Marginal Donors and Kidney Transplant Outcomes

Marginal Donors/
Expanded Criteria Donors Kidneys
Issues and outcomes
Dr Abdullah Ansari
SR Nephrology
SGPGI Lucknow

The burden of ESRD patients
• As per a report from 2001, the population of ESRD patients was increasing
worldwide at a rate of 7% per year
• This is coupled with rising prevalence of diabetes mellitus and hypertension
• In Asia, the number of dialysis patients is increasing at a much higher rate
compared to that of West
• In India, Philippines and China, the annual rise ranges from 10% to 30%1,2,3
• The prevalence of CKD increases with age: 27.6% between 60 and 70 years old
and 34.3% above 70 years old
1. Lee G. End-stage renal disease in the Asian-Pacific region. Semin Nephrol 2003;23:107-14.
2. Agarwal SK, Dash SC, Irshad M, Raju S, Singh R, Pandey RM. Prevalence of chronic renal failure in adults in Delhi, India. Nephrol Dial Transplant 2005;20:1638-42.
3. Jha V, Garcia-Garcia G, Iseki K, Li Z, Naicker S, Plattner B, et al. Chronic kidney disease: Global dimension and perspectives. Lancet 2013;382:260-72.

The treatment for ESRD
• Survival, cardiovascular stability and quality of life have been found superior in
allograft recipients compared with similar patients on wait list
• This benefit has been observed among recipients older than 60 years as well1
1. Wolfe RA, Ashby VB, Milford EL, Ojo AO, Ettenger RE, Agodoa LY, Held PJ, Port FK. Comparison of mortality in all patients on dialysis, patients on dialysis awaiting
transplantation, and recipients of a first cadaveric transplant. N Engl J Med 1999; 341: 1725-1730
Kidney transplantation is the treatment of choice for end stage renal disease

The Indian scenario
• In India about 80,000 patients are added annually to the pool of ESRD, however
only 2.4% undergo transplant1
• This low transplantation rate in India is due to
• The lack of an appropriate cadaveric transplant program
• The inability to afford a transplant due to socioeconomic status
1. Kumar A, Mandhani A, Verma BS, Srivastava A, Gupta A, Sharma RK, et al. Expanding the living related donor pool in renal transplantation: Use of marginal
donors. J Urol 2000;163:33-6.

The organ demand
• The number of renal transplants has increased rapidly over the last two decades
• There is a large gap between the number of patients waiting for a transplant and
the number receiving a transplant
• This lead to renewed interest in the use of so called marginal or border line donor
kidneys in an effort to increase the donor pool, particularly for elderly recipients

The organ demand
• According to the UNOS Scientific Registry of Transplant Recipients1
• The patients on waiting list for kidney transplant increase by 10% annually
• The annual increase in the number of renal transplants is only 4%
• The average waiting period for cadaveric graft is more than 5 years in the US2
• Annually 7% of the waiting list candidates die and the mortality rate decrease
dramatically after transplantation
1. Cecka JM. The UNOS scientific renal transplant registry. In: Cecka JM, Terasaki PI, editors. Clinical transplants 1996. UCLA Tissue Typing Laboratory: Los Angeles;
1997. p. 1-14.5.
2. United Network for Organ Sharing Web site. Organ procurement and transplantation network data. Available from: http://www.unos.org.

Marginal donors: Definition
• Marginal donors are not clearly defined
• Simply means usage of suboptimal quality cadaveric renal grafts, non heart
beating donors and living donors with some acceptable medical risks
• Metzger et al. first described the classification of SCD and ECD in 2002
• The criterion has undergone various modifications, with the key aims of
optimizing organ procurement rate while minimizing discard and rejection rates

Types of marginal donor
1. Complex living donor
2. Donation after Circulatory Death (DCD)
3. Expanded Criteria Donor (DCD)

Complex Living Kidney Donor
• The term “Marginal living donor” was used by Matas1
• In the marginal living donor, focus is on the potential harm to the donor
1. Matas AJ. Transplantation using marginal living donors. Am J Kidney Dis 2006;47:353-5
2. Reese PP, Caplan AL, Kesselheim AS, Bloom RD. Creating a medical, ethical and legal framework for complex living kidney donors. Clin J Am Soc Nephrol
2006;1:1148-53
• The term “Complex living donor” was used by Resse2
• He referred to all suboptimal donors where decision-making is a problem, due to
lack of sound medical data or consensus guidelines
• He further categorized complex living donors based on certain risk factors

Risk factors associated with complex living donor
(Resse et al.)
Evidence of current renal disease: Hematuria, proteinuria, nephrolithiasis
Direct risk for CKD: Hypertension, obesity
Reduced nephron mass: Age ≥65 years
Genetic risk factor: Family h/o of ESRD in 1st relative
Risk factor for CKD: Diabetes in a first-degree relative, Impaired fasting glucose
Cardiovascular risk factor: Smoking, hyperlipidemia, hypertension
Others: Black race, sickle trait
1. Reese PP, Caplan AL, Kesselheim AS, Bloom RD. Creating a medical, ethical and legal framework for complex living kidney donors. Clin J Am Soc Nephrol
2006;1:1148-53

