A Challenging Diagnosis in Kidney Transplantation: A case study on how the Molecular Microscope Diagnostic System for Kidney (MMDx Kidney) provides added confidence and alters management

Case Study

Divya Raghavan, MD
Clinical Assistant Professor of Medicine • Division of Nephrology, University of Utah

 

Case Background: A Highly Sensitized Patient Receives Zero-Antigen Mismatch Kidney 

We report the case of a 43-year-old woman with kidney failure due to lupus nephritis who received a fourth kidney transplant from a deceased donor. The first two kidney transplants had failed due to rejection, the third due to BK virus nephropathy.  The patient had a cPRA of 100% and was transplanted with an excellent quality kidney. The KDPI was 1%, the cold ischaemic time was 10 hours, and the kidney was a zero-antigen mismatch by third field tissue typing. 

Immunosuppression was with Thymoglobulin (rATG) induction followed by tacrolimus, mycophenolic acid and prednisone. There was prompt graft function with good urine output and a falling serum creatinine. However, by post-operative day seven, the kidney function had stopped improving (2 mg/dL), and so a kidney transplant biopsy was performed. 

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First Biopsy: Empirical Treatment for ABMR Despite Normal Banff Score  

The kidney transplant biopsy was reported as normal by light microscopy, other than some mild arteriosclerosis. Immunohistochemistry was strongly positive for C4d. The Banff score was g0, i0, t0, v0 cg0, ci0, ct0, cv0, ah0, aah1, mm0, ptc0, C4d3 and i-ifta0

In view of suboptimal graft function and the patient’s highly sensitized status, she was empirically treated for antibody-mediated rejection (ABMR) with plasma exchange (PLEX), IVIg, and high dose steroids. Non-HLA antibody screening confirmed the presence of an anti-angiotensin type 1 (AT1R antibody). Post-treatment, the kidney function improved to 1.46 mg/dL before deteriorating again to 2.21 mg/dL and settling at around 1.6 mg/dL without proteinuria. 

Second Biopsy: MMDx Kidney Reveals Evidence of Severe ABMR 

At three months post-transplant, a second biopsy was performed, and a small sample of cortex was sent for testing with MMDx® Kidney. The histopathologist reported that the biopsy was abnormal: there was some interstitial inflammation but no tubulitis, there was no glomerulitis, but there was focal endothelialitis and mild peritubular capillaritis. This time the immunohistochemistry for C4d was negative. The biopsy was reported as Banff 2a Acute Tell Cell-mediated Rejection (TCMR). The Banff score was g0, i0, t0, v1, cg0, ci0, ct0, cv0, ah0, aah0, mm0, ptc2C4d0, and i-ifta0

In accordance with the center’s protocol, the patient was treated with high dose intravenous steroids and Thymoglobulin was prescribed. Before the Thymoglobulin was administered, the MMDx Kidney report became available and showed discordance with the histology and no molecular evidence of TCMR but severe “fully developed” ABMR. The MMDx Kidney report was more in keeping with the clinical impression, and so the Thymoglobulin was not administered. Instead, the patient received further treatment for ABMR (PLEX, IVIg, and later Rituximab).  The serum creatinine peaked at 3.1 mg/dL but fell to 1.6-1.7 mg/dL thereafter. With time, the creatinine gradually rose to 2 mg/dL. When the patient’s blood pressure permitted, she was commenced on losartan (because of the positive AT1R antibody). 

Post-Transplant Monitoring: Continued Treatment Informed by MMDx Kidney 

At six months post-transplant, with a serum creatinine of 2.2 mg/dL, a third biopsy was  performed, and again a sample was sent for MMDx Kidney. The histopathologist again reported an abnormal biopsy result: now showing no tubulitis, the endothelialitis had resolved; there was persisting peritubular capillaritis, and one glomeruli showed mild glomerulitis. The immunohistochemistry for C4d was negative. The histopathologist deemed this biopsy to show mild microcirculatory inflammation, and it was suggested that this could be consistent with treated/resolved ABMR. The Banff score was g1,i0, t0, v0, cg0, ci0, ct0, cv0, ah0, aah0, mm0, ptc2, C4d0 and i-ifta0. However, the recent MMDx Kidney report showed molecular evidence of severe, fully developed ABMR. The patient was again treated for ABMR, this time with PLEX, IVIg and Bortezomib. At the time of discharge the creatinine had improved to 1.78mg/dL. 

At an ongoing follow-up, a rise in the serum creatinine to 2.5mg/dL was associated with significant BK viraemia (5.3log copies/mL), requiring a reduction in her immunosuppression (mycophenolic acid dose halved) and the initiation of maintenance IVIg. 

Conclusion and Summary 

In this case, a biopsy performed at seven days post-transplant for suboptimal graft function showed C4d positivity but no other evidence of ABMR. Subsequent MMDx Kidney tests were consistent in showing molecular ABMR. The treating clinicians suspect that had the first biopsy been sent for MMDx Kidney, it too would have shown ABMR, confirming the decision to treat empirically. Further, because the second biopsy was sent for MMDx Kidney meant, unnecessary exposure to further Thymoglobulin was avoided in the nick of time. 

The treating clinician commented that the MMDx Kidney report made her more confident in her diagnosis and that the reports were more consistent with the patient’s clinical course. As a result of this positive experience of including molecular biopsy assessment in the diagnostic armoury, the team is looking forward to increasing their utilization of MMDx Kidney.