1. Kidney Transplantation

   Aetna considers kidney transplantation medically necessary when all of the following criteria below are met:

   1. Member has completed an evaluation and been accepted by the kidney transplant committee at the kidney transplantation center; and Note: Frequently requests for evaluation for transplantation are confused with requests for the transplantation itself.  While the transplant evaluation of persons with kidney disease may be indicated, the medical necessity for transplantation itself depends on the results of the evaluation.
   2. Member meets transplanting institution's protocol eligibility criteria regarding age; and
   3. Absence of malignancy or the malignancy has had curative therapy (e.g., surgical resection of non-invasive squamous cell or basal cell skin cancer) or the estimated risk of recurrence of the malignancy is less than 10 % within the next 2 years.  For example, renal cell carcinoma treated by nephrectomy with no evidence of metastatic disease 2 years after the nephrectomy, prostate cancer with negative prostate-specific antigen levels after treatment, surgically treated colon cancer, thyroid cancer with normal thyroglobulin levels after therapy, and others.  Women should have a negative Pap smear within the past 3 years and mammography, where indicated, within the past 2 years; and
   4. Absence of systemic infection; and

   5. Absence of symptomatic HIV infection, as defined by all of the following:

      1. CD4 count greater than 200 cells/mm3 for more than 6 months; and
      2. HIV-1 RNA (viral load) undetectable; and
      3. On stable anti-viral therapy for more than 3 months; and
      4. No other complications from AIDS, such as opportunistic infection (e.g., aspergillus, coccidiomycosis, resistant fungal infections, tuberculosis), Kaposi's sarcoma or other neoplasms.
          
   6. Attending physician determines that there is no prohibitive cardiovascular risk; and
   7. Attending physician determines that there is no prohibitive pulmonary risk; and
   8. Attending physician determines that there is no prohibitive hepatic risk; and
   9. Severity of disease
      
      
      1. Member is already on hemodialysis or continuous ambulatory peritoneal dialysis (CAPD); or
      2. Member has chronic renal failure with anticipated deterioration to end stage renal disease, where member is seeking precertification for cadaveric kidney transplantation**; or
      3. Member has end stage renal disease, evidenced by a creatinine clearance below 20 ml/min or development of symptoms of uremia, and member is seeking precertification for a living donor kidney transplantation.

         ** Note: Given waiting periods for cadaveric donors averaging 1 to 4 years, kidney transplantation is considered medically necessary for persons with severe chronic renal failure with anticipated progression to end stage renal disease.  Severe chronic renal failure is defined as a creatinine clearance of less than 30 ml/min.

   10. Kidney transplant is not considered medically necessary for persons who do not meet the transplanting institution's protocol selection criteria, or in the absence of a protocol, for persons who have any of the following (not an all-inclusive list):

       1. Active vasculitis; or
       2. Age over 70 years with severe co-morbidities; or
       3. Life threatening extra-renal congenital abnormalities; or
       4. Ongoing alcohol or drug abuse; or
       5. Severe neurological or mental impairment, in persons without adequate social support, such that the person is unable to adhere to the regimen necessary to preserve the transplant; or
       6. Untreated coagulation disorder
           

2. Combined Kidney/Pancreas Transplantation

   For persons undergoing kidney transplantation due to diabetic nephropathy, a combined kidney/pancreas transplantation may be considered medically necessary under some circumstances (see CPB 0587 - Pancreas Kidney Transplantation).  Other multi-organ transplants (e.g., kidney/heart, liver/kidney) should be referred to Aetna's National Medical Excellence Program for review.

3. Renal Autotransplantation and Ex-Vivo Bench Surgery

   Aetna considers autotransplantation and ex-vivo repair medically necessary where repair of the kidney, renal artery or its branches are not amenable to in-situ reconstruction.

4. Gene Microarrays for Diagnosis of Rejection

   Aetna considers the use of gene microarrays in diagnosis of rejection of kidney transplantation experimental and investigational because of insufficient evidence of their effectiveness.

5. Evaluation of Urine Immunocytology

   Aetna considers evaluation of urine immunocytology for T cells experimental and investigational for the diagnosis of acute kidney rejection because of insufficient evidence of its effectiveness.

