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Keywords:

  • Arteriolar hyalinosis;
  • cyclosporine A;
  • nephrotoxicity;
  • renal allograft;
  • reproducibility;
  • tacrolimus

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

Arteriolar hyaline thickening (AH) is the most characteristic lesion of chronic calcineurin inhibitor nephrotoxicity. This study was performed to compare the inter-observer reproducibility of AH scoring using Banff criteria and a newly proposed criterion. Forty-five nonprotocol post-transplant biopsies from 38 patients immunosuppressed with tacrolimus or cyclosporine A (CsA) were included. The severity of AH was blindly scored by three observers. According to the new criteria, AH is graded based on circular vs. noncircular involvement and the number of arterioles involved. The kappa statistics were used to assess the inter-observer reproducibility. Twenty-seven (60%) biopsies showed AH. The AH grades by both criteria were correlated with serum creatinine at biopsy and inversely correlated with estimated glomerular filtration rate (GFR) (p < 0.05). The recent AH criteria improved the mean pairwise agreement (79.4% vs. 68%) and the overall kappa value (0.67 vs. 0.52) (p = 0.02) compared to Banff criteria. The mean inter-slide variation using Banff and the new criterion were 23% and 27.6%, respectively (p > 0.05). The new AH criterion results in better inter-observer reproducibility, and is clinically validated against serum creatinine and estimated GFR. There is substantial intra-biopsy variation, therefore, evaluation of more than one section is crucial to determine severity of arteriolar damage more accurately.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

The introduction of cyclosporine A (CsA) and other novel immunosuppressive agents has resulted in a substantial improvement in short-term renal allograft survival (1,2). CsA and tacrolimus, known as calcineurin inhibitors (CNI), share a related molecular mechanism of action for the inhibition of T-cell-dependent immune interactions and both drugs cause the same functional and structural nephrotoxicity, although they are completely different in chemical structure (1,3–8).

Despite the dramatic reductions in acute rejection rates and the improvement in early graft survival (9,10), the rate of late graft failure has remained basically unchanged (1). Furthermore, chronic CsA nephrotoxicity emerges as the second most important diagnosis responsible for late graft loss (11). CsA or CNI nephrotoxicity can be classified as acute toxicity without morphological lesions (functional toxicity) or with isometric tubular vacuolization and/or thrombotic microangiopathy, and chronic toxicity affecting the afferent arterioles, glomeruli and tubulointerstitium (11–16). De novo or progressive arteriolar hyaline thickening (AH) is the most pathognomonic lesion of chronic CNI nephrotoxicity (15,17). This lesion consists of vacuolization of endothelial and smooth muscle cells, and focal or circular lumpy protein deposits in the arteriolar wall which usually replace necrotic smooth muscle cells and eventually narrow the vascular lumen (4,12,13). This arteriolopathy is probably important for the development of interstitial fibrosis and tubular atrophy (14,18).

In the Banff classification of renal allograft biopsies, AH is quantitatively graded as mild, moderate and severe according to the intensity and the distribution of the lesions (18). Reproducibility studies on AH scoring using Banff criteria showed substantial to poor inter-observer agreement with the kappa values of 0.63 to 0.18 (19–21). This inter-observer variation is probably not only related to the method used but also may be partly explained by the focal and patchy nature of the arteriolar lesions or by the variation of severity of damage from one arteriole to the other, which makes the examination of every arteriole in the renal biopsy crucial. Supporting this view, Strom et al. (14) observed that a maximum of 24.9% of arterioles showed hyaline thickening at 90 days post-transplant in a total of 557 renal biopsies.

