Delayed Graft Function in Kidney Transplantation: Developing Drugs for Prevention Guidance for Industry

Administrative guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

Delayed Graft Function in
Kidney Transplantation:
Developing Drugs for
Prevention
Guidance for Industry
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
July 2019
Clinical/Medical

Delayed Graft Function in
Kidney Transplantation:
Developing Drugs for
Prevention
Guidance for Industry
Additional copies are available from:
Office of Communications, Division of Drug Information
Center for Drug Evaluation and Research
Food and Drug Administration
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor
Silver Spring, MD 20993-0002
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353; Email: druginfo@fda.hhs.gov
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs
and/or
Office of Communication, Outreach, and Development
Center for Biologics Evaluation and Research
Food and Drug Administration
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Silver Spring, MD 20993-0002
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https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-
guidances
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
July 2019
Clinical/Medical

TABLE OF CONTENTS
I. 	INTRODUCTION............................................................................................................. 1
II. 	BACKGROUND AND DEFINITIONS .......................................................................... 2
III. 	DEVELOPMENT PROGRAM ....................................................................................... 4
A. 	General Considerations ................................................................................................................. 4
1. Efficacy Considerations ................................................................................................................... 4
2. Safety Considerations ...................................................................................................................... 4
B. 	Specific Efficacy Trial Considerations ......................................................................................... 4
1. Study Design, Randomization, Stratification, and Blinding ............................................................ 4
2. Study Population and Specific Populations ..................................................................................... 5
3. Entry Criteria ................................................................................................................................... 5
4. Organ Storage Conditions and Use of Concurrent Immunosuppressants and Other Medications . 5
5. Dose Selection.................................................................................................................................. 5
6. Choice of Comparators .................................................................................................................... 6
7. Efficacy Endpoints ........................................................................................................................... 6
a. 	Primary efficacy endpoint ......................................................................................................... 6
b. 	Secondary efficacy endpoints ................................................................................................... 7
8. Safety Considerations ...................................................................................................................... 7
9. Study Procedures and Timing of Assessments ................................................................................. 8
10. 	Endpoint Adjudication ................................................................................................................. 8
11. 	Statistical Considerations............................................................................................................ 8
12. 	Accelerated Approval (Subpart H) Considerations..................................................................... 9
13. 	Risk-Benefit Considerations ........................................................................................................ 9
REFERENCES............................................................................................................................ 10

Contains Nonbinding Recommendations
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Delayed Graft Function in Kidney Transplantation:
Developing Drugs for Prevention
Guidance for Industry1
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on
this topic. It does not establish any rights for any person and is not binding on FDA or the public. You
can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.
To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the
title page.
I. 	INTRODUCTION
The purpose of this guidance is to assist sponsors in the clinical development of drugs for the
prevention of delayed graft function (DGF) in kidney transplantation.2 Specifically, this
guidance addresses the Food and Drug Administration’s (FDA’s) current thinking regarding the
overall development program and clinical trial designs for systemic drugs administered to the
kidney transplant recipient to support an indication of prevention of DGF.
This guidance does not address the treatment of DGF in the recipient or the treatment of the
donor or the graft for the purpose of preserving or improving graft quality. These issues may be
addressed in separate guidances.
This guidance does not contain discussion of the general issues of statistical analysis or clinical
trial design. Those topics are addressed in the ICH guidances for industry E9 Statistical
Principles for Clinical Trials (September 1998) and E10 Choice of Control Group and Related
Issues in Clinical Trials (May 2001), respectively.3
In general, FDA’s guidance documents do not establish legally enforceable responsibilities.
Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only
1 This guidance has been prepared by the Division of Transplant and Ophthalmology Products in the Center for
Drug Evaluation and Research in cooperation with the Center for Biologics Evaluation and Research at the Food and
Drug Administration.
2 For purposes of this guidance, unless otherwise specified, references to drugs and drug products include drugs
submitted for approval or approved under section 505(b) or (j) of the Federal Food, Drug, and Cosmetic Act (FD&C
Act) and biological products licensed under section 351 of the Public Health Service Act, other than biological
products that also meet the definition of a device in section 201(h) of the FD&C Act (21 U.S.C. 321(h)).
3 We update guidances periodically. To make sure you have the most recent version of a guidance, check the FDA
guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents.

