Lung Ultrasound-Guided Dry Weight Assessment and Echocardiographic Measures in Hypertensive Hemodialysis Patients: A Randomized Controlled Study.

RATIONALE & OBJECTIVE: Left ventricular (LV) hypertrophy and dysfunction are associated with adverse outcomes in hemodialysis patients. Hypertension and hypervolemia play important roles in these cardiac abnormalities. We report on the prespecified secondary outcome, echocardiographic indexes of LV function, from a previously reported study of the effect of lung ultrasound (US)-guided dry weight reduction on systolic blood pressure. STUDY DESIGN: Single-blind randomized trial. SETTINGS & PARTICIPANTS: 71 clinically euvolemic hypertensive hemodialysis patients in Greece and Slovenia. INTERVENTION: The active intervention group's (n=35) volume removal was guided by the total number of lung US B-lines observed every week before a midweek dialysis session. The usual-care group (n=36) was treated using standard-of-care processes that did not include acquisition of US data. OUTCOMES: 2-dimensional and tissue Doppler echocardiographic indexes at baseline and study end (8 weeks) that evaluated left and right heart chamber sizes, as well as systolic and diastolic function. RESULTS: Overall, 19 (54%) patients in the active intervention and 5 (14%) in the usual-care group had ultrafiltration intensification (P<0.001) during follow-up; changes in US B-lines (-5.3±12.5 vs+2.2±7.6; P<0.001) and dry weight (-0.71±1.39 vs+0.51±0.98kg; P<0.001) significantly differed between the active and usual-care groups. Inferior vena cava diameter decreased in the active compared with the usual-care group (-0.43±4.00 vs 0.71±4.82cm; P=0.03) at study end. Left (LA) and right (RA) atrial dimensions decreased more in the active group (LA surface, -1.09±4.61 vs 0.93±3.06cm2; P=0.03; RA surface -1.56±6.17 vs 0.47±2.31; P=0.02). LA volume index nominally decreased more in the active group (-2.43±13.14 vs 2.95±9.42mL/m2), though this was of borderline statistical significance (P=0.05). Reductions in LV end-diastolic diameter and volume were marginally greater in the active group. The change in LV filling pressures was significantly different in the active compared with the usual-care group (early transmitral diastolic velocities ratio [E/e'], -0.38±3.14 vs 1.36±3.54; P=0.03; E wave deceleration time, 35.43±85.25 vs-18.44±50.69; P=0.002]. Systolic function indexes were unchanged in both groups. In multivariable analysis, US B-line reduction was associated with a reduction in the E/e' LV ratio (OR, 4.542; 95% CI, 1.266-16.292; P=0.02). LIMITATIONS: Exploratory study; small sample size. CONCLUSIONS: A US-guided strategy for dry weight reduction is associated with decreased cardiac chamber dimensions and LV filling pressure, but no difference in systolic performance compared with usual care in hypertensive hemodialysis patients. FUNDING: European Renal Association-European Dialysis and Transplant Association. TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT03058874.

Histological grading in primary membranous nephropathy is essential for clinical management and predicts outcome of patients.

AIMS: Diagnosis of primary membranous nephropathy (PMN) is mainly based on immunofluorescence/immunohistochemistry findings. However, assessment of specific features on optical microscopy can help to estimate the severity of the disease, guide treatment and predict the response. The aim of this study was to identify, classify and grade the precise histological findings in PMN to predict renal function outcome and guide treatment. METHODS AND RESULTS: Histological parameters, including focal segmental sclerosis (FSGS), tubular atrophy (TA), interstitial fibrosis (IF) and vascular hyalinosis (VH), were re-evaluated in 752 patients with PMN. Their predictive value was estimated separately, and also in a combination score (FSTIV) graded from 0 to 4. Finally, the impact of histology was assessed in the response to immunosuppressive treatment. Mean age of patients was 53.3 (15-85) years and most presented with nephrotic syndrome. FSGS was present in 32% and VH in 51% of the patients, while TA and IF were graded as stage ≥1 in 52% and 51.4%, respectively. The follow-up period was 122.3 (112-376) months. FSGS, TA and IF and VH were associated with impaired renal function at diagnosis (P = 0.02, P < 0.0001, P = 0.001 and P = 0.02, respectively) and at the end of follow-up (P = 0.004, P < 0.0001, P < 0.0001 and P = 0.04, respectively). In multiple regression and binary logistic analysis, the presence of FSGS and degree of TA were the most significant parameters predicting renal function outcome, defined either by eGFR (end), FSGS (r = 0.6, P < 0.0001) and TA (r = 0.6, P < 0.0001), or by the endpoint of >50% eGFR reduction, FSGS (P = 0.001) and TA (P = 0.02). Also, patients presented with FSGS, IF, VH and/or with FSTIV > 1 could benefit from immunosuppression, regardless of clinical presentation. CONCLUSIONS: The presence and degree of four histological indices, FSGS, VH, TA and IF, assessed separately or in combination, and FSTIV score not only predict renal function outcome after long-term follow-up, but can also help in the choice of appropriate treatment. Decisions concerning immunosuppressive treatment can be guided by pathology regardless of clinical findings.

