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ALLOGRAFT SURVIVAL

Despite the greatly improving one-y kidney graft survival, the rate of chronic graft loss after the 1st y still crucial, however, it appears improving

 

ALLOGRAFT SURVIVAL

 

Abbreviations (Read twice please):

o   AB: Antibodies

o   Ac Rj: acute allograft rejection

o   ADH: antidiuretic hormone (vasopressin).

o   Ag: antigen

o   ALERT: Assessment of Lescol in Renal Transplantation

o   AMR: Antibody-mediated rejection

o   ATN: Acute tubular necrosis

o   BB: Beta blocker

o   BDD: Brain-dead donors

o   BP: Blood pressure

o   BTx: Blood transfusion

o   C: Complement

o   CAN: Chronic allograft nephropathy

o   CAD: Coronary artery disease

o   CAV1: Caveolin-1

o   CCR5: Chemokine receptor 5 

o   CIT: Cold ischemia time.

o   CMS: Centres for Medicare and Medicaid Services  

o   CMV: Cytomegalovirus

o   CNI: Calcineurin inhibitor

o   DCDs: Deceased cardiac donors

o   DDK: Deceased-donor kidney.

o   DGF: Delayed allograft function

o   DI: Diabetes insipidus

o   DSAs: Donor-specific antibodies

o   DX: Dialysis

o   ECDs: expanded-criteria donors.

o   ELISA: enzyme-linked immunosorbent assay.

o   ESRD: end-stage renal disease.

o   FAVORIT: Vascular Outcomes Reduction in Transplant Recipients

o   GFR: Glomerular filtration rate

o   Gm: Glomerular

o   GN: Glomerulonephritis

o   GSc: Glomerulosclerosis

o   HIV: Human immunodeficiency virus

o   HLA: Human leukocyte antigen

o   HR: Hazard ratio

o   HT: Hypertension

o   im/m: Immunosuppressive/Immunosuppression

o   KDPI: Kidney Donor Profile Index

o   KTx: kidney transplants

o   KwRw: weight of the kidney to the weight of the recipient ratio

o   LDK: living-donor kidney

o   LRD: Living related donor

o   MHC: Major histocompatibility complex

o   MR: mortality rate

o   OPTN: Organ Procurement and Transplantation Network.

o   PP: pulse pressure

o   PRA: Panel reactive antibody

o   Preetx: Pre-emptive Transplant

o   RCT: randomized control trial

o   RADR: Renal Allograft Disease Registry

o   Rh: Rhesus blood group

o   RI: Resistive index

o   Rj: Rejection

o   RR: Relative risk

o   SCDs: Standard-criteria donors

o   SCr: Serum creatinine

o   Snz: Sensitization

o   SRTR: Scientific Registry of Transplant Recipients.

o   TPA: Tissue plasminogen activator.

o   TR: Transplant recipients

o   Tx: Transplants/transplantation.

o   U/S: Ultrasonographic

o   UNOS: United Network of Organ Sharing

o   USRDS: United States Renal Data System.

o   VC: Vasoconstriction

o   Wt: Weight

o   WIT: Warm ischemia time.

 

Despite the greatly improving one-y kidney graft survival, the rate of chronic graft loss after the 1st y still crucial, however, it appears improving by time. A 2004 study: analysed 1st KTx proceeded between 1995 & 2000 reported that despite the reduced Ac Rj episodes, the long-term graft longevity was not improving over the last 10 ys. However, the rate of drop in renal graft function seems to be slowing that suggests that improving the long-term allograft longevity is greatly amenable. The annual data (2016) reported of the OPTN/SRTR highlights current, despite incremental, improved allograft & ptn survival for both DDK & LDK Tx. The kidney graft longevity rates are also variable with different ethnic cohorts that can be partially explained by the finding of a disproportionate increasing number of risk agents among specific cohorts with variable accesses of health support.

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I will promote various variables of short- & long-term graft longevity. However, this distinction is to some extent arbitrary as many factors can impact both survivals. Any short-term agent may predispose to episodic Ac Rj will then induce greater possibility of chronic graft loss. Moreover, many of these agents affect each other, e.g., mismatched HLA that may trigger the risk of Ac Rj with subsequently expected premature allograft loss.

