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PREEMPIVE TRANSPLANT

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PREEMPTIVE TRANSPLANT

 

 

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   Bc: biocompatible

o   CKD: chronic kidney disease

o   CKD: chronic kidney disease

o   CST: Canadian Society of Transplantation.

o   DCGF: death-censored graft failure

o   DDK: deceased-donor kidney

o   DGF: delayed graft function

o   DNOTR: Dutch National Organ Transplant Registry

o   DW: dry weight

o   DX: dialysis

o   eGFR: estimated glomerular filtration rate

o   ESKD: end-stage kidney disease

o   HDX: Hemodialysis.

o   Hptn: hypotension

o   KTx: kidney transplant

o   LDK: living-donor kidney

o   MDRD: Modification of Diet in Renal Disease equation. 

o   MR: mortality rate

o   Nc: nephrectomy

o   NKF/KDOQI: National Kidney Foundation/Kidney Disease Outcomes Quality Initiative guidelines

o   NS: nephrotic syndrome

o   Preetx: Preemptive transplantation

o   RRT: renal replacement therapy

o   Sms: symptoms

o   Sns: signs

o   TR: transplant recipients

o   Tx: transplantation

o   UF: ultrafiltration

o   UNOS: United States, United Network for Organ Sharing

o   USRDS: United States Renal Data Systems

o   W/L: waiting-list

 

Ptns receiving a KTx have marked decline in MR as compared to ptns maintained on DX.  Preetx, defined as elective Tx prior to the need for chronic DX, allows the TR to avoid DX entirely. Preetx can improve ptn survival as compared to Tx after commencing DX. However, DX is usually required by ptns awaiting Tx or receiving Tx that does not start immediate function.  

 

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TIMINE OF TX: Preetx can be defined as elective Tx prior to commencing chronic DX. The improved ptn & graft survival observed with Preetx may be attributed to lowered rates of DGF as well as biopsy-proven Ac Rj for both DDK & LDK-Tx. Furthermore, a relatively diminished clearance given by DX, as compared to a Tx kidney, leading to accumulated harmful substances associated with atherosclerotic lesions, malnutrition, and chronic inflammatory states. Generally, ptns undergoing Preetx seem to have more educated level, with high socioeconomic standard, and be early referred to their nephrologist along all stages of CKD, each factor have been participating in a better longevity post-Tx. This effect has been further highlighted by the new payment model (US) rewarding/penalizing the clinician performance in Preetx via the AAKHI.

Indications for PreetxPreetx is mostly indicated in ptns with ESKD with suitable candidate for Tx. Preetx is generally preferred as it leads to improved allograft & ptn survival if compared to Tx after commencing DX therapy:

o   Study: about 40,000 primary kidney TR, with Preetx > 25 & 27 % reduced relative risk for allograft failure for LDK & DDK Tx, resp. Risk for ptn MR were also declined by 16 & 31 %.

o   Analysis: 7948 ptns identified via the DNOTR, the 10-y survival was higher among ptns performing LDK Preetx as compared to ptns performed DDK-Tx after 3 ys DX (73 vs 45 %, resp). Comparing to ptns on W/L on DX, ptn survival with Preetx was almost 7.5-9.9 ys for 40-y-old ptns & 4.3-6 ys for 70-y-old ptns.

 

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The magnitude of timing the ptn spends on DX before Tx is directly related to the higher MR that suggests a dose-dependent impact of DX. Improving allograft and ptn longevity observed with Preetx can be attributed to the declined rates of DGF & biopsy-confirmed Ac Rj for both DDK & LDK-Tx. Moreover, the relative lowered clearance given by DX, as compared to Tx kidney, may induce an accumulation of several mediators associating atherosclerosis, malnourishment, & chronic inflammatory states. Despite these clear benefits, only 20 % of LDK & 5 % of DDK Tx are proceeded with Preetx in the US. This is mainly can be attributed to the rapid rise in the potential Tx candidates with no associated availability in the donor pool. Consequently, the W/L and waiting timing for a DDK has dramatically expanding along the last 15 ys.

