The finding of anemia among HDX ptns is commonly observed and underlying some of the symptoms associated with renal function decline
Anemia in HDX
o AMI: acute myocardial infarction
o BTx: blood transfusion
o CBC: complete blood count
o CBC: complete blood count
o CKD: chronic kidney disease
o CVS: cardiovascular disease
o Dc: diabetic (retinopathy).
o Depo: darbepoetin
o ESA: erythropoiesis-stimulating agent.
o FDA: US Food and Drug Administration
o Hct: haematocrit
o HDX: haemodialysis
o HF: heart failure,
o HT: Hypertension
o HT: hypertension
o IHD: ischemic heart disease
o IV: intravenous
o KDIGO: The Kidney Disease: Improving Global Outcomes guidelines
o KDOQI: The Kidney Disease Outcomes Quality Initiative
o KDQ: Kidney Disease Questionnaire
o LVH: left ventricular hypertrophy
o MI: myocardial infarction
o MR: mortality rate
o NHT: Normal Haematocrit Trial
o OBS: occult blood in stool
o PD: peritoneal dialysis
o PRCA: Pure red cell aplasia.
o Retics: reticulocyte count
o Sms: symptoms
o SOB: Shortness of breath
o TIBC: total iron-binding capacity
o TSAT: transferrin saturation
o Tx: transfusion
o WHO: World Health Organization.
The finding of anemia among HDX ptns is commonly observed and underlying some of the Sms associated with renal function decline, e.g., easy fatigability, depressive mood, decreased exercise tolerance, and SOB. Anaemia can be also associated with higher morbidity and MR related to CVS with increasing risk of hospitalization and hospital longevity. Management of anemia is routinely sharing the current care of HDX ptns.
Defining anemia: the WHO criteria for defining anemia are commonly applied by most nephrologist as follows: HB level of <13 g/dL for adult men and postmenopausal ladies and an HB level of <12 g/dL for pre-menopausal females. However, this definition does not recognize the goals of therapy among HDX ptns. Typically treated HDX ptns will still anaemic according to this definition. One explanation is that anemia therapy is typically involving ESAs to prevent severe anemia and decline the need for BTx but with no HB level normalization. Several studies have reported that, among CKD ptns (including HDX ptns), the administration of ESAs to normalize HB augments the risk of adverse sequalae.
Anemia screening: Initially all ptns should be screened for the presence of anemia with commencing maintenance DX with a CBC, especially if they have not previously monitored and have no recent CBC at the start of DX. Anaemic ptns (HB <12-13 g/dL) should be assessed for an underlying aetiology. Primary assessment of anemia is globally similar in CKD ptns to that in the general population. General evaluation should involve RBCs indices, Retics, s. iron, TIBC, % TSAT, s. ferritin, s. folate and vit. B12, and testing for OBS.
Continuous monitoring: After the initial screen and evaluation, we continue to routinely monitor ALL HDX ptns for anemia & iron deficiency with HB, % TSAT = (plasma iron divided by TIBC x 100), and s. ferritin levels. The recommended frequency of repeated testing is not certain. A suggested approach considering the KDIGO guidelines is as follows:
o Not anaemic (HB >12-13): monitor HB on 3 monthly bases. Consider TSAT & s. ferritin with anemia evolution.
o Anaemic but HB not under threshold for ESA therapy: monitor HB at 3 monthly bases. Consider TSAT & ferritin assessment if anemia became worse.
o Anaemic + ESA: measure HB on monthly bases at least; in many DX centres, HB is regularly checked weekly. HB should be assessed after ESA commencing and with dose titration to evaluate their response.
o Anaemic + stable ESA protocol: assess HB every mo (many DX centres assess HB on a weekly basis).
Moreover, HB checking with clinical indication (e.g., after surgical interference, hospitalization, or bleeding). A suggested approach to monitor iron deficiency that is consistent with the KDIGO guidelines with screening for iron deficiency if anemia was diagnosed or worsened, as follows:
o Ptns on ESA therapy, assess TSAT and s. ferritin on 3 monthly bases.
o ESA starting or rising ESA dose, assess TSAT & s. ferritin on a monthly basis.
o With the finding of or suspected blood losses and with evaluating the response of IV iron therapy, assess TSAT & s. ferritin on a monthly basis.
