Anemia can be defined as HB <12 g/dL in females & <13 g/dL in males, is commonly observed before and after KTx.
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Anemia can be defined as HB <12 g/dL in females & <13 g/dL in males, is commonly observed before and after KTx. It’s mostly related to iron deficiency, graft Rj or dysfunction, EPO deficiency, viral infection, im/m, and infection Prox agents. We will discuss the epidemiology, pathogenesis, evaluation, and ttt of anemia in KTR. TR mostly have an average eGFR <60 mL/min/1.73 m2, a level that’s consistent with the current definition of CKD.
The prevalence of anemia after KTx varies according to the given definition of anemia, the post-Tx timing, im/m protocol, and frequency of ttt. While anemia is found in almost 90 % of ptns within the 1st mo post-Tx, this prevalence declines to % among ptns > one y. post-Tx. At the timing of Tx, most adult ptns can be termed anemic as target levels for HB among US DX ptns are mostly g/dL. Mean HB levels rise to > 11 g/dL by 3 mo post-Tx and to > 12 g/dL at mo post-Tx. The evolution of acute/chronic graft dysfunction is mostly associated with worsened anemia, e.g.:
PATHOGENESIS & RISK FACTORS
Pathogenesis of anemia after Tx varies by the timing after Tx. Common risk factors linked to anemia development may include female sex, age, graft dysfunction, ACEi/ARBs use, and im/m agents. Administration of ESA or iron therapy may be paradoxically associated with anemia owing to ttt via indication bias.
Early post-Tx: Immediate anemia after Tx is almost entirely due to lower-than-normal HB targets in the CKD & ESKD cohorts, surgical blood losses, and frequent phlebotomies. Dilutional anemia also occurs due to aggressive peri-operative volume expansion. Recovery to normal adult HB can be impeded by graft dysfunction and other comorbidities, higher donor age, and iron deficiency.
Later (>3 mo) post-Tx
The PLS is a very rare syndrome for hemolytic anemia in SOT recipients that observed with ABO-compatible or Rh-compatible, but non-identical, donor and TR mismatching. PLS is most commonly reported after Tx of an organ from a donor with ABO-O blood type into a TR with ABO-A or -B blood type or from an Rh--ve donor into an Rh-+ve TR. The donor graft containing B cells & plasma cells (so-called passenger leukocytes) producing anti-isoagglutinin or anti-Rh AB leading to the syndrome development. PLS typically presented as a mild hemolytic anemia with an acute onset within the 1st few wks after Tx. Dgx can be made by the direct antiglobulin (Coombs) test. However, ttt is commonly supportive, despite Pph & cytolytic agents can be used. Clinical behavior is typically self-limiting, despite AB may be persisting at detectable values for d.s after Tx.
SCREENING: KTR should be currently screened for anemia after Tx via regular CBC. Most Tx centers obtain a CBC at least weekly for the 1st 3 mo and then every weeks for a year and then monthly to every 3 monthly after that. Most TR are anemic at the timing of Tx and within the early post-Tx period, but HB levels are expected to gradually elevated along the 1st 3 mo post-Tx if the ptn has a well-functioned graft. So, the suggested approach to anemic ptns on routine screening:
KTR having persistent (i.e., HB fail to be normalized at 3 mo post-Tx) or NOA should proceed to diagnostic evaluation to recognize the etiology of anemia. This assessment should evaluate the cause(s) of anemia shared with non-Tx ptns, and other specific causes confined to KTR, via evaluating:
Routine evaluation of all anemic TR for infection with parvovirus B19 or other viruses is not performed. However, if the initial diagnostic assessment may not show a clear etiology for anemia, testing for parvovirus B19 can be proceeded via NAAT. Distinct evaluation of iron stores in KTR could be challenging. As lowered ferritin & TSAT means true deficiency, inflammation may suppress TSAT & elevate ferritin, masking the diagnostic value of these tests. Moreover, as no trials defining specified ferritin & TSAT levels for TR, criteria from the 2012 KDIGO Guideline for Anemia in CKD can be applied to determine iron deficiency. The concomitant finding of leukopenia, thrombocytopenia, and/or acute graft dysfunction are suggesting the following potential etiology for anemia:
On contrary, parvovirus B19 infection or anti-EPO AB, expected with
1) Lone anemia, (no leukopenia or thrombocytopenia)
2) Lowered RETIC &
3) No nutritional deficits.
