Journal List > J Korean Soc Transplant > v.28(3) > 1034426

Kim, Lee, Myoung, Dong, Beom, Kyu, Soon, Yu, and Hyeon: Changes of Kidney Injury Molecule-1 Expression and Renal Allograft Function in Protocol and for Cause Renal Allograft Biopsy

Abstract

Background

Kidney injury molecule-1 (KIM-1) is known as a good ancillary marker of acute kidney injury (AKI) and its expression has also been observed in acute rejection and chronic graft dysfunction. We tested usefulness of KIM-1 as an indicator of acute and chronic renal graft injury by correlating KIM-1 expression with renal graft function and histology.

Methods

A total of 133 zero-time biopsies and 42 follow-up biopsies obtained within 1 year posttransplantation were selected. Renal tubular KIM-1 staining was graded semiquantitatively from 0 to 3 and the extent of staining was expressed as the ratio of KIM-1 positive/CD10 positive proximal tubules using Image J program.

Results

KIM-1 was positive in 39.8% of zero-time biopsies. KIM-1 positive cases were predominantly male and had received grafts from donors with older age, deceased donors, and poor renal function at the time of donation, compared with KIM-1 negative cases. KIM-1 expression showed correlation with delayed graft function and acute tubular necrosis. In comparison of KIM-1 expression between stable grafts (n=23) and grafts with dysfunction (n=19) at the time of repeated biopsy, the intensity/extent of KIM-1 staining and renal histology at zero-time did not differ significantly between the two groups. Histologically, KIM-1 expression was significantly increased with both acute and chronic changes of glomeruli, tubules and interstitium, peritubular capil-laritis, and arteriolar hyalinosis.

Conclusions

KIM-1 can be used as an ancillary marker of AKI and a nonspecific indicator of acute inflammation and tubulointerstitial fibrosis. However, KIM-1 expression at zero-time is not suitable for prediction of long-term graft dysfunction.

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Fig. 1.
Scoring of renal tubular kidney injury molecule-1 expression: (A) 0.5, focal staining, (B) 1, weak and entire staining, (C) 2, moderate and entire staining. and (D) 3, strong and entire staining (×400).
jkstn-28-135f1.tif
Fig. 2.
Renal tubular kidney injury molecule-1 (KIM-1) expression in patients with stable graft function and dysfunction (×200). (A, B) In a patient with stable renal function, tubular KIM-1 expression increased in the repeat biopsy (B, score 2) compared with zero time (A, score 0.5). (C, D) Tubular KIM-1 expression became prominent in the repeat biopsy (D, score 3) in a patient with graft dysfunction, who showed negative KIM-1 staining at zero time (C).
jkstn-28-135f2.tif
Table 1.
Patient’ s demography according to zero-time KIM-1 expression
Parameter KIM-1 positive (n=53) KIM-1 negative (n=80) P-value
Donor      
Age, yr 50.0 (19.0∼70.0) 43.5 (18.0∼63.0) 0.005
Male/Female 35/18 26/54 <0.001
BUN (mg/dL) at Tx 20.0 (2.0∼84.3) 12.4 (6.1∼52.2) <0.001
Serum creatinine (mg/dL) at Tx 0.9 (0.2∼5.1) 0.7 (0.5∼2.6) <0.001
Type of donor (deceased/living) 40/13 15/65 <0.001
Recipient      
Age, yr 45.0 (11.0∼70.0) 49.0 (15.0∼65.0) 0.238
Male/Female 26/27 52/28 0.068
BUN (mg/dL)      
At time of Tx 46.0 (20.3∼96.5) 52.2 (25.1∼95.1) 0.028
At 1 wk post-Tx 25.6 (11.8∼106.3) 20.8 (9.2∼75.5) 0.007
Serum creatinine (mg/dL)      
At time of Tx 8.7 (3.1∼17.4) 8.4 (2.4∼16.6) 0.760
At 1 wk post-Tx 1.4 (0.5∼7.5) 1.3 (0.5∼5.9) 0.018
Graft function: DGF/IGF 12/41 7/73 0.025

Data are presented as median (range).