S. ferritin and TSAT can be evaluated mostly 24-48 hs after a BTx if indicated.
THERAPEUTIC INDICATIONS: Once anemia diagnosed it should be managed. In the HDX cohort, untreated anemia is commonly severe (typical of HB 6-8 g/dL) and, if not managed, complicated with a higher MR with disabling Sms. Therapy of anemia may involve ESAs and/or IV iron. The target of anemia therapy is to alleviate Sms related to anemia and to limit the need for BTx. The option of an individual therapeutic line primarily dependent on the degree of anemia severity and on the finding of iron deficiency. The indication for therapy is usually dependent on FDA guidelines for ESA therapy, that can be modified accordingly. A suggested approach that is consistent with the 2012 KDIGO guidelines. TSAT & ferritin assessment for commencing therapy with iron are variable in ptns having HB <10 g/dL OR are on an ESA vs those with HB ≥10 g/dL.
Low HB <10 g/dL + TSAT ≤30 % + ferritin ≤500 ng/mL: should be managed with IV iron. Despite they’re unlikely to be iron deficient as recognised via bone marrow biopsy, iron supplements may elevate the HB levels. Such ptns may necessitate an ESA, an iron loading dose should be provided first with repeated evaluation of HB before commencing the ESA. After iron stores repletion and if HB still < 10 g/dL, most ptns should start an ESA. Ptns developing iron deficiency considering these criteria with ongoing an ESA are also treated with IV iron.
o HB ≥10 g/dL & TSAT ≤20 % and ferritin ≤200 ng/mL: those ptns are mostly have iron deficiency and IV iron should be provided.
o HB ≥10 g/dL & TSAT >20 % and ferritin >200 ng/mL: those ptns should not be treated with either iron or an ESA, rather continue close monitoring. Despite they may be defined anaemic according to WHO values, they are currently not meeting the recommended criteria for ESA administration.
o Low HB <10 g/dL & TSAT >30 %: Such ptns can be provided an ESA, with considering specific ptn criteria, e.g., functional & cognitive situation, life expectancy, and other factors. Ptns having a history of stroke or malignancy or an active malignancy should be excepted. ESAs have been associated with increasing risk of stroke and death related to malignancy.
I. Iron: Iron therapy for HDX ptns, revised elsewhere.
II. Erythropoiesis-stimulating agents (ESAs)
Indications & CI (contraindications): ESAs are mostly given to HDX ptns with HB <10 g/dL and are Not iron deficient. ESAs are proved to be effective in correcting anemia. Considering HDX ptns with severe anaemia, ESAs can limit the requirements for Bld Tx with better quality-of-life, Sms, exercise tolerance, and LVH, that has been complicated with higher MR. Crucial exceptions are ptns with cancer, particularly ptns in whom cancer cure may be anticipated or having had a stroke, as such ptns may be at increasing risk for adverse impacts related to ESAs therapy. Commencing therapy in those ptns should be currently individualized after discussing the possible risk/benefit ratio of ESA therapy. However, optimal goal HB for ESA dosages still uncertain. More detail will be given below.
Dosing: EPO is mostly provided as 50 units/kg 3 times/wk that is a relatively low initial dose; but with severely symptomatizing anemia, a higher dose (100 units/kg 3 times/wk) may be required. The FDA-recommended initial dose is 50-100 units/kg 3 times/wk for the IV & SC routes. Considering the KDOQI & KDIGO anaemia guidelines, no specific recommendation for initial dose but generally should be individualized.
EPO alfa-epbx (EPO a biosimilar), was approved by the FDA in 2018 for the CKD anemic ptns. The recommended dose is similar to EPO alfa. One trial: evaluating efficacy/safety of EPO alfa-epbx, 612 ptns with ESKD on HDX and stable anemia (mean HB 10.4 g/dL) treated with IV EPO alfa were randomly assigned to 24 wks of either IV EPO alfa-epbx or EPO alfa. Doses were provided according to the prescribing information for EPOa to keep the target HB from 9 to 11 g/dL. After 24 wks, no difference in the mean wkly HB levels, mean wkly EPO dose, or incidence of adverse impacts between both groups.