 

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Exceptions to Preetx: Ptns with severe NS may get benefits from DX before Tx with the current residual kidney function, so, nephrosis, will be greatly improved. Ptns with severe NS are hypercoagulable, if they proceed to Tx, they are more likely prone to thrombose the Tx graft if they commence Preetx. On the other hand, DX tends to limit the thrombotic tendency associating NS. Optimal modality to limit severe nephrosis before KTx (e.g., Nc, embolization, or medical Nc) still unclear. Ptns receiving their 2nd Tx after the 1st Tx kidney has failed within one y may also get benefit from a short interval of DX before the 2nd Tx.  

GFR threshold for Tx: As Tx should be mostly performed before the need for DX, the exact level of renal function (i.e., GFR) at which we may proceed to Tx still uncertain. Expert physicians generally agreed that Tx should NOT be performed until the eGFR lowered to <20 mL/min/1.73 m2 and with an evidence of a progressing and irreversible decline in renal function along the previous 6-12 mo. The UNOS rules inform that the eGFR needs to be 20 mL/min/1.73 m2 or less before commencing a Preetx. This is also in agreement with the guidelines of the CST. The eGFR can be calculated via the MDRD formula.  

Commencing a Tx with a high eGFR cannot be justified, even with the presence of an irreversible renal lesions. As ptns are generally showing few Sns & Sms of ESKD requiring DX at this level of renal profile, moreover, there is No benefit can be expected by proceeding to a Tx before it is indicated. Analysis: 19,461 1st time, Preetx ptns reported to the UNOS between 1995 & 2009  No difference can be determined in ptn survival or DCG survival among ptns Tx at eGFRs <10, from 10-15, between 15-20, & >20 mL/min/1.73 m2, resp. Once the eGFR is < 20 mL/min/1.73 m2, deciding to proceed to an elective preetx should depend primarily on individual ptn (& donor) preference. Unlike the decision to start chronic DX, the Tx should not be delayed until the emergence of uremic Sms.  

Referral for assessment by a Tx team should be initiated before this level of eGFR. Ptn may be referred for Tx assessment with a diagnosis of a progressing CKD & an eGFR < 30 mL/min/1.73 m2. The assessment of a TR candidate and the recognition and identification of potential donor are time consuming. Hence, the early referral threshold may allow the proper candidate to be waitlisted at the timing with eGFR dropped to 20 mL/min/1.73 m2 and enhancing the chance that the TR can avoid DX before Tx. Of note, this approach is in consistency with the NKF/KDOQI guidelines that recommending ptn referral for Tx assessment at an eGFR <30 mL/min.

 

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 However, referring TR at this level of renal function is usually not proceeded for many reasons:

1)    Many physicians are not recognizing the benefits provided by Preetx,

2)    Ptns still reluctant in considering RRT option until he’s currently obligated.

3)    Absence of streamlined access to pre-Tx assessment in several zones.

Ptns already on DX: ptns who’re maintained on DX and are suitable for Tx should be proceeded for Tx as early as possible. As the adverse impacts of DX on post- Tx outcome are greatly duration dependent. As mentioned before, Tx is associated with better outcome than DX for almost many ptns. Only 19 % of the US' ptns maintained on DX ptns in 2019 on a Tx W/L.  

The USRDS data bases have declared that pre-Tx DX duration of 6 mo or more can passively decline allograft survival. One study: DX duration for 36 mo conferred a 68 % rise in DCGF. Another analysis: the 10-y adjusted allograft survival for both DDK & LDK-Tx was higher for Preetx ptns as compared to ptns still on DX for 2 ys before Tx (69 & 75 for Preetx vs 39 & 49 % for DX followed by Tx, resp.). MR risk with a functioning graft & all-cause MR is also higher among ptns dialyzed for > 6 mo before Tx. Duration of DX before Tx may also trigger the risk of malignancy. Registry study: ptns on DX for > 4.5 ys before Tx had a 60 % higher risk of malignancy as compared to ptns on DX for < 1.5 ys.