Abbreviations: KIM-1, kidney injury molecule-1; BUN, blood urea nitrogen; Tx, transplantation; DGF, delayed graft function; IGF, immediate graft function.

Table 2.
Patient’ s demography according to zero-time KIM-1 staining intensity
Variable Grades of KIM-1 staining P-value
0 (n=80) 0.5 (n=20) 1 (n=22) 2 (n=8) 3 (n=3)
Donor type           <0.001
Living 65 (81.3) 8 (40.0) 4 (18.2) 1 (12.5) 0 (0.0)  
Deceased 15 (18.7) 12 (60.0) 18 (81.8) 7 (87.5) 3 (100.0)  
Graft function           0.017
IGF 73 (91.3) 14 (70.0) 20 (90.9) 5 (62.5) 2 (66.7)  
DGF 7 (8.7) 6 (30.0) 2 (9.1) 3 (37.5) 1 (33.3)  
Serum creatinine (mg/dL)            
At time of Tx 8.35 (2.41∼16.56) 7.25 (3.96∼12.18) 8.66 (3.10∼14.90) 14.01 (9.03∼17.37) 12.89 (12.76∼14.19) 0.001
At 1 wk post-Tx 1.26 (0.52∼5.89) 1.42 (0.50∼5.75) 1.21 (0.77∼5.52) 2.1 (1.27∼7.50) 1.42 (0.81∼5.01) 0.039
BUN (mg/dL)            
At time of Tx 52.15 (25.1∼95.1) 41.2 (20.3∼69.9) 44.9 (23.9∼96.5) 52.45 (33.4∼73.5) 52 (39.3∼52.5) 0.126
At 1 wk post-Tx 20.8 (9.2∼75.5) 21.8 (11.8∼97.9) 27.45 (12.6∼83.1) 31.25 (19.8∼91.8) 23.7 (16.4∼106.3) 0.048

Data are presented as number (%) or median (range).

Abbreviations: KIM-1, kidney injury molecule-1; IGF, immediate graft function; DGF, delayed graft function; Tx, transplantation; BUN, blood urea nitrogen.

Table 3.
Correlation between KIM-1 expression and light microscopic features
Variable KIM-1 positive KIM-1 negative P-value
Global sclerosis (%) 3.1 (0.0∼34.1) 0.0 (0.0∼50.0) 0.036
g0/g1/g2/g3 53/0/0/0 80/0/0/0 >0.999
t0/t1/t2/t3 52/1/0/0 79/1/0/0 >0.999
i0/i1/i2/i3 50/3/0/0 79/1/0/0 0.301
v0/v1/v2/v3 53/0/0/0 80/0/0/0 >0.999
cg0/cg1/cg2/cg3 52/1/0/0 80/0/0/0 0.399
ct0/ct1/ct2/ct3 15/38/0/0 53/27/0/0 <0.001
ci0/ci1/ci2/ci3 45/8/0/0 79/1/0/0 0.003
cv0/cv1/cv2/cv3 43/9/1/0 71/9/0/0 0.293
ah0/ah1/ah2/ah3 42/10/0/1 74/6/0/0 0.039
mm0/mm1/mm2/mm3 52/1/0/0 80/0/0/0 0.399
ptc0/ptc1/ptc2/ptc3 53/0/0/0 80/0/0/0 >0.999

Data are presented as median (number).

Abbreviation: KIM-1, kidney injury molecule-1.

