Overview of Kidney Transplantation

Rowena Delos Santos

General Principles

Over 500,000 people in the United States have end-stage renal disease (ESRD), with over 100,000 new cases of ESRD yearly.¹
Treatment options for ESRD include hemodialysis, peritoneal dialysis, and kidney transplantation.
For most patients, renal transplantation is the preferred treatment for ESRD after careful evaluation of those patients, as it improves quality of life as well as quantity of life compared with those who remain on dialysis.²
These improvements in patient outcomes accompanied by the limited supply of organs have resulted in a remarkable increase in the number of patients on the waiting list for kidney transplant.
Approximately 100,000 people are currently listed on the kidney transplant waiting list.³
Highest growth of waitlisted patients is among those aged 65 to 74, with the proportion on the waitlist of approximately 22%.⁴
The percentage of elderly patients (age ≥65) increased from 14.5% in 2005 to reach 22% in 2015.
A third of the patients on the waiting list are African Americans and a third are Caucasians. More Hispanics were listed in 2015 (19,188 patients) compared to 2005 (10,254 patients), which represents 20% of patients in 2015 compared to 17% in 2005.
Diabetes and hypertension are the top two diseases leading to ESRD in those who are awaiting a kidney transplant.⁴
Indications for kidney transplant include ESRD and irreversible kidney disease with an estimated glomerular filtration rate (eGFR) ≤20 mL/min.
Approximately 17,000 patients receive a kidney transplant annually. Roughly two-thirds of kidneys transplanted are from deceased donors, and one-third from living donors.⁴
Wait times for a kidney transplant can vary due to ABO blood type and history of sensitization. Median wait time on the deceased donor waitlist for a patient listed for the first time is approximately 3.5 years.¹ Wait times are longer for blood type O and B patients.
When other solid organs are affected by their own irreversible damage, then combined organ transplant is a consideration (i.e., heart–kidney for irreversible cardiomyopathy, liver–kidney for primary oxalosis, and kidney–pancreas for type 1 diabetes mellitus).
Due to the renal side effects of chronic calcineurin inhibitor use for prevention of rejection, some people who have had other solid organ transplants may eventually require a kidney transplant.
Preemptive transplants (transplanted before need for dialysis) are recommended when possible.

Transplant and Outcomes

As of 2015, the number of people alive with a functioning kidney allograft was over 200,000.⁴
One-year allograft survival rates for living and deceased donor kidney transplants were 98% and 94%, respectively in 2015.
One-year patient survival rates in 2015 were 99% for living donor kidney recipients and 97% for deceased donor kidney recipients.¹
Five-year allograft survival was the lowest for those whose cause of renal disease was diabetes or hypertension (approximately 70% graft survival for each).⁴
Ten-year allograft failure rates were better among those who received a living donor kidney compared with those who received a deceased donor kidney (47% vs. 63%).⁴
Transplant allograft median survival for a deceased donor kidney transplant has reached 9 years, while the median survival for a living donor kidney transplant has reached nearly 13 years.³
Early graft loss is usually referred to graft loss in the first 12 months post-transplant. Early graft loss is largely due to technical failures, surgical compilations, primary nonfunction, severe rejection, or severe recurrent glomerulonephritis (e.g., recurrent focal segmental glomerulosclerosis).
Beyond the first year, the most common reason for allograft failure is death with allograft function, with patients usually dying from cardiovascular disease, cerebrovascular disease, malignancy, or infection.
The incidence of acute rejection within the first year decreased for both living and deceased donor transplant recipients from 10% in 2009–2010 recipients to 7.9% in 2013–2014 recipients.
In a greater proportion of acute rejection episodes, renal function did not return after treatment to pre-rejection baseline values, and this was associated with an incremental increase in the relative hazard for graft survival.

Waitlist Management

Patients listed for transplant wait several years before they receive a deceased donor kidney transplant. Periodic review of waitlisted patients should occur including: any new medical diagnoses, hospitalizations, overall functional status, and new medications. Retesting is also done periodically depending on center protocols.
Blood transfusions should be avoided due to the risk of human leukocyte antigen (HLA) sensitization; if required, leukocyte-depleted blood should be given.
Immunizations for pneumococcus, influenza, hepatitis B, and varicella should be given prior to transplantation. Live vaccines are avoided after transplant due to the risk of leading to active disease.

