Sonography of the renal allograft: Correlation between doppler sonographic resistance index (RI) and histopathology

Abstract

INTRODUCTION:

Allograft rejection (AR), chronic allograft injury (CAI) and acute tubular necrosis (ATN) can lead to renal allograft dysfunction after kidney transplantation. Interstitial fibrosis/tubular atrophy (Banff classification 2005) describes chronic allograft injury with no specific etiology, thus explaining the common final endpoint of various (immunologic and non immunologic) etiologies. The aim of this study was to evaluate correlations between the Doppler sonographic RI-values and histopathological changes of renal allografts biopsies during rejection, acute tubular necrosis and chronic allograft injury as well as the influence of donor and recipient features on the intrarenal RI-values.

METHODS:

102 allograft biopsies and ultrasound reports of 69 patients with kidney transplantation performed at the hospital Klinikum rechts der Isar (Technische Universität München, Germany) between 2009 and 2013 were analyzed retrospectively (41 biopsies of living donors, 61 biopsies of deceased donors). Chronic allograft injury was described using the IFTA (interstitial fibrosis and tubular atrophy) or the ECAI score (extended chronic allograft injury score). The ECAI score was built out of the chronic histological lesions glomerulopathy, interstitial fibrosis, tubular atrophy and fibrous intimal thickening (cg + ci + ct + cv) of the BANFF scoring.

RESULTS:

Intrarenal RI-values were significantly higher in patients with allograft rejection than without rejection (median 0,79 vs. 0,73; inter quartile range: 0,20 vs. 0,13; p = 0,018). The same was found for T-and non-T cell mediated rejection (median 0,78 vs. 0,73; inter quartile range 0,20 vs. 0,13; p = 0,039). There were no significant differences in the RI-values between the subtypes of T-cell mediated rejection (type IA-IIB). Furthermore, there were no significant differences of RI-values regarding antibody-mediated rejection (present vs. not present) or type of rejection (T-cell- vs. antibody mediated rejection). Patients with rejection and simultaneously chronic allograft injury showed significantly higher RI-values than patients with only chronic allograft injury. Analyses using the IFTA or the ECAI score showed comparable results (IFTA p = 0,043; Score p = 0,021). The intrarenal RI-value was neither able to detect chronic allograft injury nor to distinguish between acute tubular necrosis and rejection. The intrarenal RI-value showed a significant correlation with recipient age (p < 0,001) but not with donor features.

CONCLUSION:

In summary, the intrarenal RI-value can indicate a rejection but gives no clear hint to acute tubular necrosis and cannot differentiate from it. Since patients with rejection can have normal RI-values, a biopsy should always be performed in case of suspected rejection. The intrarenal RI-value has no unambiguous validity to determine intrinsic values of the renal allograft, but should rather be understood and interpreted as a systemic parameter influenced by multiple factors.

1. Introduction

Allograft rejection (AR), chronic allograft injury (CAI) and acute tubular necrosis (ATN) can lead to renal allograft dysfunction after kidney transplantation [1 –4]. The former term “chronic allograft nephropathy” was replaced by “interstitial fibrosis/tubular atrophy” in the revised Banff classification in 2005 to describe chronic allograft injury with no specific etiology, thus explaining the common final endpoint of tubular atrophy and interstitial fibrosis of various (immunologic and non-immunologic) etiologies [5].

While kidney biopsy is considered the diagnostic gold standard to detect causes of renal allograft dysfunction [6 –8], also ultrasound fulfills an important role in the follow-up examinations of patients with kidney transplantation, e.g. diagnosing hydronephrosis and lymphoceles by B-mode and detecting vascular complications by Doppler ultrasound [9 –14]. However, B-mode sonography alone cannot diagnose allograft rejection [9 , 16] and also the use of the non-invasive resistance index (RI) is discussed controversially. While various authors described an association between elevated intrarenal RI and rejection and accepted the RI-value as a valuable diagnostic tool [17, 18], others questioned the validity and use of RI-values to diagnose rejection [16 , 19–24].

The resistance index (RI) is defined as follows:

RI = (peak systolic velocity-end-diastolic velocity)/peak systolic velocity

RI is angle independent [10] and values <0,7 are regarded as normal values in transplanted patients [9].

Asphyxia or ischemic edema can reduce renal blood flow and end-diastolic velocity (EDV) [25, 26 in Gao et al. 2011] and thus increase RI-values as seen in acute tubular necrosis or acute rejection [25 , 28]. Possibly explanations include interstitial edema, change of vessel tone or endovasculitis during acute vascular rejection [19].

Gao et al. discussed a greater influence of intrarenal flow pattern by fibrotic compared to non-fibrotic alterations, as fibrosis might compromise vascular compliance and distensibility [25]. The number of allograft rejections may influence the RI because of increased vascular resistance due to rejection-mediated interstitial fibrosis [29].