6. Belatacept (Nulojix)

   Aetna considers the use of belatacept (Nulojix) medically necessary for the prevention of acute rejection in kidney transplant recipients who are sero-positive for the Epstein Barr virus (EBV). 

   Aetna considers belatacept is experimental and investigational for the prophylaxis of organ rejection in other transplanted organs because its effectiveness for the prevention of acute rejection in organ transplant other than kidney has not been established.

7. Aetna considers measurement of pre-transplantation soluble CD30 level as a predictor of acute rejection in kidney transplantation experimental and investigational because its clinical value has not been established.

8. Aetna considers measurement of cytokines (e.g., cytokine-14, interleukin-1 beta (IL-1β), IL-2, IL-4, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor-alpha (TNF-α); not an all-inclusive list) for the diagnosis of acute renal allograft rejection experimental and investigational because the effectiveness of this approach has not been established.

Chronic renal failure (CRF) occurs in approximately 2 out of 10,000 people.  It results in the accumulation of fluid and waste products in the body, causing azotemia and uremia.  Azotemia is the build-up of nitrogen waste products in the blood.  It may occur without symptoms.  Uremia is the state of ill health resulting from renal failure since most body systems are affected by CRF.  Treatment of the underlying disorders may help prevent or delay development of CRF.

Chronic renal failure is slowly progressive over a number of years and most often results from any disease that causes gradual destruction of the internal structures of the kidneys.  It can range from mild dysfunction to severe kidney failure, termed end stage renal disease (ESRD).  In the early stages, there may be no symptoms.  In fact, progression may be so gradual that symptoms do not occur until kidney function is less than 1/10 of normal.  Because of the reversible nature of acute renal failure, all patients with this diagnosis should be supported with dialysis, at least for some period of time, to allow return of renal function.

The 3 diseases most commonly leading to CRF and treated by kidney transplantation are (i) type 1 diabetes mellitus, (ii) glomerulonephritis, and (iii) hypertensive nephrosclerosis, accounting for about 75 % of the total candidate population.  Numerous subsets of patients in several study populations have shown that patients have a better survival if they receive a renal transplant than if they remain on dialysis therapy.

Patients with ESRD have 3 options for renal replacement therapy: (i) hemodialysis; (ii) chronic ambulatory peritoneal dialysis; or (iii) transplantation.  The choice should be based on the relative risks and benefits.  With the increasing appreciation that transplantation results are superior to those of chronic dialysis, the indications for transplantation have been broadened.  Improvements in peri-operative care and immunosuppression have allowed many patients who would previously have been denied transplantation consideration as acceptable candidates.  The best recipients for transplantation are young individuals whose renal failure is not due to a systemic disease that will damage the transplanted kidney or cause death from extra-renal causes.

The time a patient has spent on dialysis is an independent predictor of a poorer outcome from renal transplantation.  Pre-emptive renal transplantation generally leads to better outcomes than transplantation after dialysis is initiated, and should be pursued in most cases for live donor transplants.  The current shortage of cadaveric kidneys makes it unlikely that pre-emptive transplants will be a practical option for recipients of cadaveric kidney transplants.

No specific cause of intrinsic and irreversible renal failure is considered a contraindication to kidney transplantation.  Nonetheless, all patients still should have reversible causes of renal dysfunction excluded before considering renal replacement therapy e.g., obstructive nephropathy has to be removed, chronic pyelonephritis secondary to recurrent infection has to be adequately treated, and reflux has to be fixed.

The evaluation of all transplant candidates, in addition to a standard medical work-up, should include cytomegalovirus (CMV) antibody titer; creatinine clearance; serology for syphilis, and hepatitis B (HBV) and C (HCV) viruses; evaluation of parathyroid status; coagulation profile; Pap smear; ABO and histocompatibility typing; urologic evaluation (including a voiding cystourethrogram in selected patients to assess outlet obstruction and reflux); gastro-intestinal evaluation (as warranted by history of ulcer, diverticulitis, or other symptoms); and psychosocial evaluation.

