Transplantation
Figure 1: Arteriolar Hyalinosis Due to Chronic Calcineurin Inhibitor Toxicity
A
Table 1: Clues in Allograft Biopsy for Causes of Interstitial Fibrosis/Tubular Atrophy (IF/TA)
Aetiology
Chronic active T-cell- mediated rejection
Chronic active antibody-mediated rejection
Clues in Kidney Biopsy Arterial intimal fibrosis with
mononuclear cell infiltration in fibrosis, formation of neointima
C4d staining in peritubular capillaries;
glomerular double contours, and/or peritubular capillary basement membrane multilayering, and/or IF/TA, and/or fibrous intimal thickening in arteries; microcirculatory changes
Chronic obstruction Chronic hypertension
Dilated tubules, atubular glomeruli and intratubular Tamm–Horsfall protein casts with interstitial extravasation
Fibrointimal thickening of arteries with internal elastica duplication, arteriolar and small artery hyalinosis and glomerulosclerosis
Chronic calcineurin inhibitor toxicity
B Peripheral hyaline nodule in arteriole,
arteriolar hyalinosis, thrombotic microangiopath picture, isometric vacuolisation of tubular cells; ‘striped’ fibrosis (see Figure 1)
Hy
Chronic inflammation related Intranuclear viral inclusions to Polyoma infection
Chronic pyelonephritis related Lymphoid follicle formation and to bacterial infection
intratubular and peritubular neutrophils
Table 2: Grading of ‘Interstitial Fibrosis and Tubular Atrophy, No Evidence of Any Specific Etiology’
Grade Grade I: mild
Grade II: moderate Grade III: severe
A. Circumferential large hyalinosis in the wall of an arteriole (solid arrow), but not in the small artery (toluidine blue stain, x200).
B. The hyalin deposit appears as granular electron-dense material (hy) in the arteriolar media (electron microscopy, x8,000).
In some patients, antibody-mediated changes, such as circulating DSAs and C4d deposition, can be seen without histopathologic evidence of active rejection. Chronic allograft arteriopathy, defined by the presence of arterial intimal fibrosis with mononuclear cell infiltration in fibrosis and formation of neointima, indicates chronic active T-cell-mediated rejection.4
The last category, listed as
‘interstitial fibrosis and tubular atrophy, no evidence of any specific etiology’, includes non-specific vascular and glomerular sclerosis, the severity of which is graded by degree of chronic tubulointerstitial changes (see Figure 2). Grades I, II and III represent mild (<25 %), moderate (25–50 %), and severe (>50 %) IF/TA, respectively (see Table 2).
Chronic transplant glomerulopathy (CTG) is characterised by duplication of basement membrane usually affecting the entire renal capillary network,5
without evidence of mesangial proliferation or
immune deposits (see Figure 3). Usually, it is antibody-mediated, as evidenced by the presence of complement fragment deposition (C4d) in the peritubular capillaries and the higher incidence of this disorder in patients with anti-donor antibodies prior to kidney transplantation.
156
Percentage of Cortical Area Involved with Interstitial Fibrosis and Tubular Atrophy
<25 %
25–50 % >50 %
There are data to suggest that activated effector T-cells may also play a role in the development of transplant glomerulopathy.6
Despite these
succinct definitions, it is important to realise that ‘interstitial fibrosis and tubular atrophy’ is the final common pathway for all kidney diseases, independent of aetiology. The footprints seen in kidney biopsy may provide ‘clues’ to a specific aetiology, but they cannot rule out other contributors to fibrosis.
Risk Factors – The Usual Suspects Alloantigen-dependent and -independent factors play a significant role in the development of chronic allograft injury and there may be a close interplay between these individual risk factors. In addition, it is important to realise that kidney function may be reduced due to de novo kidney disease or recurrent kidney disease in the allograft.
Alloantigen-independent factors include hypertension, low nephron mass and resultant hyperfiltration injury, diabetes, dyslipidaemia and medications. Since an allograft represents a solitary kidney model with reduced nephron mass as compared with two native kidneys, hyperfiltration injury is always a concern. Size disparity between the donor and the recipient may also result in relatively reduced nephron mass. Another risk factor for low nephron mass may be related to our liberalisation of donor selection criteria. Many transplant centres
EUROPEAN NEPHROLOGY
Page 1 |
Page 2 |
Page 3 |
Page 4 |
Page 5 |
Page 6 |
Page 7 |
Page 8 |
Page 9 |
Page 10 |
Page 11 |
Page 12 |
Page 13 |
Page 14 |
Page 15 |
Page 16 |
Page 17 |
Page 18 |
Page 19 |
Page 20 |
Page 21 |
Page 22 |
Page 23 |
Page 24 |
Page 25 |
Page 26 |
Page 27 |
Page 28 |
Page 29 |
Page 30 |
Page 31 |
Page 32 |
Page 33 |
Page 34 |
Page 35 |
Page 36 |
Page 37 |
Page 38 |
Page 39 |
Page 40 |
Page 41 |
Page 42 |
Page 43 |
Page 44 |
Page 45 |
Page 46 |
Page 47 |
Page 48 |
Page 49 |
Page 50 |
Page 51 |
Page 52 |
Page 53 |
Page 54 |
Page 55 |
Page 56 |
Page 57 |
Page 58 |
Page 59 |
Page 60 |
Page 61 |
Page 62 |
Page 63 |
Page 64 |
Page 65 |
Page 66 |
Page 67 |
Page 68 |
Page 69 |
Page 70 |
Page 71 |
Page 72 |
Page 73 |
Page 74 |
Page 75 |
Page 76 |
Page 77 |
Page 78 |
Page 79 |
Page 80 |
Page 81 |
Page 82 |
Page 83 |
Page 84 |
Page 85 |
Page 86 |
Page 87 |
Page 88 |
Page 89 |
Page 90 |
Page 91 |
Page 92