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SHORT-TERM SURVIVAL

The risk of allograft loss has commonly been classified into an early, high-risk period and a late period of constantly lower risk. The great improvement in the kidney allograft longevity in the past 20 ys has been attributed to the relatively eliminated early risk period. A variety of factors have been incriminated in the progress in the short-term allograft survival. These may include DGF, HLA AB, type of donor graft, donor illnesses, centre policy, and others.

Delayed graft function: Development of DGF has a major adverse impact upon both short- & long-term graft survival. Single-centre report: 518 ptns, multivariate analysis showed: DGF was the fundamental agent underlying kidney graft longevity at one y; in contrary, Ac Rj, HLA matching, degree of Snz, & re-Tx did NOT seriously impact short-term survival.

HLA AB: Certain data suggest that the finding of HLA AB is complicated by a higher risk of early allograft failure. Considering data from about 5000 TR, the prevalence of HLA AB was 21 % among kidney TR. Almost > 2000 ptns have been followed prospectively, with 91 allograft failure and 34 deaths. The risk of allograft loss at one y. was increasingly elevated among those with HLA AB (6.6 vs 3.3 %), as well as among TR developing such AB de novo (8.6 vs 3 %). Moreover, such AB place ptns on W/L with a remarkable disadvantage waiting for a kidney graft that is markedly extended with an increasing risk of both DGF & Rj in the peri-operative period of Tx.  

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The finding of HLA AB also has an adverse impact on the long-term allograft longevity.

Type of the graft: It is well-known that not all grafts offered for Tx are currently equal. These allografts have long been characterizing by the donor source, either living or cadaveric. LDK Tx have a higher short-term longevity as compared with DDK. The Graft survival rates for LDK Tx and cadaveric, non-ECDs; now referred to as KDPI (>85 %) are 98 vs 96 % at 3 mo and 96 vs 92 % at one y, resp. An allograft survival benefits with LDK has been also observed with the 2nd allografts, a difference reflecting the optimized circumstance in the setting of living, related donation as compared to the potentially injuring events of DDK donation.

Before 2014, DKD were classified into SCDs & ECDs. ECD kidneys are from BDD that’re further recognised by a rise of 1.7 in the RR of premature graft failure within the 1st y post-Tx. Such kidneys collected from donors >60 ys of age, as well as those with HT or stroke as a direct cause of death. ECD grafts are commonly associated with lowered short-term graft survival, especially among TR planning for re-Tx. However, application of this primitive classification shows the limitation of the presence of currently overlapped outcomes and allograft quality as the ECD class is large and non-uniformly including allografts with variable outcomes. The ECD category may include-for example- both an entirely healthy 60 y old donor with a normal kidney profile and a 55-y old one with DM, HT, & a SCr of 1.6 mg/dL.

A recognizing centrally featured and revised renal allocated system that was accomplished in the US in 2014, is the KPI that is a continuing, rather than a dichotomous, index of the qualities of the donor grafts, from the highest quality (carrying the longest functional post-Tx lifetime), to the lowest one (carrying the shortest functional post-Tx lifetime). The more granulated KDPI, entirely based upon donor criteria, comprising a variety of donor risk factors for allograft failure into a solitary number. One study: using the KDPI (or KDRI) to categorise DDK, the highest quintile (equal to the highest risk for allograft failure or lowest project longevity) had a calculated 5-y survival of 63 % as compared to the lowermost 2 risk quintiles that showed projected 5-y survivals of 82 & 79 %, resp. The KDPI system may overlap with the ECD/SCD system in that the % of ECD grafts rose with an elevated risk quintile. However, 32 % of ECD kidney grafts studied showed KDRI < the 85th percent.  

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Centre effect
: In the US, Europe, & Canada, a crucial centre impact regarding short-term graft longevity has been reported that can’t be explained by various clinical criteria of enrolled TR. It seems to be a persistent finding that has been seen along the last decades, an era of highly effective im/m therapy. Possible background explanations may include centre effect and variabilities in long-term TR therapeutic policies.

Donor age: an older donor age is complicated with lowered longevity of grafts offered from a cadaveric donor. Analysing 6490 DDK Tx identified from the UK Tx registry, compared with donor age <40 ys, donor age >60 ys was complicated with a higher risk of allograft failure (HR 95%).