Table 4.
Changes of renal function and histology in KIM-1 positive cases at zero-time (n=5)
Parameter Time zero biopsy Repeat biopsy P-value
KIM-1 positivity 5 (100) 4 (80) 0.421
Staining intensity of 1 or more 2 (40) 4 (80) 0.310
KIM-1 staining extent     0.421
Less than 5% 3 (60) 0  
5∼10% 1 (20) 1 (20)  
More than 10% 1 (20) 3 (60)  
BUN (mg/dL) 39.8±19.2 24.6±12.3 0.310
Serum creatinine (mg/dL) 5.9±4.0 1.5±1.0 0.016
eGFR (mL/min/1.73 mm2) 10.1±6.3 39.3±28.0 0.151
Acute rejection within 1 yr   2  
Graft histology      
Global glomerulosclerosis (%) 1.8±4.1 0 0.317
Tubular atrophy 0.8±0.4 0.6±0.5 0.690
Interstitial fibrosis 0.6±0.5 0 0.151
Arterial fibrous intimal thickening 0 0 0.151

Data are presented as number (%) or mean±SD.

Abbreviations: KIM-1, kidney injury molecule-1; BUN, blood urea nitrogen; eGFR, estimated glomerular filtration rate.

Table 5.
Changes of renal function and histology in KIM-1 negative cases at zero-time (n=37)
Parameter Time zero biopsy Repeat biopsy P-value
KIM-1 positivity 0 22 (59.5) <0.001
Staining intensity of 1 or more 0 15 (40.5) <0.001
KIM-1 staining extent     <0.001
Less than 5% 0 11 (29.7)  
5∼10% 0 3 (8.1)  
More than 10% 0 8 (21.6)  
BUN (mg/dL) 51.5±15.0 22.3±11.8 <0.001
Serum creatinine (mg/dL) 8.5±3.5 1.7±1.4 <0.001
eGFR (mL/min/1.73 mm2) 10.6±10.7 54.2±22.1 <0.001
Acute rejection within 1 yr   3  
Graft histology      
Global glomerulosclerosis (%) 4.8±9.9 3.4±8.8 0.536
Tubular atrophy 0.3±0.5 0.6±0.6 0.015
Interstitial fibrosis 0 0.2±0.5 0.033
Arterial fibrous intimal thickening 0.1±0.3 0.3±0.7 0.105

Data are presented as number (%) or mean±SD.

Abbreviations: KIM-1, kidney injury molecule-1; BUN, blood urea nitrogen; eGFR, estimated glomerular filtration rate.

Table 6.
KIM-1 positivity and renal histology according to graft dysfunction at repeat biopsy
Parameter Stable function (n=31) Graft dysfunction (n=11) P-value
Time-zero Repeat biopsy Time-zero Repeat biopsy Time-zero Repeat biopsy
KIM-1 positivity 4 (12.9) 15 (48.4) 1 (9.1) 9 (81.8) 0.607 0.056
Serum creatinine (mg/dL) 8.1±3.7 1.1±0.2 8.5±3.5 3.2±1.9 0.714 <0.001
Graft histology            
Global GS 5.0±10.3 2.9±7.7 2.8±6.3 3.3±10.4 0.632 0.778
Glomerulitis 0 0.16±0.58 0 0.5±0.7 1 0.211
Tubulitis 0.03±0.18 0.65±1.02 0 1.1±0.99 0.888 0.124
Interstitial inflammation 0.03±0.18 0.42±0.85 0 1.2±1.03 0.888 0.054
Vasculitis 0 0.1±0.4 0 0.2±0.4 1 0.592
Tubular atrophy 0.32±0.48 0.52±0.51 0.36±0.5 0.8±0.79 0.844 0.308
Interstitial fibrosis 0.06±0.25 0.1±0.3 0.09±0.3 0.4±0.84 0.91 0.632
Arteriolar hyalinosis 0.16±0.37 0 0 0 0.445 1.
Arterial thickening 0.06±0.25 0.42±0.72 0.09±0.3 0 0.91 0.117

Data are presented as number (%) or mean±SD.

Abbreviation: KIM-1, kidney injury molecule-1.

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