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NDT Advance Access originally published online on August 5, 2006
Nephrology Dialysis Transplantation 2006 21(10):2916-2920; doi:10.1093/ndt/gfl203
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Early assessment of renal resistance index after kidney transplant can help predict long-term renal function

Angelo Saracino1,, Giovanni Santarsia2, Angela Latorraca1 and Vito Gaudiano1

1Basilicata Referral Centre for Transplantation and 2Division of Nephrology and Dialysis, Hospital of Matera, Italy

Correspondence and offprint requests to: Dr Angelo Saracino, Centro Regionale Trapianti, Ospedale Madonna delle Grazie, Contrada cattedra ambulante, 75100, Matera, Italia. Email: asaracino{at}inwind.it



   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
Background. Color Doppler ultrasonography of intrarenal arterial resistance index (RI), performed early after kidney transplant, has proven to reliably predict short-term allograft function. The aim of this study was to assess whether it could also predict long-term renal function.

Methods. We retrospectively analysed 76 kidney transplant patients who underwent RI assessment within 1 month after the transplant, subdivided into two groups according to RI values, lower (group A) or higher (group B) than its median value (0.635).

Results. Compared with group A subjects, the patients of group B were older at the time of transplant (42 ± 9 vs 35 ± 8 years; P = 0.001), the donor age was also older (41 ± 16 vs 33 ± 13 years; P = 0.02) and had a slightly higher proteinuria (0.54 ± 0.5 vs 0.32 ± 0.2 g/24 h; P = 0.02). Serum creatinine, ciclosporin or tacrolimus trough level, arterial blood pressure, number of human leukocyte antigen (HLA) mismatches, anti-hypertensive medications and incidence of delayed graft function were not significantly different between the two groups.

By univariate analysis, RI turned out to directly correlate with the recipient age, donor age and daily proteinuria (P = 0.007, P = 0.0007 and P = 0.02, respectively). Multivariate analysis showed that only donor and recipient age maintained their independent predictive value on RI.

Kaplan–Meier analysis, considering a serum creatinine increase >50% as the endpoint of the study, showed a statistically significant different graft survival in the two groups (log-rank test = 5.489; P = 0.01). The univariate relative risk of deterioration of graft function among patients with higher RI was 3.77. Proteinuria and recipient age increased the risk as well.

Conclusions. Our data seem to suggest that early determination of RI can help predict long-term graft function in kidney transplant recipients.

Keywords: color Doppler ultrasonography; graft survival; intrarenal arteries; renal resistance index



   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
Kidney transplant is the treatment of choice in end-stage renal disease patients, as it reduces morbidity and mortality rates and improves the quality of life [1]. Although, a number of factors are known to affect long-term graft survival, including recipient age, presence of diabetes, delayed graft function, number of HLA mismatches, period of warm and cold ischemia [2–4], as well as acute rejection episodes and cytomegalovirus infection, none of them, alone or in combination, has been shown to have a predictive value for differentiating between patients with a good or poor chance of long-term graft survival.

Color Doppler ultrasonography (US) of the intrarenal arteries is one of the principal examinations performed in the clinical management of kidney transplant patients [5,6].

It has been demonstrated that the resistance index (RI) is a haemodynamic index, which is particularly affected by the vascular compliance of the recipient [7], and that an increase of RI is observed in the presence of acute rejection and acute tubular necrosis [8].

Previously, the assessment of RI, early after the transplant, has been shown to be a good predictor of short-term allograft function [9].

The aim of the current study was to assess whether early determination of the RI could also help predict long-term renal function.



   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 Acknowledgements
 References
 
We conducted a retrospective study on all patients of our centre who had received a kidney transplant from a cadaveric donor between 1994 and 2005.

Patients
Color Doppler US was performed by a single investigator in 117 consecutive kidney transplant patients. Forty-one patients were excluded because we were unable to perform the test within the first 4 weeks from the transplant (n = 31), or because they had been transplanted for <6 months (n = 4), or owing to the presence of interfering factors at the time of US examination that may have influenced the RI values. Such factors included clinical signs of acute rejection (n = 1) or rapid deterioration of the renal function for other reasons (n = 2), as well as a stenosis of the transplanted renal artery (by Doppler US; n = 1) or evidence of obstruction of the urinary tract (by standard US; n = 2).

Thus, a total of 76 patients (18 females, 58 males), aged 38 ± 9 years (range 21–58), followed-up for a period of 6–126 months (mean 49 ± 34) after kidney transplant, were included in the present analysis. All data were obtained from the patients’ clinical records.