Impact of long-term cinacalcet, ibandronate or teriparatide therapy on bone mineral density of hemodialysis patients: a pilot study.

BACKGROUND: Insufficient evidenced-based information is available for the treatment of osteoporosis in hemodialysis (HD) patients. METHODS: In 102 HD patients, bone mineral density (BMD) was measured twice 16 ± 3 months apart. In the second BMD measurement 66 of them had a femoral neck (FN) T-score <-2.5. Of these 66 patients, 38 consented to a bone biopsy. Depending on both the bone biopsy findings and parathyroid hormone levels, patients were assigned to treatment groups. Eleven patients with osteitis fibrosa and iPTH >300 pg/ml received cinacalcet, 11 with osteitis fibrosa and iPTH <300 pg/ml received ibandronate, 9 with adynamic bone disease received teriparatide, and 7 with mild abnormalities received no treatment. A third BMD measurement was done after an average treatment period of 13-16 months. We compared the annual percent change of FN and lumbar spine (LS) BMD before and during treatment. RESULTS: FN and LS BMD decreased significantly in the cinacalcet group, with an annual change of 3.6 and 3.4% before treatment to -4.2% (p = 0.04) and -7.7% (p = 0.02) during treatment, respectively. In the teriparatide group, FN and LS BMD increased, although not significantly, with an annual change of -5.4 and -2.6% before treatment to 2.7 and 4.9% during treatment, respectively. In both the ibandronate and the no treatment groups, BMD change rate remained negative during the whole study. CONCLUSIONS: Teriparatide administration improved BMD in HD patients with adynamic bone disease, although these results did not reach statistical significance. In HD patients with osteitis fibrosa, ibandronate did not improve BMD while cinacalcet reduced BMD.

Impact of C-reactive protein on absolute reticulocyte count in haemodialysis patients: the role of iron status.

BACKGROUND: The exact mechanisms by which the effects of inflammation on erythropoiesis occur are still to be determined. We aimed to examine the relation between C-reactive protein (CRP) and erythropoiesis as quantified by the absolute reticulocyte count (RTC) and the possible effect of iron status on this relationship. METHODS: As part of a study that follows the changes of haematologic parameters after the intravenous (IV) administration of iron in 93 stable haemodialysis (HD) patients, we made a cross-sectional analysis of baseline measurements and an analysis of changes in RTC 1 week after baseline measurements and iron administration. RESULTS: Multiple linear regression analysis revealed that RTC had a positive correlation with CRP; RTC had a negative correlation with reticulocyte haemoglobin content (CHr). An interaction was also found between CRP and CHr in that CRP had a significant relation to RTC only in those patients whose CHr was more than 31.2 pg. At lower values of CHr, the correlation between CRP and RTC was not significant. Five days after the IV administration of 200 mg iron sucrose, a significant increase of RTC was observed, only in those patients with elevated baseline CRP levels who also showed an increase in CHr levels from ≤ 31.2 pg at baseline to ≥ 31.2 pg post-administration, supporting the presence of an independent positive correlation between CRP and RTC when iron is adequate. CONCLUSIONS: It is indicated that, in HD patients, elevated CRP values are associated with increased erythroid production only when CHr is quite satisfactory.

Haemodialysis and peritoneal dialysis patients have severely impaired post-occlusive skin forearm vasodilatory response assessed with laser speckle contrast imaging.