Donor illnessDDK graft survival may also affected by the aetiology of donor mortality and/or history of the associated co-morbid diseases. For example, KTx due to stroke event showed a lowered one-y graft survival rate than observed with DDK Tx (79 vs 84 %).

DX & Preetx: Early graft longevity may vary with maintained DX and possibly the module of DX before Tx.  

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LONG-TERM SURVIVAL:
The recognition of clinical risk agents determining the long-term allograft loss has been evaluated via several reports proceeded in the current im/m era, e.g., in the ALERT study, along 5-6 y, 2000 ptns were randomly exposed to Fluvastatin or to placebo. The placebo g. showed graft loss in 137 ptns that was primarily induced by CAN. Multivariate analysis showed that the independent risk factors for increased risk of graft loss may include:

1)    Higher SCr (RR: 3.12/every 100 micromol/L rise),

2)    Proteinuria (RR of 1.6 /1 g/d), &

3)    PP (RR of 1.12/every rise of 10 mmHg).

4)    Declined graft function at one y.

One study showed progressive drop in the graft ½-life for each incremental rise in the SCr level at 6 mo & at one y. The underlying pathogenetic mechanism responsible of CAN and result in long-term graft loss still uncertain. Both allo-Ag-dependent & independent factors have been incriminated. Long-term allograft survival is usually assessed in terms of the ½ -life that’s defined as:

Time elapsed after the 1st post-Tx y., where 50 % of the function of allograft has been lost.

 

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1)    History of Ac Rj,

2)    Infectious episodes,

3)    Inadequate im/m agents.

4)    Higher degrees of HLA mismatch.

These factors are consistent with the crucial impact of the immunological or allo-Ag-dependent injury in the consequent evolution of chronic graft malfunction.  

Ac Rj Episodes: Ptns with frequent history of Ac Rj episodes are more prone to experience a late allograft loss. Study: 63,045 primary renal TR with episodic Ac Rj from 1996-1997 was complicated with a 5.2-fold increasing risk for CAN as compared to TR with no Rj in a control g. from 1988-1989.

HLA matching: An increasing degree of HLA Ag mismatching is usually accompanied with a higher risk of chronic allograft loss, possibly due to persistent particular immunologic stress. If graft allocation is primarily based on HLA typing, one crucial concern is the impact of CIT, cold ischemic time on long-term longevity. The beneficial impact of HLA matching seems to be outweighing the harmful impact of prolonging the cold ischemic time in Tx kidney. The currently available registries inform that the 5-y allograft survival of 6-Ag-matched cadaveric kidney is similar regardless the kidney grafts underwent 3 or 36 hs of cold ischemic time.

However, the hazardous impact of prolonged CIT appears more evident in TR of mismatched grafts. A stepwise 1-2 % decline in survival has been reported associated with incremental 12-h rises in CIT. The adverse impacts of CIT can also be seen if graft survival is compared between the TR of a 1st cadaveric donor Tx and the recipient of the 2nd donor kidney Tx (mean of 19.9 vs 25.6 h.s CIT). The 5- & 10-y survival was 72 & 55 % for the 1st KTx, resp, as compared to 65 & 40 % for the 2nd KTx.

Considering the relative contributors to graft survival of HLA matching & CIT is also provided if we consider the allograft longevity rates of living, unrelated kidney. The allograft survival rate of a kidney offered by a spouse are remarkably similar to the kidney donated by a family member with a one-haplotype mismatch (½ -life of 12 ys). If HLA mismatching were the sole factor affecting allograft longevity, the living, unrelated allografts should show poorer long-term longevity, possibly in the range of randomly matched cadaveric graft (that is mostly have 3 HLA mismatches & an average ½ -life of 8.4 ys).

So, both CIT & HLA matching exert crucial impacts on the long-term allograft survival. However, 6-Ag matching entirely overcomes the impact of ischemia, and lesser magnitude of matching (even with the presence of ischemia) yield superior results than zero-Ag-matched grafts. The graft immunogenicity alterations induced by tissue injury before death in deceased Tx may be also contributing to the lowered long-term longevity with DKD in contrary to LDK.  


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Sensitization (Snz): AB against HLA class I (A, B, C) or class II (DR, DQ) have been observed in subjects with prior immunization to these glycoproteins via:

1)    BTx, or

2)    Pregnancy,

3)    previous HLA-mismatched grafting.