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as recommendations, unless specific regulatory or statutory requirements are cited. The use of
the word should in Agency guidances means that something is suggested or recommended, but
not required.
II. 	BACKGROUND AND DEFINITIONS
DGF, presenting as suboptimal renal function immediately following kidney transplantation, is a
manifestation of ischemia-reperfusion injury (IRI) in the transplanted kidney allograft. For the
purpose of this guidance, DGF is defined as the need for dialysis within 7 days of
transplantation, although other definitions and methods to assess early graft dysfunction have
also been published (Mallon et al. 2013; Yarlagadda et al. 2008), including the following:
• 	The need for one or more hemodialysis treatments following transplantation (not limited
to 7 days) before the onset of graft function (Singh et al. 2011).
• 	Days to reach a calculated estimated glomerular filtration rate of greater than or equal to
10 milliliters (mL) per minute (min) post-transplant. The duration of DGF was defined
as number of days for the kidney to attain the threshold of 10 mL per min (Giral-Classe et
al. 1998).
• 	Creatinine reduction ratio between Day 0 and Day 7 of less than 70 percent (Johnston et
al. 2006).
DGF (and other manifestations of early graft dysfunction after transplantation) is caused by
kidney allograft injury sustained during donor management, organ recovery, storage,
implantation, reperfusion, and recipient-related factors. Changes consequent to brain death in
donors (i.e., donation after brain death (DBD)) and IRI affect organ quality. Periods of warm
ischemia related to hypotension and hypoperfusion during donor management and/or prolonged
cessation of perfusion in a donor after cardiac death (DCD) cause acute injury in the allograft.
The injuries sustained by the kidney allograft, along with subsequent innate and adaptive
immune responses, contribute to the complex pathophysiologic mechanisms resulting in DGF.
DGF is observed more frequently after deceased donor (including DBD and DCD) kidney
transplantation than after living donor (LD) kidney transplantation.
Although DGF episodes with different types of donors (DCD, DBD, or LD) have similar short-
term manifestations following transplantation, they may represent different pathophysiological
processes with different long-term allograft outcomes. As described in the published literature,
despite higher rates of DGF and acute rejection reported in recipients of DCD kidneys compared
to recipients of DBD or LD kidneys, subsequent survival and organ function in recipients of
DCD kidneys with DGF may be better than in recipients of DBD kidneys with DGF (Singh et al.
2011). Therefore, potential treatments may have a different effect on the prevention of DGF
after transplantations of kidneys from the different types of donors. Overall, the outcome is
likely to depend on the relative contribution of different donor, preservation, or recipient-related
factors with a consequent differential response to the investigational drug.

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In addition to DGF, other grades and severities of inadequate renal function have been defined in
the published literature, including primary nonfunction (PNF) and slow graft function (SGF) or
functional DGF (fDGF).
PNF describes the condition in which the kidney never functions adequately after
transplantation, and the patient continues to need dialysis despite the transplant. The diagnosis
of PNF generally does not become established before 2 to 3 months (60–90 days) after
transplantation (Stevens et al. 2009; Woo et al. 1999).
SGF or fDGF describes kidney allograft dysfunction occurring early after transplantation, but the
dysfunction may not be severe enough to warrant dialysis. These other forms of dysfunction
may still portend a diminished graft and/or patient survival. Various definitions of SGF and/or
fDGF are used in the published literature, including the following:
• 	fDGF defined as failure of serum creatinine level to decrease by at least 10 percent daily
on 3 consecutive days during the first postoperative week irrespective of dialysis
requirement (Moore et al. 2010)
• 	SGF defined as serum creatinine greater than 3 milligrams (mg) per deciliter and no need
for dialysis at Day 5 post-transplant (Humar et al. 1997; Humar et al. 2002)
• 	Mild DGF defined as a serum creatinine reduction ratio from post-transplant Day 1 to
Day 2 (CRR2) less than or equal to 30 percent plus 24-hour urine creatinine excretion
(UC2) on Day 2 greater than 1,000 mg (Govani et al. 2002; Rodrigo et al. 2004)
• 	Severe DGF defined as a serum CRR2 less than or equal to 30 percent plus 24-hour UC2
on Day 2 less than or equal to 1,000 mg (Govani et al. 2002; Rodrigo et al. 2004)
The main reason to prevent DGF is to avoid the need for dialysis. Dialysis is a choice of last
resort and puts the graft at risk because of potential hypotension, risk of thrombosis, increase in
hospitalization, and worse clinical outcome, as reported in various publications cited above.
It has further been reported that DGF is associated with adverse effect on important graft
outcomes such as graft survival, acute rejection, and renal function (Yarlagadda et al. 2009). A
web-based model for predicting DGF after renal transplantation was developed using factors
such as cold ischemia time, donor creatinine, body mass index, donation after cardiac death, and
donor age (Irish et al. 2010). In addition to predicting DGF, this model also predicted long-term
graft failure, thus demonstrating an unfavorable effect of DGF (or the factors leading to DGF) on
long-term graft survival. Although prevention of DGF may result in long-term benefits, such as
improved patient and graft survival, these benefits have yet to be demonstrated.