BACKGROUND: Endothelial dysfunction is associated with cardiovascular events and mortality in various disease states, including end-stage renal disease (ESRD). Novel technological approaches have emerged for real-time assessment of endothelial reactivity. This study examined skin microcirculation using laser speckle contrast imaging (LSCI) before and after arterial occlusion in ESRD patients undergoing haemodialysis (HD) or peritoneal dialysis (PD). METHODS: The 38 HD patients were matched in a 1:1 ratio with 38 PD patients (for age, sex and dialysis vintage) and 38 controls (for age and sex). Skin microvascular reactivity parameters assessed with LSCI included baseline perfusion, occlusion perfusion and peak perfusion during post-occlusive reactive hyperaemia (PORH); time to peak perfusion; proportional change from baseline to peak perfusion; baseline and peak cutaneous vascular conductance (CVC); proportional change from baseline to peak CVC and amplitude of the PORH response (i.e. the difference between peak and baseline CVC). RESULTS: Baseline perfusion [HD: 46.97 ± 14.6; PD: 49.32 ± 18.07; controls: 42.02 ± 11.94 laser specle perfusion units (LSPU), P = 0.097] and peak post-occlusion perfusion (104.77 ± 28.68 versus 109.04 ± 40.77 versus 116.96 ± 30.96 LSPU, P = 0.238) did not differ significantly between groups. However, the post-occlusive vascular response was completely different since the proportional increase from baseline to peak perfusion (HD: 133 ± 66; PD: 149 ± 125; controls: 187 ± 61%, P = 0.001) was significantly lower in ESRD patients and time to peak response was lower in HD but similar in PD patients compared with controls (HD: 7.24 ± 6.99; PD: 10.68 ± 9.45; controls: 11.11 ± 5.1 s, Kruskal-Wallis P = 0.003; pairwise comparisons: HD versus controls, P = 0.002; HD versus PD, P = 0.154; PD versus controls, P = 0.406). ESRD patients also had lower levels of peak CVC, indicating the maximum capillary recruitment (HD: 1.05 ± 0.3; PD: 1.07 ± 0.44; controls: 1.57 ± 0.52 LSPU/mmHg, P < 0.001), lower proportional increase of CVC at peak (P < 0.001) and lower amplitude of the PORH response, a measure of the difference between baseline and maximum capillary recruitment (P = 0.001). CONCLUSIONS: Using this novel non-invasive technology, endothelial post-occlusive forearm skin vasodilatory response was found to be similar between HD and PD patients and significantly impaired compared with controls. Future studies are needed to assess the prognostic implications of this microcirculatory functional defect.

Normal white blood cell counts predict long-term mortality of hemodialysis patients.

PURPOSE: It is unclear whether normal white blood cell (WBC) counts are predictive of subsequent mortality in hemodialysis patients. METHODS: All patients aged 17 years or more, who initiated hemodialysis at a tertiary Hospital from January 2000 to August 2017 with a dialysis vintage of greater than 90 days and normal median WBC count of their first dialysis year were included in the study. They were followed until they died, transferred to other dialysis facilities, switched to peritoneal dialysis, received a renal transplant or reached the end of the study (August 31, 2018). Cox regression was used to estimate hazard ratios for mortality of tertiles of WBC counts, adjusting for baseline demographic, clinical and laboratory variables. RESULTS: 611 patients [median (interquartile range) age 65.2 (53.3-72.6) years, 62.4% male] were studied. During a median follow-up of 3.9 (1.6-7.2) years, 270 participants died. Patients in the mid- (6.25-7.73 × 103/µL, n = 203) and top-tertile (7.73-10.50 × 103/µL, n = 203) of normal WBC counts had significantly higher mortality than patients in the bottom-tertile (3.50-6.25 × 103/µL, n = 205). The adjusted hazard ratio for mortality relative to the bottom-tertile was 1.54, 95% confidence interval (CI) 1.05-2.25 and 2.20, 95% CI 1.46-3.32, for the mid- and top-tertiles, respectively. CONCLUSIONS: In hemodialysis patients, higher WBC count within the normal range is associated with increased long-term mortality. This finding is described for the first time and provides further insight into the clinical significance of a "normal" WBC count result in dialysis patients.

Efficacy and safety of a low monthly dose of intravenous iron sucrose in peritoneal dialysis patients.

PURPOSE: Scientific data regarding intravenous iron supplementation in peritoneal dialysis (PD) patients are scarce. In attempting to administer the minimum monthly IV iron dose that could improve erythropoiesis, we wanted to assess the safety and efficacy of monthly maintenance intravenous administration of 100 mg iron sucrose in PD patients. METHODS: In a 9-month prospective study, all clinically stable PD patients received intravenously 200 mg of iron sucrose as a loading dose, followed by monthly doses of 100 mg for five consecutive months. Levels of hemoglobin (Hb), ferritin, transferrin saturation (TSAT), reticulocyte hemoglobin content (CHr) and C-reactive protein (CRP) were measured before each administration and 3 months after the last iron infusion. Also, doses of concurrent erythropoietin administration were recorded. RESULTS: Eighteen patients were eligible for the study. Mean levels of Hb and ferritin increased significantly (from 10.0 to 10.9 mg/dL, p = 0.01 and from 143 to 260 ng/mL, p = 0.005), as well as the increase in TSAT levels approached borderline significance (from 26.2 to 33.1%, p = 0.07). During the 6 months of iron administration, the erythropoietin dose was reduced in five patients and discontinued in one. During the 3 months following the last iron infusion, three of them again raised the erythropoietin dose to previous levels. None of the patients experienced any side effects related to IV iron administration. CONCLUSIONS: A monthly maintenance intravenous dose of 100 mg iron sucrose may be a practical, effective, and safe in the short term, treatment of anemia in PD patients resulting in improved hemoglobin levels, iron indices, and erythropoietin response.