Patients with renal failure induced by diabetes (Kimmelstiel-Wilson disease) make up the greatest population of patients currently referred for transplantation.  Actually, this has become the treatment of choice because persons with diabetes clearly do better with transplantation than with dialysis.  In fact, both graft and patient survival for 1 to 2 years are reported to be as good in persons with diabetes as in other patients, whereas on chronic dialysis, less than 20 % of persons with diabetes survive 5 years.  If diabetic patients can undergo transplantation before extensive damage occurs in other organs, such as the eye and heart, rehabilitation will be more satisfactory.  Even patients with diseases in which the transplanted kidney may eventually be damaged by recurrent disease (e.g., lupus erythematosus, cystinosis, and amyloidosis) are often better palliated by transplantation than by dialysis.  Indeed, the current results of transplantation mandate serious consideration of this therapy in virtually any patient with terminal renal disease.  Not only is the quality of life far better with transplantation than with dialysis, but because the mortality of patients in the first year after transplantation is now less than 5 %, survival is also superior.

Careful attention must be given to eradication of all infections including those of the urinary tract, lungs, teeth, and skin.  Since cardiovascular complications are as common as infection as a cause of post-transplantation mortality, the patient's cardiovascular status should be carefully evaluated and optimized.  In older patients and diabetic patients, this might require stress testing, cardiac catheterization, or even pre-transplant coronary artery bypass.  Age is never an absolute contraindication for kidney transplantation.  Although infants have had successful transplantations, most centers maintain infants on dialysis until body size is increased to 10 to 20 kg.  Older patients are becoming more numerous in transplant clinics.  Older age (greater than 65 years) never precludes transplantation, but it increases the risk of complications.  Transplant centers usually encourage older patients who have multiple medical problems (rather than isolated kidney failure) to remain on dialysis.  On both ends of the age spectrum, however, transplantation is becoming more common.  Malignancy is considered a contraindication for kidney transplantation, as is severe atherosclerotic or pulmonary disease.  Patients with active liver disease are also usually excluded.  Both hepatitis B and C can result in eventual liver failure in some patients after transplantation.

The proper timing of transplantation is a delicate decision because the progression of renal dysfunction is variable and premature imposition of the risks of transplantation is not justified.  However, dialysis or transplantation should not be withheld until advanced uremic symptoms, such as pericarditis, cardiac failure, severe anemia, osteodystrophy and neuropathy, ensure because these complications may become irreversible.

There are 3 sources of donor kidneys for kidney transplantation: (i) living related donors; (ii) cadaver donors; and (iii) living unrelated donors.  A donor left kidney is usually transplanted to the right iliac fossa, with the renal artery anastomosed end-to-end to the hypogastric artery, and the renal vein end-to-end to the common iliac vein.  The ureter is implanted into the bladder and under special conditions a uretero-ureteral anastomosis or uretero-pyelostomy may be performed.  Autotransplantation has developed as an outgrowth of the technique used in renal transplantation.  The simultaneous development of an apparatus that could preserve kidneys extracorporeally for long periods of time and of preservation solutions led to extracorporeal renal repair (work-bench surgery) and subsequent autotransplantation for conditions mentioned above.

On rare occasions, kidneys with lesions of the renal artery or its branches are not amenable to in-situ reconstruction.  In these circumstances, temporary removal of the kidney, ex-vivo preservation, microvascular repair (work-bench surgery), and autotransplantation may permit salvage.

Some examples of clinical conditions where the renal artery or its branches are not amenable to in-situ reconstruction such that a person might benefit from autotransplantation and/or ex-vivo repair include but are not limited to:

• Abdominal aortic aneurysms that involve the origin of the renal arteries; or
• Disease of the major vessels extends beyond the bifurcation of the main renal artery into the segmental branches; or
• Extensive atheromatous aortic disease when an operation on the aorta itself may prove hazardous; or
• Multiple vessels supplying the affected kidney are involved; or
• Persons who have large aneurysms, arteriovenous fistulas, or malformations of the kidney; or
• Traumatic arterial injuries.