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III. 	DEVELOPMENT PROGRAM
A. 	General Considerations
1. 	Efficacy Considerations
Trials to demonstrate that treatments reduce the risk of DGF should be superiority trials in which
an active treatment is compared to placebo because there is no approved drug that reduces the
risk of DGF and there is no standard of care that has been demonstrated to be effective.
If the drug is an unapproved drug, in general, we recommend two adequate and well-controlled
trials to provide evidence of effectiveness. A single adequate and well-controlled trial supported
by confirmatory information, such as a trial in a closely related indication (e.g., based on
mechanism of action, target receptor), could potentially provide evidence of effectiveness in the
prevention of DGF. A single adequate and well-controlled trial could provide evidence of
effectiveness if the results were statistically strong and the trial had other strong features (many
sites, consistent results). Sponsors should discuss with the Agency the confirmatory evidence
that could support a significant finding from a single adequate and well-controlled trial.
2. 	Safety Considerations
In general, we recommend a preapproval safety database of 300 patients or more on the
investigational drug.4 If the same or greater dose and duration of therapy for the prevention of
DGF were used in clinical trials for other disease indications, the safety information from those
clinical trials can be part of the overall preapproval safety database.
For new drugs that have an important clinical benefit compared to current management
strategies, depending on the benefit demonstrated, a smaller preapproval safety database may be
sufficient. Sponsors should discuss the appropriate size of the preapproval safety database with
the Agency during clinical development.
B. 	Specific Efficacy Trial Considerations
1. 	Study Design, Randomization, Stratification, and Blinding
The clinical trial population for efficacy trials should include de novo kidney transplant
recipients and be representative of a U.S. patient population, including race, age, sex, and other
baseline characteristics.
4 A safety database large enough to rule out a serious adverse event that occurs at the rate of 1 in 100 or higher may
be suitable when there are limited therapeutic options. For example, when there are no serious and unexpected
adverse events in approximately 300 patients, then the true rate of serious and unexpected adverse events is likely to
be fewer than 1 in 100 or 1 percent (Hanley and Lippman-Hand 1983).

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The type of donors, preferably graded by the kidney donor profile index implemented by the new
Kidney Allocation System,5 should be specified in the protocol. Consideration should be given
to stratifying the study population, for example, based on study center and/or the type of
induction treatment (if there is more than one). If the sponsor plans to enroll recipients of the
DCD donor kidneys or donor kidneys preserved by machine perfusion, we highly recommend
stratification based on the type of donor (DCD versus DBD) and organ preservation method.
The trials should be randomized and double-blinded.
2. 	Study Population and Specific Populations
Enrichment strategies can be used to select a study population at a higher risk for developing
DGF compared to the overall kidney transplant recipient population for these clinical trials, as
discussed in the guidance for industry Enrichment Strategies for Clinical Trials to Support
Determination of Effectiveness of Human Drugs and Biological Products (March 2019).
3. 	Entry Criteria
The protocol should specify the inclusion and exclusion criteria that will be used to select
patients to participate in the clinical trial, including any enrichment strategies.
4. 	Organ Storage Conditions and Use of Concurrent Immunosuppressants and
Other Medications
The protocol should specify the type of organ recovery, storage, and transport conditions:
machine perfusion (cold or warm) or static cold storage.
Immunosuppressive (IS) therapy after transplantation should be specified, including the
induction regimen(s) and the maintenance therapy. In clinical trials of DGF, the Agency highly
recommends that the type of induction, including the initial intravenous corticosteroid boluses at
the time of transplantation and the maintenance IS therapy, be standardized across the treatment
groups to minimize the potential confounding effect of these factors on the study endpoints.
The protocol should state that data on the IS and other medications used in the study patients
should be collected on the case report forms (CRFs). For drugs managed using therapeutic drug
monitoring, drug trough levels should be collected on the CRF.
5. 	Dose Selection
Sponsors should conduct dose-ranging studies during phase 1 or phase 2 testing. Generally,
trials to prevent DGF (and other forms of early graft dysfunction) would be expected to have a
short duration of treatment, so different dosage regimens could be evaluated in the first week
after transplantation.
5 See the U.S. Department of Health and Human Services Kidney Allocation System web page at
https://optn.transplant.hrsa.gov/learn/professional-education/kidney-allocation-system/.