It seems that more objective criteria for the assessment of CNI-induced arteriolopathy are needed in order to improve inter-observer and intra-observer reproducibility. Mihatsch et al. (13) described CNI arteriolopathy as replacement of degenerated smooth muscle cells by focal or circular lumpy hyaline deposits which are often arranged in a beaded or clover-leaf-like pattern in the media. Recently, a new quantitative scoring system for CNI arteriolopathy has been proposed by M. J. Mihatsch so that the severity of arteriolopathy is quantified according to the presence of circular or noncircular involvement and the number of involved arterioles (M. J. Mihatsch: personal communication, 2004). The present project is designed to test the inter-observer reproducibility and clinical validity of this new scoring system for AH and to determine whether it has superiority to the current Banff 97 AH criteria to ensure a reasonable reproducibility.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

A total of 45 nonprotocol renal allograft biopsies from 38 patients were randomly selected without the knowledge of clinical status including both AH negative and AH positive cases. The biopsies were performed for unexplained deterioration of renal function. Seven patients had two sequential biopsies at at least 1-week intervals. Pertinent clinical data were reviewed from medical records of the University of Alberta Hospital and renal transplant clinic files. The clinical data included recipient age and gender, donor age, post-transplantation time, serum creatinine at biopsy, type of immunosuppressive drugs and blood levels of CNI drugs. Estimated glomerular filtration rate (GFR) was calculated for adult patients (n = 36) using the abbreviated Modification of Diet in Renal Disease (MDRD) formula (22). Of the 38 patients, 28 had time-zero biopsies at the time of implantation and these were reviewed for the presence of donor origin AH.

All biopsies were adequate for interpretation according to the criteria set up by Banff classification of renal allograft biopsies (18) that the biopsies contain at least seven glomeruli and an artery. These were routinely processed for paraffin embedding and sectioned at 2 μm thickness. Three hematoxylin and eosin, three periodic acid-Schiff (PAS), one silver, one Masson trichrome and one Martius Scarlet blue stain were done on each biopsy.

Three PAS-stained glass slides from different levels of the tissue (level 1,10 and 14), with one section on each, were used for this study. Three observers (B. S., F. D., F. K.) scored AH according to both Banff 1997 guidelines (18) and a new scoring system proposed by M. J. Mihatsch (personal communication, 2004). One observer (B. S.) is a faculty-level renal pathologist and has been regularly working on renal allograft biopsies in a diagnostic setting and other two observers (F. D., F. K.) are renal pathology fellows. The quantitative criteria for AH set up by Banff 97 classification (18) are as follows: No PAS-positive hyaline thickening (AH0), mild to moderate PAS-positive hyaline thickening in at least one arteriole (AH1), moderate to severe PAS-positive hyaline thickening in more than one arteriole (AH2) and severe PAS-positive hyaline thickening in many arterioles (AH3). Mihatsch et al. (13) described CNI arteriolopathy as replacement of degenerated and necrotic smooth muscle cells by focal or circular lumpy hyaline deposits which are often arranged in a necklace-like pattern along the outer aspect of arterioles and within the media. The recent quantitative criteria for CNI arteriolopathy proposed by M. J. Mihatsch include the following: No typical lesions of CNI arteriolopathy (score 0), replacement of degenerated smooth muscle cells by hyaline deposits present in only one arteriole, but no circular involvement (score 1), replacement of degenerated smooth muscle cells by hyaline deposits present in more than one arteriole, but no circular involvement (score 2), replacement of degenerated smooth muscle cells by hyaline deposits with circular involvement, independent of the number of arterioles involved (score 3) (Figures 1 and 2). This scoring system is actually based on the findings in a previous study by Mihatsch and Morozumi (23).

image

Figure 1. Circumferential severe hyaline deposition in the arteriolar wall narrowing the lumen (PAS, original magnification ×600).

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image

Figure 2. Noncircumferential hyaline deposition in the arteriolar wall replacing smooth muscle cells (PAS, original magnification ×600).

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Inter-slide variation

To investigate the variation in arteriolar lesions among three levels of section, all observers scored each slide for the severity of AH. This evaluation was carried out to assess the intra-biopsy variation, focality of the arteriolar lesions and the importance of evaluating more than one section representing different levels of the biopsy. AH is scored separately on three PAS-stained slides per case and the greatest score is accepted as the total score.

Ethics

The study was covered by approval (Protocol #5718) from the Institutional Review Board (Health Research Ethics Board, University of Alberta, Edmonton, Alberta, Canada).