Highly Snz ptns have a lowered statistical chance of being Tx owing to the higher likelihood of a +ve pre-Tx crossmatch. Enhanced Snz to lymphocyte Ags (measured via PRA), incrementally triggers the risk of allograft failure. 5-y DDK, non-ECD graft survival rates in the 2007 SRTR annual report were:

o   71 % for ptns with PRA of 0-9 %

o   61 % with a PRA of 10-79 %

o   69 % with a PRA of >80 %

UNOS retrospective analysis: the 10-y graft survival = 44 % for highly Snz ptns (PRA 98 %), as compared to 52 % for non-Snz ptns (PRA = 0). It is greatly considered that the finding of pre-formed HLA DSAs has an adverse impact on allograft longevity. With the advent of overly sensitive HLA-specified assays, allograft outcome at 8 ys was assessed among 43 ptns with & 194 ptns without pre-formed DSAs. Allograft longevity = 68 vs 77 % for those with & without DSAs, resp. Moreover, the incidence of AMR rates was 9-folds higher in TR with pre-formed DSAs.

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C-binding HLA DSAs are particularly associated with declined allograft survival. This was shown in a study of 1016 TR who received a KTx at 2 centres between 2005 & 2011. All ptns were examined for circulating HLA DSAs via stored serum samples collected at the time of Tx and at the time of graft biopsy (taken either at one y after Tx or within episodic Ac Rj in the 1st y after Tx). Serum samples of TR having HLA DSAs were further examined for the presence of C1q-binding HLA DSAs via single- Ag flow bead assay. Generally, ptns with HLA DSAs had worse 5-y allograft survival as compared to those with lack of such AB (83 vs 94 %, resp). TR with C1q-binding DSA HLA AB (n = 77) had worsened allograft survival as compared to ptns with non-C1q-binding DSA HLA AB (n = 239) and compared to ptns with no DSA HLA AB (n = 770; 54 vs 93 & 94 %, resp). With adjusted various clinical, functional, histological, and other immunologic agents, the finding of C1q-binding DSA HLA was complicated by > 4-fold higher risk of allograft loss ([HR 4.78, 95%). C1q-binding AB were also complicated by a higher rate of AMR with increasing deposited C4d in the graft. However, the C1q -binding assessment is not widely applied and has not been approved yet in many centres. Moreover, there’re some non-C-binding DSAs that are clinically incriminated in allograft failure that cannot be identified by this assay.

Limited data suggesting that Snz may, sometimes, representing non-HLA immunity, with higher levels associated with lowered longevity. Retrospective study: > 4000 TR of HLA-identical sibling Tx assessing the long-term longevity associating PRA levels. Considering that the Tx were between HLA-identical siblings, the finding of PRA was thought representing anti-HLA Ags AB not present in the Tx kidney. However, the 10-y survival was the highest among TR devoid of PRA (72 %) vs those with either 1-50 % PRA (63 %) or >50 % PRA (56 %) that suggesting: non-HLA Tx immunity, as identified by PRA, may play a role in long-term graft survival.

The significant role of non-HLA immunity was further supported by 2-y prospective study: 2231 ptns. At 2 ys, graft longevity was more significant among 1781 ptns with No HLA AB (93 vs 85 %). Outcomes could be better correlated with the finding of cytotoxicity examination vs ELISA or HLA beads suggesting: the finding of non-HLA AB can be correlated to a lowered longevity. Although mismatching at the Rh blood g. Ag is NOT dealt as risk factor for graft Rj, a multivariate analysis of UNOS data found that Rh incompatibility may grant a worsened long-term survival. In this study, Rh identification between the TR & donor was significantly correlated with a better graft longevity (RR 0.43). {Role of Rh in allograft survival has to be re-evaluated}.

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Allo-Ag-independent factors: Variable clues from clinical Tx database support the impact of the following in the evolution of chronic graft dysfunction with poor long-term renal outcome:

1)    Post-Tx HT,

2)    Post-Tx hyperlipidemia,

3)    More marginal grafts,

4)    Inadequate graft mass,

5)    Previous/current tissue injury,

6)    Recurrent/de novo Gm disorder

7)    And, on the long run:

o   CNI toxicity &

o   Death of the TR.

