External validation of the 2-year mortality prediction tool in hemodialysis patients developed using a Bayesian network.

Background: In recent years, a number of predictive models have appeared to predict the risk of medium-term mortality in hemodialysis patients, but only one, limited to patients aged over 70 years, has undergone sufficiently powerful external validation. Recently, using a national learning database and an innovative approach based on Bayesian networks and 14 carefully selected predictors, we have developed a clinical prediction tool to predict all-cause mortality at 2 years in all incident hemodialysis patients. In order to generalize the results of this tool and propose its use in routine clinical practice, we carried out an external validation using an independent external validation database. Methods: A regional, multicenter, observational, retrospective cohort study was conducted to externally validate the tool for predicting 2-year all-cause mortality in incident and prevalent hemodialysis patients. This study recruited a total of 142 incident and 697 prevalent adult hemodialysis patients followed up in one of the eight Association pour l'Utilisation du Rein Artificiel dans la région Lyonnaise (AURAL) Alsace dialysis centers. Results: In incident patients, the 2-year all-cause mortality prediction tool had an area under the receiver curve (AUC-ROC) of 0.73, an accuracy of 65%, a sensitivity of 71% and a specificity of 63%. In prevalent patients, the performance for the external validation were similar in terms of AUC-ROC, accuracy and specificity, but was lower in term of sensitivity. Conclusion: The tool for predicting all-cause mortality at 2 years, developed using a Bayesian network and 14 routinely available explanatory variables, obtained satisfactory external validation in incident patients, but sensitivity was insufficient in prevalent patients.

Laboratory diagnosis of heparin-induced thrombocytopenia: A retrospective experience.

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is a severe complication of heparin therapy associated with thrombosis that requires a quick diagnosis. Therefore, laboratory assays must provide an accurate and swift answer. This work aims to evaluate the performances of an ELISA assay, especially when combined with 4T risk score, and a functional assay. METHODS: Data were collected for 894 patients treated by heparin who underwent anticoagulant switch because of HIT suspicion and were examined by a multidisciplinary expert team who confirmed or ruled out HIT diagnosis. All patients were tested for anti-PF4 IgG with Asserachrom HPIA IgG (ELISA), and 307 were tested with a platelet aggregation test done on platelet-rich plasma (PRP-PAT). The 4T risk score was available for 607 of them. RESULTS: HIT was diagnosed in 232 patients. 4T risk score had a 94.2% negative predictive value (NPV) for risk scores ≤3 and 77.3% for risk scores ≤5. The sensitivity of ELISA was 90.9%, its specificity 79.0%, and its NPV 96.1%. When combined with 4T risk score, its NPV reached 100% and 97% for risk scores ≤3 and ≤5, respectively. PRP-PAT sensitivity was 70.4%, and its specificity was 92.3%. Combination of ELISA and PRP-PAT had a 0.7% false-negative rate. CONCLUSION: This study shows that ELISA can rule out HIT with an excellent NPV, especially when combined with the 4T risk score. Nonetheless, it has low specificity; hence, it needs to be associated with a functional assay.

Protective antibody response to mRNA-1273 and BNT162b2 vaccines in patients on maintenance haemodialysis: a prospective cohort study.

Background: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is more frequent and severe in patients with chronic kidney disease (CKD) on maintenance haemodialysis (HD). Vaccines are now available, but the protective response rates and determinants of humoral response to the vaccine are poorly described. Methods: This prospective observational study describes the response rates of detectable and protective antibody titres 1 month after each dose of an mRNA vaccine in a cohort of 851 patients on maintenance HD. Findings: Among naïve SARS-CoV-2 patients, a vast majority produced detectable (95.2%) or protective levels of antibodies (69.6%) 1 month after the second vaccine dose. In addition, the response rate was significantly higher with the mRNA-1273 than with the BNT162b2 vaccine 1 month after the second dose (79.8 versus 59.1%, respectively; P < 0.001). The main determinants for an inadequate humoral response were older age, treatment with immunosuppressants or oral anticoagulants and low serum albumin. All the patients who encountered coronavirus disease 2019 before vaccination also reached a highly protective humoral response. Interpretation: We found an acceptable humoral response rate in patients on maintenance HD, much higher than in transplant recipients. Therefore the third dose of vaccine may be justified in those patients with an inadequate humoral response, particularly those with a history of organ transplantation or immunosuppressive treatment.