Complex Living Kidney Donor
Elderly living donors
Hypertensive living donors
Diabetic living donors
Obese living donors
Living donors with dyslipidemia
Living donors with nephrolithiasis
Living donors at risk ADPKD
Living donors with history of malignancy
Living donors with potential transmissible infections
Living donors of Childbearing Age

• Normal GFR decreases with age, approximately 1 ml/min per year after age of 40
• A GFR >80 ml/min is generally accepted, some may consider GFR >60 ml/min
GFR corrected to age rather than age itself determines acceptability for donation

• Inferior outcomes of an older kidney might be a function of an anatomical and
physiological changes that occur with aging
• The rates of short term morbidity and mortality do not seem to be higher for
elderly donors
1. Kerr SR, Gillingham KJ, Johnson EM, Matas AJ. Living donors > 55 years: To use or not to use? Transplantation 1999;67:999-1004.
Kerr et al. identified donor age greater than 55 years to be a significant factor for
late graft loss1

Hypertensive living donors
• BP should preferably be measured by ambulatory blood pressure monitoring
• Patients with BP >140/90 mmHg by ABPM are generally not acceptable as donors
1. Delmonico F; Council of the transplantation society. A report of the Amsterdam forum on the care of the live kidney donor: Data and medical guidelines.
Transplantation 2005;79:S53-66
Low risk groups: easily controlled hypertension (>50 years of age, GFR >80 ml/min,
urinary albumin excretion <30 mg/day) - may be acceptable as kidney donors
(Amsterdam forum)1
• Donors with hypertension should be regularly followed by a physician

Diabetic living donors
• Generally excluded – increased risk of post operative complications, diabetic
nephropathy and renal failure in donors
• DN occurs in familial clusters and heredity – determine susceptibility
Individuals with a history of diabetes or fasting blood glucose of >126mg/dl on at
least two occasions (or 2-hour glucose with OGTT >200mg/dl) should not donate

Obese living donors
• Obesity defined as BMI >30 kg/m2
• Increased BMI associated with
• High risk for proteinuria, FSGS
• Increased rates of DM, HTN, metabolic syndrome
BMI >35 kg/m2 - discouraged for kidney donation
BMI <35 kg/m2 - without any comorbidity may be acceptable for donation and
encouraged to lose weight prior to donation

Living donors with dyslipidemia
• Dyslipidemia associated with faster rates of progression of CKD
• However, isolated dyslipidemia is not a contraindication for donation

• A potential donor should be screened for metabolic stone forming abnormalities
• It is reasonable to accept only those as donors who are stone-free at the time of
evaluation and the metabolic stone work-up is negative
• Stones at high risk of recurrence, caused by inherited disorders, systemic disease,
inflammatory bowel disease - should not be considered for donation

The Amsterdam Forum
• An asymptomatic potential donor with history
of a single stone may donate if
 No hypercalciuria, hyperuricemia or metabolic
acidosis
 No cystinuria or hyperoxaluria
 No urinary tract infection
 If multiple stones or nephrocalcinosis are not
evident on CT
• An asymptomatic potential donor with a
current single stone may donate if:
 The current stone <1.5 cm in size, or
 Potentially removable during the transplant
American Society of Transplantation
• An asymptomatic potential donor with small
incidental renal stones may donate if
 They are left with the stone-free kidney
 The metabolic stone work-up is negative
• A symptomatic potential donor with a distant
history of a single passed stone may be
considered if
 There are no stones on current imaging
 The metabolic stone work-up is negative
1. Delmonico F; Council of the transplantation society. A report of the Amsterdam forum on the care of the live kidney donor: Data and medical guidelines. Transplantation 2005;79:S53-66
2. American Society of Transplantation (AST) Live Donor Toolkit. https://www.myast.org/patient-information/live-donor-toolkit. Accessed on September 20th, 2018

Living Donors at Risk for ADPKD
• Adult relatives may be accepted for donation if they have a normal CT or USG scan
• The USG criteria have a 100% negative predictive value for exclusion in a 40 years old
• Diagnostic uncertainty is a concern particularly in younger donors (aged 20-40 years)
• CT and MRI have increased sensitivity for detection of renal cysts down to 1 mm in
diameter, useful in excluding donors <40 years
1. Huang E, Samaniego-Picota M, McCune T, Melancon JK, Montgomery RA, Ugarte R, et al. DNA Testing For Live Kidney Donors At Risk For Autosomal Dominant
Polycystic Kidney Disease. Transplantation. In press
 Huang et al. provided a diagnostic strategy based upon genetic testing of live kidney
donors at risk for ADPKD in whom renal imaging studies are inconclusive
 The diagnostic sensitivity of direct sequencing is relatively low, especially for the PKD1
gene because it is highly polymorphic

