Clinical role of the renal transplant biopsy

Abstract

Percutaneous needle core biopsy is the definitive procedure by which essential diagnostic and prognostic information on acute and chronic renal allograft dysfunction is obtained. The diagnostic value of the information so obtained has endured for over three decades and has proven crucially important in shaping strategies for therapeutic intervention. This Review provides a broad outline of the utility of performing kidney graft biopsies after transplantation, highlighting the relevance of biopsy findings in the immediate and early post-transplant period (from days to weeks after implantation), the first post-transplant year, and the late period (beyond the first year). We focus on how biopsy findings change over time, and the wide variety of pathological features that characterize the major clinical diagnoses facing the clinician. This article also includes a discussion of acute cellular and humoral rejection, the toxic effects of calcineurin inhibitors, and the widely varying etiologies and characteristics of chronic lesions. Emerging technologies based on gene expression analyses and proteomics, the in situ detection of functionally relevant molecules, and new bioinformatic approaches that hold the promise of improving diagnostic precision and developing new, refined molecular pathways for therapeutic intervention are also presented.

Figure 1

Timing of complications after kidney transplantation in allograft recipients. The differential diagnosis varies with the time since transplantation. Conditions above the line are related to immune rejection, and those below it to nonrejection causes of graft failure. Analysis of biopsy samples is needed to distinguish between these two categories of complications, which require different treatment. In the first few days after transplantation, the major concerns are post-transplantation acute tubular injury, anastomic complications of vessels and ureter with thrombosis, or obstruction, and hyperacute rejection. The following several weeks are dominated principally by acute antibody or cell-mediated rejection, acute drug toxicity, infection, occasionally recurrent disease, as well as lingering acute tubular injury and vascular complications. Up to 1 year post-transplantation, the issues include chronic drug toxicity, infection, recurrent disease, acute rejection, obstruction and renal artery stenosis. After the first year the major problems leading to graft dysfunction are chronic antibody-mediated rejection, chronic calcineurin inhibitor toxicity, recurrent glomerular disease and infection. Acute rejection can also occur at any time, particularly as a consequence of reduced immunosuppression (patient initiated or iatrogenic). *Rejection can be humoral or cell mediated. Abbreviation: CNI, calcineurin inhibitor. Permission obtained from Nature Publishing Group © Chapman et al. Kidney Int. Suppl. 99, S108–S112 (2005).

Figure 2

Pathological findings in renal biopsy samples taken 0–3 days after transplantation. a | Acute tubular injury, with loss of brush borders and nuclei in proximal tubules (arrow) and little infiltrate. These findings also persist beyond 3 days after transplantation in patients with delayed graft function. b | Hyperacute rejection, with neutrophils in glomerular capillaries (arrow). The inset image shows foci of C4d deposition (red staining) in some peritubular capillaries (arrow), but not others (asterisk). c | Acute tubulopathy resulting from the toxic effects of calcineurin inhibitors, with characteristic isometric vacuolization (arrow). This complication can occur at any time after transplantation. d | Urine leaks that cause obstruction typically demonstrate only a focal infiltrate (arrow), but can mimic acute cellular rejection. Permission obtained from Amirsys © Colvin, R. B. et al. Diagnostic Pathology: Kidney Diseases (Salt Lake City, 2011).

Figure 3

Pathological findings observed in renal biopsy samples obtained 3–30 days after transplantation. a | Acute cell-mediated rejection with tubulitis (arrow) and a mixed mononuclear interstitial infiltrate. b | Acute cell-mediated rejection with endarteritis (arrow) superimposed on chronic intimal fibroelastosis resulting from pre-existing donor disease, which can mimic chronic rejection. c | Acute AMR with prominent neutrophils in peritubular capillaries (arrows), a common finding in acute AMR. d | C4d deposition (brown staining) in acute AMR is typically widespread in peritubular capillaries (arrow) and can also be detected in glomeruli by immunohistochemistry. Abbreviation: AMR, antibody-mediated rejection. Permission obtained from Amirsys © Colvin, R. B. et al. Diagnostic Pathology: Kidney Diseases (Salt Lake City, 2011).

Figure 4

Pathological findings observed in renal biopsy samples obtained 1–12 months after transplantation. a | Polyomavirus nephropathy is initially suggested by detection of intranuclear inclusions (arrow). Inset image shows nuclear immunohistochemical staining for polyomavirus large T antigen. b | Adenovirus nephropathy characteristically has a granulomatous appearance and occasional enlarged nuclei. Diagnosis is confirmed by detection of adenoviral antigens by immunohistochemistry (inset image). c | Thrombotic microangiopathy is usually caused by the toxic effects of calcineurin inhibitors in transplant recipients. Glomeruli and small arteries show focal thrombi (arrow). d | Recurrent focal segmental glomerulosclerosis can occur at any time after transplantation and is characterized by segmental scarring and adhesions (black arrow) and occasional prominent podocytes (white arrow). Permission obtained from Amirsys © Colvin, R. B. et al. Diagnostic Pathology: Kidney Diseases (Salt Lake City, 2011).

Figure 5

Pathological findings observed in renal biopsy samples obtained after the first year post-transplantation. a | Chronic AMR is characterized by duplication of the glomerular basement membrane, which is best observed in periodic acid-Schiff-stained sections. Inset image: C4d deposition (blue staining) is usually present in peritubular capillaries (stained brown with CD34, an endothelial marker) but can be focal, with only a minority of the peritubular capillaries affected, or even absent. b | The multilaminated glomerular basement membrane (black arrow) in chronic AMR can be observed by electron microscopy, which also reveals the loss of normal fenestrations in glomerular endothelial cells (red arrow). c | The most distinctive feature of calcineurin inhibitor toxicity in renal grafts ≥1 year after transplantation is severe hyalinosis of the arterioles, often with a peripheral nodular pattern (arrows). d | De novo focal segmental glomerulosclerosis can occur at any time after renal transplantation, but is most common ≥1 year after transplantation. Focal segmental glomerulosclerosis can also be a manifestation of the toxic effects of calcineurin inhibitors, which in this image shows a collapsing pattern with prominent podocytes (arrow). Abbreviation: AMR, antibody-mediated rejection. Permission obtained from Amirsys © Colvin, R. B. et al. Diagnostic Pathology: Kidney Diseases (Salt Lake City, 2011).