Diabetic kidney disease versus non-diabetic kidney disease in type 2 diabetic patients on dialysis: An observational cohort.

BACKGROUND: All chronic kidney diseases in diabetic patients are not diabetic kidney diseases. The objective was to compare the clinical characteristics, survival and access to transplantation in diabetic patients starting dialysis and classified either as diabetic kidney disease (DKD) or non-diabetic kidney disease in diabetic patients (NDKD). METHODS: We used the nationwide French REIN registry to analyse baseline clinical characteristics at dialysis inception and outcomes defined as kidney transplantation, deaths and their causes. The probability of death or transplantation was analysed using a multivariate Cox model and the Fine and Gray competing for risk model (sdHT). RESULTS: We included 65,136 patients from January 2009 to December 2015 with a median follow-up of 31 months. The cumulative incidence of kidney transplantation over eight years was 46.9% (44.8-48.9) in non-diabetic patients (ND), higher than the 19.3% (17.5-21.2) in the DKD group and 22.2% (18.4-26.7) in the NDKD group. The risk of death was significantly higher in the NDKD group than in the DKD group, even after accounting for the competing risk of transplantation (NDKD/sdHR 1.22; 95%CI 1.18-1.27; p < 0.005 vs. DKD/sdHR 1.12; 95%CI 1.08-1.16; p < 0.005 with adjustment for age, sex, major adverse cardiovascular events, cancer and chronic respiratory failure, compared to ND). CONCLUSIONS: In diabetic patients starting dialysis, patients in the DKD group had reduced access to kidney transplantation. NDKD patients had a higher risk of mortality than DKD. The distinction between DKD and NDKD should be accounted for in the plan of care of diabetic patients starting dialysis.

Evaluation of a predictive model of end-stage kidney disease in a French-based cohort.

BACKGROUND: The risk of ESKD is highly heterogeneous among renal diseases, and risk scores were developed to account for multiple progression factors. Kidney failure risk equation (KFRE) is the most widely accepted, although external validation is scarce. The objective of this study was to evaluate the usefulness of this score in a French case-control cohort and test the pertinence of the proposed thresholds. METHODS: A retrospective case-control study comparing a group of patients starting renal replacement therapy (RRT) to a group of patients with CKD stages 3-5. Multivariate analysis to assess the predictors of ESKD risk. Discrimination of 4-, 6- and 8-variable scores using ROC curves and compared with eGFR alone and albumin/creatinine ratio (ACR) alone. RESULTS: 314 patients with a ratio of 1 case for 1 control. In multivariate analysis, increasing age and higher eGFR were associated with a lower risk of ESKD (OR 0.62, 95% CI 0.48-0.79; and OR 0.72, 95% CI 0.59-0.86, respectively). The log-transformed ACR was associated with a higher risk of ESKD (OR 1.25 per log unit, 95% CI 1.02-1.55). The 4-variable score was significantly higher in the RRT group than in the CKD-ND group, and was more efficient than the eGFR (AUROC 0.66, 95% CI 0.60-0.72, p = 0.018) and the log-transformed ACR (AUROC 0.63 95% CI 0.60-0.72, p = 0.0087) to predict ESKD. The 6-variable score including BP metrics and diabetes was not more discriminant as the 4-variable score. The 8-variable score had similar performance compared with the 4-score (AUROC 8-variable score: 0.70, 95% CI 0.64-0.76, p = 0.526). A 40% and 20% score thresholds were not superior to eGFR < 15 and 20 mL/min/1.73 m2, respectively. A 10% threshold was more specific than an eGFR < 30 mL/min/1.73 m2. CONCLUSION: KFRE was highly discriminant between patients progressing to ESKD vs those non-progressing. The 4-variable score may help stratify renal risk and referral in the numerous patients with stage 3 CKD. Conversely, the proposed thresholds for creating vascular access or preemptive transplantation were not superior to eGFR alone.

Effects of high- vs low-dose native vitamin D on albuminuria and the renin-angiotensin-aldosterone system: a randomized pilot study.