Living donors with history of malignancy
• The risk of clinical/subclinical malignancy increases with age, esp. over 50 years
• Currently malignancy is a contraindication for organ donation, except for low-
grade non-melanoma skin cancer1
• Colon cancer (Dukes A, >5 years ago), non-melanoma skin cancer or carcinoma insitu of the cervix
A history of malignancy may be acceptable if prior treatment of the malignancy:
Does not decrease renal reserve or place the donor at increased risk for ESRD
Does not increase the operative risk of nephrectomy
Has cured the cancer and is not potentially transmissible

HIV:
• HIV positive status is a contraindication for donation
• HIV positive deceased donor kidney transplant to HIV positive recipient are being
tried in South Africa and the US1
Cytomegalovirus and Ebstein-barr virus:
• Some centers delay transplant till PCR for CMV becomes negative
• Most of the adults are EBV and CMV-positive
• The risk of post-transplantation lymphoproliferative disorder is the concern in CMV
and EBV-negative individuals receiving positive donors
• However, the risk is not as high to prohibit renal transplantation
1. Muller E, Barday Z, Mendelson M, Kahn D. HIV-positive–to–HIV-positive kidney transplantation — results at 3 to 5 years. N Engl J Med 2015;372:613-20.

Hepatitis C Virus:
• Kidneys from HCV-seropositive deceased donors should be given to only HCV RNA-positive
recipients (KDIGO guidelines 2018)
• The high cure rates with new effective DAA may change this approach
• There are promising pilot trials of the transplantation of HCV RNA-positive kidneys into HCV
RNA-negative recipients
Hepatitis B Virus:
• Kidneys from HBsAg+ donors is contraindicated for HBV- recipients (KDIGO guidelines 2017)
• May be considered for HBsAg+ recipients or recipients with HBV protective immunity, with
possible antiviral HBV treatment of the recipient and post transplant monitoring
• Kidney transplant recipients from anti-HBc+/HBsAg-/HBV DNA- donors appear to have little
risk of acquiring active HBV infection

Pulmonary tuberculosis
• Past history is not a contraindication for donation
• Genitourinary tract should be examined prior
Syphilis
• Potential donors with a positive serology should be confirmed with fluorescent
treponemal antibody (FTA) absorption test
• Donation should be delayed till successful treatment
Schistosomiasis
• Treated Schistosomiasis is not a contraindication for donation

Women of Childbearing Age
• The absolute risk of gestational hypertension or pre-eclampsia increases from
4.8 to 11.5% in women after kidney donation
• The increased risk of these complications was significantly higher among those
older than 32 years than in younger women
• Nonetheless, available evidence does not support the exclusion of women of
childbearing age as kidney donors
1. Garg AX, McArthur E, Lentine KL; Donor Nephrectomy Outcomes Research (DONOR) Network. Gestational hypertension and preeclampsia in living kidney donors.
N Engl J Med. 2015 Apr; 372(15): 1469–70.

Ethical issue in accepting complex living kidney donor
• Marginal donors may themselves add up the pool of chronic kidney disease in long term
• Consent by both donor and recipient should be taken regarding delayed graft function,
expected decrease in graft survival, expected decrease in waiting time, expected
increase in survival
• Cost factors
• Need for hemodialysis, further hospital readmissions due to poor or late onset graft
function
• Opportunistic infections
The basic ethical principles of beneficence to the recipient, non-maleficence
regarding the donor and the donor’s right to autonomy

Donation after circulatory death

Donation after Circulatory Death (DCD) or
Non Heart Beating Donor (NHBD)
• The DCD/NHBD is a donor who has suffered an irreversible brain injury (usually
from trauma or stroke) but does not fulfill the criteria for brain death
• The patient is pronounced dead only after sustained cardiac asystole, which
results in prolonged warm ischemia and damage to the procured organs
• This is in contrast to a standard cadaver donor who has been pronounced brain
dead and the heart is still beating until the very moment of flushing of the donor
organs with cold preservation solution

Donation after Brain death Donation after Circulatory death

DCD kidney transplantation
The drawbacks of non-heart-beating donor kidneys
1. A higher rate of delayed graft function
2. A higher incidence of primary nonfunction
DCD kidney transplant function and survival are generally reported as comparable
with those from DBD kidneys

• Yong Cho et al. presented a multicenter review of 77 transplant centers in the US from 1995-1998
• 377 NHBD kidney transplants were compared 12156 brain-dead HBD kidney transplants
• There was a significant increase in early dialysis (47% vs. 25%), primary nonfunction (3% vs. 1%)
and serum creatinine at discharge (4.4 mg/dL vs. 3.2 mg/dL) in NHBD group
• There were no significant differences in one and three-year graft survival rates
1. Cho YW, Cecka JM. Successful graft outcome of non-heart beating donor kidneys in the United States: A multicenter review. Transplantation 2000;69:S404-5.

• Alanso et al. presented a single-center study
of 14-year period from Spain (1989 and 2004)
• Delayed graft function (84% vs 26%) and
primary nonfunction (16% vs 10%) was higher
in the NHBD group
• The short-term and long-term renal function,
determined by the serum creatinine levels and
patient and graft survival were not different
1. Alonso A, Fernandez-Rivera C, Villaverde P, Oliver J, Cillero S, Lorenzo D, et al. Renal transplantation from non-heart-beating donors: A single center 10-year
experience. Transplant Proc 2005;37:3658-60.

