Drugs Used in Renal Transplantation

I use these drugs rather a lot. In fact, all the time. This would be a good time to revise their actual indications and what they are; I mean it will be embarrassing if someone asks what EXACTLY do they do and I cannot answer… so, without much further ado:


Induction Therapy

Basiliximab (Simulect) : IL2 receptor antagonist. Interleukin 2 (IL2) is a cytokine signallfing molecule for T cells proliferation. IL-2 is activated via calcineurin-mediated pathways of transcription, translation and section of IL-2 by activated T cells, dendritic cells and B cells. IL-2 then binds to IL-2 receptor expressing cells further activating proliferation of CD4+ and CD8+ cells, NK cells and macrophages. It also produces regulatory T cells in the thymus – has roles in both tolerance and immunity.

Alemtuzumab (Campath) : humanized anti CD52 panlymphocytic (B and T cells) monoclonal antibody. CD52 is a protein present on mature lymphocytes (not in the stem cells) and Campath binds to these lymphocytes and it is removed by our immune system

ATG; rabbit antithymocyte globulin : Polyclonal antibody against a wide variety of T-cell surface antigens including the MHC (major histocompatibility complex) antigens.

Rituximab : anti CD 20 antibody. Anti CD20 is expressed on the surface of all B cells in the early pre-B cells to later in differentiation but not present in terminally differentiated plasma cells. Function of CD20 is not fully known, but it allows activation of the B cell by maintaining intracellular calcium concentrations. RTX sticks to CD20 forming a cap drawing NK cells to kill it.

Maintainence Therapy

Calcineurin Inhibitors : Cyclosporin (CyA) & Tacrolimus (FK52) : selectively inhibit calcineurin thus prevents transcription of IL-2 and other cytokines in T lymphocytes

Cyclosporin : binds to cyclophillins; Tacrolimus : binds to FK-binding protein; both part of the family of cytoplasmic proteins present in most cells. When bound (CyA-Cyclophillins , FK52-FK) these drug-receptor complex binds and selectively inhibits calcineurin, a calcium/calmodulin-dependant phosphatase thus preventing transcription of IL2, IL3, IL4, TNF, granulocyte-macrophage colony-stimulating factor, and interferon-gamm :  ultimately preventing the formation of T cells

Problems with CNIs:

System Target Mechanism of Action Side Effects
Renal Vasoconstriction of afferent & efferent arterioles Endothelial cell impairment

Reduced production of vasodilators (PG & NO)

Enhanced release of vasoconstrictors (thromboxane & endothelin)

Increased sympathetic tone

Reduced renal blood flow (RBF)

Reduced GFR

Renal vasoconstriction and sodium retention

Stimulation of the Na-Cl cotransporter


– calcium channel blockers are considered drug of choice to Rx HTN e.g. diltiazem; also reduces acute vasoconstriction (in the short term)

Inhibition of Na-K-ATPase in the cortical collecting duct Hyperkalaemia


Damage to tubules and reduced RBF Decreased uric acid secretion Hyperuriecaemia


Reduced Mg reabsorption HypoMg
Phosphate wasting Hypophosphatemia
Impaired acid secretion

Decreased aldo activitu

Metabolic acidosis (type 4 RTA)
Injury to the vascular endothelial cells HUS


Obliterative arteriolopathy (suggesting primary endothelial damage), ischemic collapse or scarring of the glomeruli, vacuolization of the tubules, global and focal segmental glomerulosclerosis, and focal areas of tubular atrophy and interstitial fibrosis (producing a picture of “striped” fibrosis) Chromic CIN toxicity
Liver Substrate for cytochrome P450 3A4/5 & CYP3A4/5 Drugs such as ketoconazole, diltiazem increases CNI concentratioins
Neuro Tremor


Marrow oedema seen on MRI CNI-pain syndrome. Symmentrical bone pain of lower extremeties. Helped by Ca channel blocker


Reversible toxicity to islet cells May directly affect transcriptional regulation of insulin expression &

severe swelling and vacuolization of islet cells

Cosmetic – only with CyA Gums Gingival hyperplasia
Hair Hirsustism



Mycophenolate mofetil (MMF) : Reversibly inhibits inosine monophosphate , the enzyme that controls the rate of synthesis of guanine monophosphate in de novo pathway of purine synthesis used in the proliferation of B and T lymphocytes.