Statistical analysis

The kappa statistics were used to test the inter-observer reproducibility (24). Reproducibility was tested on each of the three PAS-stained sections and an overall kappa value was calculated. A kappa value of 0 indicates a level of agreement that would be explained solely by chance, whereas a value of 1 indicates full agreement. The level of agreement for various kappa values are generally accepted as follows: 0.0–0.2, slight; 0.21–0.4, fair; 0.41–0.6, moderate; 0.61–0.8, substantial; 0.81–1.0, almost perfect (25). The kappa coefficients were compared for statistical significance with use of paired test (Wilcoxon signed-ranks test) (26,27). In addition, we calculated Spearman's rank correlation coefficient (Rho) to test the agreement between pairs of observers. The extent of inter-slide variation in AH scores using both scoring systems were compared by McNemar test. The relationship between clinical and pathological variables was investigated using Mann-Whitney U, Kruskal-Wallis or chi square test. The level of significance was set at p < 0.05. All analyses were performed using Scientific Package for Social Sciences software (SPSS 12.0, Chicago, IL).

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

Demographic data

The clinical data from 38 renal allograft recipients are shown in Table 1. All patients received a triple immunosuppressive therapy consisting of prednisolone, CsA (n = 17) or tacrolimus (n = 21), and mycophenolate mofetil or azathioprine (n = 37 or n = 1, respectively). At the time of biopsy, the mean blood CsA level was 116.2 ± 61.7 ng/mL and the mean blood tacrolimus level was 8.6 ± 5.8 ng/mL. The mean serum creatinine at the time of biopsy was 195.3 ± 81.1 μmol/L and the mean estimated GFR calculated by MDRD equation was 37.7 ± 14.9 mL/min/1.73 m2. The period following renal transplantation till biopsy ranged from 4 months to 21 years (mean time 4.3 ± 5.2 years).

Table 1.  Demographic and clinical characteristics of patients (n = 38)
 Mean ± SDMinimum– maximum
  1. aGFR = glomerular filtration rate predicted by the MDRD equation (22).

Recipient age (year)39.7 ± 15.56–71
Recipient gender (m/f)27/11 
Donor age (year)40.1 ± 1625–72
Cadaveric/living donor21/17 
Time since transplantation (year)4.3 ± 5.20.33–21
Creatinine at biopsy (μmol/L)195.3 ± 81.158–531
GFRa at biopsy (mL/min/1.73 m2)37.7 ± 14.910–48
CNI blood level (at biopsy; ng/mL)Tacrolimus8.6 ± 5.8
 CsA116.2 ± 61.7

Histology

All biopsies were graded according to the Banff classification (18). Of the 28 implantation biopsies, 6 (21%) showed donor origin AH (mean Banff AH score: 1.6). CNI toxicity was not diagnosed in these patients unless AH score increased in the subsequent biopsy specimen. The diagnoses on 45 post-transplant biopsies were as follows: chronic allograft nephropathy (CAN) with CNI toxicity, 6 (13.3%); CNI toxicity, 5 (11.1%); CAN, 5 (11.1%); CAN with recurrent IgA nephropathy, 1 (2.2%); BK virus nephropathy, 1 (2.2%); CNI toxicity with recurrent or de novo immune complex glomerulonephritis, 4 (8.8%); borderline changes with CNI toxicity, 1 (2.2%); borderline changes with CAN, 2 (4.4%); borderline changes, 3 (6.6%); acute tubulointerstitial rejection, 2 (4.4%); acute vascular rejection, 3 (6.6%); CAN with residual acute rejection, 1(2.2%); antibody-mediated rejection, 2 (4.4%); acute tubulointerstitial rejection with focal proliferative glomerulonephritis, 2 (4.4%); miscellaneous, 7 (15.5%).

Of the 45 biopsies, 27 (60%) showed AH. Table 2 demonstrates the correlation between AH and clinical characteristics and Banff scores. The biopsies with AH had significantly increased serum creatinine at biopsy (p < 0.001), decreased estimated GFR by the MDRD equation (p < 0.001), increased interstitial fibrosis (ci) (p = 0.002), tubular atrophy (ct) (p = 0.002), ci + ct scores (p = 0.002), glomerulosclerosis (p = 0.002), and increased post-transplant day (p = 0.008). No significant correlation was determined between the presence of AH and the blood levels of CsA or tacrolimus, donor age, recipient age and the other Banff lesions (p > 0.05).

