inotropic molecules such as peroxynitrite, malondialdehyde, and high-mobility group box 1 protein. Based on these data, we suggested that low-dose methylprednisolone might prevent lipopolysaccharide-induced decline in cardiac intrinsic contractility and LV internal resistance, possibly through its ability to reduce the aforementioned myocardial depressant substances. However, since our results were obtained in anesthetized open-chest rats, extrapolation to what may occur in conscious intact animals should be done with caution.

B cells and immunoglobulin in ABO-incompatible renal transplant patients receiving rituximab and double filtration plasmapheresis.

BACKGROUND/PURPOSE: The effect of rituximab on B cell and immunoglobulin production after therapeutic apheresis has not been studied in ABO-incompatible renal transplant patients. METHODS: Twenty consecutive ABO-incompatible renal transplant patients receiving rituximab induction and double filtration plasmapheresis were enrolled; one case was excluded because of repeated plasmapheresis and immunoglobulin therapy (Incompatible group). The B cell count of the Incompatible group was compared to another group of 18 ABO-compatible renal transplant patients who were operated on during the same period (Compatible group). In the Incompatible group, the total IgM, IgG, and IgG1-4 subclasses after transplantation were compared to those before desensitization. Tacrolimus, mycophenolate mofetil, and steroids were used for both groups. RESULTS: The B cell count of the Incompatible group was significantly lower than the Compatible group post-transplant from Month 1 to Month 11 only. The B cell count of the Compatible group also decreased for the first 6 months, suggesting that maintenance immunosuppressive agents suppress B cells. Total IgG and IgM levels after transplantation were significantly lower than before desensitization during the 24-month follow-up period. The post-transplant IgG3 level was significantly lower than before desensitization for only 3 months. CONCLUSION: With the aid of tacrolimus and mycophenolate mofetil, rituximab resulted in sustained suppression of B cell count and total IgG and IgM. Among the IgG subclasses, IgG3 was less sensitive to rituximab.

Multidisciplinary care program for advanced chronic kidney disease: reduces renal replacement and medical costs.

BACKGROUND: Multidisciplinary care is advocated as an effective chronic kidney disease treatment program in a few, but not all, studies. Our study aimed to evaluate the effect of multidisciplinary care on renal outcome and patient survival using a larger cohort. METHOD: A total 1382 chronic kidney disease patients, ages 18-80 years, with chronic kidney disease stage 3B-5, in nephrology outpatient clinics were enrolled. Using age, sex, chronic kidney disease stage, and diabetes mellitus as variables, 592 multidisciplinary care program participants were matched with 614 nonmultidisciplinary care patients. The primary outcomes were long-term renal replacement therapy and mortality. Secondary outcomes included changes of biochemical markers and blood pressure, infection hospitalization, cardiovascular events, and emergent start of long-term dialysis. Annual medical costs were compared. RESULTS: There were no between-group differences regarding mortality. In the multivariate competing-risk regression model, the multidisciplinary care group had a better renal survival (hazard ratio 0.640; 95% confidence interval, 0.484-0.847; P = .002). This effect was most prominent in stage 4 (hazard ratio 0.375; 95% confidence interval, 0.219-0.640; P < .001), but not in stage 3B and 5 patients. The multidisciplinary care group showed a slower estimated glomerular filtration rate decline (-2.57 vs -3.74 mL/min/1.73 m(2), P = .021), and a smaller increase in phosphate (+ 0.03 vs + 0.33 mg/dL, P = .013). Cardiovascular and infection events were both decreased in the multidisciplinary care group (P < .001). There was also less requirement of emergent start dialysis (39.6% vs 54.5%, P = .001). The annual cost for the multidisciplinary care group was lower than the nonmultidisciplinary care group (US $2372 vs $3794, P < .001). In addition, considering the reduction of patients requiring renal replacement therapy, the multidisciplinary care program saved a total US $1931 per patient annually. CONCLUSIONS: Our analysis demonstrated that the multidisciplinary care program provided better health care and reduced renal replacement therapy in patients with advanced chronic kidney disease. By decreasing hospitalizations, emergent start, and the need for renal replacement therapy, the multidisciplinary care program was cost-effective.