The challenges in DCD kidney transplantation
Whether it is ethically justified to withdraw life support for obtaining organs?
• The decision to withdraw life support has to be separate from organ donation
• Only when decision to withdraw support has been taken by the family and the
physician, the talk about organ donation starts
When and where to withdraw life support ?
• Life support is withdrawn either inside the operation theatre, or in a separate room
close to the theatre in presence of family members
• Whereas withdrawal in theatre limits warm ischemia, it may not be ethically correct
How long should one wait with asystole to declare death?
• The time ranges from 2 - 10 minutes, but 5 minutes is probably a wider accepted time

The status of DCD kidney transplantation
• Many transplant centers are reluctant to use DCD kidneys
• DCD transplants are primarily Maastricht Category 3 (i.e. controlled donors)
• In 2013, 13.6% of deceased donor kidney transplants in the US were from DCD
donors compared with 40% in the UK
• In India, the biggest challenge to DCD is lack of clarity in law and there is no
practice of withdrawal of life support in end of life situation

Expanded Criteria Donors (ECD)
• The Scientific Registry of Transplant Recipients define
• The criteria for definition of ECD was based on the presence of variables that increased
the risk for graft failure by 70% (relative hazard ratio 1.70) compared with an SCD kidney
• SCD was defined as a donor who does not meet criteria for DCD or ECD
1. Metzger RA, Delmonico FL, Feng S, Port FK, Wynn JJ, Merion RM. Expanded criteria donors for kidney transplantation. Am J Transplant 2003; 3 Suppl 4: 114-125
ECD kidneys are those either from
A brain-dead donor ≥ 60 years of age, or
A donor 50 to 59 years of age with at least two of the following:
1. History of hypertension
2. Terminal serum creatinine > 1.5 mg/dL
3. Cerebrovascular cause of death

ECD kidney transplantation: Epidemiological data
Pros
• Annual mortality rate in dialysis patients
exceeds 20%
• Survival advantage of ECD kidney transplant
recipients over dialysis patients remaining on
transplant waiting list
• Rapidly growing transplant waiting lists and
subsequent increased longer waiting times
Cons
• 70% increased risk for graft failure vs SCD kidneys
• 17% primary graft non-function vs SCD kidneys
• 38% of ECD kidneys were discarded vs 9% for all
other kidneys
• Increased treatment cost and resource use
• Mortality in perioperative period greater in ECD
kidney recipients
• Higher DGF rates, more acute rejection episodes
and decreased long-term graft function in ECD vs
SCD kidneys

Outcomes of ECD kidney transplantation
FACTORS –
1. Prolonged cold ischemia time
2. Increased immunogenicity
3. Impaired ability to repair tissue
4. Impaired function with decreased nephron mass
ECD vs SCD kidneys
• High rate of delayed graft function
• More acute rejection episodes
• Decreased long term graft function

Outcomes of ECD kidney transplantation
• Studies have shown that, for younger patients, it is generally worth waiting for a
higher quality kidney
• For older patients, in the absence of a living donor, accepting an ECD kidney
rather than waiting for a SCD kidney has significantly improved survival
The recipients of ECD kidneys generally have improved survival compared with
matched dialysis-treated patients

• Five-year graft and patient survival was 53% and 74% for marginal kidney
recipients compared with 67% and 80% for ideal kidney recipients
• The average increase in life expectancy for marginal kidney recipients compared
with the waitlisted dialysis cohort was 5 years
• The transplantation of a marginal kidney is associated with a significant survival
benefit when compared with maintenance dialysis
1. Ojo A.O., Hanson J.A., Meier-Kriesche H., et. al.: Survival in recipients of marginal cadaveric donor kidneys compared with other recipients and wait-listed
transplant candidates. J Am Soc Nephrol 2001; 12: pp. 589-597.

• A large retrospective cohort study using data from a US national registry
comparing mortality after ECD kidney transplantation vs those receiving dialysis
• Long-term relative mortality risk was 17% lower for ECD recipients
• The survival benefit was apparent only at 3.5 years after transplantation due to
high early mortality rate in ECD recipients
• Subgroups with significant ECD survival benefit included
Patients >40 years
Patients of low immunological risk
Patients with diabetes or hypertension
A long median waiting time (>3.7 years) for transplantation
1. Merion RM, Ashby VB, Wolfe RA, Distant DA, Hulbert-Shearon TE, Metzger RA, Ojo AO, Port FK. Deceased-donor characteristics and the survival benefit of kidney
transplantation. JAMA 2005; 294: 2726-2733

• A systematic review of kidney transplant from MEDLINE and EMBASE databases
• ECD kidneys have worse long-term survival than SCD kidneys
• Patients younger than 40 years of age or scheduled for kidney re-transplantation
should not be listed for an ECD kidney
• Patients >40 years, with a long expected waiting time >4 years for transplantation
show better survival receiving an ECD kidney than remaining on dialysis therapy
1. Pascual J, Zamora J, Pirsch JD. A systematic review of kidney transplantation from expanded criteria donors. Am J Kidney Dis 2008; 52: 553-586

