Patients receiving a KTx have greatly declined mortalitiesas compared to Patients maintained on dialysis.
Abbreviations (read twice please):
o AAKHI: Advancing American Kidney Health initiative.
o AB: antibody
o Ac Rj: acute rejection
o AKI: acute kidney injury.
o Bic: biocompatible membrane.
o Binc: bioincompatible
o C: Complement
o CKD: chronic kidney disease
o CRRT: Continuous renal replacement therapy
o CST: Canadian Society of Transplantation
o DCGF: death-censored graft failure
o DCGL: death-censored graft loss
o DCGS: death-censored graft survival
o DDKT: Deceased-donor kidney transplant.
o DGF: delayed graft function
o DNOTR: Dutch National Organ Transplant Registry
o DX: dialysis
o eGFR: estimated glomerular filtration rate
o ESKD: end-stage kidney disease.
o H/C: hypercoagulable
o HDX: hemodialysis
o Hpt: hypotension
o Kru: residual kidney function
o Kt/V: urea kinetic modelling.
o KTx: Kidney transplantation
o LDKT: Live-donor kidney transplants
o MDRD: Modification of Diet in Renal Disease
o MR: mortality
o Nc: Nephrectomy
o NKF/KDOQI: National Kidney Foundation/Kidney Disease Outcomes Quality Initiative.
o NS: nephrotic syndrome
o PD: peritoneal dialysis
o Preetx: Preemptive transplantation
o RR: relative risk
o RRT: renal replacement therapy
o Sms: symptoms
o Sns: signs
o TR: transplant recipients
o ttt: treatment.
o Tx: transplantation
o UF: ultrafiltration
o UNOS: United Network for Organ Sharing
o USRDS: United States Renal Data Systems
o W/L: waiting list
o Wt: weight
Ptns receiving a KTx have greatly declined MR as compared to ptns maintained on DX. Preetx that can be defined as an elective Tx before the need for maintenance on chronic DX, may allow the TR to avoid DX entirely. Preetx can improve ptn outcome compared to Tx after commencing DX. However, DX is often needed by ptns whilst awaiting Tx or receiving a Tx that has no immediate function. This article will discuss the proper timing of KTx and the suggested optimal DX modality to be prescribed for ptns requiring DX either prior to or after Tx.
TIMING OF TRANSPLANT
Preemptive transplantation (Preetx):
Preetx can be defined as elective Tx before the start of chronic DX. A better ptns & graft survival associating Preetx may be attributed to the lowered rates of DGF and biopsy-proven Ac Rj for both DDKT & LDKT. Moreover, a relative lowered clearance given by DX, as compared to a Tx graft, may induce accumulated materials related to:
1) Malnutrition states,
2) Atherosclerotic alterations &
3) Chronic inflammatory states.
Generally, ptns commencing Preetx are also probably have a more education level, with a higher socioeconomic standard, and usually evaluated by a nephrologist earlier in their course of the CKD, all of these factors have been contributing to a better survival after Tx. This has been further emphasized by the new payment systems in the US rewarding or penalizing the clinician performance in Preetx in the AAKHI.
Indications for Preetx: The Preetx has been advised for most ptns with ESKD who are eligible candidate(s) for Tx. Preetx is the best therapeutic option for ESRD ptns as it provides improved graft & ptns outcomes if compared to Tx after a transitory period of DX treatment:
o Study: about 40,000 primary renal TR, those undergoing Preetx had 25 & 27 % decline in the RR for graft loss for DDKT & LDKT, resp. Corresponding risk (s) of ptns MR were declined by 16 & 31 %.
o Analysis: of 7948 ptns chosen from the DNOTR, the 10-y survival was higher among ptns commencing a Preetx LDKT as compared to ptns receiving DDKT after an average time of 3 ys on DX (73 vs 45 %, resp). Comparing TR on W/L on DX, ptns longevity benefits with Preetx was = 7.5-9.9 ys for 40-y-old ptns & 4.3-6 ys for 70-y-old ptns. The magnitude of timing spent on DX before Tx is directly related to a higher MR that may suggest a dose-dependent impact of DX.