Patients with chronic kidney disease have significant abnormalities of bone remodeling and mineral homeostasis and are at increased risk of fracture.  The fracture risk for kidney transplant recipients is 4 times that of the general population and higher than for patients on dialysis.  Ebeling (2007) noted that organ transplant candidates should be assessed and pre-transplantation bone disease should be treated.  Preventive therapy initiated in the immediate post-transplantation period is indicated in patients with osteopenia or osteoporosis, as further bone loss will occur in the first several months following transplantation.  Long-term organ transplant recipients should also have bone mass measurement and treatment of osteoporosis.  Bisphosphonates are the most promising approach for the management of transplantation osteoporosis.  Active vitamin D metabolites may have additional benefits in reducing hyper-parathyroidism, particularly after kidney transplantation.  The author stated that large, multi-center treatment trials with oral or parenteral bisphosphonates and calcitriol are recommended.

In a Cochrane review, Palmer et al (2007) assessed the use of interventions for treating bone disease following kidney transplantation.  Randomized controlled trials (RCTs) and quasi-RCTs comparing different treatments for kidney transplant recipients of any age were selected.  All other transplant recipients, including kidney-pancreas transplant recipients were excluded.  Two authors independently evaluated trial quality and extracted data.  Statistical analyses were performed using the random effects model and the results expressed as relative risk (RR) with 95 % confidence intervals (CI) for dichotomous variables and mean difference (MD) for continuous outcomes.  A total of 24 trials (n = 1,299) were included.  No individual intervention (bisphosphonates, vitamin D sterol or calcitonin) was associated with a reduction in fracture risk compared with placebo.  Combining results for all active interventions against placebo demonstrated any treatment of bone disease was associated with a reduction in the RR of fracture (RR 0.51, 95 % CI: 0.27 to 0.99).  Bisphosphonates (any route), vitamin D sterol, and calcitonin all had a beneficial effect on the bone mineral density (BMD) at the lumbar spine.  Bisphosphonates and vitamin D sterol also had a beneficial effect on the BMD at the femoral neck.  Bisphosphonates were more effective in preventing BMD loss when compared head-to-head with vitamin D sterols.  Few or no data were available for combined hormone replacement, testosterone, selective estrogen receptor modulators, fluoride or anabolic steroids.  Other outcomes including all-cause mortality and drug-related toxicity were reported infrequently.  The authors concluded that treatment with bisphosphonates, vitamin D sterol or calcitonin after kidney transplantation may protect against immunosuppression-induced reductions in BMD and prevent fracture.  However, they state that adequately powered clinical studies are needed to ascertain if bisphosphonates are better than vitamin D sterols for fracture prevention in this population.  Moreover, the optimal route, timing, and duration of administration of these interventions remains unknown.

Acute rejection is an immune process that begins with the recognition of the allograft as non-self and ends in graft destruction.  Histological features of the allograft biopsy are currently used for the differential diagnosis of allograft dysfunction.  In view of the safety and the opportunity for repetitive sampling, development of non-invasive biomarkers of allograft status is an important objective in transplantation.  Khatri and Sarwal (2009) stated that in the past 10 years, microarray technology has revolutionized biological research by allowing the screening of tens of thousands of genes simultaneously.  These investigators reviewed recent studies in organ transplantation using microarrays and highlighted the issues that should be addressed in order to use microarrays in the diagnosis of rejection.  Microarrays have been useful in identifying potential biomarkers for chronic rejection in peripheral blood mononuclear cells, novel pathways for induction of tolerance, and genes involved in protecting the graft from the host immune system.  Microarray analysis of peripheral blood mononuclear cells from chronic antibody-mediated rejection has identified potential non-invasive biomarkers.  In a recent study, correlation of pathogenesis-based transcripts with histopathological lesions is a promising step towards inclusion of microarrays in clinics for organ transplants.  The authors concluded that despite promising results in diagnosis of histopathological lesions using microarrays, the low dynamic range of microarrays and large measured expression changes within the probes for the same gene continue to cast doubts on their readiness for diagnosis of rejection.  They stated that more studies are needed to resolve these issues.  Dominating expression of globin genes in whole blood poses another challenge for identification of non-invasive biomarkers.  In addition, studies are also needed to demonstrate effects of different immunosuppression therapies and their outcomes.