General concepts: The general lines of anemia therapy in ptns with CKD or ESKD can be also applied to the ttt of anemia in KTR. These include ttt of the underlying cause(s) (if identified), ttt of iron deficiency, and the administration of ESA to decrease the need for RBCs transfusion. As applied in non-Tx ptns with CKD or ESKD, options of individual therapy relied mainly upon the severity of anemia and the finding of iron deficiency. Anemic ptns with iron deficits should be ttt with iron before commencing ESAs therapy.
Special considerations in ttt of anemia in KTR may include:
Approach based on timing from Tx: suggested approach to the ttt anemia in KTR varies mainly with the timing from Tx and the defined etiology of anemia.
Ptns on waiting list: Anemia in ptns on waiting list should be ttt with the same approach applied in treat anemia in the CKD or ESKD cohort. Using RBC transfusion should be prohibited, if possible, to limit the risk of immunological Snz, that any delay or limit the option of future KTx. This’s consistent with the 2012 KDIGO guidelines for anemia ttt in ptns candidate for SOT.
Ptns perioperative/early post-Tx: Suggested approach is as follows:
o Perioperative targeted HB of >10 g/dL that seems safe & limiting CVS events in the early post-Tx timing. The pre-Tx use of ESAs & iron in DX and pre-DX ptns should maintain HB between g/dL, hence limiting peri-Tx RBC requirements. We limit RBC Tx to ptns with HB <7 g/dL or <8 g/dL in those with preexisting CVD that’s consistent with the 2016 CPGAABB.
o With HB <10 g/dL and iron deficiency (i.e., TSAT ≤20 % and S. ferritin ≤200 ng/mL) at the timing of Tx, we provide 1 g of IV iron (typically iron sucrose) with anticipated iron loss with phlebotomy during the early post-Tx timing. This’s based on a clinical experience and not based on high-quality evidence.
o TR with previous ESA therapy, we often hold ESA at the timing of Tx as hypo-responsiveness to ESAs in the early post-Tx period, thrombotic & CVS risks of these agents, and the expected effect of endogenous EPO will ensue post-Tx. We do not provide ESAs to ptns with DGF, as using ESA agents in this population is debated and response to ESAs may be currently poor.
ESA agents immediately after-Tx may shorten the timing to correct HB but has not been proved to improve the clinical outcome. In RCT:104 ptns examining the effect of high-dosing EPO B before Tx and during the 1st 2 weeks after Tx, there was no difference in the rate of DGF between TR receiving and not receiving EPO. Also, a retrospective study: no difference in 3-mo HB values or DGF between TR receiving and not receiving EPO during the 1st 6 mo post-Tx.
2 studies: assessed the impact of high-dose EPO on DGF. One study: 72 ptns were assigned to get an intra-arterial EPO (40,000 units) or placebo at the timing of reperfusion of the graft. No difference seen between g.s in the need for DX within the 1st week or in the % of “slow graft function” (= ≤40 % decline in SCr by the 3rd day postoperatively). The 2nd trial: assigned 92 TR to IV EPO (33,000 units)/d./3 doses, starting hs before Tx. EPO ttt had NO impact on the rate/duration of DGF but did augment the risk of thrombotic events at one mo. to one y.
Ptns later (>3 mo) post-Tx: Anemia in immediately post-Tx typically improved within mo with endogenous EPO production from the graft. However, several factors, including im/m medications, others (e.g., ACEi/ARBs), graft dysfunction, and infection, may be contributing to persisting or NOA after the early post-Tx timing. Such potentially correctable factors should be recognized and ttt properly before starting ESA therapy. Moreover, the inlet to ttt of anemia in TR >3 mo post-Tx relied primarily upon the functional status of the renal allograft.