Table 2.  Clinical features and Banff scores in biopsies with and without arteriolar hyalinosis (mean ± SD)
 Arteriolar hyalinosis − (n = 18)Arteriolar hyalinosis + (n = 27)pa
  1. aMann-Whitney U or chi square test. NS, not significant (p > 0.05)

  2. bGFR = Glomerular filtration rate predicted by the MDRD equation (22).

CNI blood level (at biopsy; ng/mL)
 Tacrolimus9.6 ± 7.48.4 ± 3.4NS
 CsA129.2 ± 93.1120.2 ± 40.1NS
Creatinine at biopsy (μmol/L)146 ± 41.3227.5 ± 85.0<0.001
GFRb at biopsy (mL/min/1.73 m2)50.4 ± 12.928.3 ± 7.5<0.001
Time since transplantation (year)1.9 ± 2.25.9 ± 6.00.008
Donor age (year)32.5 ± 7.845.8 ± 18.5NS
Glomerulitis (g)0.1 ± 0.30.07 ± 0.3NS
Interstitial inflammation (i)1.2 ± 1.01.4 ± 0.8NS
Tubulitis (t)1.1 ± 0.90.5 ± 0.7NS
Vasculitis (v)0.2 ± 0.70.0 ± 0.0NS
Allograft glomerulopathy (cg)0.1 ± 0.40.3 ± 0.8NS
Interstitial fibrosis (ci)0.8 ± 0.81.8 ± 0.70.002
Tubular atrophy (ct)0.8 ± 0.71.8 ± 0.70.002
ct + ci1.7 ± 1.63.5 ± 1.50.002
Arterial fibrous intimal thickening (cv)0.6 ± 0.91.3 ± 0.9NS
Glomerulosclerosis, %4.2 ± 8.423.8 ± 24.50.002

Serum creatinine at the time of biopsy increased and estimated GFR decreased in proportion to the severity of AH scores by both Banff and M. J. Mihatsch's criteria (p < 0.05). However, no significant correlation was found between the degree of AH and blood levels of CsA or tacrolimus, post-transplant day, interstitial fibrosis, tubular atrophy, ci + ct scores, the percentage of glomerulosclerosis, fibrous intimal thickening in arteries and the other Banff lesions (p > 0.05).

AH scoring according to the Banff 97 classification

The AH score distribution (n = 45) for each observer is presented in Figure 3. Complete agreement among all three observers was seen in 27 of 45 cases (60%). Of these, 16 were AH0, 7 were AH1, 3 were AH2, and 1 was AH3. Paired comparisons revealed an overall kappa value of 0.52 with a range from 0.38 to 0.74 (Table 3). The rate of pairwise agreement was between 55% to 84% with a mean rate of 68%. The mean kappa values per each of three PAS-stained sections were 0.50, 0.56 and 0.51. Inter-observer agreement rates for PAS-stained section 1, 10 and 14 were 67%, 70% and 67.6%, respectively. (Table 4). Inter-slide variation rates were 23.7%, 21.5% and 23.7% for three observers, with a mean inter-slide variation rate of 23% (Table 5).

image

Figure 3. Banff AH score distribution for each of the three observers in the present study.

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Table 3.  Inter-observer reproducibility (kappa values) and Spearman's correlation coefficients (rho) and p-values for arteriolar hyaline thickening scored by three observers using 1997 Banff classification
ObserverObserver
BC
kapparhopkapparhop
A0.450.871<0.0010.380.867<0.001
B 0.740.908<0.001
Table 4.  The mean inter-observer kappa values and agreement rates for arteriolar hyaline thickening according to the different levels of section
Scoring systemLevel of sectionInter-observer kappa valueInter-observer agreement rate
Banff 97 classification10.5067%
100.5670%
140.5167.6%
Mihatsch's system10.6679.2%
100.6779.2%
140.6779.9%
Table 5.  The inter-slide variation rates among arteriolar hyaline thickening (AH) scores using Banff or Mihatsch's criteria
ObserverInter-slide variation (%) in AH scoresa
Banff criteriaMihatsch's criteria
  1. ap > 0.05.