DX modality before TX: Despite the impending risks, many ptns need DX before commencing Tx. The current DX modalities may include HDX, either in a DX center or at home DX, or PD. There are no robust, objective data permitting a decision in regard to the choice of DX modality before Tx. Practiced pattern is highly center-related, and the choice the modality should be individualized, with considering ptn preferences and medical facilities. Choosing a modality generally depending on factors that’re not related to Tx including current facilities and convenience, co-morbid disorders, socioeconomic status & DX-center facilities, , etc...  

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Most reports comparing pre-Tx DX modalities with post-Tx outcome have declared no obvious benefit of certain modality on allograft or ptn longevity. One study: almost 23,000 primary kidney TR showed 15 % higher risk of DCGF among PD-treated ptns in relation to others treated with HDX before Tx, with the risk is mostly restricted to the early Tx timing. If the analysis was confined to the 1st 3 mo after Tx, the relative risk for graft loss with PD was 33 % greater than that of HDX. However, these results have not been confirmed by more recent reports. Causes of excessive graft loss with pre-Tx PD, if present, is not certain. Limited data may suggest: impending allograft thrombosis may be increased among ptns on PD prior to Tx, mechanism of PD predisposition to allograft thrombosis is not certain.

 

 

DX IMMEDIATELY BEFORE TX:

Routine (i.e., scheduled) DX should be held 24 hs before Tx, which is different from ptns proceeding to a non-Tx surgery, where DX is generally advised in the 24 h.s before surgery. DX is not recommended within 24 h before Tx as it may trigger the risk of DGF. The robust likelihood of post-Tx allograft recovery makes even very small risks associating DX less accepted. The impact of elective DX on short-term post-Tx outcome still uncertain. One study: DX within 24 h.s of Tx trigger the risk of DGF, particularly if a bioincompatible dialyzer was utilized and UF was included. However, trial: 110 ptns receiving HDX (one 3-h session with no UF) or no HDX immediately before Tx, No difference could be detected in DGF or eGFR 5 d.s after Tx. So, avoiding UF 16-24 hs before Tx may limit the risk of DGF incidence.

Added to the possible risk of DGF, DX may induce electrolyte/fluid imbalance that is requiring several h.s to be optimized, and could theoretically contributing to sudden death. Retrospective report: 80 chronic DX ptns with documented sudden death, a 1.7 relative risk was reported in the 12-h period starting with commencing the DX therapy. For non-Tx ESKD ptns, this risk may be justified by the documented benefits expected with DX therapy to ptns with no kidney function. In contrary, TR proceeding to Tx mostly restoring immediate renal function.

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However, despite the expected recovery of renal function, DX may be commenced in some TR to correct metabolic alterations that is difficult to manage by conservative therapy or have unaccepted anesthetic risk. Hyper-K+ is the most common indication for DX immediately prior to Tx. Mild hyper-K+ at baseline is commonly seen with CKD ptns that could be deteriorated during intraoperative period. Hyper-K+ related to Tx surgery is mostly mild and amenable to be corrected conservatively. We can dialyze TR with a K+ >5.4 mEq/L, with variable polices among centers. The exact threshold of s. K+ at which proceeding to surgery is not safe without prior DX has not been determined among Tx ptns, with no available data advice preoperative normalization of s. K+. Volume overloaded ptns is a further indication to commence DX.  

Whenever DX is indicated, UF (i.e., removing fluid) should be prohibited in most Tx ptns as there is evidence that fluid shifting can be complicated by DGF, possibly owing to the increased risk of intravascular volume depletion with or without Hptn. Moreover, observational data: showed lowered incidence of DGF in PD ptns comparing to HDX ptns. Some ptns, however, may need DX to correct volume overloading. For these ptns, performing DX with low rate of UF (e.g., 5-10 mL/kg/ h), allowing adequate plasma refilling prior to surgery and avoiding depleted intravascular volume and Hptn during DX. To avoid intravascular Hptn is particularly crucial as ptns proceeding to Tx usually receiving intraoperative AB medications that are usually associated with Hptn that can be deteriorated with recent, large UF.