Despite the proven benefits, almost only 20 % of LDKT & 5 % of DDKT are proceeded as Preetx in the US. This can be attributed to the rapid rise in the potentially arranged Tx candidates with no a corresponding rise in the donors’ offers. So, the current waiting timing for a DDKT has dramatic rise over the elapsed 15 ys.
Exceptions to Preetx:
1) Severe NS ptns may benefit from DX before Tx with expected Kru, and thus nephrosis, will be significantly declined. As severely nephrotic ptns are H/C. H/C ptns preceding to Tx are more prone to thrombosis in the Tx kidney if they perform Preetx. In contrary, DX tends to limit the thrombotic tendency related to NS. The optimal module to limit severe nephrosis prior to KTx (e.g., Nc, embolization, or medical Nc) still uncertain.
2) TR receiving their 2nd Tx after the 1st Tx has been failed within one y., may also gain benefits from a short timing of DX before commencing the 2nd Tx.
GFR threshold for Tx:
Despite that the general concept that Tx is better to be mostly performed in ptns before the requirement of DX, the exact level of renal function (i.e. eGFR) at which we perform Tx is not certain. Expert clinicians have a general consensus that Tx should not be performed before eGFR reaches <20 mL/min/1.73 m2 with existing evidence of a progressive/irreversible decline in renal function along the last 6-12 mo. In the US, UNOS rules emphasize that the eGFR should be 20 mL/min/1.73 m2 or less before Preetx that is in agreement with the general guidelines of the CST. The eGFR is generally calculated via the MDRD equation.
Proceeding to a KTx at a higher eGFR has no justification, even in case of an irreversible kidney disorder. As ptns usually have little Sns/Sms of ESKD requiring DX at this level of renal dysfunction, and there is no more gains with performing a Tx prior to its indication. This is best evident via analysing 19,461 1st -time, Preetx observed by the UNOS between 1995 & 2009. Analyzing this large report showed no detected difference in ptn survival or DCGS among TR performed Tx at eGFRs <10, at 10-15, at 15-20, & >20 mL/min/1.73 m2, resp. Once the eGFR declined < 20 mL/min/1.73 m2, deciding to proceed to an elective Preetx should be primarily relying upon individual ptn (& donor) preference. In the contrary to deciding to initiate chronic DX, the Tx should not be postponed until emergent uremic Sms ensue.
Referring TR for assessment by a Tx team should undergone before this level of eGFR has been reached. Ptn referral for Tx evaluation with progressing CKD should be at eGFR of <30 mL/min/1.73 m2. Assessment of a Tx candidate and the recognition & evaluation of a potential donor is usually time consuming. This earlier referring threshold may allow proper candidate to be W/L at the timing the eGFR drop to 20 mL/min/1.73 m2 allowing more chance to the candidate avoiding DX before Tx. This attitude is agreed with the NKF/KDOQI recommendations that advise ptn referral for Tx assessment at an eGFR <30 mL/min. However, referring ptns at this level of renal function is usually not performed for many reasons, as many clinicians do not consider the benefits provided by Preetx, and the ptns are usually denying and reluctant to consider any option of RRT until it is currently mandated. Moreover, there’s a defect in direct accesses to pre-Tx assessment in many areas.
Ptns already on DX: Ptns already commencing DX and are suitable candidates for Tx should be prepared for Tx as early as possible. As the adverse drawbacks of DX treatment on post-Tx survival are currently duration dependent. As mentioned before, Tx is associated with better survival than DX mostly among all ptns. With only 19 % of the US' DX ptns in 2019 ordered on a Tx W/L, more options still existing.
Analyses of the USRDS data bases have reported that pre-Tx DX duration of 6 mo or more declines allograft survival. One study: DX duration for 36 mo conferred a 68 % elevation in DCGL. Another analysis: the 10-y adjusted graft longevity for both DDKT & LDKT was higher for TR commencing Preetx as compared to those maintained on DX for 2 ys before Tx (69 & 75 for Preetx vs 39 & 49 % for DX followed by Tx, resp). The observed risk of mortality with a functioning allograft and all-cause MR is also greater among ptns who were dialyzing > 6 mo prior to Tx. The duration of DX before Tx may also trigger the risk of cancer. One study: ptns on DX for > 4.5 ys prior to Tx had a 60 % higher risk of cancer as compared to ptns on DX for < 1.5 ys.