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6. 	Choice of Comparators
Trials should be placebo-controlled, as at present there are no approved therapies and no
standard of care for the prevention of DGF.
7. 	Efficacy Endpoints
a. 	Primary efficacy endpoint
Sponsors should consider the following when choosing a primary efficacy endpoint:
• 	Short-term assessment endpoint
‒ 	Short-term assessment of the graft function for efficacy — In the short-term
assessment of the graft function, the common definition of DGF (i.e., the requirement
for hemodialysis treatment within the first 7 days post-transplant) can be used as the
primary endpoint. Sponsors can also propose other definitions of DGF supported by
literature.
As an alternative to the assessment of the occurrence of DGF as a binary endpoint,
DGF severity scoring systems can be proposed. These could include the number of
hemodialysis sessions required until recovery of renal function or time to recovery of
renal function after the diagnosis of DGF. If the DGF severity scoring endpoint is
chosen as the primary endpoint, the sponsor should provide a justification for the
clinical significance and relevance of the proposed score difference to be
demonstrated.
In addition to recording any hemodialysis sessions during the first 7 days post-
transplant, information on hemodialysis sessions after Day 7 until post-transplant Day
30, regardless of the reason for dialysis, should be collected on the CRFs to evaluate
the durability of treatment and should be submitted in the final study report.
‒ 	Short-term endpoint using SGF and fDGF — Another option is to select a short-term
primary endpoint based on definitions of suboptimal renal allograft function, such as
SGF or fDGF. The protocol should include the specific definition of SGF and/or
fDGF that will be used. If the primary endpoint definition includes a particular
definition of renal allograft function, the sponsor should justify the clinical benefit of
such an endpoint and the sponsor should discuss the proposed endpoint definition
with the FDA. Long-term clinical benefit such as an improvement in graft or patient
survival may need to be demonstrated.
• 	Long-term efficacy and improved renal function — If an additional goal of the clinical
trial is to demonstrate that the drug leads to an overall sustained improvement in renal
function, compared to placebo, then renal function data need to be collected for all
patients for a minimum of 12 months. A clinically meaningful difference in renal

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function (assessed using serum creatinine levels or glomerular filtration rate) should be
justified before study initiation.
b. 	Secondary efficacy endpoints
Sponsors should consider the following when choosing secondary efficacy endpoints:
• 	DGF — If one of the DGF severity scoring methods is chosen for the primary endpoint,
the classic definition of DGF (i.e., requirement of dialysis within the first 7 days post-
transplant) should be among the secondary endpoints
• 	Day 30 analysis — The purpose of this analysis is to evaluate the durability of treatment
effect after the first week post-transplant
• 	Renal function — The comparison of renal function (measured or calculated) between
the treatment and placebo arms at prespecified time points for 12 months post-transplant
should be among the secondary endpoints
• 	Definitions of SGF or fDGF can be among the secondary endpoints.
8. 	Safety Considerations
Because dosing is expected to occur during the first week post-transplant, intensive laboratory
testing and collection of adverse event data for 30 days of follow-up may be sufficient.
Depending on the pharmacokinetic/pharmacodynamic (PK/PD) properties of the drug, longer
clinical and laboratory follow-up for drug-associated adverse events could be needed.
As noted above, the primary efficacy endpoint can be evaluated when data are available for the
first 30 days post-transplant. However, additional follow-up is needed to understand the long-
term effect of a drug to prevent DGF on the kidney allograft and patient.
For this indication, the mechanism of action of the drug is related to preventing injury and
inflammation. The primary mechanism of action is not as an immunosuppressant (these drugs
are not primarily intended to suppress T-cells and B-cells, per se). However, one cannot assume
the drug for DGF is neutral with respect to IS or other related effects (low white blood cell,
cytomegalovirus pneumonia). Therefore, acute rejection, graft loss, and death are not efficacy
endpoints; rather, they are safety endpoints in trials of drugs to prevent DGF. The reason for
longer follow-up is to assess whether the DGF drug has an unintended effect on the kidney
allograft (toxicity) and whether that toxicity affects the kidney’s ability to function, making it
susceptible to rejection or other injury and affecting survival (either favorably or adversely). The
general duration of follow-up for safety should be a minimum of 12 months, and information
should be collected on the survival and function of the graft (including episodes of rejection), the
occurrence of hospitalization, and other serious adverse events, patient survival at a minimum at
Month 3 (approximately Day 90), Month 6, and Month 12, as follows:

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• 	Patient and graft survival — Patient and graft survival data should be among the safety
endpoints, and data for at least 12 months post-transplant should be collected
• 	Rejection — Acute cellular rejection and antibody mediated rejection episodes should be
recorded on the CRFs for at least 12 months post-transplant and analyzed as part of the
safety endpoints
• 	Hospitalizations — Data on hospitalizations should be collected for at least 12 months
post-transplant and analyzed as part of the safety endpoints
9. 	Study Procedures and Timing of Assessments
The primary endpoint can be assessed at Day 7 post-transplant. The need for dialysis between
Day 7 and Day 30 should also be evaluated, including the number of dialysis sessions captured
on the CRF, for assessment of the durability of treatment effect.
To evaluate the comparability of the study groups, dialysis sessions in the week before transplant
should be captured on the CRF.
For the assessment of safety, information on all adverse events and laboratory tests should be
collected for up to Day 30 for drugs with short half-lives. However, depending on the PK
characteristics and duration of PD effect, longer follow-up with collection of laboratory data and
adverse event assessments may be needed.
Data on the following types of serious adverse events should be collected for a minimum of 12
months: acute rejection, graft loss, hospitalizations (e.g., for infection, new onset diabetes after
transplantation, neurologic adverse events, malignancies), and patient death. All attempts should
be made to collect these data; missing information on hospitalizations or acute rejection should
be minimized.
10. 	Endpoint Adjudication
There should be no endpoint adjudication, meaning that for the intent-to-treat (ITT) analysis, all
dialysis sessions that occurred within the first 7 days post-transplant should be included in the
analysis. However, sponsors can perform sensitivity analyses to look at subsets of patients
where the specific reason for the dialysis session (e.g., hypervolemia) is taken into consideration.
These analyses can be done in addition to the ITT population analysis but should not replace it.
11. 	Statistical Considerations
The protocol should specify how information will be collected and how it will be analyzed. All
patients with DGF, defined as dialysis within 7 days post-transplant, should be included as
treatment failures in the analysis. Patients who experience graft loss, or death, or who are lost to
follow-up in the first 7 days should be imputed as treatment failures. However, no patient should
be lost to follow-up in the first 30 days post-transplant.

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The primary efficacy endpoint should be analyzed based on the ITT population, defined as all
patients randomized who receive a kidney transplant.
If the protocol specifies SGF or fDGF as part of the primary endpoint, the planned analysis
should be specified in the protocol and statistical analysis plan (SAP). Strategies to handle
missing data should be defined; however (as noted above), there should be no missing data in the
first 30 days post-transplant.
If other measures of treatment success, such as severity scores or time to graft function recovery,
are used as the primary endpoint, the protocol and SAP should describe how the results will be
analyzed. For patients who experience graft loss or death in the first 30 days, an appropriate
analysis strategy should be defined (e.g., imputing three dialysis sessions per week should be
considered when actual data are not available).
As a secondary endpoint, a Day 30 analysis should look at the percentage of patients who
received dialysis within the first 30 days post-transplant, using similar analysis strategies as for
the primary endpoint. This analysis is to assess durability of the treatment. The direction and
magnitude of the treatment effect should be comparable to the primary endpoint.
Safety should be analyzed in those ITT patients who received at least one dose of the
investigational drug or control drug (e.g., placebo) and were evaluated for acute rejection, graft
loss, hospitalization for serious adverse events, and patient death at least at Month 3, Month 6,
and Month 12.
12. 	Accelerated Approval (Subpart H) Considerations
While a primary endpoint that includes prevention of hemodialysis treatment during the first 7
days post-transplant is associated with clinical benefit and could be used to support a traditional
approval, sponsors should discuss with the FDA plans to use any surrogate endpoints that are
reasonably likely to predict clinical benefit to support accelerated approval.6 An accelerated
approval pathway will require confirmation of clinical benefit through postmarketing confirmatory
trials to verify and describe the anticipated effect on irreversible morbidity, mortality, or other
clinical benefit.7
13. 	Risk-Benefit Considerations
The early benefit of preventing DGF should be compared to the safety of the drug, evaluated
directly in the first 30 days post-transplant and the effect, if any, on the subsequent rates of acute
rejection, graft loss, serious adverse events requiring hospitalization, and patient death for a
minimum of 12 months post-transplant. The benefit of preventing DGF should outweigh the
risks of treatment.
6 See section 506(c) of the FD&C Act; 21 CFR part 314, subpart H; and 21 CFR part 601, subpart E.
7 See 21 CFR 314.510; 21 CFR 601.41.