Azathioprine : A prodrug that gets broken down to 6 mercaptopurine (6 MP) by reductive cleavage of the thioester and mediated by glutathione and other enzymes.6MP is metabolised to natural purines, collectively we shall call them 6 thioguanine nucleotides (6 TGN) which:

  1. blocks purine synthesis ie blocking DNA synthesis, particularly in B and T cells
  2. incorporated into RNA, compromising functionality
  3. causes activation of T cell apoptosis
  4. blocks CD28 stimulation; required for T cell activation
  5. aza-mech-action


Sirolimus/Rapamycin : inhibits the mammalian/mechanistic targetof rapamycin (mTOR); a serine/threonine specific protein kinase. mTOR regulates cellular metabolism, growth and proliferation through signalling via 2 protein complexes mTORC1 and mTORC2. Sirolimus enters the cytoplasm -> binds to FK binding protein -> inhibits IL2 mediated signal transduction -> cell cycle arrest G1-S phase. Blocks the cytokines -> unable to activate B and T cells to proliferate (in contrast, CNIs inhibit the production of cytokines).

Finally, the picture below illustrates where these drugs all work and for ease sake:


and just because the above doesn’t cater to all my needs and understanding, here is another coloured picture that shows oust IL-2 receptor is also known as CD 25, CD52 is also found on the surface of T cells and ATG affects loads of other CD receptors on the T cell.




Complement and renal TMA

Alright, this is totally complicated. What is the best way to approach this?

Slowly. And my way of understanding it.

Ok, let’s start with what TMA actually is: thrombosis in capillaries and arterioles, due to an endothelial injury.

Clinical features?

  1. Thrombocytopenia
  2. MAHA
  3. Organ injury

Simply put, TMA can be subcategorised MANY different ways.

They include HUS, TTP,disseminated intravascular coagulation, scleroderma renal crisis, malignant hypertension, antiphospholipid antibody syndrome, and drug toxicities, e.g. calcineurin inhibitor toxicity

For the purpose of this entry, I will focus on HUS (typical and atypical), TTP, aHUS and just very quickly, because it is renal – TMA in transplant rejection.

Haemolytic Uraemic Syndrome

The syndrome of:

  • MAHA (shearing of RBC through platelet micro thrombi)
    • Tests: Coombs (will be negative), haemolytic screen, blood film, LDH
  • Thrombocytopenia
  • AKI (normally hypertensive)



  • Infection
    • Shiga toxin-producting E. Coli (STEC)/verotoxin 0157
    • Shigella
    • Strep Pneumonia
    • HIV
  • Drugs
  • Preganancy
  • Other autoimmune conditions

Other organs affected:

  • Central nervous system – Manifestations of central nervous system (CNS) involvement include seizures, coma, stroke, hemiparesis, and cortical blindness.In addition, severe hypertension may result in CNS symptoms and require emergent therapy to decrease blood pressure. The presence of severe hypertension and the response to antihypertensive therapy differentiates CNS involvement due to elevated blood pressure.
  • Gastrointestinal tract – Any area from the esophagus to the perianal area can be involved. The more serious manifestations include severe hemorrhagic colitis (which may be misdiagnosed as ulcerative colitis), bowel necrosis and perforation, rectal prolapse, peritonitis, and intussusception. Transmural necrosis of the colon may lead to subsequent colonic stricture.
  • Cardiac dysfunction – Cardiac dysfunction can be due to cardiac ischemia detected by elevated levels of troponin and fluid overload.
  • Pancreas – During the acute phase, up to 10 percent of patients develop glucose intolerance. Transient diabetes mellitus may occur, and rarely permanent diabetes mellitus, which may develop years later.
  • Liver – Hepatomegaly and/or increased serum transaminases are frequent findings.
  • Hematology – In addition to anemia and thrombocytopenia, leukocytosis is common in diarrhea-induced HUS; the prognosis is worse with increased white blood cell counts


Thrombotic Thrombocytopenic Purpura


  • Severe AKI is unusual in TTP
  • Hereditary TTP (also called Upshaw–Schulman syndrome) is caused by homozygous or compound heterozygous ADAMTS13 mutations.
  • Acquired TTP is an autoimmune disorder caused by autoantibody inhibition of ADAMTS13 activity
    • ADAMTS13 is a von Willebrand Factor cleaving protease
    • Inhibition leads to large multimers of vWF, increasing risk of platelet thrombi leading to damage to endothelium
    • This leads to TMA and organ failureADAMTS13


  • In a nutshell, if you suspect TTP, TREAT! but send ADAMTS13 assay. If it is negative, it generally rules out TTP.

2ndy causes TMA copy

TMA in Transplant Rejection

  • Antibody mediated rejection
  • C4d + : Acute humoral rejection(AHR); C4d – : Acute cellular rejection (ACR)
  • Risk of graft loss is greater in AHRSlide2
    The Ab-Ag complex in AHR activates C1 which starts the pathway. C4d is a by product of this


Renal histology findings:

  • thrombosis of vessels
  • fibrinoid necrosis of arterioles
  • oedematous expansion of arteries – double contouring


  1. Plasma exchange
  2. Eculizumab, an a monoclonal antibody to C5 that blocks the terminal complement cascade
  3. Renal +/- hepatic transplant