Chronic kidney disease is an important public health burden worldwide. The survival advantage of transplantation has been well proven over and above that on dialysis. Patients who have undergone transplantation have definite survival advantage in terms of mortality benefits. The overall graft survival has improved to nearly 85% for 10 years from 55% in 10 years over the past few decades. This is due to better immunosuppressive medications and better monitoring. The graft survival in Taiwan and the United States are nearly 92-95%. Deceased donor programs have also resulted in better survival rates based on better allocation of kidneys according to Kidney donor profile index (KDPI) and estimated post-transplant survival rates (EPTS). The survival rate in Europe and Australia has been reported to be better than the United States as the insurance coverage for the medications are extended in these 2 continents.

During the first year the reasons for graft loss are technical issues like vascular causes, acute rejection (cellular and antibody mediated rejection) and infection. The leading cause of death with a functioning graft is due to cardiovascular causes followed by infection and cancer.

Improving transplant rates focuses on improving graft outcomes from a very early stage like adequate organ perfusion to treatment of acute rejection episodes and avoidance of infection if possible

Immunosuppression after renal transplant

They form the corner stone of the treatment after renal transplantation. Immunosuppression are divided into induction agents and maintenance agents. Induction agents are given at the time of transplantation to prevent immediate graft rejection and avoid delayed graft function. Rabbit anti-thymocyte globulin or Anti Lymphocyte globulin and Anti CD25 Basiliximab have been used as 2 induction agents in high risk sensitized transplants. There are number of transplant units where these induction agents are not used if the HLA matching is more than 50% with no sensitization. Induction agents have reduced the incidence of delayed and slow graft function and contribute to overall improvement in graft survival in the long term

The maintenance immunosuppression regimen is a standard 3 drug regimen namely oral steroids, Calcineurin inhibitors (Cyclosporine and Tacrolimus) and Antimetabolites (Mycophenolate Moeftil and Azathioprine). Steroids have been used as the mainstay with tapering doses after renal transplantation. Many steroid free regimens have been used in countries with increased doses of other medications especially in pediatric age group, but they have been considerable increase in the rate of acute rejections. Cyclosporine has been replaced by Tacrolimus in most of the countries due to its better immunogenicity and better bioavailability. But they are inherently nephrotoxic and the pharmocokinetics is different for individuals and many metabolize this drug differently based on the Genotype. They require frequent monitoring for the drug levels. Calcineurin free regimens are also available with a significant increase in the rates of acute rejection. Antimetabolites are MMF and Azathioprine. Mycophenolate sodium is better tolerated than MMF. Azathioprine is the drug of choice during pregnancy. Other immunosuppressive agents are Mammalian target of Rapamycin inhibitors – mTOR inhibitors namely sirolimus and everolimus and they play an important role in steroid free and calcineurin free regimes. Other agents like belatacept which require periodic infusions have been used in trials with steroid free and calcineurin free regimens.

Post transplantation events that affect long term survival are Delayed Graft function (which is improved by better organ allocation using KDPI, less cold ischemia time, pulsatile perfusion machines), acute rejections and infections.

Acute rejections can be of 2 types namely Acute Cellular Rejection and Acute Antibody Mediated Rejection. Acute Antibody Mediated Rejection is usually avoided in the post-transplant period by monitoring of CDC cross match, Flow cytometry cross match, Donor specific antibodies by Luminex. Late Antibody mediated rejection is usually because of De novo DSA produced after a year which is a usually a result of under immunosuppression after episodes of infection. Acute Cellular rejection is usually diagnosed by renal biopsy. The rate of acute cellular rejection is 10 – 15% and subclinical cellular rejection is 15 to 20% according the Banff score. Treatment of acute cellular rejection involves steroids and Antithymocyte globulin. Treatment of acute antibody mediated rejection involves plasmaphresis, Anti CD20 Rituximab and IVIG. Antiproteosomal bortezomib is still used in many small trials but no clear RCT exists on the use towards treatment of ABMR

The novel concept of diagnosis of acute rejection non-invasively is by cfDNA. Circulating Cell free DNA sensitivity is about 59% in diagnosing antibody mediated rejection and high specificity. But the exact role in clinical transplant is yet to be proven. Urinary FOXP3 mRNA has been used as the urinary marker to diagnose acute cellular rejection, but awaits many studies to confirm the clinical picture.

References:

1. El Nahas AM, Bello AK. (2005). Chronic kidney disease: the global challenge. Lancet, 365:331–40.
2. Florit E, Diekmann F, Budde K, et al. (2015). Living Donor Transplantation: Long-Term Evolution Related to Age Matching. Transplantation proceedings, Elsevier, pp. 2346–350.
3. Hassanzadeh J, Hashiani A, Rajaeefard A, et al. (2010). Long-term survival of living donor renal transplants: A single center study. Indian J Nephrol, 20:179–84.
4. Chhabra D, Grafals M, Skaro AI, Parker M, Gallon L, et al. (2008). Impact of anemia after renal transplantation on patient and graft survival and on rate of acute rejection.Clin J Am SocNephrol, 3:1168–174.

Dr Balaji Kirushnan
Consultant Nephrologist
Kauvery Hospital, Chennai