• Study of 145,470 patients using the Scientific Registry of Transplant Recipients
• ECD kidneys were associated with higher mortality and higher risk of transplant
loss among recipients between 18 to 70 years of age
• No significantly increased mortality or increased risk of transplant loss were
noted among recipients older than 70 years of age
1. Molnar MZ, Streja E, Kovesdy CP, Shah A, Huang E, Bunnapradist S, Krishnan M, Kopple JD, Kalantar-Zadeh K. Age and the associations of living donor and
expanded criteria donor kidneys with kidney transplant outcomes. Am J Kidney Dis 2012; 59: 841-848

• A meta-analysis of 29 studies to assess the results of ECD transplantation
• ECD recipients seemed to have poorer prognosis than SCD recipients
1. Querard A-H, Foucher Y, Combescure C, Dantan E, Larmet D, Lorent M,et al. Comparison of survival outcomes between expanded criteria donor and standard
criteria donor kidney transplant recipients: a systematic review and meta-analysis. Transpl Int Off. (2016) 29:403–15.
5‐year pooled survival probabilities ECD SCD
Patient‐graft survival (%) 59.2 75.1
Patient survival (%) 78.4 86.4
Death‐censored graft survival (%) 75.6 84.6

Subgroups with significant survival benefit after ECD
kidney transplantation
Patients older than 40 years
Long median waiting time (>4 years)
Patients with diabetes or hypertension
Patients of low immunological risk
Dialysis patients with vascular access problems
Dialysis patients whose life expectancy in dialysis is lower than
the estimated waiting time for kidney transplantation

The immunological risk of ECD kidneys
Kidneys from older donors are generally more immunogenic than kidneys from young donors
Experimental studies have shown an intense inflammatory response and increased T-cell immune
reactivity in recipients of deceased or older donor kidney allografts1
Subsequently, increased incidence of acute rejection is observed among ECD kidney transplant
recipients in the early post-transplantation period
The Eurotransplant Senior Program (ESP) demonstrated acute rejection rate of 30%2
Aged kidneys have an increased susceptibility to ischemia-reperfusion injury
Further, kidneys from older donors seem to have an impaired cellular repair mechanism
1. Pratschke J, Merk V, Reutzel-Selke A, Pascher A, Denecke C, Lun A, Said A, Schönemann C, Ulrich F, Reinke P, Frei U, Neuhaus P, Tullius SG. Potent early immune
response after kidney transplantation in patients of the European senior transplant program. Transplantation 2009; 87: 992-1000
2. Frei U, Noeldeke J, Machold-Fabrizii V, Arbogast H, Margreiter R, Fricke L, Voiculescu A, Kliem V, Ebel H, Albert U, Lopau K, Schnuelle P, Nonnast-Daniel B, Pietruck F,
Offermann R, Persijn G, Bernasconi C. Prospective age-matching in elderly kidney transplant

The immune response in elderly recipients
ECD kidney transplant recipients are mostly of advanced age
The immune response, both innate and adaptive, decrease with increased age, resulting in
decreased risk of immunologic rejection and increased risk of infection
For patients 18 years of age, the rejection rate was 28% compared to only 14% for those aged 70
years1
This finding is consistent with previous experimental data showing that ageing is associated with a
reduced cellular immunity and CD4+ T-cell response and a reduced ability to reject the skin allograft2
1. Tullius SG, Milford E. Kidney allocation and the aging immune response. N Engl J Med 2011; 364: 1369-1370
2. Miller RA, Garcia G, Kirk CJ, Witkowski JM. Early activation defects in T lymphocytes from aged mice. Immunol Rev 1997; 160: 79-90

The transplant recipients: elderly vs younger
Independent of real rejection rates, the risk of transplant loss from rejection is higher in
older recipients compared with younger recipients
There is an increased risk of chronic allograft nephropathy among older recipients, which
is enhanced if the graft is from an older donor1
Despite less overall immunosuppression, the older patients still had an increased risk of
infectious death2
The elderly transplant recipients aged 65 year or older showed a fivefold increase in the
risk of malignancies3
1. Meier-Kriesche HU, Cibrik DM, Ojo AO, Hanson JA, Magee JC, Rudich SM, Leichtman AB, Kaplan B. Interaction between donor and recipient age in determining
the risk of chronic renal allograft failure. J Am Geriatr Soc 2002; 50: 14-17
2. Knoll GA. Kidney transplantation in the older adult. Am J Kidney Dis 2013; 61: 790-797
3. B.L.Kasiske, J. J.Snyder,D. T.Gilbertson, and C.Wang, “Cancer after kidney transplantation in the United States,” American Journal of Transplantation, vol. 4, no. 6,
pp. 905–913, 2004.