Immunology of Transplant

Human Leukocyte Antigen/Major Histocompatibility Complex

HLA or major histocompatibility complex (MHC) genes encode for molecules that define self and the combination of them on cell surfaces differs between individuals.
Genes that encode for HLA are on chromosome 6.
HLA class I molecules encode for HLA A, B, C and are found on all nucleated cells.
HLA class II molecules encode for HLA DR, DQ, DP and are found on antigen-presenting cells (e.g., B cells, macrophages, and dendritic cells).
HLA molecules all have a peptide-binding groove, immunoglobulin-like region, transmembrane, and intracytoplasmic region. The peptide-binding region is where molecules of self or a foreign antigen are presented to T cells.
Individuals inherit one set, or haplotype, of HLA class I and class II from each parent. The HLA genes (genotype) then encode for the HLA molecules located on the surface of cells (phenotype).
High genetic variability of HLA and subsequently the peptide-binding area between individuals leads to uniqueness between individuals.
Because siblings inherit one haplotype of HLA from each parent, there is a 1 − (0.75)ⁿ probability that siblings could be a 2-haplotype match or HLA identical (i.e., possess the same set of HLA genes).
Once T cells recognize foreign HLA, they can activate other T cells and B cells to incite an immune response. T cells are involved in cellular rejection; B cells are involved in antibody-mediated rejection.

Antigen Presentation by HLA Molecules to Cells of the Immune System

Antigen-presenting cells include B cells, macrophages, and dendritic cells.
T cells are activated either through a direct or indirect pathway (Fig. 25-1).
The direct pathway is where donor antigen–presenting cells in the allograft circulate through the blood stream of the recipient early after transplant and present donor HLA to recipient T cells.
The indirect pathway is where recipient donor antigen–presenting cells take up and process donor HLA peptides, then present the donor HLA peptides to recipient T cells.

HLA Typing

Designation of HLA is through letters and numbers (e.g., HLA A2, B7, DR4).
Determination of HLA type is done by several methods.
- Sequence-specific oligonucleotide (SSO): DNA is extracted from cells, the target gene undergoes polymerase chain reaction (PCR) amplification, then is hybridized to oligonucleotide probes, which go through flow cytometry, and results in HLA type.
  
  FIGURE 25-1. Donor antigen presentation to recipient cells.
- Sequence-specific primers (SSP): DNA is extracted from cells, the target gene undergoes PCR amplification with sequence-specific primers for specific HLA, then goes through gel electrophoresis, which allows detection of HLA specificities due to known gene lengths.
SSO and SSP provide the basic HLA designation; to get a more specific designation, sequence-based typing is done.

HLA Donor and Recipient Matching

HLA matching is an important component of allograft survival for kidney transplantation.
Best allograft survival is seen in 2-haplotype living-related kidney transplants, with lower survival for less well-matched living donor kidneys. Deceased donor kidneys have lower survival compared to living donor kidneys, and better-matched kidneys have higher survival compared to less well-matched kidneys (Fig. 25-2).
For kidney transplantation, HLA A, B, and DR matching are most important. Since there are two genes each, one can match for a total of 6 HLA, best 0/6 mismatched, worst 6/6 mismatched (Fig. 25-3).

Barriers to Transplantation

ABO compatibility is a barrier to transplant—if blood types are incompatible, transplantation is not usually done.
Preformed HLA antibodies against a potential kidney allograft are a barrier to transplant as antibodies can lead to significant kidney allograft rejection.
Preformed anti-HLA antibodies arise as a result of sensitization events including blood transfusions, pregnancy, and previous transplantation.

FIGURE 25-2. Kidney allograft survival according to HLA mismatch.
ABO incompatibility and presence of preformed antibodies can be overcome, but is usually done at select centers with expertise in the process. This usually requires plasmapheresis
and administration of rituximab (monoclonal antibody against B-lymphocyte CD20) and intravenous immunoglobulin (IVIG) prior to transplantation.