Since higher RI-values were associated with cardiovascular risk factors and sub-clinic atherosclerosis (intima media thickness, ankle-brachial index), RI-values should not be interpreted as a specific marker for kidney problems [30].

It was shown, that RI-values are not only elevated because of increased resistance of renal vessels but also by other factors such as blood pressure amplitude [31]. Peripheral [29 , 32–35] as well as central increased blood pressure amplitude [34 , 37] can lead to elevated intrarenal RI.

Cardiac factors such as left ventricular outflow velocity [34] and left ventricular hypertrophy influence RI [35, 38]. Heart rate, too, has an impact on RI [33, 39]. Since tachycardia was associated with reduced RI, a heart rate adapted correction formula was described [39].

Adult RI-values increase with age [29 , 41] and higher RI-values were seen in women than in men [30 , 34].

Allograft compression (hematoma, ultrasound transducer) may increase intrarenal RI by reduced diastolic flow [42] or by pressure in the ureter with consecutive increase in interstitial and vascular pressure [43].

While usually aa. interlobares/arcuatae are used for RI measurement [13 , 44–46], measuring the more distally located aa. interlobulares may lead to falsely low RI-values and velocities [10 , 46].

The aim of this study was to evaluate correlations between the Doppler sonographic RI-value performed with high-end ultrasound machines by specially trained physicians and histopathologic changes of renal allografts biopsies examined by reference nephropathologists.

Additionally, the influence of donor and recipient features on the intrarenal RI-value was examined.

2. Methods

Biopsies and ultrasound findings of patients with kidney transplantation were analyzed retrospectively.

Patients with the following criteria were included into the study:

Kidney transplantation between 01/2009 and 08/2013 at the hospital Klinikum rechts der Isar (Technische Universität München, Germany)

Allograft biopsy at the hospital Klinikum rechts der Isar (Technische Universität München, Germany)

Histopathologic examination by a nephropathologic reference unit of the Institute of Pathology at the University of Erlangen, Germany (Banff- classifications 2007 and 2009)

Ultrasound of renal allograft seven days before/after biopsy at the hospital Klinikum rechts der Isar (Technische Universität München, Germany).

Chronic allograft injury was described using the interstitial fibrosis and tubular atrophy (IFTA) score of the revised Banff Classification in 2005 [5] or the extended chronic allograft injury score (ECAI score), which was especially developed for the present study (Fig. 1). The ECAI Score (cg + ci + ct + cv) (Table 1) was built out of the chronic histological lesions of the BANFF scoring: Glomerulopathy (cg 0–3), interstitial fibrosis (ci 0–3), tubular atrophy (ct 0–3) and fibrous intimal thickening (cv 0–3) [2]. The total sum of the different lesions was classified as none (0 points), minor (1–2 points), moderate (3–4 points) or severe (>4 points) chronic alterations.

Fig.1

Extended chronic allograft injury score (ECAI Score).

Table 1

Grades of the extended chronic allograft injury score (ECAI score)

Extended chronic allograft injury score	Sum of Banff lesions (cg + ci + ct + cv)
No chronic alterations	0 points
Minor chronic alterations	1–2 points
Moderate chronic alterations	3–4 points
Severe chronic alterations	>4 points

cg = glomerulopathy; ci = interstitial fibrosis; ct = tubular atrophy; cv = fibrous intimal thickening.

The ultrasound examinations were performed by the nephrology-specialized ultrasound unit using curved array multi-frequency transducers (1–4 MHz) and the following high-end ultrasound machines: Toshiba Xario (Toshiba Medical Systems Corporation, Shimoshigami, Otawara-Shi, Tochigi-ken, 324-8550 Japan), Siemens Acuson S2000™ (Siemens Medical Solutions USA Inc., Mountain View, California 94043-4045 USA) and Siemens Acuson Sequoia 512 (Siemens Healthcare, Erlangen, Germany). Patients were examined using conventional B-mode ultrasound, high-frequency ultrasound and color-coded duplex sonography with power Doppler for the evaluation of kidney perfusion. Gain and pulse repetition frequency were modified individually for each patient.

Intrarenal peak systolic velocity (PSV) and end-diastolic velocity (EDV) were measured in three arteries (aa. interlobares upper pole, middle third and lower pole at the transition of renal cortex/medulla) with pulsed wave Doppler to measure angle-independent resistance indices (Fig. 2).

Fig.2

Measurement of intra-renal RI.

The mean RI-value of the three measurements was used for further statistic evaluation.

Additionally, the influence of donor and recipient features on the intrarenal RI-value was examined.

Serum creatinine was used to determine the calculated glomerular filtration rate using the CKD-EPI formula designed by the chronic kidney disease epidemiology collaboration and was given as eGFR in ml/min/1,73 m² [47].