BACKGROUND: Residual albuminuria is associated with an increased risk of progression to ESKD. We tested whether a supplementation with native vitamin D could reduce albuminuria in stable CKD patients under maximal renin-angiotensin system (RAS) blockade. METHODS: We conducted a randomized controlled study of high (cholecalciferol 100 000 UI per 10 days over 1 month) vs low-dose (ergocalciferol 400 UI/days over 1 month) supplementation with native vitamin D on urinary albumin/creatinine ratio, blood pressure and the RAS over 1 month in stable CKD patients with albuminuria and maximum tolerated RAS blockade. RESULTS: We included 31 patients, 21 in the high dose group and 10 in the low dose group. In contrast with a low dose, high dose vitamin D normalized plasma 25(OH)D, decreased iPTH but slightly increased plasma phosphate. High dose vitamin D decreased geometric mean UACR from 99.8 mg/mmol (CI 95% 60.4-165.1) to 84.7 mg/mmol (CI 95% 51.7-138.8, p = 0.046). In the low dose group, the change in geometric mean UACR was not significant. Blood pressure, urinary 24 h aldosterone and peaks and AUC of active renin concentrations after acute stimulation by a single dose of 100 mg captopril were unaffected by the supplementation in native vitamin D, irrespective of the dose. Native vitamin D supplementation was well tolerated. CONCLUSIONS: We found a small (- 15%) but significant decrease in albuminuria after high dose vitamin D supplementation. We found no effect of vitamin D repletion on blood pressure and the systemic RAS, concordant with recent clinical studies.

Effect of emergency start and central venous catheter on outcomes in incident hemodialysis patients: a prospective observational cohort.

BACKGROUND: Unfavorable conditions at hemodialysis inception reduce the survival rate. However, the relative contribution to outcomes of predialysis follow-up, symptoms, emergency start or central venous catheter (CVC) is unknown. METHODS: We analyzed the determinants of survival according to dialysis initiation conditions in the nationwide REIN registry, using two methods based either on clinical classification or data mining. We divided patients into four groups according to dialysis initiation (emergency vs planned, symptoms or not, previous follow-up). "Followed planned starters" began dialysis as outpatients and with an arteriovenous fistula (AVF). "Followed symptomatic non-urgent starters" were patients who started earlier because of any non-urgent symptomatic event. "Followed urgent starters" had seen a nephrologist before inception but started dialysis in an emergency condition. "Unknown urgent starters" were patients without any follow-up and who had a CVC at inception. RESULTS: "Followed urgent" starters had the lowest 2-year survival rate (66.8%) compared to "followed planned" (77.3%), "followed symptomatic non urgent" (79.2%), and "unknown urgent" (71.7%). Compared to other groups, the risk of mortality was lower in followed symptomatic non urgent (HR 0.86 95% CI 0.75-0.99) and higher in followed urgent starters (HR 1.05 (95% CI 0.94-1.18). In data mining Classification And Regression Tree regrouping in five categories, the lowest 2-year survival (52.3%) was in over 70-year-old starters with a CVC. The survival was 93.2% in under 57-year-old patients without active cancer, 82.5% in 57-70-year-old individuals without cancer, 72.4% in over 70-year-old patients without CVC and 61.4% in under 70-year-old subjects with cancer. The hazard ratio of data mining categories varied between 2.12 (95% CI 1.73-2.60) in 57-70-year-old subjects without cancer and 4.42 (95% CI 3.64-5.37) in over 70-year-old patients with CVC. Therefore, regrouping incident patients into five data mining categories, identified by age, cancer, and CVC use, could discriminate the 2-year survival in patients starting hemodialysis. CONCLUSIONS: Although each classification captured different prognosis information, both analyses showed that starting hemodialysis on a CVC has more dramatic outcomes than emergency start per se.

Dialysis dose and mortality in haemodialysis: is higher better?