DX MODALITY BEFORE TX
In spite the current risks, many ptns may require DX before Tx. The current DX modalities may include HDX, either in a DX center or home DX, or PD. There are no precise, objective data to suggest a decision in regard to the choosing DX modality before Tx. Practice attitudes are usually center related, and the option of therapy is recognized on an individual basis considering ptn preference and co-morbid disorders. Choosing a DX modality generally rely upon factors not related to Tx; these may include center facilities and convenience, co-morbid disorders, socioeconomic standard and other DX-center related conditions. Several reports comparing the pre-Tx DX modality on post-Tx outcome have observed NO clear benefit of one modality over others on total allograft or ptn longevity. One study: about 23,000 primary renal TR showed 15 % higher risk of DCGF among PD-treated ptns than those ptns maintained on HDX before Tx, with the risk mostly limited to the earlier Tx period. If the analysis was confined to the 1st 3 mo after Tx, the RR for allograft loss related to PD was 33 % greater than that for HDX. However, this finding was not confirmed by other recent reports. The etiology of greater allograft loss associating pre-Tx PD, is not clear. However, limited data suggesting allograft thrombosis rates may be greater among ptns on PD before Tx. The mechanism by which PD induces graft thrombosis still uncertain.
IMMEDIATE DX BEFORE TX: Routinely performed (i.e., scheduled) DX should be prohibited in the last 24 hs before Tx. This recommendation is differing from that provided for ptns commencing non-Tx surgery, for whom DX is usually advised in the last 24 hs before surgery. Avoiding DX within 24 hs before Tx is advised as it may trigger the risk of DGF. The robust likelihood of renal function recovery after Tx made minute risks associating DX less accepted. The impact of elective DX on the short-term post-Tx outcome still uncertain. One study: observed that DX within 24 hs prior to Tx may trigger the risk of DGF, particularly if a Binc diayzer was utilized and UF was undergone. However, trial: random assignment of 110 ptns receiving HDX (one 3-h. session with no UF) or no immediate HDX before Tx, NO differences in DGF or eGFR rates 5 d.s after Tx. Thus, avoiding the UF for 16-24 hs prior to Tx may help reducing the DGF risk.
Added to the potential risk of DGF, DX may induce electrolyte/fluid alterations that need several hours to be balanced, and may theoretically contributing to a sudden death. Despite the lack of enough studies in the perioperative Tx timing, a retrospective study: 80 chronic DX ptns with reported sudden death, a 1.7 RR was seen in the 12-h period starting with the beginning of the DX ttt. Among non-Tx ESKD ptns, this risk and other associated risks with DX can be justified by the well-known proven benefit (s) given by DX to ptns with lack kidney function. In contrary, most ptns proceeding to Tx will develop a rapid recovery of renal function in the immediate post-operative period.
However, despite the predicted renal recovery, DX may be required in some Tx ptns to control metabolic alterations difficult to be managed by conservative means or considered unacceptable risk for the ptns to be anaesthetized. Hyper-k+ is the most considerable reason for DX immediately before Tx. Mild hyper-k+ is commonly observed among CKD ptns with expected exacerbation intraoperatively. Hyper-k+ resulting from Tx surgery is mostly mild and can be controlled conservatively. TR having k+ > 5.4 mEq/L are generally dialyzed, with variable policies between Tx centers. The optimal threshold s. k+ considered safely to proceed with surgery with no prior DX has not been properly assessed among Tx ptns, and there are no available data recommended that s k+ should be normalized prior to surgery. Volume overloaded TR can be also indicated to commence DX.
If DX is indicated, UF (i.e., removing fluids) should be discouraged in most Tx centers as there is evidence that fluid shifting can be complicated by DGF, probably related to the risk of resultant intravascular depleted volume with/without Hpt that may elucidate the findings of some observational reports showing lower DGF in PD ptns as compared to HDX ptns. Some ptns, however, may need DX to control their volume overload. For those ptns, we may use a relatively lower rate of UF (e.g., 5-10 mL/kg/h) allowing adequate plasma refill before surgery and avoiding intravascular depleted volume & Hpt during DX treatment. Prevention of intravascular Hpt is particularly crucial as ptns proceeding to Tx usually receiving intraoperative AB medications that are usually inducing Hpt that may be deteriorated in a TR performing recent, large UF amount.