 

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Tissue injuryAllograft injury exerts a crucial role in both short- & long-term allograft function, as well as in the development of kidney graft Rj. Such injury may be induced via variable agents, including:

1)    CIT,

2)    Brain death,

3)    infectious episodes

4)    ischemia and/or reperfusion injury.

Brain death: Traumatic brain death or devastating intracranial hemorrhage is complicated by variable adverse events on the donated organs before Tx. Under this environment, graft tissue became "primed" and TR T-cell activation by donor allo-Ag is more prone to develop. In BDD the following cascades have been expected:  

1)    Brain oedema > increased intracranial pressure > compressed cerebral tissue & venous congestion > increased brain turgor & rigidity. Massive catecholamines efflux then ensues inducing profound VC with endothelial injury.

2)    Injury-induced inflammation > upregulated adhesion molecules & class-II MHC on graft endothelium.

3)    Pro-coagulation state due to endothelial activation, cytokine release, C activation, & depleted TPA.

4)    Anterior pituitary hormonal release leading to reduced levels of thyroid hormones, cortisol, insulin, and ADH.

5)    DI rapidly developed; cardiac arrhythmia & rapidly fluctuated BP are common.

- Such events may clearly adversely impact the function as well as allograft integrity.

Ischemia and/or reperfusion injury is thought to be a crucial risk factor for both early DGF & late graft dysfunction. One report: 3829 adult TR of a 1st DDK, there was a proportionate rise in the risk for graft loss & death over 12 ys for each hour of CIT. The dominant aetiology of DGF is post-ischemic ATN. ATN incidence increased if the CIT > 18 h.s, especially with older donated grafts. CIT alone is also a crucial factor impacting long-term allograft longevity.  

Preserved grafts with pulsatile preservation may improve long-term longevity as compared to that seen with simple cold storage. Injury alone may NOT impact graft longevity in absence of Rj, as reported in some reports, e.g., > 9000 grafts retrieved & analysed from the UK national Tx databases, reported injury at graft retrieval or placement was NOT significantly correlated with allograft survival at 3 ys.

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The environmental factors related to organ removing, storage, & engraftment may trigger allograft immunogenicity. These factors may include:

o   Upregulation of MHC Ags &

o   Cytokine-adhesion molecule cascade enhancement.

Such factors may ultimately enhance the evolution of chronic allograft dysfunction, e.g., blocking co-stimulatory pathways can alleviate organ dysfunction in rat models of ischemia/reperfusion. There’re limited data concerned with the relative magnitude of injury with grafts harvested from DDK with or without a heart beating. Grafts from donors with no heart beating or DCDs can be complicated with certain degree of irreversible damage that leads to relative degree of poor long-term graft longevity. However, some reports suggest outcome may be satisfactory.  

CMV: The finding of CMV seropositivity enhances both acute & chronic allograft loss development. Seronegative TR of seronegative grafts appear to have a 10 % higher allograft survival than TR of seropositive allografts that is can be explained by an activated CMV-induced cytokine promoting allograft injury. Allograft longevity rates are also affected by previous CMV serostatus and by prior CMV prophylaxis.  

Inadequate kidney massTx of inadequate renal mass may be complicated by an increasing risk of allograft failure. Data in favour of this hypothesis in humans depends on the observation of lowered allograft survival rates with older & very young donor kidney, TR in whom donor graft has disproportionately fewer nephrons, and ratio of donor kidney Wt to TR Wt:

o   Old & very young donor kidneys: Old & very young kidneys have relatively lowered numbers of actively functioning nephrons with less survival rate after Tx.   Inherited factors of the older kidney may also impact the overall graft longevity.

o   Disproportionate fewer nephrons: Large-sized TR require a wide physiologic demand on the Tx graft. The increasing demand with "inadequate" Tx nephrons may induce lowered long-term graft survival rate seen in ptns of >100 kg BW.

o   Several trials have assessed the relation between graft function/longevity and the ratio of donor kidney Wt to TR Wt. Largest study:1189 renal TR, the ratio of KwRw was assessed regarding risk of proteinuria, GSc, & graft failure. A lowered KwRw ratio (<2.3 g/kg) was complicated by a higher risk of GSc (17 vs 4.7 %), proteinuria, & long-term graft failure (1.55-fold higher risk starting 2 ys after surgery). The level of risk for cadaveric graft survival with lowered KwRw ratio is nearly simulating the risk related to an Ac Rj episodes or DGF.

