Chronic Allograft Injury : Factors Contribution, Pathogenesis

The first-year graft survival rate after a transplant is 94%. The first-year acute rejection rate is 12%. Chronic Allograft Rejection is the rejection of the transplanted organ after several months to years. There can be various reasons for transplant rejection. The loss of graft kidney is 4% per year. MC's cause of chronic allograft injury is immunological, which is a chronic antibody-mediated rejection. The 2nd most common cause is the Non-immunological causes.

Factors Contributing to Late Graft Loss

Donor Factors

• Decreased donor kidney (DBD - Brain dead donor - the kidney is taken from patients with brain death and DCD - Donor with cardiac death - the kidney is taken from the patients with cardiac death)
• Older donor age and female donors can also be a reason for organ transplantation rejection.
• Donor vascular disease
• Ischemia/ reperfusion injury and long ischemia time
• Delayed graft function

Recipient Risks (Nonimmune)

• Obesity
• Urinary tract infection
• Transplant ureteral Obstruction
• BK virus nephropathy
• Calcineurin inhibitor toxicity
• Recurrent renal disease or de novo glomerulonephritis
• Hypertension, dyslipidemia, Smoking
• Diabetes or (preexisting or post-transplantation)

Recipient Risks (Alloimmune)

• Child or adolescent recipient
• Variable medication through concentrations from malabsorption or nonadherence
• HOA mismatches, presentation status (donor-specific HLA alloantibodies)
• Acute rejection that is severe, corticosteroid resistant, vascular, antibody-mediated, or late-occurring
• Late de novo donor-specific antibodies and chronic (antibody-non-mediated) rejection

Pathogenesis 

Non Immunological Factors

1. Donor Related 

2. Transplantation Related

Ischemia Perfusion Injury or Long Ischemia Times

In the case of ischemia perfusion injury or long ischemic injury, there are lower chances of graft survival rates post graft rejection 

• Triggers immune-mediated damage.
• It activates the adaptive immune system, APC, and TLR, releasing pro-inflammatory cytokines.
  • Leads to acute rejection and IFTA (Interstitial Fibrosis and Tubular Atrophy).
• Prevention of transplant related graft failure 
  • Pretreatment with low-dose dopamine.
  • Therapeutic hypothermia.
  • Pulsatile machine perfusion.
• Warm ischemia time - During kidney recovery.
  • Time from clamping the vehicular pedicle of the kidney to keeping it in storage.

Cold ischemia time - Time from cold perfusion of the kidney to the start of venous anastomosis.

Delayed Graft Rejection

• Acute kidney injury - occurring in 1st week of kidney transplantation.
  • Necessitates dialysis intervention.
• High rate of acute cellular rejection.
• Shorter graft survival. 
• Mechanism of delayed graft rejection

After anastomosis 

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Innate immunity activates

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Releases DAMPs and activates the complement system

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Transmits signals to TLR - mainly in PCT

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Release of inflammatory cytokines

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The adaptive immune system activates.

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Acute rejection 

Risk Factors of Delayed Graft Rejection

• Donor Related
• Preservation
• Transplant Related
  • Sensitization - high-risk transplant.
    • 2nd transplant
    • Multiparous lady 
    • ABO incompatibility
• Recipient Related 

Kidney Donor Profile Index 

• The kidney donor profile index is the predictor of the functioning of the disease donor kidney.
• Depends on 9 factors
  • Age
  • Height
  • Weight
  • Ethnicity
  • History of hypertension or diabetes
  • Cause of death 
  • Serum creatinine 
  • Hepatitis C infection 
  • Donation after Cardiac Death
• This index is not used in India, but is used in other countries.

Clinical Implications of Delayed Graft Function

• Short term
  • Worse baseline kidney transplantation function.
  • Dialysis - impacts the cost.
  • Limited use of CNI - rejection.
• Long term
  • 3 to 5 years shorter graft life

Treatment Delayed Graft Function

• Hypothermia pump perfusion.
• Dopamine, superoxide dismutase infusions, and fenoldopam are used.
• Nor very successful. 

3. Recipient Related

A. BK virus nephropathy 

• It is acquired in childhood.
• It persists in the urinary tract and is activated in an immunocompromised state.
• 1st 6 months - 10 to 30% viremia(virus in the blood)
  • 1 to 10% nephropathy. 
• Diagnosis is made after the presence of SV40 positivity in biopsy.
• It is important to make a differential diagnosis from acute cellular rejection.
• Treatment - Reduction of immunosuppression. 

Bk virus - present in the urinary tract

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Dormant in normal people

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Activated in Immunosuppression 

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Leads to viruria

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Viremia

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Enters the blood and then the kidney

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This leads to BK virus nephropathy.