BACKGROUND: The effect of dialysis dose on mortality remains unsettled. Current guidelines recommend targeting a single-pool Kt/V (spKt/V) at 1.20-1.40 per thrice-weekly dialysis session. However, the optimal dialysis dose remains mostly disputed. METHODS: In a nationwide registry of all incident patients receiving thrice-weekly haemodialysis, 32 283 patients had available data on dialysis dose, estimated by Kt/V and its variants epuration volume per session (Kt) and Kt indexed to body surface area (Kt/A). Survival was analysed with a multivariate Cox model and a concurrent risk model accounting for renal transplantation. A predictive model of Kt in the upper quartile was developed. RESULTS: Regardless of the indicator, a higher dose of dialysis was consistently associated with better survival. The survival differential of Kt was the most discriminating, but marginally, compared with the survival differential according to Kt/V and Kt/A. Patient survival was higher in the upper quartile of Kt (>69 L/session) then deteriorated as the Kt decreased, with a difference in survival between the upper and lower quartile of 23.6% at 5 years. Survival differences across Kt distribution were similar after accounting for kidney transplantation as a competing risk. Predictive factors for Kt in the upper quartile were arteriovenous fistula versus catheters and graft, haemodiafiltration versus haemodialysis, scheduled dialysis start versus emergency start, long weekly dialysis duration and spKt/V measurement versus double-pool equilibrated Kt/V. CONCLUSIONS: Our data confirm the existence of a relationship between dialysis dose and survival that persisted despite correcting for known confounders. A model for predicting a high dose of dialysis is proposed with practical relevance.

A regimen with caplacizumab, immunosuppression, and plasma exchange prevents unfavorable outcomes in immune-mediated TTP.

The anti-von Willebrand factor nanobody caplacizumab was licensed for adults with immune-mediated thrombotic thrombocytopenic purpura (iTTP) based on prospective controlled trials. However, few data are available on postmarketing surveillance. We treated 90 iTTP patients with a compassionate frontline triplet regimen associating therapeutic plasma exchange (TPE), immunosuppression with corticosteroids and rituximab, and caplacizumab. Outcomes were compared with 180 historical patients treated with the standard frontline treatment (TPE and corticosteroids, with rituximab as salvage therapy). The primary outcome was a composite of refractoriness and death within 30 days since diagnosis. Key secondary outcomes were exacerbations, time to platelet count recovery, the number of TPE, and the volume of plasma required to achieve durable remission. The percentage of patients in the triplet regimen with the composite primary outcome was 2.2% vs 12.2% in historical patients (P = .01). One elderly patient in the triplet regimen died of pulmonary embolism. Patients from this cohort experienced less exacerbations (3.4% vs 44%, P < .01); they recovered durable platelet count 1.8 times faster than historical patients (95% confidence interval, 1.41-2.36; P < .01), with fewer TPE sessions and lower plasma volumes (P < .01 both). The number of days in hospital was 41% lower in the triplet regimen than in the historical cohort (13 vs 22 days; P < .01). Caplacizumab-related adverse events occurred in 46 patients (51%), including 13 major or clinically relevant nonmajor hemorrhagic events. Associating caplacizumab to TPE and immunosuppression, by addressing the 3 processes of iTTP pathophysiology, prevents unfavorable outcomes and alleviates the burden of care.

Impact of first-wave COronaVIrus disease 2019 infection in patients on haemoDIALysis in Alsace: the observational COVIDIAL study.

BACKGROUND: There are only scarce data regarding the presentation, incidence, severity and outcomes of coronavirus disease 2019 (COVID-19) in patients undergoing long-term haemodialysis (HD). A prospective observational study was conducted in eight HD facilities in Alsace, France, to identify clinical characteristics of HD patients with COVID-19 and to assess the determinants of the risk of death. METHODS: All HD patients tested positive for COVID-19 from 5 March to 28 April 2020 were included. Collected data included patient characteristics, clinical features at diagnosis, laboratory data, treatments and outcomes. RESULTS: Among 1346 HD patients, 123 tested positive for COVID-19. Patients had a median age of 77 years (interquartile range 66-83), with a high number of comorbidities (3.2 ± 1.6 per patient). Symptoms were compatible in 63% of patients. Asthenia (77%), diarrhoea (34%) and anorexia (32%) were frequent at diagnosis. The delay between the onset of symptoms and diagnosis, death or complete recovery was 2 (0-5), 7 (4-11) and 32 (26.5-35) days, respectively. Treatment, including lopinavir/ritonavir, hydroxychloroquine and corticosteroids, was administered in 23% of patients. The median C-reactive protein (CRP) and lymphocyte count at diagnosis was 55 mg/L (IQR 25-106) and 690 Ly/µL (IQR 450-960), respectively. The case fatality rate was 24% and determinants associated with the risk of death were body temperature {hazard ratio [HR] 1.96 [95% confidence interval (CI) 1.11-3.44]; P = 0.02} and CRP at diagnosis [HR 1.01 (95% CI 1.005-1.017); P < 0.0001]. CONCLUSIONS: HD patients were found to be at high risk of developing COVID-19 and exhibited a high rate of mortality. While patients presented severe forms of the disease, they often displayed atypical symptoms, with the CRP level being highly associated with the risk of death.