Immunosuppressive regimens based on Cyclophospamide or Calcineurin inhibitors: Comparison of their effect in the long term outcome of Primary Membranous Nephropathy.

INTRODUCTION: Management of the Primary Membranous Nephropathy (PMN) usually involves administration of immunosuppressives. Cyclophosphamide (Cyclo) and Calcineurin Inhibitors (CNIs) are both widely used but only limited data exist to compare their efficacy in long term follow-up. AIM: The aim of the present study was to estimate and compare long term effects of Cyclo and CNIs in patients with PMN. PATIENTS-METHODS: Clinical data, histologic findings and long term outcome were retrospectively studied. The response to treatment and rate of relapse was compared between patients treated with CNIs or Cyclo based immunosuppressive regimens. RESULTS: Twenty three centers participated in the study, with 752 PMN patients (Mean age 53.4(14-87) yrs, M/F 467/285), followed for 10.1±5.7 years. All patients were initially treated with Renin Angiotensin Aldosterone System inhibitors (RAASi) for at least 6 months. Based on their response and tolerance to initial treatment, patients were divided into 3 groups, group I with spontaneous remission, who had no further treatment, group II, continued on RAASi only, and group III on RAASi+immunosuppression. Immunosuppressive regimes were mainly based on CNIs or Cyclo. Frequent relapses and failure to treatment were more common between patients who had started on CNIs (n = 381) compared to those initially treated with Cyclo (n = 110), relapse rate: 25.2% vs. 6.4%, p<0.0001, and no response rate: 22.5% vs. 13.6%, p = 0.04, respectively. CONCLUSIONS: Long term follow up showed that administration of Cyclo in PMN is followed by better preservation of renal function, increased response rate and less frequent relapses, compared to CNIs.

Initial dosing of paricalcitol based on PTH levels in hemodialysis patients with secondary hyperparathyroidism.

BACKGROUND: Adjustment of the initial dose of paricalcitol in hemodialysis patients with secondary hyperparathyroidism (SHPT) on the basis of severity of SHPT generally is preferred in current practice. Whether the proposed dose, based on the formula baseline intact parathyroid hormone (iPTH [picograms per milliliter]) divided by 80, is the most appropriate has not been assessed adequately. METHODS: A double-blind randomized trial comparing iPTH/80 dose with the immediately lower iPTH/120 dose was undertaken. Forty-three hemodialysis patients with iPTH levels between 300 and 900 pg/mL (300 and 900 ng/L) were followed up for 12 weeks. The primary outcome was control of iPTH levels within a target range between 150 and 300 pg/mL (150 and 300 ng/L). RESULTS: No difference between the 2 dose groups was noted in time to achieve target iPTH levels of 150 to 300 pg/mL (150 to 300 ng/L). More episodes of excessive decrease in iPTH levels occurred in the iPTH/80 group compared with the iPTH/120 group (P = 0.003). Nine patients in the iPTH/80 group (45%) versus 2 patients in the iPTH/120 group (10%) had iPTH levels less than 150 pg/mL (<150 ng/L) in at least half the measurements performed during the second half of the study (P = 0.034). Increases in calcium levels were greater in the iPTH/80 group at all times during the study (P < 0.05 at weeks 4 and 10). The number of required dose reductions was significantly greater in the iPTH/80 group compared with the iPTH/120 group (P = 0.008). CONCLUSION: In hemodialysis patients with SHPT, a lower initial dose of iPTH/120 shows efficacy similar to that of the already widely used iPTH/80 scheme in reaching target iPTH levels (150 to 300 pg/mL [150 to 300 ng/L]), with less required dose adjustments, lower increase in calcium levels, and lower cost. In addition, the initial dose of paricalcitol based on the iPTH/80 formula leads significantly more patients to excessive suppression of iPTH (<150 pg/mL [<150 ng/L]) than the iPTH/120 dose.

Do serum and red blood cell folate levels indicate iron response in hemodialysis patients?