Ptns with stable allograft function: with stable allograft function (eGFR ≥45 mL/min/1.73 m2), suggested approach may include:
Optimum target HB level for TR with stable allograft function is not certain. Studies in KTR have suggested that MR may be triggered with HB >12.5 g/dL. However, one study has showed that allograft survival could be better among ptns with high HB level. The 2-y, open-label trial CAPRIT: 125 KTR with eCrCl <50 mL/min/1.73 m2 assigned ptns to get EPO targeting g/dL (full correction g.) or g/dL (partially corrected). Compared with the partially corrected g., complete correction g. had a little decline in eCrCl (5.9 vs 2.4 mL/min/1.73 m2), lowered rate of ESKD (21 vs 4.8 %), & higher DCGS (80 vs 95 %). This trial is limited by shortened duration, open-label design, and smaller size.
These findings are highly different from that reported by the much larger CHOIR & TREAT trials that randomly assigned non-Tx CKD ptns. The CHOIR & TREAT trials found a higher risk of CVS events and non-delay in progressive renal failure via normalizing HB by ESA agents. The CREATE trial applied anemia management like CAPRIT and showed that randomization to a higher HB level induced significant rise in chronic DX. It’s difficult to conclude the mechanism by which higher HB and/or more ESA may protect TR but not native one. Much larger trials comparing ESA with placebo are currently required to determine the risk/benefit ratio of anemia control among TR. Providing darbepoetin alfa is also often efficacious in KTR. Retrosp., 12-wk study: 36 ptns, 81 % achieving target HB of >12 g/dL (average 4.4 wks). A longer duration of ttt was needed with established anemia and/or exposing to concurrent ACEi agents.
Ptns with a failed allograft: TR in stage 4/5 CKD usually became anemic, and ESA agents may be urgently provided to ameliorate Sms and limit the risk of BTx. Control of anemia in this population is simulating that in CKD/ESKD cohort, except that higher dosing of ESAs usually required to overcome the impact of chronic inflammation. Ptns with stable allograft function, any potential reversible cause should be addressed (e.g., nutritional deficits, iron deficiency, im/m, etc.). We start ESA therapy if HB between g/dL and the iron stores seems adequate. We also evaluate the risks related to ESA agents that’re usually greater in ptn with CVD, previous thrombotic events, stroke, or prior cancer. With higher risks of ESA agents, we may avoid ESAs until the extent of anemia is more intense (i.e., HB <9 g/dL). KTR returning to DX have lowered HB levels if compared with non-Tx CKD ptns (HB of 8.9 vs 10.2 g/dL, resp.) that correlated with higher hospitalization and increased MR. Using ESAs may decrease the frequency/intensity of anemia in ptns with failed Tx but have not been reported to decrease MR. Ptns returned to DX with ESAs resistance may benefit from graft nephrectomy.
Special populations: Ptns with parvovirus B19 infection: Anemia can be corrected by IVIG + decreasing im/m burden to enhance viral clearance.
PROGNOSIS: debated findings have been reported regarding the prognosis of KTR with anemia. For better definition of this relation, the correlation between anemia (= <12 g/dL in females % <13 g/dL in males) and ptn allograft outcome was assessed in a prospective study: 938 KTR, at 4 ys, multivariate analysis showed that anemia was complicated with higher risk of MR & allograft failure. Similar findings were seen if anemia was defined = <11 g/dL. However, analyzing 825 KTR over 8.2 ys showed no relationship of anemia to MR.
In the ALERT study: 2102 KTR, 29 % of females & 30 % of males were anemic, HB were not complicated with any effect on CVS morbidity & MR or all-cause death after advanced adjustment for clinical & demographic factors. HB value, however, were passively associated with allograft loss. LVH, a crucial risk factor for CVS MR among CKD ptns, may be partially showing an impact of un-ttt anemia. As CVD is the leading cause of death in diabetic KTR, the adverse impacts of anemia may be clearer in diabetic KTR in the US, if compared with other countries, as the US Tx population has a relative increase in CVS risk, with a higher % in diabetics. Unfortunately, the current trials have not proved that robust ttt of anemia regresses /retards LVH progression, and any benefit of ESA use may be outweighed by their associated risks.