Metabolic syndrome in haemodialysis patients: prevalence, determinants and association to cardiovascular outcomes.

BACKGROUND: In the general population, metabolic syndrome (MetS) is predictive of major adverse cardiovascular events (MACE). Waist circumference (WC), a component of the MetS criteria, is linked to visceral obesity, which in turn is associated with MACE. However, in haemodialysis (HD) patients, the association between MetS, WC and MACE is unclear. METHODS: In a cross-sectional study of 1000 HD patients, we evaluated the prevalence and characterised the clinical predictors of MetS. The relationship between MetS and its components, alone or in combination, and MACE (coronary diseases, peripheral arteriopathy, stroke or cardiac failure), was studied using receiver operating characteristics (ROC) curves and logistic regression. RESULTS: A total of 753 patients were included between October 2011 and April 2013. The prevalence of MetS was 68.5%. Waist circumference (> 88 cm in women, 102 cm in men) was the best predictor of MetS (sensitivity 80.2; specificity 82.3; AUC 0.80; p <  0.05). In multivariate analysis, MetS was associated with MACE (OR: 1.85; 95CI 1.24-2.75; p <  0.01), but not WC alone. There was a stronger association between the combination of abdominal obesity, hypertriglyceridaemia and low high-density lipoprotein cholesterol with MACE after exclusion of impaired fasting glucose and hypertension. CONCLUSIONS: MetS is frequent and significantly associated with MACE in our haemodialysis cohort and probably in other European dialysis populations as well. In HD patients, a new simplified definition could be proposed in keeping with the concept of the "hypertriglyceridaemic waist".

CERA conversion to darbepoetin alfa in 154 hemodialysis patients.

PURPOSE: Anemia is a common complication in dialysis patients, usually treated with erythropoietin (EPO). Among available EPOs and analogs, continuous erythropoietin receptor activator (CERA) and darbepoetin alfa (DA) are the only two agents with a long duration of action, although they have almost never been formally compared in terms of efficacy. We took advantage of an accidental disruption in CERA supply to study the effect of its replacement with DA in the same patients. METHODS: The clinical and biological characteristics of 154 hemodialysis patients were retrospectively reviewed during the last 3 months on CERA compared to the first 4 months after replacement by DA, both ASE being administered by IV route. The comparison included EPO doses, hemoglobin levels, factors interfering with anemia (iron status assessment, iron doses, inflammation, quality of treatment) and was performed under the Bayesian paradigm. RESULTS: We found no significant differences between the two EPOs in terms of doses or hemoglobin concentrations. Factors that could potentially influence hemoglobin concentrations also did not differ under CERA or DA. The stability of hemoglobin was identical with both EPOs. We provide a conversion factor which allows comparison of cost according to local prices. CONCLUSIONS: We conclude that, in this observational "real life" study, the two EPOs are to be considered as equivalent.

Short- and long-term renal outcomes following severe rhabdomyolysis: a French multicenter retrospective study of 387 patients.

BACKGROUND: Rhabdomyolysis is a life-threatening disease that can lead to severe hyperkalemia, acute kidney injury (AKI) and hypovolemic shock. The predictive factors of AKI and acute to chronic kidney disease (CKD) transition remain poorly described. METHODS: This multicenter retrospective study enrolled 387 patients with severe rhabdomyolysis (CPK > 5000 U/L). Primary end-point was the development of severe AKI, defined as stage 2 or 3 of KDIGO classification. Secondary end-points included the incidence of AKI to CKD transition. RESULTS: Among the 387 patients, 315 (81.4%) developed AKI, including 171 (44.1%) with stage 3 AKI and 103 (26.6%) requiring RRT. Stage 2-3 AKI was strongly correlated with serum phosphate, potassium and bicarbonate at admission, as well as myoglobin over 8000 U/L and the need for mechanical ventilation. 42 patients (10.8%) died before day 28. In the 80 patients with available eGFR values both before and 3 months after the rhabdomyolysis, the decrease in eGFR (greater than 20 mL/min/1.73 m2 in 23 patients; 28.8%) was correlated to the severity of the AKI and serum myoglobin levels > 8000 U/L at admission. CONCLUSIONS: Severe rhabdomyolysis leads to AKI in most patients admitted to an ICU. Mechanical ventilation and severity of the rhabdomyolysis, including myoglobin level, are associated with the risk of stage 2-3 AKI. The long-term renal decline is correlated to serum myoglobin at admission.