What should be our plan?
Avoid “ECD”
Rather “Optimized Allocation”
X

Life is a journey
Remaining life years
Remaining miles to travel

Optimized Matching
Lucknow to Kanpur
Lucknow to Mumbai

Optimized Allocation of ECD kidney
Modifying allocation rules for ECD kidneys in an effort to match the appropriate kidney to
the appropriate recipient
Minimizing risk factors for DGF: Lowering CIT, pulsatile perfusion preservation
Preimplantation renal biopsy for ECD kidney recipients
Simultaneous dual ECD kidney transplantation
Restricting the use of ECD kidneys to patients of low immunological risk
Applying individualized immunosuppressive regimens

Optimized Allocation strategy by Bryce Kiberd
The strategy proposed by Bryce Kiberd et al. was to retrieve all kidneys
• Visibly scarred kidneys should be discarded
• Biopsy some deceased donors kidneys
 Age >65
 Age >55 and donor CrCl <70 ml/min
 Discard advanced arteriolar sclerosis or interstitial fibrosis
• Allocate to
 Older (>59) or diabetic
 Avoid the sensitized
 Minimize cold ischemic time
 Avoid large weight or age mismatches
1. Bryce Kiberd. Optimizing ECD Utilization Expanded Criteria Donor: Revisited? (2011) http://www.cdha.nshealth.ca/multi-organ-transplant-program/documents, 3
may2011

Role of pre-implantation kidney biopsy
• In 1999, Karpinski et al. documented the relevance of a pre-implantation biopsy
of the donor kidney over the transplant outcomes
• Scores from 0-3 in 4 areas: glomerulosclerosis, interstitial fibrosis, tubular atrophy
and vascular disease
• A donor vessel score of 3/3 is associated with a 100% incidence of delayed graft
function and a significantly worse renal function at one year
1. Karpinski J, Lajoie G, Cattran D, et al (19990. Outcome of kidney transplantation from high risk donors is determined by both structure and function.
Transplantation. 1999; 67:1162-1167.

Role of pre-implantation kidney biopsy
• Remuzzi et al. histologically scored ECD kidney on the severity of chronic changes
• Score 0-3 each component: vessels, glomeruli, tubules and interstitium
• Total score (0-12)
0-3 single kidney
4-6 dual kidneys
>6 discard
• Additionally, the study documents the importance of the pre-transplant biopsy
for donors >60 years when comparing renal outcomes with and without biopsy
1. Remuzzi G, Cravedi P, Perna A, Dimitrov BD, Turturro M, Locatelli G, Rigotti P, Baldan N, Beatini M, Valente U, Scalamogna M, Ruggenenti P; Dual Kidney Transplant
Group. Long-term outcome of renal transplantation from older donors. N Engl J Med 2006; 354: 343-352

Deceased Donor Score (DDS)
• Nyberg et al. developed Deceased Donor Score or Nyberg score to predict renal
function at 12 months and graft survival at 6 years
• Five clinical variables as predictive of a poorer outcome
1. Age
2. Cause of death
4. Creatinine clearance
5. HLA mismatch
• Scores of 0-39 points and stratifies deceased kidneys into four grades (A, B, C, D)
• They reported a significant number of cadaveric donor kidneys (10.7%) identified
by the DDS system as likely to have decreased post-transplant function and graft
survival that were missed by the ECD system
1. Nyberg SL, Matas AJ, Kremers WK, Thostenson JD, Larson TS, Prieto M, Ishitani MB, Sterioff S, Stegall MD. Improved scoring system to assess adult donors for
cadaver renal transplantation. Am J Transplant 2003; 3: 715-721

KDRI vs KDPI
1. Rao PS, Schaubel DE, Guidinger MK, Andreoni KA, Wolfe RA, Merion RM, Port FK, Sung RS. A comprehensive risk quantification score for deceased donor kidneys: the kidney
donor risk index. Transplantation 2009; 88: 231-236
2. OPTN. Organ Procurement and Transplantation Network. http://optn.transplant.hrsa.gov//converge/resorces/allocationcalculators.asp?index=81isSubmit=trueextra=true#bottom
In 2009, Rao et al1 analyzed 69440 deceased donor adult transplants registered in
the Scientific Registry of Transplant Recipients and proposed a new continuous the
Kidney Donor Risk Index (KDRI)
KDRI included 14 donor and transplant factors, each associated with shorter graft
survival
The United Network for Organ Sharing (UNOS) Kidney Transplantation Committee
announced a new allocation criterion in 2013, based on KDRI, which was then
revamped and finalized to the Kidney Donor Profile Index (KDPI)2
KDPI compiled ten donor only factors that are independently associated with graft
survival

KDPI scoring system
No need of a kidney biopsy
KDPI based on:
1. Donor age
2. Height
3. Weight
4. Ethnicity
6. History of diabetes
7. Cause of death
8. Serum creatinine
9. Hepatitis C virus status
10.Donation after circulatory death
• KDPI scores range from 0-100%
• Lower KDPI is associated with better
graft survival