A23.730.3
B21.527.4
C23.725.2
 23 (mean)27.6 (mean)

CNI arteriolopathy scoring according to Mihatsch's scoring system

The CNI arteriolopathy score distribution (n = 45) for each observer is presented in Figure 4. Complete agreement among all three observers was seen in 32 of 45 cases (71.1%). Of these, 17 were CNI arteriolopathy 0, 1 was CNI arteriolopathy 1 and 14 were CNI arteriolopathy 3. Paired comparisons revealed an overall kappa value of 0.67, with a range from 0.62 to 0.74 (Table 6). The rate of pairwise agreement was between 73.3% and 88.8%, with a mean rate of 79.4%. The mean kappa values for each of the three PAS sections were 0.66, 0.67 and 0.67. Inter-observer agreement rates for PAS-stained section 1, 10 and 14 were 79.2%, 79.2% and 79.9%, respectively (Table 4). Inter-slide variation were 30.3%, 27.4% and 25.2% among three observers, with a mean inter-slide variation rate of 27.6% (Table 5).

image

Figure 4. CNI arteriolopathy score distribution based on the recent criteria for each of the three observers in the present study.

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Table 6.  Inter-observer reproducibility (kappa values) and Spearman's correlation coefficients (rho) and p-values for arteriolar hyaline thickening scored by three observers using Mihatsch's scoring system
ObserverObserver
BC
kapparhopkapparhop
A0.650.888<0.0010.620.926<0.001
B 0.740.967<0.001

The difference in the kappa correlation coefficients based on Banff and the new criteria was statistically significant (p = 0.02). The inter-slide variation rates in AH scores using both criteria was not statistically different (p > 0.05).

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

Chronic CNI nephrotoxicity is one of the most important nonimmune mechanisms responsible for the late graft deterioration (11). The immunosuppressive effects of CsA and tacrolimus are due to the inhibition of calcium dependent enzyme, calcineurin in T cells (1,3,4,28). The inhibition of calcium–calcineurin pathway may also have a role in the imbalance between vasoconstriction and vasodilation, since CNI nephrotoxicity is primarily due to endothelial injury and vasoconstriction in the afferent arterioles (1,11,28). It has been suggested that altered release of vasoactive substances from vascular endothelial cells, such as angiotensin II, endothelin, prostaglandins and nitric oxide plays a crucial role in the pathogenesis of CNI arteriolopathy (1,29).

Chronic CNI nephrotoxicity is represented by the pathological structural changes in arterioles, glomeruli and tubulointerstitium including arteriolopathy, glomerular sclerosis, granular juxtaglomerular cell hyperplasia, tubular atrophy and interstitial fibrosis (11–16,30). The initial reversible lesion consists of vacuolization of endothelial and smooth muscle cells in afferent arterioles. Later, these injured cells undergo necrosis and plasma proteins insudate into the arteriolar wall forming hyaline deposits in areas of necrotic smooth muscle cells (4). These hyaline deposits are typically arranged with a necklace-like pattern along the outer aspect of the arterioles leading to the segmental thickening of vessel walls (11–16). This lesion may involve the entire circumference of the vessel wall or may be noncircular (4,13,23). At later stages, severe hyaline thickening with narrowing of the vascular lumen leads to hypoxia and irreversible damage such as focal segmental glomerular sclerosis, tubular atrophy and interstitial fibrosis either in striped or diffused form (1,4). Mihatsch and Morozumi et al. (23) reported that complete regression of CsA-associated arteriolopathy and remodeling of arterioles occur in many cases even with severe arteriolopathy several months after stopping or reducing the dose of CsA. These results indicate the possible reversibility of CsA-associated arteriolopathy with reduction of CsA dose and the new proposed scoring system is actually based on the morphological observations in this study by Morozumi (23).