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REFERENCES
Giral-Classe M, Hourmant M, Cantarovich D, Dantal J, Blanche G, Daguin P, Ancelet D, and
Soulillou JP, 1998, Delayed Graft Function of More Than Six Days Strongly Decreases Long-
Term Survival of Transplanted Kidneys, Kidney Int, 54(3):972–978.
Govani MV, Kwon O, Batiuk TD, Milgrom ML, and Filo RS, 2002, Creatinine Reduction Ratio
and 24-Hour Creatinine Excretion on Posttransplant Day Two: Simple and Objective Tools to
Define Graft Function, J Am Soc Nephrol, 13(6):1645–1649.
Hanley JA and Lippman-Hand A, 1983, If Nothing Goes Wrong, is Everything All Right?
Interpreting Zero Numerators, JAMA, 249: 1743–1745.
Humar A, Johnson EM, Payne WD, Wrenshall L, Sutherland DE, Najarian JS, Gillingham KJ,
and Matas AJ, 1997, Effect of Initial Slow Graft Function on Renal Allograft Rejection and
Survival, Clin Transplant, 11(6):623–7.
Humar A, Ramcharan T, Kandaswamy R, Gillingham K, Payne WD, and Matas AJ, 2002, Risk
Factors for Slow Graft Function After Kidney Transplants: A Multivariate Analysis, Clin
Transplant, 16(6):425–429.
Irish WD, Ilsley JN, Schnitzler MA, Feng S, and Brennan DC, 2010, A Risk Prediction Model
for Delayed Graft Function in the Current Era of Deceased Donor Renal Transplantation, Am J
Transplant, 10:2279–2286.
Johnston O, O’Kelly P, Spencer S, Donohoe J, Walshe JJ, Little DM, Hickey D, and Conlon PJ,
2006, Reduced Graft Function (With or Without Dialysis) vs Immediate Graft Function — A
Comparison of Long-Term Renal Allograft Survival, Nephrol Dial Transplant, 21:2270–2274.
Mallon DH, Summers DM, Bradley JA, and Pettigrew GJ, 2013, Defining Delayed Graft
Function After Renal Transplantation: Simplest Is Best, Transplantation, 96(10):885–889.
Moore J, Shabir S, Chand S, Bentall A, McClean A, Chan C et al., 2010, Assessing and
Comparing Rival Definitions of Delayed Renal Allograft Function for Predicting Subsequent
Graft Failure, Transplantation, 90(10):1113–1116.
Rodrigo E, Ruiz JC, Pinera C et al., 2004, Creatinine Reduction Ratio on Posttransplant Day
Two as Criterion in Defining Delayed Graft Function, Am J Transplant, 4:1163–1169.
Singh RP, Farney AC, Rogers J, Zuckerman J, Reeves-Daniel A, Hartmann E, Iskandar S,
Adams P, and Stratta RJ, 2011, Kidney Transplantation From Donation After Cardiac Death
Donors: Lack of Impact of Delayed Graft Function on Post-Transplant Outcomes, Clin
Transplant, 25(2):255–264.
Stevens RB, Skorupa JY, Rigley TH, Yannam GR, Nielsen KJ, Schriner ME, Skorupa AJ,
Murante A, Holdaway E, and Wrenshall LE, 2009, Increased Primary Non-Function in

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Transplanted Deceased-Donor Kidneys Flushed With Histidine-Tryptophan-Ketoglutarate
Solution, Am J Transplant, 9(5):1055–1062.
Woo YM, Jardine AG, Clark AF et al., 1999, Early Graft Function and Patient Survival
Following Cadaveric Renal Transplantation, Kidney Int, 55 (2):692–99.
Yarlagadda SG, Coca SG, Formica Jr RN, Poggio ED, and Parikh CR, 2009, Association
Between Delayed Graft Function and Allograft and Patient Survival: A Systematic Review and
Meta-Analysis, Nephrol Dial Transplant, 24:1039–1047.
Yarlagadda SG, Coca SG, Garg AX, Doshi M, Poggio E, Marcu RJ, and Parikh CR, 2008,
Marked Variation in the Definition and Diagnosis of Delayed Graft Function: A Systematic
Review, Nephrol Dial Transplant, 23:2995–3003.