B. CNI (Calcineurin inhibitor) toxicity

• CNI causes nephrotoxicity.
• All compartments are affected.
  • Blood vessel - Medial arterial hyalinosis
    • Most reliable diagnostic marker.
    • Nodular hyaline deposits - in the media of afferent arterioles. 
    • Vacuolization and necrosis of smooth muscle cells.
    • Differential diagnosis - diabetes, hypertension. 
  • Striped interstitial fibrosis
    • Pathognomonic CNI toxicity.
    • Dense stripe of atrophic tubules and cortical fibrosis next to the normal area.
    • Arteriopathy and narrowing of the lumen - contribute to watershed infarct and atrophy. 
    • Mechanism - local free radicals release, TGF, beta release.
  • Glomerulosclerosis
  • Tubular microcalcification

C. Other Non–Immune Causes

• Denovo and recurrent glomerular disease.
  • Risk increases as duration post-transplant increases.
• Cardiovascular risk factors
  • Systemic vasculopathy with risk factors.
• The most important cause of graft loss post-transplant
  • Death with a functioning graft (1st cause to choose in the exam).
  • Chronic antibody-mediated rejection. 

D. Immunological Factors

• Early acute T cell rejection
  • Treated adequately.
  • No impact.
• Late chronic active-graft injury due to not returning Serum creatinine to baseline.
• Donor-specific antibodies can develop.
• Leads to antibody-mediated rejection.

Antibody-Mediated Rejection

• Diagnosed by Banff criteria.
• C4d negative antibody-mediated rejection - look for expression of gene transcripts.
• Acute rejection early can lead to chronic rejection due to:
  • Vascular damage
  • Exposure to epitopes 
• Denovo DSA - due to insufficient Immunosuppression.
  • Chronic Antibody Mediated Rejection.

Occurrence of Denovo DSA

• Non-adherence to Immunosuppression. 
• Steroid-free protocols.
• CNI-free protocols.
• Reduction of Immunosuppression for infection malignancy.
• HLA class 2 DR mismatch between donor and recipient. 
• Younger age of the recipient. 
• Prior acute cellular rejection.
• Non-HLA antibodies - anti-MICA, anti endothelin antibody.

DSA-Induced Graft Loss

Insufficient Immunosuppression Causes Graft Failure

Also Read: Membranous Nephropathy : Types, Epidemiology and Investigation

Clinical Manifestations of Insufficient Immunosuppression

• Elevated Serum creatinine - late feature.
• Elevated proteinuria - late feature. 
• Renal biopsy.

Pathology of Insufficient Immunosuppression

• Chronic IFTA
  • Early graft damage
    • Ischemia Perfusion Injury. 
    • Overt or subclinical rejection.
    • Pre-existing disease of the donor.
  • Late graft damage
    • Secondary CNI toxicity. 
    • Hypertension
    • Hyperlipidemia 
    • Rejection
    • Recurrent glomerular disease 
    • BKV nephropathy 
  • Unknown etiology.

Structural Changes of Insufficient Immunosuppression

• Transplant Glomerulopathy
  • Duplication of GBM - endothelial injury. 
  • Mesangial matrix expansion.
  • Absence of immune deposits.
  • Deposition of C4d in the peritubular capillary.
  • EM - Subendothelial windowing with deposition of flocculent material.
• Peritubular Capillaropathy
• Transplant Arteriolopathy

Diagnosis of Insufficient Immunosuppression

• History 
• Elevated creatinine / increased proteinuria. 
• Doppler ultrasonography- Vascular abnormality, resistive index.
• BK viruria and viremia, anti-HLA antibodies.
• Allograft biopsy

Prevention of Antibody-mediated rejection (ABMR)

• Pre-transplant
  • Avoid Sensitization
  • Complete donor and recipient typing.
  • Precise knowledge of anti-HLA antibodies.
• Transplantation
  • Minimize ischemia-reperfusion injury. 
  • Minimize ischemia times.
• Post-transplant
  • Avoid insufficient Immunosuppression. 
  • Screen for CytoMegaloVirus, Human polyomavirus BK.
  • Monitor anti-DSA antibodies.
  • Protocols biopsies: after the transplant has been performed there should be biopsy done on the patient’s organ that has been transplanted so that any kind of cell changes can be seen beforehand.
  • Review for non-adherence.

Treatment 

• Non-immune
  • These changes are related to a person’s comorbidities. These diseases have small contributions that lead to the transplant rejection.
    • Treat hypertension 
    • Treat diabetes 
    • Lifestyle changes
    • Prevention and treatment of Urinary Tract Infections
    • Target CNI toxicity 
• Immune
  • Treatment of early ACR by steroids / ATG.
  • Treatment of AMR by plasmapheresis / IVIG.
  • Treatment of chronic ABMR.
  • Treatment of refractory ABMR.

Hope you found this blog helpful for your NEET SS Nephrology Preparation. For more informative and interesting posts like these, keep reading PrepLadder’s blogs.