Hemodialysis without anticoagulation: Less clotting in conventional hemodialysis than in predilution hemodiafiltration.

INTRODUCTION: Hemodialysis patients with contraindication to systemic anticoagulation require a heparin-free hemodialysis technique. Among several alternatives to heparin, predilution hemodiafiltration (HDF) is often used, albeit without any confirmation of its effectiveness. METHODS: Patients hospitalized in a nephrology ICU and hemodialysed for stage 5 CKD or AKI and with contraindication to systemic anticoagulation were randomized to either standard HD with a polysulfone membrane, or to predilution HDF with the same membrane. Coagulation activation was evaluated clinically by the need for premature termination and by the measurement of D-dimers. FINDINGS: Two hundred dialysis sessions were performed in 155 patients. Survival curves showed better circuit survival in HD (P = 0.046). In HD, 12% of sessions were interrupted for coagulation versus 23% in predilution HDF (P = 0.04). DISCUSSION: Predilution HDF was associated with more premature clotting than conventional HD without improvement in dialysis duration or performance epuration indices. When aiming for a 4-hour duration session, conventional heparin-free hemodialysis can be safely proposed in most patients with high bleeding risk.

[Sodium, hypertension, chronic kidney diseases, and public health]. / Sodium, hypertension, maladies rénales et santé publique.

Salt consumption has substantially increased these last years in our modern societies and far exceeds our needs. It has a great impact on cardiovascular and renal disease and represents a major issue in public health. The present work is a review of observational and interventional studies exploring the relationship between salt consumption, high-blood pressure and cardiovascular morbimortality in the general population but also in chronic kidney diseases.

[What is the goal blood pressure in non-diabetic chronic kidney disease?] / Quelles cibles tensionnelles dans la maladie rénale chronique non diabétique ?

High blood pressure during renal disease is highly prevalent and an important risk factor for cardiovascular disease and renal progression. Its optimal management is therefore necessary to improve the prognosis of patients. Several trials concerning the blood pressure target in patients with chronic non-diabetic kidney disease have been published in recent years, we will detail them in this article in order to determine which blood pressure target provides the best benefit in terms of progression of renal diseases and cardiovascular prevention.

Survival advantage of planned haemodialysis over peritoneal dialysis: a cohort study.

Background: Previous studies comparing the outcomes in haemodialysis (HD) with those in peritoneal dialysis (PD) have yielded conflicting results. Methods: The aim of the study was to compare the survival of planned HD versus PD patients in a cohort of adult incident patients who started renal replacement therapy (RRT) between 2006 and 2008 in the nationwide REIN registry (Réseau Epidémiologie et Information en Néphrologie). Patients who started RRT in emergency or stopped RRT within 2 months were excluded. Adjusted Cox models, propensity score matching and marginal structural models (MSMs) were used to compensate for the lack of randomization and provide causal inference from longitudinal data with time-dependent treatments and confounders including transplant censorship, modality change over time and time-varying covariates. Results: Among a total of 13 767 dialysis patients, 13% were on PD at initiation of RRT and 87% were on HD. The median survival times were 53.5 months or 4.45 years and 38.6 months or 3.21 years for patients starting on HD and PD, respectively. Regardless of the model used, there was a consistent advantage in terms of survival for HD patients: hazard ratio (HR) 0.76 [95% confidence interval (95% CI) 0.69-0.84] with the Cox model using propensity score; HR 0.67 (95% CI 0.62-0.73) in the Cox model with censorship for each treatment change; and HR 0.82 (95% CI 0.69-0.97) with MSMs. However, MSMs tended to reduce the survival gap between PD and HD patients. Conclusion: This large cohort study using various statistical methods to minimize the bias appears to demonstrate a better survival in planned HD than in PD.