Hartono et al (2010) noted that urinary cell and peripheral blood cell mRNA profiles have been associated with acute rejection of human renal allografts.  Emerging data support the idea that development of non-invasive biomarkers predictive of antibody-mediated rejection is feasible.  The demonstration that intra-graft microRNA expression predicts renal allograft status suggests that non-invasively ascertained microRNA profiles may be of value.  These researchers stated that they are pleased with the progress to date, and anticipate clinical trials investigating the hypotheses that non-invasively ascertained mRNA profiles will minimize the need for invasive biopsy procedures, predict the development of acute rejection and chronic allograft nephropathy, facilitate preemptive therapy capable of preserving graft function, and facilitate personalization of immunosuppressive therapy for the allograft recipient.

Mihovilovic and colleagues (2010) evaluated urine immunocytology for T cells as a method for non-invasive identification of patients with acute renal allograft rejection in comparison to renal biopsy.  In this prospective study, a cohort of 56 kidney, or kidney-pancreas transplant recipients was included.  Patients either received their transplant at the University Hospital "Merkur", or have been followed at the "Merkur" Hospital.  Patients were subject to either protocol or indication kidney biopsy (a total of 70 biopsies), with simultaneous urine immunocytology (determination of CD3-positive cells in the urine sediment).  Acute rejection was diagnosed in 24 biopsies; 23 episodes were T-cell mediated (6 grade IA, 5 grade IB, 1 grade IIA, 1 grade III and 10 borderline), while in 1 case acute humoral rejection was diagnosed.  A total of 46 biopsies did not demonstrate acute rejection.  CD3-positive cells were found in 21 % of cases with acute rejection and in 13 % of cases without rejection (non-significant).  A finding of CD3-positive cells in urine had a sensitivity of 21 % and specificity of 87 % for acute rejection (including borderline), with positive predictive value of 45 % and negative predictive value of 68 %.  The authors concluded that although tubulitis is a hallmark of acute T cell-mediated rejection, detection of T cells in urine sediment was insufficiently sensitive and insufficiently specific for diagnosing acute rejection in this cohort of kidney transplant recipients.

Belatacept, a selective T-cell co-stimulation blocker, is a cytotoxic T-lymphocyte-associated antigen 4-immunoglobulin.  It is designed to block CD28, a critical activating receptor on T cells, by binding and saturating its ligands B7-1 and B7-2.  In phase II and III clinical trials, belatacept was compared with cyclosporine (in combination with basiliximab, mycophenolate mofetil, and steroids).  Advantages observed with belatacept include superior graft function, preservation of renal structure and improved cardiovascular risk profile.  Concerns associated with belatacept are a higher frequency of cellular rejection episodes and more post-transplant lymphoproliferative disorder (PTLD) cases especially in Epstein-Barr virus (EBV) sero-negative patients, who should be excluded from belatacept-based regimens (Wekerle and Grinyo, 2012).

On June 15, 2011, the Food and Drug Administration approved belatacept (Nulojix) for the prevention of acute rejection in adult kidney transplant recipient.  Nulojix is approved for use with other immunosuppressants, specifically basiliximab, corticosteroids, and mycophenolate mofetil.  The approval of Nulojix was base on 2 open-label, randomized, multi-center, controlled phase III clinical trials that enrolled more than 1,200 patients and compared 2 dose regimens of Nulojix with another immunosuppressant, cyclosporine.  These trials demonstrated that the recommended Nulojix regimen is safe and effective for the prevention of acute organ rejection. 

Nulojix carries a Boxed Warning for an increased risk of developing PTLD.  The risk of PTLD is higher for transplant patients who have never been exposed to EBV.  Transplant patients who have not been exposed to EBV have more difficulty mounting an effective immune response to the virus if they get infected after transplant; typically they get exposed to the virus at time of transplant, as it is carried in around 80 % of donated organs.  Patients should be tested for EBV and should only receive Nulojix if the test shows they have already been exposed to EBV.  Another Boxed Warning on the Nulojix label, as well as labels of other immunosuppressants, warns of an increased risk of serious infections and other cancers.  Common adverse reactions observed in transplant patients in the trials included anemia, constipation, kidney or bladder infection, and swollen legs, ankles, or feet.  Any transplant patients, including those receiving Nulojix, should limit the amount of time spent in sunlight because of the risk of skin cancer and should not get live vaccines because of the risk of infection.