End-stage renal disease was due to chronic glomerulonephritis (30%), autosomal dominant polycystic kidney disease (4%), chronic pyelonephritis or nephrolithiasis (10%), diabetes (3%) or unknown causes (53%).

All patients were taking immune suppressive therapy consisting of a calcineurin inhibitor (ciclosporin A: n = 62 or tacrolimus: n = 14) and methylprednisolone; 66 patients were also taking a third immune suppressive drug: mycophenolate mofetil (n = 44), azathioprine (n = 21) or rapamycin (n = 1).

Within the first 4 weeks after the transplant, all the selected patients underwent assessment of serum creatinine, daily proteinuria, ciclosporin or tacrolimus trough level, systolic arterial pressure, diastolic arterial pressure, pulse pressure, mean arterial pressure (diastolic pressure + 1/3 pulse pressure), number of anti-hypertensive drugs taken, number of HLA mismatches, number of episodes of delayed graft function and color Doppler US with measurement of RI.

Biochemical assays
Serum creatinine concentration was determined using a kinetic enzymatic UV assay method. Urinary protein excretion, ciclosporin and tacrolimus trough level were measured by standard automated clinical chemistry analysers.

Creatinine and immune suppressive drug blood concentrations were assayed on blood samples taken on the day of the color Doppler examination, while proteinuria was determined on a sample from the urine collected during the 24 h preceding the ultrasonographic examination.

Doppler examination
In all the selected patients, Doppler US examination with measurement of RI was performed, at least 12 h after the last dose of calcineurin inhibitor. During the examination, patients were asked to refrain from forced inspiration, that could modify the endo-abdominal pressure. A heart rate <50 beats/min led to the deferral of Doppler examination. Indeed, no such case occurred in any of the patients studied.

Color Doppler examination was performed with a 3.5 MHz convex-array transducer (ATL Ultrasound) in supine position. In interlobar and segmental renal arteries, RI was calculated from the Doppler spectra using the system software, according to the following formula:

RI = (peak systolic frequency shift – minimum diastolic frequency shift)/peak systolic frequency shift.

The average values of six different spectra sampling were calculated to yield the mean RI of the graft. All color Doppler examinations were performed by a single investigator, who was unaware of the patient's history or laboratory findings.

Statistical analysis
All data were analysed with Stat View 5 software (SAS Institute Inc. version 5.0). Data are expressed as mean ± SD.

After calculating the median RI value, the patient sample was subdivided into two groups: group A (RI < median) and group B (RI ≥ median).

Student's t-test for unpaired data, chi-square analysis, or Kaplan–Meier analysis with the log-rank test were used as appropriate to assess the differences between groups.

Univariate linear regression was used to assess the association between RI (dependent variable) and all the renal function parameters (independent variables). Multiple linear regression analysis was performed to avoid overestimation of potentially linked variables.

Cox proportional hazard analysis was used to calculate univariate hazard ratios as estimates of relative risks. A value of P < 0.05 was considered statistically significant.

The only endpoint of the study was a stable increase of creatinine >50% with respect to the value obtained at the end of the 1st month after the transplant. All patients who died with a functioning graft as well as patients lost to follow-up, were considered censored.



   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 Acknowledgements
 References
 
Mean RI was 0.63 ± 0.07 (range 0.49–0.79), with a median RI value of 0.635. The clinical features of the patients, divided into two groups according to the median RI value: [group A (RI < 0.635): n = 37; group B (RI ≥ 0.635): n = 39], are shown in Table 1.


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  		Table 1. Clinical characteristics of the two groups: group A (RI <0.635), group B (RI ≥0.635)

 
Patients in group B were significantly older at the time of the transplant than those in group A (42 ± 9 vs 35 ± 8 years; P = 0.001), the donor age was higher (41 ± 16 vs 33 ± 13 years; P = 0.02), and they had more severe proteinuria (0.54 ± 0.5 vs 0.32 ± 0.2 g/24 h; P = 0.02). All the other parameters examined were not significantly different between the two groups.

As shown in Figure 1, univariate analysis demonstrated a statistically significant correlation between RI and recipient age (A), donor age (B) and proteinuria (C) (P = 0.007, P = 0.0007 and P = 0.02, respectively). Multivariate analysis showed that only donor and recipient age maintained their independent predictive value (Table 2).


Figure 1
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  		Fig. 1. Correlation between RI and recipient age (A), donor age (B) and daily proteinuria (C).