Estimated graft half life
1. United States Renal Data System. Annual Data Report: Atlas of End Stage Renal Disease in United States. National Institute of Diabetes and Digestive and Kidney
Disease, Bethesda, MD: National Institutes of Health (2016).
Lower KDPI is associated with better graft survival

Why KDPI over ECD?
Issues with ECD
• Donor age - main criteria in assessment of quality of an organ
• Low predictive value because of binary (yes/no) characteristics
• High discard rate of 40%
Benefits of KDPI
• KDPI scoring system represent a continuum
• KDPI is a measure of the donor and is not specific for each kidney taken
individually

Estimated Post-Transplant Survival Score
• The EPTS score was developed by the Scientific Registry of Transplant Recipients
to classify transplant candidates
• The score was established by analyzing the relationship between characteristics
of deceased donor kidney recipients and their survival times after transplant
• EPTS scores range from 0 to 100%
• Candidates with a lower EPTS score are expected to have better graft survival
1. https://optn.transplant.hrsa.gov/media/1511/guide_to_calculating_interpreting_epts.pdf

Estimated Post-Transplant Survival Score
The factors included are:
1. Candidate’s age (years)
2. Duration on dialysis (years)
3. Current diagnosis of diabetes
4. Whether a prior solid organ transplant
Candidates with EPTS scores of 20% or less will receive increased priority for offers
for kidneys with KDPI scores of 20% or less
The intent of longevity matching is to ensure that those kidneys expected to function the
longest are most often transplanted into those candidates expected to live the longest

United Network of Organ Sharing allocation policy
• The UNOS approved a new allocation policy, based on the Kidney Donor Profile
Index (KDPI)
• KDPI represents an improvement over the old ECD/SCD dichotomy, considering
that not all ECD kidneys are alike
• Kidneys with KDPI >85% are offered to a wider geographic area to promote
broader sharing and expedite utilization
1. Tso PL Access to renal transplantation for the elderly in the face of new allocation policy: a review of contemporary perspectives on “older” issues. Transplant Rev
(Orlando) 2014; 28:6–14.

Overall Changes to Allocation System
Waiting time
calculation
• Pre-registration dialysis time added
Candidate
classification
• Estimated Post Transplant Survival Score
(EPTS)
Kidney donor
classification
• Replaced SCD/ECD with Kidney Donor Profile
Index (KDPI)

Longevity matching
• The KDPI is used in tandem with EPTS to introduce the concept of “longevity
matching”
• The concept consists of allocating kidneys with a higher KDPI to patients on
dialysis with a lower life expectancy
“Old for old”
• Common practice in the United States as well as Europe is to place older donor
kidneys in older patients (Voiculescu et al, 2002; Smits et al, 2002; Kasiske et al,
2002; Lee et al, 1999)

EPTS & KDPI in the New System
Longevity Matching
EPTS
0-20%
KDPI
0-20%
The intent is to realize the most benefit from the highest quality kidneys

Calculated PRA
Calculated PRA is the percentage of donors expected to have HLA antigens listed as
unacceptable for a candidate on the waiting list
cPRA is determined using an algorithm and HLA frequencies derived from the HLA
phenotypes of more than 12,000 donors entered into the US OPTN registry
cPRA scores range from 0% to 100%
1. Zachary AA and Steinberg AG. Statistical Analysis and Applications of HLA Population Data. In, NR Rose, EC de Marcario, JD Folds, HC Lane, and RM Nakamura, Eds.,
Manual of Clinical Laboratory Immunology, 5th Edition, Washington, DC, ASM Press, 1997:132-40.

cPRA priority points
Sensitized candidates receive increased priority through a sliding scale points system for
cPRA, and regional and national priority for very highly sensitized candidates (cPRA > 98%)
0 0 0 0.08 0.21 0.34 0.48 0.81 1.09
1.58 2.46
4.05
6.71
10.82
12.17
17.30
0
2
4
6
8
10
12
14
16
18
20
0 10 20 30 40 50 60 70 80 90 100
Points
CPRA Sliding Scale (Allocation Points)
(CPRA<98%)

Pulsatile perfusion machine
Conventionally, kidneys were maintained in static cold storage before implantation
Hypothermic machine perfusion reduces cell metabolism by dropping the
temperature while maintaining tubular, glomerular and endothelial function with
the pulsatile flow, resulting in reduced intra-renal resistance
Normothermic machine perfusion adopts the passage of warmed, oxygenated, red
cell-based solution through the kidney, to allow for ex vivo preservation and
characterization of the kidney

Dual Kidney Transplantation
• Following the Remuzzi’s scoring, DKT is increasingly utilized to compensate for the risk of poor
long-term graft survival outcomes associated with age-related low nephron mass
• In adult recipients, DKT can be performed either bilaterally or unilaterally
• Unilateral placement offers the advantages of single surgical access and shorter operating time,
and allows the contralateral iliac fossa to be available for future re-transplantation