Other members of ESAs given for anemia in HDX ptns include Depo, with FDA-recommended initial weekly dose of 0.45 mcg/kg or biweekly 0.75 mcg/kg, and methoxy polyethylene glycol- EPO, with FDA-recommended initial biweekly dose of 0.6 mcg/kg. The incidence of major CVS events and all-cause MR with the less frequent ESAs seems to be comparable to that of EPOa.
Upward Dosage titration as needed to get the target HB level. Dosage of ESA provided to reach this target varies greatly among HDX ptns. In general, dosing should be adjustment on a monthly basis in response to the Hct value. The HB rise should be mostly in the range of 1-2 g/dL/mo. Dosing of ESA should be decreased in ptns with HB rise above this level. Among ptns with an HB rise > 2.5-3 g/dL/mo, the ESA dose should be withdrawn or declined by minimum 50 %. While some nephrologists decline the ESA dose (as per KDIGO guidelines), the ESA withdrawal completely may decrease the number of events that the HB exceeding the target and limit the ESA administered per DX session.
Route of administration: Either IV or SC ESA administration can be provided. Several reports have observed that the SC dose of ESA required to get certain target HB is about 30 % lower than that required with IV route.
The largest prospective studies: 208 HDX ptns were randomly assigned to either SC or IV EPO. At 26 wks, average SC EPO to get the target HB levels was less than the IV dose (95 vs 140 units/kg/wk). This’s crucial consideration as a higher ESA dosing (independent of HB) may be complicated with a worse CVS outcome. Retrospective study: 62,000 HDX ptns reported that equivalent HB levels were obtained with 25 % less EPO provided SC as compared to IV route but also reported that the composite adverse events of death and/or hospitalization for CVS sequelae (HF, AMI, or stroke) were more commonly reported with the IV EPO-treated ptns, possibly due to the greater EPO dose.
However, the IV route is usually favoured with HDX as the SC route is associated with great intolerability and IV access is already available for the DX therapy. Report 2004: in the US, > 90 % of HDX ptns received IV ESAs. SC route is used more widely outside the US. However, the limits in application of SC ESAs following an outbreak of PRCA related to SC use of certain ESA formulae that was not provided in the US. IV route was the main route in 11 of 12 countries according to this report.
Target level: Despite the clear benefits given by ESAs administration as compared to no ESAs, the optimal level of HB for HDX ptns still uncertain. In most DX ptns on ESAs therapy, we can maintain the HB target between 10-11.5 g/dL. ESAs therapy should be individualized in ptns with improving in quality of life at HB ≥11.5 g/dL and will be prepared to tolerate the risk expected with a higher HB target. HB level should NOT exceed >13 g/dL. The lowest ESA dose required to maintain a target HB level should be provided, and an excessive higher dose in ptns with ESA with limited response should NOT be attempted. A limited evidence may suggest a higher MR can be attributed to the higher ESA dosing.
Clinically wise, it is hardly to keep individual ptn HB levels within narrow ranges. Trial to keep HB level between 10-11.5 g/dL in most ptns, HB levels >11.5 g/dL can be presented transiently in many ptns owing to the variability of agents affecting HB level. Consequently, gradual limiting the dosage of the ESA should be attempted. Such transient upgrade of HB >11.5 g/dL is not likely to be followed by clinical sequelae, despite some (not all) reports have observed a link between higher levels of HB variations and the adverse clinical impacts.
The recommended target of HB is reflecting the current regulatory and fiscal policies, in addition to the findings of clinical trials. The US/FDA boxed warning on ESAs states that, for ptns on DX, one should start ESA therapy if the HB level is <10 g/dL and decrease/interrupt the ESA dosing if the HB level reach or exceeds 11 g/dL. This is greatly consistent with the KDIGO 2012 recommendations.