After data were coded numerically in Microsoft Office Excel 2007, data were processed using IBM SPSS Statistics 22.0 and 23.0 Software (IBM Corp., Armonk, NY, USA). Descriptive results were presented as mean values, minimum, maximum and standard deviation (SD); for better visualization boxplots, tables and pie charts were established. Furthermore, Mann-Whitney-U Test, Kruskal-Wallis-Test and Wilcoxon-Test and linear regression were used. P-values≤0,05 were considered to indicate statistical significance.

The local ethic commission (Fakultät für Medizin, Ethikkommission, Technische Universität München) agreed to perform the retrospective analysis.

3. Results

102 allograft biopsies and ultrasound reports of 69 patients with kidney transplantation (41 biopsies of living donors, 61 biopsies of deceased donors) were analyzed (Table 2).

Table 2
Patient’s characteristics

Characteristics Results

Recipient (n = 102) Age at biopsy (years) 53 (±15,084)

Serum creatinine at biopsy (mg/dl) 3,38 (±1,953)

Sex

female n = 35

male n = 67

Donor (n = 102) Sex

female n = 47

male n = 55

Age at donation (years)^* 56 (±11,808)

Serum creatinine at donation (mg/dl) 0,96 (±0,408)

Allograft (n = 102) type of donation

living donor n = 41

deceased donor n = 61

Age of allograft at biopsy (months)^ 4 (±8,157)^*

Biologic age of allograft at biopsy (years) ^**** 56 (±11,790)

	Characteristics	Results
Recipient (n = 102)	Age at biopsy (years)	53 (±15,084)
	Serum creatinine at biopsy (mg/dl)	3,38 (±1,953)
	Sex
	female	n = 35
	male	n = 67
Donor (n = 102)	Sex
female	n = 47
male	n = 55
Age at donation (years)^*	56 (±11,808)
Serum creatinine at donation (mg/dl)	0,96 (±0,408)
Allograft (n = 102)	type of donation
living donor	n = 41
deceased donor	n = 61
	Age of allograft at biopsy (months)^**	4 (±8,157)^***
	Biologic age of allograft at biopsy (years) ^****	56 (±11,790)

All results (except number of cases) are given as mean (± SD). Abbreviation: n= number of cases. *calculated as time between date of transplantation and date of birth of donor (years). **calculated as time between date of transplantation and date of biopsy (months). ***age of allograft at biopsy: minimum 0 months (5 days), maximum 40 months. ****calculated as sum of donor age plus time between transplantation an biopsy (years).

The total number used in this article refers to the total number of biopsy results (n = 102), and not to the total number of patients (n = 69).

The mean interval between biopsy and ultrasound was 3±2 days (mean±SD).

39 rejections (37 T-cell- and 6 antibody-mediated rejections) were diagnosed. Four biopsies showed both types of rejections simultaneously. 30 cases had rejection and acute tubular necrosis at the same time.

Although the mean intrarenal RI-value of patients with rejection was above the standard range (RI-values ≥0,70 (0,70–1,00) in 27 cases (69%)), the RI-values were normal in 12 cases ((31%) with <0,70 (0,53–0,69)).

38 cases (60%) without rejection had increased RI-values ≥0,70 (0,71–0,96), 25 cases (40%) without rejection had normal RI-values <0,70 (0,43–0,69).

Patients with rejection and simultaneously chronic allograft injury showed significantly higher RI-values than patients with only chronic allograft injury. Analyses using the IFTA or the ECAI score showed comparable results (IFTA p = 0,043; Score p = 0,021).

The intrarenal RI-value was neither able to detect chronic allograft injury nor to distinguish between acute tubular necrosis and rejection.

49 (68%) of the 72 cases with ATN had increased RI-values ≥0,70 and 23 (32%) had normal RI-values <0,70. 16 of 30 cases (53%) without acute tubular necrosis had RI-values ≥0,70 (0,71–0,88) and 14 (47%) RI-values <0,70 (0,43–0,68).

There were no significant differences in RI-values in patients with (n = 72) and without (n = 30) ATN (median 0,74 vs. 0,72; interquartile range 0,15 vs. 0,16; p = 0,130).

The intrarenal RI-value showed a significant correlation with recipient age (p < 0,001) but not with donor features.

4. Discussion

The aim of this study was to evaluate correlations between allograft histopathology and intrarenal RI-values measured with high-end ultrasound machines [16–24 , 48].

When RI-values <0,70 are regarded as normal [9], the RI-values in patients with rejection were increased with a mean RI-value of 0,79 (median; interquartile range 0,20) and RI-values in patients with rejection were significantly higher than in patients without rejection. The same was found for T- and non T- cell mediated rejection. The subtypes of T-cell-mediated rejection (type IA-IIB) did not show significant differences in RI-values and there were not significant differences in RI-values between antibody-mediated rejection (present vs. not present) or type of rejection (T-cell- vs. antibody mediated rejection).

