In analogy to prince Hamlet's famous speech – To biopsy is not the question!
Whether 'tis nobler in the mind to suffer
The slings and arrows of outrageous fortune,
Or to take arms against a sea of troubles (in deteriorating kidney transplants)
And by opposing (diagnosing) end (and treat) them.
Kidney transplantation is currently the only cure for irreversible renal failure and thus maintaining a functioning allograft is paramount for patients' quality of life. Over the last decades, great success has been achieved, but roughly 4% of grafts are lost every year even in the most recent eras (Figure 1). The main reason for failing long-term grafts is the smoldering alloimmune response, but other entities such as viral infections, recurrence of disease of the native kidneys in the transplant or progressive arteriolosclerosis are not uncommon. All of these entities can only be reliably diagnosed by a transplant biopsy. This is also true for the most common viral infections leading to graft attrition such as BK nephropathy. Urinary or blood polymerase chain reaction tests may provide a hint, but ultimately, only the biopsy allows for a quantitative estimate of the renal infestation.
Annual graft attrition rate per era and time after transplantation, data from United Network for Organ Sharing (UNOS-SRTR) (reprinted from Wekerle et al. ).
In the first weeks after transplantation, indication biopsies are liberally performed in all centres to detect T-cell-mediated rejection or early antibody-mediated rejection (ABMR), mostly in sensitized patients. However, the rate of early rejections has declined significantly over the last decade and is now in the single-digit range.
Once the patient is in the maintenance phase of her/his transplant and usually managed by the referral centre or the general practitioner, slightly but continuously declining glomerular filtration rate (GFR) over longer time periods usually does not trigger a diagnostic response. In my opinion, one likely explanation is a lack of awareness of the logarithmic relationship of serum creatinine and GFR. Once a chronic alloimmune response is ongoing and de novo sensitization against the graft has taken place, therapeutic options are very limited. To avoid such a scenario, early and liberal transplant biopsies are mandatory. There is a long ongoing debate on whether sequential management or protocol biopsies of well-functioning grafts are to be performed for improving outcomes. According to the conclusion by Jeremy Chapman, I am an advocate for such management biopsy programmes because it is the only measure to discover potentially treatable processes in time, and most importantly, ultrasound-guided transplant biopsies are safe. The rate of major complications has been reported to be well below 1% (for review, see Boban and Tiefenthaler). In most transplant centres worldwide, kidney transplant biopsies are performed as an outpatient procedure.
The histopathological work-up of an experienced pathologist with insight into the excellent but more and more complex Banff classification is certainly of great advantage to discuss lesions and potential therapeutic strategies. However, in 2021, telepathology is readily available for those colleagues without easy access to an expert in-house pathologist. The detailed work-up of transplant biopsies include routine staining with haematoxylin and eosin, periodic acid–Schiff, silver and trichrome. Furthermore, immunohistochemistry primarily for IgG, IgM and IgA, as well as complement components (C3, C1q and C4) and C4d staining of the peritubular capillaries, completes the routine work-up. Electron microscopy is only necessary in selected cases of unclear glomerular pathology. Recently, validated new molecular analysis methods for the allograft biopsy have become available. The most prominent tool, coined as the 'Molecular Microscope', allows for an unbiased and quantitative assessment of lesions in the different compartments and also provides a prognostic estimate on graft patency.[5,6]
The histopathological diagnosis always needs to be seen in the context of the clinical course and additional diagnostic measures. The clinical course should include a review and evaluation of the organ donor, the peri-transplant procedure and the donor organ histology at implantation, although the latter is under debate. Recent papers question the prognostic value of pre-implantation biopsies. The additional diagnostic work-up should include the determination of anti-HLA donor specific antibodies (DSAs) in the context of the immunosuppressive regimen and upfront imaging of the allograft to rule out mechanical causes of graft deterioration such as hypoperfusion or hydronephrosis.
In cases of advanced and chronic impaired transplant function, a biopsy is mandatory to estimate the chronic and potentially irreversible damage and balance the effectiveness with potential toxicity of available therapeutic interventions. Once a large area of the interstitium is fibrosed and scarred and atubular glomeruli are observed, it does not make sense to invest in lymphodepletion therapies, which may only harm the patient but will not provide any benefit.[8,9] On the contrary, if, for example, a chronic active ABMR is the main cause of graft attrition, then it may well be worth considering anti-B-cell therapies or anti-interleukin-6 antibodies.
In summary, an ultrasound-guided kidney biopsy is the state-of-the-art diagnostic procedure in the work-up of deteriorating transplants. It is not a matter of discussion whether this procedure should be applied, but rather the opposite is true. One needs very good reasons to not perform this golden standard of transplant diagnostics. What is still under discussion, however, is the utility of management biopsies in stable maintenance patients and whether borderline changes detected by such protocol biopsies should be treated. My personal opinion is that borderline lesions should be considered as minimal alloimmune responses and thus require therapy. The lack of positive results for treated borderline rejections is merely an issue of statistical power.
Nephrol Dial Transplant. 2022;37(9):1627-1628. © 2022 Oxford University Press