The duration of the DX session should be adjusted and individualized according to the preoperative target of the ttt. Generally, hyper-k+ can be managed safely within 2 hs of DX with no need to provide a lower-k+ bath. Ptns requiring UF may need prolonged ttt (3-4 hs) for safe fluid removal and with no expected Hpt. Unlike non-Tx ptns cohort, Kt/V, should NOT be utilized to manage ttt, as there is an expected kidney function recovery and there is no available data that correlate the Kt/V with Tx outcome. Dialysate constituents is usually similar to that for non-Tx ptns. However, Ca+, Mg+, Na+, & glucose efflux should be limited during the ttt, and the choice of k+ & HCO3 baths should be optimized to limit the evolution of hypo-k+ & metabolic alkalosis. Dialysate C0 should be also adjusted for every ptn. A preferable level of 3 mEq/L Ca+, 1 mEq/L Mg+, 140 mEq/L constant Na+, & 100 mg/dL glucose dialysate bath. We adjust the dialysate C0 to typically be 0-1 degrees Celsius below the ptn's body C0.
The out-ptn DX ttt mostly running with systemic anticoagulation using heparin infusion. So, it is preferable not using heparin among the TR proceeding to Tx within 24 hs of DX. The normal ½-life of the commonly used 10-50 IU/kg bolus heparin dosing within HDX is almost 30-90 min. that is prolonged in an ESKD ptn than a non-ESKD ptn and may vary according to other settings of the DX ttt. The current utilization of intraperitoneal heparin sometimes used for fibrin management in PD does not induce systemic anticoagulation.
A Bic membrane should be utilized for all TR who’re undergoing DX before Tx. C -activating or Binc membrane dialyzers (e.g., cuprophane dialyzer) have been complicated with DGF. Study: 44 graft TR were dialyzed within a 24-h interval before Tx, the recovery of renal function was greater among ptns dialyzed with the Bic membrane compared with a Binc one.
IMMEDIATE DX AFTER TX
Almost 20 % of ptns may need temporary DX after Tx. The requirement for DX in the 1st post-operative week after Tx is currently named DGF, whatever the cause of renal dysfunction. DGF has been independently complicated with about 2-3 fold rises in:
2) TR mortality, &
3) Allograft failure.
The DGF risk can be evaluated via a nomogram in several studies. The prescribed indications for acute DX among TR in the immediate Tx period are similar to that in non-Tx ptns developing AKI.
However, the optimal DX modality required postoperatively is not certain. Most clinician, use HDX after Tx, considering the disruption of peritoneal membrane during Tx surgery, with possible leaking of glucose-rich peritoneal dialysate with higher rates of infection. Some clinicians usually remove the PD catheter at the timing of Tx surgery avoiding about 5 % or higher risk of peritonitis even in ptns not performing DX. However, PD has been utilized successfully in some ptns with DGF. Generally, there’s no current indication for CRRT. The DX prescription is generally similar to that in non-Tx ptns. Greater amounts of UF should be discouraged in order to prevent the likelihood of ischemic injury to the graft. We are usually targeting a Wt (= volume indicator) within 1-2 kg of the ptn's known dry Wt with fluid removing not exceeding 10 mL/kg/h.
Post-Tx PD CATHETER REMOVAL:
Optimal timing of PD catheter removal after KTx still uncertain. Unless indicated for any reason and in spite the higher risk of peritonitis, some physicians may wait 3-4 mo after surgery, as considerable number of ptns may require either transient/permanent DX after Tx. However, many ptns at higher risk for peritonitis may get beneficial effects from early catheter removal. Retrospective study: 232 PD ptns found significant higher incidence of peritonitis observed with the following criteria:
o Urine leak
o Male sex
o > 2 rejection attacks
o Surgical technical issues
o Permanently non-functioning graft.
o Staphylococcus aureus-related peritonitis
o Higher episodes of peritonitis before surgery (median 3).
PD catheter is currently removed within one mo after Tx, unless there is a highly suspicious indication for the need for DX. Catheter removal in certain centers may be at the timing of or within the 1st post-surgical week.