Chen and colleagues (2012) stated that the question of whether high pre-transplantation soluble CD30 (sCD30) level can be a predictor of kidney transplant acute rejection (AR) is under debate.  These investigators performed a meta-analysis on the predictive efficacy of sCD30 for AR in renal transplantation.  PubMed (1966 to 2012), EMBASE (1988 to 2012), and Web of Science (1986 to 2012) databases were searched for studies concerning the predictive efficacy of sCD30 for AR after kidney transplantation.  After a careful review of eligible studies, sensitivity, specificity, and other measures of the accuracy of sCD30 were pooled.  A summary receiver operating characteristic curve was used to represent the overall test performance.  A total of 12 studies enrolling 2,507 patients met the inclusion criteria.  The pooled estimates for pre-transplantation sCD30 in prediction of allograft rejection risk were poor, with a sensitivity of 0.70 (95 % CI: 0.66 to 0.74), a specificity of 0.48 (95 % CI: 0.46 to 0.50), a positive likelihood ratio of 1.35 (95 % CI: 1.20 to 1.53), a negative likelihood ratio of 0.68 (95 % CI: 0.55 to 0.84), and a diagnostic odds ratio of 2.07 (95 % CI: 1.54 to 2.80).  The area under curve of the summary receiver operating characteristic curve was 0.60, indicating poor overall accuracy of the serum sCD30 level in the prediction of patients at risk for AR.  The authors concluded that the results of the meta-analysis showed that the accuracy of pre-transplantation sCD30 for predicting post-transplantation AR was poor.  They stated that prospective studies are needed to clarify the usefulness of this test for identifying risks of AR in transplant recipients.

Lv and colleagues (2012) noted that results from published studies on the association of donor or recipient IL-6 -174G/C (rs1800795) polymorphism with AR of renal allograft are conflicting.  These investigators performed a meta-analysis to estimate the possible association.  Studies were identified by searching PUBMED and EMBASE until July 1, 2011.  Meta-analysis was performed in a fixed/random effects model using Revman 5.0.25 and STATA10.0.  A total of 7 studies addressing the association between donor high producer genotype (G/G and G/C) of IL-6 -174G/C polymorphism and AR of renal allograft were identified.  Pooled odds ratio (OR) based on 341 cases (whose recipient developed AR) and 702 controls (whose recipient did not develop AR) was 0.59 (95 % CI: 0.26 to 1.33; p = 0.20), with a strong between-study heterogeneity.  No association was observed in the subgroup analysis based on ethnicity.  A total of 13 studies evaluating the association between recipient IL-6 -174G/C polymorphism and AR were identified.  Pooled OR based on 451 cases (patients did not develop AR) and 848 controls was 1.00 (95 % CI: 0.72 to 1.37; p = 0.98), with a weak between-study heterogeneity.  The authors concluded that donor high producer genotype (G/G and G/C) of IL-6 -174G/C polymorphism had a tendency of decreased risk for AR, although it was not statistically significant.  Recipient high producer genotype was not associated with AR of renal allograft.  Moreover, they stated that additional well-designed studies with larger sample size are needed to support these findings, especially for the association between donor high producer genotype (G/G and G/C) of IL-6 -174G/C polymorphism and acute renal allograft rejection.

In an observational cross-sectional study, De Serres et al (2012) determined the utility of a non-invasive cytokine assay in screening of AR.  A total of 64 patients from 2 centers were recruited upon admission for allograft biopsy to investigate acute graft dysfunction.  Blood was collected before biopsy and assayed for a panel of 21 cytokines secreted by peripheral blood mononucleated cells (PBMCs).  Patients were classified as acute rejectors or non-rejectors according to a classification rule derived from an initial set of 32 patients (training cohort) and subsequently validated in the remaining patients (validation cohort).  Although 6 cytokines (interleukin-1 beta [IL-1β], IL-6, tumor necrosis factor-alpha [TNF-α], IL-4, granulocyte-macrophage colony-stimulating factor [GM-CSF], and monocyte chemoattractant protein-1 [MCP-1]) distinguished acute rejectors in the training cohort, logistic regression modeling identified a single cytokine, IL-6, as the best predictor.  In the validation cohort, IL-6 was consistently the most accurate cytokine (area under the receiver-operating characteristic curve, 0.85; p = 0.006), whereas the application of a pre-specified cut-off level, as determined from the training cohort, resulted in a sensitivity and specificity of 92 % and 63 %, respectively.  Secondary analyses revealed a strong association between IL-6 levels and AR after multi-variate adjustment for clinical characteristics (p < 0.001).  The authors concluded that in this pilot study, the measurement of a single cytokine can exclude AR with a sensitivity of 92 % in renal transplant recipients presenting with acute graft dysfunction.  Moreover, they stated that prospective studies are needed to determine the utility of this simple assay, particularly for low-risk or remote patients.