Associations between increased RI-values and rejection were described often in the literature [9 , 18].

While differences in RI-values regarding the presence of T-cell-mediated rejection and rejection in general (present vs. not present) were found, this was not true for RI-values regarding the presence of antibody-mediated rejection. This might be explained by the fact that in this study there were far more T-cell mediated rejections than antibody mediated rejections.

In a prospective study, patients with rejection showed significant higher RI-values than patients with normal biopsy findings (p = 0.007). In contrast to our results, this was true for the antibody-mediated and not for the T-cell-mediated rejection. Interestingly, these correlations are only valid for biopsies that had been performed because of allograft dysfunction. In protocol biopsies even rejections did not show a significant increase in RI-values compared to normal findings [32]. However, in our study, biopsies had only been performed because of suspected allograft dysfunction such as increased creatinine values.

It was reported that RI-values were normal in acute rejection [16, 20], a finding consistent with our results. Furthermore, even patients without rejections showed increased RI-values.

Although the majority of patients with ATN (68%) had increased RI-values ≥0,7 in our study in accordance with findings in the literature [9 , 32], there were also patients without ATN but elevated RI-values.

The groups “ATN” and “no ATN” were distributed similar regarding possible confounders (sex, simultaneous rejection, age). Due to missing data it could not be tested for hemodynamic confounders.

There were no significant differences in RI-values between patients with rejections and ATN in the present study (p = 0,348), this was in accordance with the literature due to missing sensitivity and specificity of the RI-values [16 , 49]. It was postulated that shortened acceleration time of the systolic flow pattern would be more suitable to detect rejection than the RI-value [50] and that the power Doppler would be more sensitive than the RI-value to detect and differentiate between early acute rejection and acute tubular necrosis [51].

While indication biopsies of kidney allografts found a correlation between intrarenal RI-value and chronic allograft changes such as IFTA [52], in the present study there were no correlations between increased RI-value and chronic lesions of the BANFF classification. This was also reported elsewhere [53] and there was no association between the RI-values and the characteristics of chronic allograft nephropathy when checked with histomorphometric point counting technique [53, 54]. Regarding the Chronic Allograft Damage Index (CADI) (= sum of histological scores for interstitial inflammation, interstitial fibrosis, tubular atrophy, increased mesangial matrix, glomerulosclerosis, intima thickening) [55], there was no significant correlation between chronic allograft nephropathy and intrarenal RI-value for protocol and indication biopsies [32].

Overall, there was a closer correlation between intrarenal RI-values and histopathologic findings when biopsies were performed because of allograft dysfunction or other specific indications than in routine protocol biopsies [32, 52].

In accordance with published results by Krumme et al. and Heine et al., in this study there was no correlation between the age of the donor [29, 30] or the donor GFR [29] and the intrarenal RI-value after transplantation in the recipient. There was no association between the heart rate or blood pressure of the donor and the RI-value in the recipient [29]. Various studies showed significant correlations between the RI-value and the characteristics of the recipient such as age [29 , 56], blood pressure amplitude [29, 32] or mean arterial blood pressure [32]. Correspondingly, we found a strong correlation between age of the recipient and the intrarenal RI-value. Correlations regarding recipient’s characteristics such as vital signs and RI-value could not be evaluated due to missing data.

Several studies postulated that the intrarenal RI-value in patients with kidney transplantation was influenced primarily by characteristics of the recipient and not of the donor and that this allows information about the recipient and not about intrinsic characteristics of the allograft [32 , 56–58]. This is why soon after kidney transplantation RI-values in the recipient should be measured in order to compare intra-individual changes in the long run [29, 59].

Several methodical problems came along with the retrospective character of this study. Biopsy samples were classified according to the Banff classifications (2007 and 2009) routinely used at the time of examination of the biopsy sample but somewhat different from the ones used today [60, 61]. Since at that time the C4d negative antibody-mediated rejection (which is accepted today) was not included, the number of antibody-mediated rejections might have been falsely low [60 –62].

Furthermore, no information about steroid therapy before biopsy could be obtained, thus histologic signs of rejections might not have been detected. Additionally, the inter-observer variability has to be taken into consideration [63].

5. Conclusion

In summary, the intrarenal RI-value can indicate a rejection in individual cases but is not a strong diagnostic tool. Its validity concerning renal allograft histopathology remains questionable, because it gives no clear hint to acute tubular necrosis and cannot differentiate from rejection.

Since patients with rejection can have normal RI-values, a biopsy should always be performed in case of suspected rejection.

The intrarenal RI-value has no unambiguous validity to determine intrinsic values of the renal allograft, but should rather be understood and interpreted as a systemic parameter influenced by multiple factors.

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