The relationship among iron status, ferritin, and folate levels, and the possible contribution of folate measurement in the prediction of iron response in hemodialysis patients, have not been assessed. In addition to serum ferritin and transferrin saturation (TSAT), serum and red blood cell (RBC) folate levels were evaluated as indices for intravenous iron therapy responsiveness in 60 hemodialysis patients. Patients were classified as iron responders or nonresponders depending on whether they exhibited a rise in hemoglobin above 1 g/dl after administration of 1 g of iron sucrose. An inverse relation between serum ferritin concentration and RBC folate levels was found in iron responders (n=26, r=-0.62, p<0.001) but not in nonresponders (n=34, r=0.07, p=nonsignificant). Only serum and RBC folate levels could predict iron response in patients with ferritin levels above 150 microg/l (n=25), with a sensitivity of 83.3% and a specificity of 94.7%. Our findings suggest that RBC folate concentration is inversely related with ferritin levels in iron-responsive but not in non-responsive hemodialysis patients. Serum and RBC folate concentration seems to predict response to iron administration better than serum ferritin or TSAT in patients with ferritin levels above 150 microg/l; therefore, in these patients, it might be used to guide iron management.

Increase in serum magnesium level in haemodialysis patients receiving sevelamer hydrochloride.

BACKGROUND: Clinical studies have shown that sevelamer hydrochloride improves lipid profiles and attenuates the progression of the cardiovascular calcifications in haemodialysis patients. It is known that both of these properties are associated with increased magnesium levels. The effect of sevelamer on serum magnesium level is not well documented. The aim of this study was to determine the effects of sevelamer treatment on serum magnesium in haemodialysis patients and to assess the association of magnesium levels with lipid profiles and intact parathyroid hormone (iPTH). METHODS: Phosphate binders were discontinued during a two week washout period. Forty-seven patients, whose serum phosphate was greater than 6.0 mg/dl at the end of washout, received sevelamer hydrochloride for eight weeks. The patients were then washed off sevelamer for another two weeks. RESULTS: Mean serum phosphorus concentration declined from 7.5 +/- 1.3 to 6.4 +/- 1.2 mg/dl (P < 0.001), mean serum magnesium levels increased from 2.75 +/- 0.35 to 2.90 +/- 0.41 mg/dl (P < 0.001) and median serum iPTH levels decreased from 297 to 213 pg/ml (P=0.001) during the eight weeks of sevelamer treatment. After the two week post-treatment washout phosphorus levels increased to 7.3 +/- 1.3 mg/dl (P < 0.001), magnesium levels were reduced to 2.77 +/- 0.39 mg/dl (P < 0.001) and iPTH levels increased to 240 pg/ml (P=0.012). No change was observed in serum calcium levels during the sevelamer treatment period and the subsequent washout period. The mean decline in total and low density lipoprotein (LDL) cholesterol during sevelamer treatment was 16.3 and 28.3 (P < 0.001), respectively. The mean increase in high density lipoprotein (HDL) cholesterol and in apolipoprotein A1 was 2.9 +/- 5.8 mg/dl (P=0.004) and 6.8 +/- 11.1 mg/dl (P=0.001), respectively. Multivariate analysis showed that the rise in serum magnesium concentration significantly correlated with reductions in iPTH levels (r=-0.40, P=0.016), but did not have any significant correlation with the changes in lipid profiles. CONCLUSIONS: Our findings indicate that patients on haemodialysis receiving sevelamer have a significant increase in serum magnesium concentrations. This increase in serum magnesium is associated with reduction in iPTH levels. The changes in lipid profiles of these patients however are not related to changes in serum magnesium levels.

Therapeutic apheresis of immune diseases in nephrology department.

OBJECTIVE: The clinical efficacy of therapeutic apheresis is still controversial. We undertook a retrospective review of apheresis treatment to ascertain its safety and efficacy. METHODS: We reviewed 31 patients (13 male, 18 female). Plasmapheresis was performed on 7 patients with hematologic disorders, 5 patients with neurologic disorders, 6 patients with systemic diseases, and 3 patients with Lyell syndrome. Immunoadsorption onto protein A sepharose was evaluated as rescue therapy in 7 patients. Low-density lipoprotein (LDL) apheresis was performed on 3 patients. RESULTS: There were five mortalities due to serious complications of their primary disease. Most complications were mild such as hypotension and hypocalcemia. Two patients who received LDL apheresis had severe anaphylactic reactions. Apheresis was effective in the remaining 24 patients. CONCLUSIONS: The therapeutic apheresis consists of a continuously improving therapeutic method for diseases with high mortality and morbidity, especially in cases with poor outcome by using current medications.