Wu and associates (2013) stated that cytokines have been implicated in the AR of solid organ transplantation.  Many studies have investigated the association between recipient or donor IL-4 polymorphism and AR, with different studies reporting inconclusive results.  These investigators searched PUBMED and EMBASE until June 2012 to identify eligible studies investigating the association between IL-4 polymorphism with AR after solid organ transplantation.  Statistical analysis was performed using STATA10.0.  A total of 12 studies were included.  Pooled ORs suggested (i) no significant association was detected between recipient or donor IL-4 -590C/T polymorphism and acute rejection of solid allograft; (ii) no significant association was detected between recipient IL-4 -33C/T polymorphism and AR of solid allograft; (iii) when stratified by transplantation type, IL-4 -590C/T polymorphism was associated with AR of liver transplantation (T/T+C/T versus C/C: OR = 0.36, 95 % CI: 0.14 to 0.90); and (iv) significantly decreased risk of AR was detected in recipient IL-4 -590*T-negative/donor T-positive genotype pairs than all other recipient-donor IL-4 -590T/C pairs (OR = 0.14, 95 % CI: 0.03 to 0.66).  The authors concluded that the findings of this meta-analysis suggested that recipient IL-4 -590C/T polymorphism was associated with AR of liver transplantation, but nor renal or heart transplantation.  It was also suggested that combined recipient IL-4 -590*T-negative/donor T-positive genotype may suffer decreased risk of AR of solid allograft.  Moreover, they stated that further well-designed studies with larger sample size were needed to verify these findings, with focus on the association of IL-4 polymorphism with AR in patients with liver transplantation and studies investigating combined recipient-donor genotype.

An UpToDate review on “Clinical manifestations and diagnosis of acute renal allograft rejection” (Chon and Brenna, 2014a) does not mention measurement of cytokines as a management tool.

Furthermore, an UpToDate review on “Investigational methods in the diagnosis of acute renal allograft rejection” (Chon and Brenna, 2014b) states that “The introduction of potent immunosuppressive drugs in the past three decades has led to a dramatic reduction in the incidence of acute rejection in kidney transplant recipients.  At the present time, renal allograft biopsy with conventional histologic evaluation remains the gold standard for diagnosing acute rejection among patients with a deterioration in kidney function as detected by measuring serum creatinine levels.  However, the lack of additional markers of rejection makes it difficult to optimize anti-rejection therapy for transplant recipients.  The evaluation of methods other than conventional renal biopsy and/or measurement of the serum creatinine to help diagnosis acute kidney rejection has been the focus of a large number of investigators.  This topic review will discuss some of the methods undergoing investigation for the diagnosis of acute rejection ….  Measuring the levels of urinary or circulating proteins and cytokines, circulating soluble interleukin-2 (IL-2) receptor, the urinary concentration of soluble adhesion molecules, or cellular activation with urinary flow cytometry may be helpful in diagnosing acute allograft rejection …. Interleukin-6 (IL-6) may be a potential biomarker for acute rejection.  In an observational study of 32 patients who presented with acute graft dysfunction, of six tested cytokines (including IL-1beta, IL-6, TNF-alpha, IL-4, GM-CSF, and MCP-1), IL-6 best predicted acute rejection.  Among a validation cohort of 32 additional patients, using a prespecified IL-6 cutoff level of 85 pg/ml, IL-6 assay had a sensitivity of 92 and specificity of 63 percent for the diagnosis of acute rejection.  These results need to be confirmed in a larger prospective trial”.