Immunosuppression in ECD
Kidney Recipients

General principles
• Optimal immunosuppression is a challenge in marginal kidney recipients
• Older patients and recipients of ECD kidneys are often excluded from clinical trials
• The pharmacokinetics of drugs are altered in older adults due to a decline in
cytochrome P450 activity
• CNI nephrotoxicity is more in older recipients of ECD kidneys
 Increased rates of acute rejections and delayed graft function, especially in the
early post-transplantation period
 Patient death is the most common cause of graft loss in elderly and infection is a
leading cause of death

General principles
Immunosuppression should be focused on:
1. Nephrotoxicity minimization
2. Adequate infection prophylaxis

Immunosuppressive strategies in ECD kidney
transplantation
Induction with ATG
Reduce overall immunosuppression, especially in elderly recipients of ECD kidneys
Reduced CNI exposure regimens (target CNI blood levels 25%-50% lower)
Delayed CNI introduction regimens
CNI-free regimens based on MMF and steroids with ATG induction
CNI-free Belatacept-based regimens
CNI-free mTOR-inhibitors-based regimens

• A retrospective analysis of United Network of Organ Sharing data from 2003 to
2008 of 14,820 elderly recipients (>60 years)
• These data suggest that ATG might be the preferred induction agent for high-risk
elderly recipients of a high-risk donor organ, such as an ECD kidney
1. Gill J, Sampaio M, Gill JS, Dong J, Kuo HT, Danovitch GM, Bunnapradist S. Induction immunosuppressive therapy in the elderly kidney transplant recipient in the
United States. Clin J Am Soc Nephrol 2011; 6: 1168-1178
Results IL2RA vs rATG
High-risk recipient and high-risk donor Higher risk of rejection and graft loss with IL2RA
Low-risk recipient and low-risk donor No difference in outcomes between IL2RA and rATG
High-risk donor or recipient Higher risk of rejection but not graft loss with IL2RA

Maintenance immunosuppression
• CNIs sparing regimens have been advocated for older recipients of ECD kidneys
• ECD kidneys may be susceptible to CNI-mediated vasoconstriction that may
prolong ischemic injury in the early post-transplant phase
• In the long term, chronic CNI nephrotoxicity is a major concern

• Strategies for CNI toxicity minimization:
Delay CNI introduction until a certain level of renal graft function is achieved
Reduced CNI exposure regimens to target towards lower CNI levels
Complete CNI-free strategies
Conversion from a CNI based regimen to a sirolimus-based regimen
• However, such regimens, have been associated with an increased incidence of
acute rejection

• Delayed CNI introduction: several studies have reported acute rejection rates of
6% to 23%, DGF rates of 31% to 54%, and patient and graft survival compared to
SCD recipients
• mTOR inhibitors: large randomized controlled studies are missing, but smaller
non-randomized studies showed acceptable results of graft survival and rejection
rate with sirolimus or everolimus

Study characteristics of trials evaluating immunosuppressive regimen in expanded criteria donors

• BENEFIT-EXT was the first randomized controlled trial of its kind to study
immunosuppression in ECD kidney recipients
• Patients were randomized (1:1:1) to receive primary immunosuppression with a
belatacept MI (more intense), belatacept LI (less intense) or cyclosporine based regimen
• All patients received basiliximab induction, MMF and steroids
• Belatacept had comparable graft loss and death rates as cyclosporine but improved renal
function at 7 years after transplant
• Mean eGFR at 7 years was 53.9, 54.2 and 35.3 mL/min for belatacept MI, belatacept LI
and cyclosporine, respectively
1. Durrbach A, Pestana JM, Florman S, Del Carmen Rial M, Rostaing L, Kuypers D, et al. long-term outcomes in belatacept- versus cyclosporine-treated recipients of
extended criteria donor kidneys: Final results From BENEFIT-EXT, a phase III randomized study. Am J Transplant 2016;16:3192-201.

The Eurotransplant Senior Program (ESP)
ESP began in January 1999 within a narrow geographic area (Austria, Belgium, Germany,
Luxembourg, The Netherlands and Slovenia)
Deceased donors aged ≥65 years are allocated to unsensitized recipients aged ≥65 years
(PRA < 5%)
Donor HLA-typing is not required, allocation is done by ABO group matching, negative
crossmatch, and a local allocation based on waiting time to minimize cold ischemia time
This policy expanded the donor and recipient pools without significantly affecting patient
and graft survival
However, 5%-10% higher acute rejections were reported due to a higher number of HLA
mismatches
1. U. Frei, J. Noeldeke, V. Machold-Fabrizii et al., “Prospective age-matching in elderly kidney transplant recipients—a 5- year analysis of the Eurotransplant Senior
Program,” American Journal of Transplantation, vol. 8, no. 1, pp. 50–57, 2008.

Conclusion
Use of marginal donors for kidney transplant increases the donor pool
It results in shorter waiting time for transplantation
Limits morbidity and mortality associated with long term dialysis therapy
Management protocols should be based on nephron protecting strategies
• Minimizing cold ischemia time
• Tailored immunosuppression with early CNI reduction or delayed CNI after induction
• Adequate infection prophylaxis

Marginal Donors and Kidney Transplant Outcomes

Marginal Donors and Kidney Transplant Outcomes

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