 

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Non-compliance
:  is one of the more crucial risks for allograft failure on the long term. Assessing the frequency of non-compliance and its impact to kidney graft loss is somehow difficult to assess owing to the wider variability in study designs & results.  

Post-Tx HT: Post-Tx HT may exert a negative impact on the long-term graft/ptn survival. Multivariate analysis: adjusting baseline kidney function, the RR of graft failure = 1.3 for each 10 mmHg rise in the mean arterial pressure at one y post-Tx.  

Hyperlipidemia: is well-known risk factor for arteriosclerosis & CAD in all ptns, including cardiac & kidney TR; it may also induce higher rates of allograft loss.  

Recurrent or de novo GN: Recurrent or de novo GN can result in significant lowered long-term allograft survival:

o   Retrospective study: assessed the outcome of 5000 KTx (in the RADR), 167 of which had clinical & biopsy-proven recurrent or de novo Gm disease. The RR for allograft loss was 1.9 for TR with Gm disease. At 5 ys, ptns with Gm disease had a much higher rate of graft loss (60 vs 32 % in those with no Gm disease).

o   For 1505 renal TR with ESRD due to GN, graft loss due to biopsy-proven recurrent GN was reported in 52 ptns (3.5 %). The 10-y incidence of graft loss due to recurrent disease was estimated to be 8.4 %; recurrent GN was the 3rd most common cause of allograft failure among this group.

The improving long-term survival seen in well-matched HLA allografts may also be less apparent in TR with a primary Gm disease. One report: 60 ptns with identical-, HLA, LRD Tx, graft survival was correlated with the original kidney disease. Among the 33 ptns with an underlying GN, the 5-, 10-, & 20-y allograft survival was 88, 70, & 63 %, resp; in contrary, no one case of allograft failure was reported among other ptns with non-Gm kidney disease. Recurrent disease seems to be the principal aetiology of allograft loss.

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Type of donated kidneyLDK Tx have a higher long-term graft longevity as compared with DDK (primarily BDD). The 2009 SRTR report: the 5-y graft survival for LDK, non-ECD, and ECD kidneys were 81, 72, & 57 %, resp. An allograft survival benefit with living Tx is also reported with the 2nd allografts. The observed difference is reflecting the optimal environment around the living, related donated grafts as compared to the current injurious events around the deceased donation. Moreover, allograft survival decline can be correlated with the lowered quality of the deceased kidney. There is also an increasing body of evidence from Japan that long-term longevity with DCD kidneys seems to be adequate. One Japanese study:  overall allograft survival at 5 & 10 ys: 72 & 53 %, resp.

It is not certain if DCD kidneys from older donors may experience worsened outcome as compared with grafts from BDD of a comparable age. One study: grafts from DCD donors >65 ys of age showed lowered GFR at one y with tendency to a lowered 5-y allograft survival as compared to younger DCD donors. However, no significant difference in allograft survival if kidneys with intense vascular lesions have been excluded. Moreover, the report of UK registry showed no difference in allograft failure for DCD donors >60 ys of age as compared to BDD with similar ages. Along the last several ys, in the US, there is observed steady improving in outcomes of the DCD kidneys. Considering the UNOS database, outcomes of DCD KTx at 5 ys post-Tx, both in terms of ptn (81 %) & graft (67 %) longevity, is not significantly different from that of kidneys from BDD.

Gene polymorphisms: Variations in the ability to mount an effective immune response against the graft, as well as difference in underlying agents involving graft fibrosis, represent allo-Ag-independent factors that may impact allograft survival:

o   CAV1: has a crucial role in the evolution of organ fibrosis. Retrospective study: CAV1 polymorphism is complicated with a higher risk of graft failure that is highly related to allograft fibrosis.

o   CCR5: Study: assessed graft survival in 1227 renal TR screened for the 32-base-pair deletion for CCR5. Ptns with homozygous deletion (leading to non-functional receptor & seen in 1 % of Europe/North America Caucasians) had significantly better graft survival than non-homozygous ptns (90 vs 25 % survival at 20 ys).

o   C3 allotypes: The impact of C3 allotypes on clinical outcome still uncertain. 2 C3 allotypes, F for fast & S for slow that seems to have an impact on the inflammatory disorders. One study: graft survival was significantly increasing with C3F/F & C3F/S donor kidney, with a benefit unique to TR with no C3F allele. However, larger study: no relation between improved survival & various types of C3.


