A rare disease following transplantation
Matthew Graham-Brown BSc, MBChB, MRCP
A 43 year old male patient with Alport’s syndrome received 1-1-0 mismatched deceased donor kidney transplant in 2012. He had been on haemodialysis for 18 months prior to this as a bridge to transplantation. Initial immunosuppression was with Prednisolone, Mycophenolate and Tacrolimus and the patient had a spontaneous creatinine fall on day 3 following transplantation. Other than a solitary E. coli urinary tact infection 6 months following transplantation he had a completely uncomplicated 18 month period post transplantation. His transplant drug levels were well controlled and his Creatinine stabilized at 120mmol/L.
18 months post transplantation he presented to the nephrology daycase unit feeling generally unwell, with lethargy, fatigue, decreased urine output and increased peripheral oedema which had all come on rapidly over the preceding 48 hours. His initial blood results showed:
He was apyrexial, normotensive and haemodynamically stable. He had no symptoms or signs of intercurrent infection and examination findings were unremarkable with clear breath sounds, soft non-tender abdomen with non-tender renal transplant and normal heart sounds. He had no rashes and no symptoms of upper respiratory tract infection or ophthalmic symptoms. Jugular venous pulse was raised and there was bilateral pitting oedema to his knees bilaterally consistent with fluid overload. An urgent transplant ultrasound scan was booked, and the radiologist was asked particularly to assess flow in the transplant vessels: The ultrasound showed a normal sized unobstructed kidney, with good perfusion to all parts and nothing to suggested thrombus in the transplant renal vein. A chest X-ray was also ordered and no focal abnormality was seen, although some pulmonary venous congestion was noted.
The reviewing registrar councelled the patient that in the absence of an obvious cause of acute kidney injury a biopsy was probably going to be needed, but that given the acute development of his symptoms there were also some urgent blood tests that needed to be sent as well. The following blood tests were ordered:
- Complement (C3/C4)
- anti-GBM antibody
- CMV titre
- EBV titre
- Pre-dose Tacrolimus levels were also put out for the following morning
The patient was admitted and catheterized. Overnight his urine output stopped completely and he became increasingly short of breath. His oxygen requirements went up, and when the on-call registrar was called to review him he found:
The acute dialysis service was called and the patient had 3 hours of dialysis (via left brachio-cephalic fistula that the patient still had from his time as a dialysis patient) with 2.5 litres fluid removed with ultrafiltration. The patient felt symptomatically much better and on repeat ausculatation the majority of crackles had resolved following fluid removal.
The patients blood count and biochemistry was re-checked at the end of dialysis:
The on-call renal registrar contacted the on-call immunology technician and asked that the immunology screen be processed as quickly as possible.
The patient remained anuric and whilst the immunology screen was processed the patient was consented for renal biopsy which was completed without complication. By early afternoon the immunology was phoned through:
- PR3 < 3
- MPO – 28
- Anti-GBM – 86
The patient was consented for immunosuppression with Prednisolone and Cyclophosphamide and a right internal jugular line was inserted for a 7-10 day treatment of plasma exchange. The diagnosis being Goodpasture’s syndrome (anti-GBM disease).
The renal biopsy confirmed crescenteric glomerular nephritis, with all 18 glomeruli in the sample sent for light microscopy affected. Unfortunately the crescents were almost entirely fibro-cellular with very little reversible renal disease found. Sadly the patient did not recover renal function and returned to being dialysis dependent.
Goodpasture’s syndrome is rare and is the clinical syndrome of acute kidney injury and pulmonary haemorrhage in the context of high circulating titres of anti glomerular basemement membrane antibody (anti-GBM Ab). Strictly speaking AKI and high titres of anti-GBM in the absence of pulmonary haemorrhage (as in this case) should be referred to as anti-GMB antibody disease. It is caused by an auto-antibody to the α3 chain of type IV collagen that is present in the glomerular and alveolar basement membranes. The binding of the antibody causes complement activation and local inflammatory response mediated by T-cells and macrophages – in the glomerulus this process leads to crescent formation. It is (unfortunately) usually catastrophic from the point of view of irreversibly damaging the kidneys and leaving the patient requiring renal replacement therapy.
Alport’s syndrome is an inherited, X-linked disorder of type IV collagen. Being X-linked, it usually manifests as severe disease in males, with clinical features of haematuria, sensorineural deafness, progressive nephritis with proteinuria and progressive renal decline and more rarely ocular abnormalities. Females tend to be affected to a lesser extent due to the presence of a normal X-chromosome. When patients with Alport’s syndrome are transplanted, de-novo anti-GBM disease develops in up to 15% of transplant recipients due to neo-antigen exposure to the α3 chain of type IV collagen.
For more information about Alport’s, Goodpasture’s and type IV collagen see this review article by Hudson et al.