Among the structural changes, de novo or progressive hyaline arteriolopathy is the most typical lesion for the diagnosis of CNI nephrotoxicity. Analysis of histological changes in native kidneys of heart and bone marrow recipients showed that this lesion was observed only in patients on CNI therapy (31). The assessment of the severity of the arteriolopathy is also of importance while the arteriolar changes potentially reflect the subsequent chronic glomerular and tubulointerstitial damage. In the present study, we compared the inter-observer reproducibility of two grading systems for arteriolar hyalinosis, Banff AH scoring and the recent scoring system proposed by M.J. Mihatsch. We observed that AH scores based on both systems were correlated with serum creatinine and estimated GFR at the time of biopsy, which further supports the clinical validity of both scoring systems. The presence of AH was significantly related to both functional and chronic histological changes such as increased glomerulosclerosis, interstitial fibrosis and tubular atrophy, but these histologic changes did not significantly differ among AH1, AH2 or AH3 by both criteria. These negative results may be related to the relatively small number of cases in each AH positive category (AH1–3). We did not find any correlation between AH scores and the blood levels of the drug, either CsA or tacrolimus, but the presence of AH is strongly correlated with post-transplant time. Previous studies have also shown that the severity of arteriolar hyalinosis is not dependent on the dosage or the concentration of CsA or tacrolimus but correlates with the time of exposure to the drug (7,8).

The current reproducibility study has showed the inter-observer agreement of Banff AH criteria as moderate with a kappa value of 0.52, demonstrating the need of more precise criteria for AH scoring. On the other hand, the recent criterion for AH scoring improved the inter-observer agreement with a kappa value of 0.67. We think that the new criterion is more objective and easier to apply and results in a better inter-observer reproducibility. One might expect that reproducibility would be higher using a scoring system more familiar to the observers, and this may produce an over-optimistic assessment of reproducibility. The observers in this study use routinely Banff AH criteria in their diagnostic work, are more familiar to Banff criteria and have not been trained by M. J. Mihatsch, the creator of the new AH scoring system. We do not think that our results reflect a bias, but rather emphasize that the new criteria reduce the inter-observer variation and results in a substantial reproducibility even among the observers who are not very familiar to this recent scoring system. On the other hand, it should be stated that the improvement even with the new criteria is still less than a perfect inter-observer concordance and reproducibility.

The reproducibility of a grading system can be improved by reducing the number of grading categories. In a study by Lang et al. (32), three pathologists independently graded 241 renal cell carcinomas according to the Fuhrman grading system. The authors yielded the best kappa value by collapsing the original four-tiered Fuhrman grading system to a three-tiered scheme, and then two-tiered scheme. Reproducibility can also be further improved by providing more precise description of lesions. From this point of view, the recent criteria for grading of hyaline arteriolopathy seem more objective. However, it is difficult to define a strict morphological criterion since arterioles are very small structures and easily loose their normal histology due to hyaline deposition. Furthermore, CNI toxicity does not diffusely affect all arterioles; there is a focal and patchy involvement that sampling errors or intra-biopsy variation make the grading more prone to inter- and intra-observer disagreement. In the current study, we observed a substantial intersection variation rate in arteriolar hyalinosis grades using both Banff AH criteria (23%) and the recent scoring system (27.6%).

Differential diagnosis of CNI-associated arteriolopathy includes thrombotic microangiopathy, diabetes, hypertension and age-related arteriolar hyalinosis. The changes of CNI arteriolopathy are very similar to those that may be found in advanced cases of thrombotic microangiopathy, independent of CNI treatment. According to Mihatsch and colleagues (4,13,23) CNI-associated arteriolopathy can be distinguished from hypertensive or diabetic hyaline arteriolopathy owing to the presence of subendothelial deposits that are situated inside of well-preserved smooth muscle cells, in comparison to the deposits in CNI-associated arteriolopathy, which are focal or circular and replace necrotic smooth muscle cells. However, in advanced cases of hypertensive or diabetic arteriolopathy, or in late stages of CNI-associated arteriolopathy, differentiation may be difficult or even impossible.

In conclusion, the new AH scoring system yielded better inter-observer reproducibility. However, the focal and patchy nature of arteriolar lesions and the variation in the severity of arteriolar damage may reduce inter-observer agreement. Thus, examination of more than one section is crucial for a more accurate diagnosis and grading on arteriolar hyalinosis. Validation of the new criteria against serum creatinine and estimated GFR at the time of biopsy and the improved reproducibility support the application of this new scoring system for AH in renal allograft biopsies.

Acknowledgment

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

This research was supported by a grant from Genome Canada.

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  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References
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