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U/S resistive index (RI): Higher RI (by Doppler U/S) has been complicated by marked decline in allograft longevity in some but not all reports:

o   Single-centre German study: assessed 601 stable ptns at least 3 mo after success-ful KTx; all ptns were followed for 3 ys. RI of >80 % that is non-specific reflection of higher vascular resistance, was reported in 20 % of ptns. Compared with ptns with a lower RI, ptns with a RI >80 % were more prone to get the composite endpoint of a 50 % decline in allograft function, need for DX, or recipient death. TR with RI of >80 % had a multivariate RR of allograft loss of 9.1.

o   Recent study: correlated RI with ptn survival, allograft longevity, and graft histology. This prospective study of 321 kidney TR confirmed the previous study’s findings that a RI >0.8 was complicated with a higher risk for a composite endpoint of a 50 % decline in allograft function, need for DX, or TR death.

 

The more recent report showed: RI ≥0.8 at 3, 12, & 24 mo was complicated with a higher MR as compared to TR with index <0.8 but not with allograft failure or with renal histopathology (protocol biopsy), and via the latter time points, a higher RI correlated mostly with TR older age; other factors included higher PP, lower mean BP, BB use, and diuretics. These data suggesting a RI obtained at certain times after Tx reflects TR but not allograft criteria. Among biopsies obtained for allograft dysfunction, higher RI correlated with AMR & ATN but could not differentiate between them. Variabilities in study design, especially timing of obtaining RI, the short follow-up period, altered im/m, and antiviral prophylaxis in addition to variabilities in the technical facilities may explain the discordancy in results.

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Hyperhomocysteinemia: Increased homocysteine levels are accompanied with declined graft survival. Prospective study: 733 renal TR comparing baseline fasting plasma total homocysteine levels with kidney allograft longevity within 6.1 ys follow-up. Higher levels of homocysteine (≥12 micromol/L) were complicated with a higher risk of allograft failure (HR 95%) & MR (HR 95%). A RCT (Folic acid for FAVORIT) did not detect any benefit of adding high-dose B complex vit. supplementation, however.

Proteinuria: The finding of proteinuria (including levels of <1 gm/d) is a predictor of long-term allograft failure. This correlation likely reflecting the finding of ischemia-reperfusion lesion (s), ongoing immunological/non-immunological graft injury.                            

Geography: may be a predictor of long-term allograft longevity. For example, one analysis indicated: long-term longevity of TR in the US is significantly declined as compared to that of TR in Australia/New Zealand, Europe, & Canada. The reason for this finding is not certain, despite variable immunotherapy plans may be implicated.

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OPTIMIZING OUTCOMES: Pre-, peri-, & post-Tx factors affecting allograft survival.

o   Pre-Tx: The aim of Tx team is engrafting as many TR as possible meanwhile limiting sequelae affecting graft/ptn survival. However, such targets may vary. The wide use of KDPI >85 % kidneys can augment the number of Tx whilst negatively impact allograft longevity. So, a key target of the organ selecting programs is to optimize such variables via secondary benefits supplies e.g., waiting time decline for candidate TR. Tx plans should consider ptn selection criteria as vital predictors of survival. Tx a higher % of "high-risk" TR will adversely affect survival rates.

o   Peri-Tx: Minimizing CIT & WIT is a crucial target to limit the risk of DGF & lowered allograft survival. In fact, allocated & transported organ delay are logistic reality with little influence of the concerned programs.

o   Post-Tx: Optimized titration of im/m is crucial after successful Tx. Control of Rj rates should be in balance with the risk of infection. Considering co-morbidities e.g., HT & dyslipidaemia can help improving the long-term outcome.

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Hemodialysis,21,My Publications,2,Peritoneal dialysis,14,Prevention of renal failure,61,Renal face,43,Renal Transplantation,49,TOP RECENT,37,
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fedo: ALLOGRAFT SURVIVAL
ALLOGRAFT SURVIVAL
Despite the greatly improving one-y kidney graft survival, the rate of chronic graft loss after the 1st y still crucial, however, it appears improving
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https://www.fedokidney.com/2021/06/allograft-survival.html
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