 

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The duration of the DX sessions should be adjusted for every ptn according to the preoperative target of therapy. For hyper-K+, it can be managed safely within 2 hs of DX with no need for a lowered-K+ bath. Ptns requiring UF may need longer session (3-4 hs) to be deloaded safely with limited risk of Hptn. Unlike non-Tx ptns, urea kinetic modelling (i.e., Kt/V) should NOT be utilized to manage therapy, as there’s anticipated renal function recovery and no available data to correlate Kt/V with the Tx outcome. The dialysate constituents is the usually similar to non-Tx ptns. However, Ca+, Mg+, Na+, and glucose fluxing should be limited during therapy, and choosing K+ & HCO3 baths should be managed carefully to avoid the evolution of hypo-K+ & metabolic alkalosis. Dialysate oC should also be adjusted for each TR. A 3 mEq/L Ca+, 1 mEq/L Mg, 140 mEq/L constant Na+, and 100 mg/dL glucose dialysate bath are usually preferred. Dialysate temperature can be adjusted to be 0-1 oC less than ptn's body temperature.

Most out-ptns DX therapies are running with systemic anticoagulants via heparin. It is advised NOT to utilize heparin among TR who are proceeding Tx within 24 hs of DX. The expected ½ -life of the usual 10-50 IU/kg bolus dosing of heparin with HDX is about 30-90 min that is prolonged in an ESKD ptn as compared with a non-ESKD ptn and vary according to other factors of the DX therapy. Intraperitoneal heparin may be used for fibrin in PD does not induce systemic anticoagulation. A Bc membrane should be utilized for all TR performing DX before Tx. Complement-activating or non-Bc membrane dialyzers (e.g., cuprophane dialyzers) have been complicated with DGF development. Study: 44 graft TR dialyzed within a 24-h befor Tx, recovery of renal function was higher with dialyzing ptns with the Bc dialyzers.

IMMEDIATE DX AFTER Tx: About 20 % of ptns may need temporary DX after Tx. Post-Tx requirement of DX in the 1st post-operative week is called DGF, whatever the cause of allograft dysfunction. DGF has independent association with about 2-3 fold rise in ptn mortality, graft failure, & DCGF. The risk factors of DGF have been evaluated in several studies. The clinical indications for acute DX among TR in the immediate Tx period are similar to that in non-Tx ptns developing AKI.  

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Choosing the optimal DX modality in the post-operative period is not certain. Most clinicians, perform HDX after Tx that can be explained by the possibility of peritoneal membrane disruption during Tx surgery, with the possible leak of glucose-containing dialysate fluid with increased risk of infection. Some experts suggested the removal of the PD catheter at the time of Tx surgery to guard against the 5 % or more risk of peritonitis (even with no prior DX). However, PD has been performed in some TR with DGF. Generally, there is no reason for continuous RRT. The prescribed DX is usually similar to that of non-Tx ptns. Large UF rates should be omitted to avoid graft ischemic injury. We targeting a weight (volume parameter) within 1-2 kg of the ptn's known DW with fluid removal not > 10 mL/kg/h.

PD CATHETER REMOVAL after Tx: optimal time of removing PD catheter after KTx is not certain. Unless otherwise prescribed and despite the higher risk of peritonitis, some physicians wait 3-4 mo after surgery as significant quantity of TR may resume temporary/ permanent DX after Tx. However, several ptns with higher risk for peritonitis may get benefit from early catheter removal. Retrospective report: 232 PD ptns found that the incidence of peritonitis can be enhanced via the following factors:

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o   Male gender

o   Urine leaking

o   > 2 Rj episodes

o   S. aureus peritonitis

o   Surgical technical difficulties

o   Permanently non-functioning graft

o   Frequent peritonitis episodes before surgery (medium 3)

 

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Post-operative catheter removal is typically performed within one month, unless DX requirement is highly suspected. However, catheter removal at the time of or within the 1st week post-operatively is proceeded in some center.

 

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