Among all CKD ptns (i.e., DX & non-DX), several reports have shown that HB value of >13 g/dL is associated with adverse outcome. The best data about HDX ptns are from the NHT: 1233 HDX ptns with cardiac disease, defined as = HF or IHD, and baseline HB value of 9-11 g/dL on an ESA were randomly assigned to reach and keep HB of either 14 or 10 g/dL. The trial was terminated after 29 mo after concerns about safety were admitted by an independent data monitoring committee. The g. with HB 14 g/dL (i.e., normal HB) showed an increased risk of the combined endpoint of death or non-fatal MI. After 29 mo, there were 183 deaths & 19 non-fatal MI in the 14 g/dL g. vs 150 & 14, resp, in the 10 g/dL g. The 1- & 2-y MR were 7 % higher in the 14 g/dL g. than in the 10 g/dL g. Moreover, the thrombotic risks of graft/fistula in the 14 g/dL g. were higher than in the 10 g/dL g. No difference has been early reported between the g.s for all-causes hospitalization or other endpoints e.g., non-fatal MI or stroke incidence. However, according to the study report that was submitted to the FDA, the higher Hct g. had an increasing risk of hospitalization, despite the difference was marginal in its significance. Adding to these data that were limited to HDX ptns, several meta-analyses & systematic reviews have been proceeded, mostly involving non-DX CKD ptns. Despite heterogeneity, mostly suggesting that targeting higher HB values via ESAs therapy does NOT decline MR & augmenting CVS risk and the risk of malignancy. ESAs also cannot improve health-related quality of life among DX ptns if we compared HB level of about 9-10 g/dL to a higher level.
Meta-analysis: 17 RCT reporting alterations in health-related quality of life applying validated tools e.g., the Short Form-36 (13 reports) and the KDQ; (4 reports). The SF-36 reports on 8 domains include physical tolerability, physical roles, body pains, global health, vitality, emotional roles, social functions, and mentality health. The KDQ reported: fatigability, depressive mood, relationship with other subjects, frustration, and physical Sms. HB level was 7.4-12 g/dL in the placebo g. and/or lowered HB target g. and 10.2-13.6 g/dL in the higher HB g.
Whilst some published reports showed statistically significant improvement in one or more of the SF-36 physical functions indices, in the meta-analysis, there was no significant difference between the g.s in any SF-36 or KDQ domains if we compared HB level of 9-12 g/dL with HB level of >11 g/dL.
However, considering the meta-analysis is somehow limited by the higher incidence of bias in many studies and by the clear heterogeneity in the study cohort, design, and achieved HB levels. It is accepted that selected subjects, especially young ptns, active ptns having severe anemia but fewer co-morbidities, may benefit from keeping the HB > 10-12 g/dL as regard the quality of life.
Adverse effects of ESAs: Untoward effects have only been observed if ESAs are provided to normalize the HB level. As mentioned above, these include:
o Higher MR,
o CVS events, &
o Malignancy-related mortality.
o Higher risk of HDX access thrombosis if ESAs are provided to normalize or near-normal HB.
Access thrombosis reported in 39 % in the 14 g/dL g. as compared to 29 % in the 10 g/dL g (NHT trial). HT may be reported if ESAs are used to target lower HB levels. The risk of HT seems to be independent of the target HB level.
A rapidly rising BP may induce HT encephalopathy with seizures, despite it is believed that this is uncommonly seen nowadays. The reported incidence was from 2-17 %, but most available trials that reported seizure were from the earliest 1990s, when ESA dosing and HB goals were higher than that recommended today.
A 2004 meta-analysis: No rise in the incidence of seizures among ptns on ESA as compared to those not managed with ESAs; however, the given studies were of both pre-DX & DX CKD ptns that may have induce underestimating of the incidence among DX ptns. A little evidence of higher incidence of seizures in normotensive ptns on ESA therapy. Also, it is not possible to anticipate which ptn will develop seizure during ESA therapy. Some prodromal Sms e.g., sustained headache or visual alterations obseved early after commencing an ESA may suggest the liability of developing seizures. The finding of some ESA-related SE (e.g., worsened HT or a rapidly rising HB) may alert the possibility of developing seizures.
RBCs Tx can immediately elevate HB level. However, they could be associated with significant sequalae including:
o Immunologic sensitization,
o Iron overload syndrome,
o Volume overloading,
o Tx reaction, and/or
o Tx-transmitted infection (rarely seen),
Tx is rarely provided to chronic DX ptns but may be indicated to manage severe or symptomatic chronic anemia with poor response to ESAs and iron supplements.
Investigational agents: ORAL ESA