 

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  		Table 2. Multiple linear regression analysis of RI and clinical parameters

 
The endpoint (increase of serum creatinine >50%) was reached by 13 patients: four in group A (10%) and nine in group B (24%).

In group B, one patient died without reaching the endpoint due to cerebral haemorrhage and one patient was lost to follow-up.

The univariate relative risk of graft function deterioration among patients with higher RI was 3.77 (95% confidence interval, 1.15–12.4). Proteinuria and recipient age also increased the risk, as shown in Table 3.


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  		Table 3. Univariate relative risk of a 50% creatinine increase associated with selected variables

 
Kaplan–Meier analysis demonstrated a statistically significant difference in graft survival between the two groups: log-rank test = 5.489; P = 0.01 (Figure 2).


Figure 2
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  		Fig. 2. Kaplan–Meyer analysis of time to the endpoint (serum creatinine increase >50%).

 


   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
Acknowledgements
 References
 
To our knowledge, the present study is the first attempt to estimate long-term renal graft function on the basis of the early determination of RI, performed within 4 weeks from the transplant. Our findings show that kidney transplant recipients with an RI >0.635 have a 3.77-fold increase in the relative risk of graft function deterioration (i.e. serum creatinine increase >50%). Then, RI levels turned out to significantly correlate with both donor and recipient age. Finally, Kaplan–Meier analysis confirmed that there was a significant difference in the incidence of graft function deterioration according to RI values, higher or lower than 0.635.

Various risk factors, including age of the donor and recipient, reduced renal function at 1 year, proteinuria, arterial hypertension, number of HLA mismatches, have been proposed as predictors of long-term renal function in transplanted patients [10]. However, none of these, alone or in combination, has been demonstrated to be a more reliable predictor of survival of the transplanted kidney than an increase in RI [10].

Color Doppler ultrasonography of the intrarenal arteries is a simple, non-invasive, repeatable method and is therefore one of the first-choice investigations in the clinical management of the kidney transplant patient. The determination of intrarenal RI makes it possible to estimate diastolic perfusion in relation to systolic perfusion: an increase in RI can be induced by any condition which provokes a reduction in diastolic renal perfusion as compared with systolic perfusion. Such conditions can occur, for instance, in acute renal failure or in the presence of an obstruction of the urinary tract with hydronephrosis, in which the increase in interstitial pressure and the consequent compression of the renal parenchyma causes a drop in renal perfusion during the diastole [8]. There is also a marked rise in RI in nephroangiosclerosis due to hypertension or diabetes mellitus. Moreover, intrarenal RI can be affected by some extrarenal factors. Increased abdominal pressure during forced inspiration can modify the index value [11], as well as a heart rate of <50 beats/min [12], or age, especially in hypertensive patients [13].

In this study, we attempted to exclude all extrarenal modifications of RI. In addition, all patients affected by potentially interfering kidney graft modifications, such as acute rejection or obstruction of the urinary tract, were excluded from the study.

Previous studies have already explored the predictive value of RI determination in renal grafts. Kahraman et al. [9] showed that RI, assessed within one week of the transplant, could forecast 1-month and 1-year graft function in 45 renal transplant recipients. Radermacher et al. [10] measured RI in a very large cohort of renal transplanted patient's and showed that RI was a good predictor of both allograft failure and patient's death despite a functioning graft. Specifically, the authors reported a better long-term graft survival in patients with RI <0.80 [10]. At variance from the present study, however, Doppler US examination was not performed soon after the transplant, but at least 3 months after engraftment (mean 40 months) [10].

Then, we confirmed the close correlation between RI and the recipient age [7,8]. Unlike the findings of previous studies, however, in our patient population there was also a statistically significant correlation between RI and donor age, at both univariate and multivariate analysis. The latter observation may be accounted for by the presence of age-related angiosclerotic modifications of the intrarenal arteries of the donor kidney, thereby reducing vascular compliance. Such phenomena would reduce the diastolic perfusion of the transplanted kidney, thus increasing intrarenal resistances. The latter hypothesis might be indirectly confirmed by the finding of a significantly higher proteinuria in patients of group B, since proteinuria is a known marker of nephroangiosclerosis, as well as by the correlation between RI and proteinuria observed at univariate analysis.

Normal RI values for kidney graft have long been established, but without any critical assessment of the factors affecting these values having been made [7,14–16]. Krumme et al. [7] demonstrated that in kidney transplant patients there is a strong correlation between intrarenal RI and age of the recipient, and concluded that the main factor influencing RI is the vascular compliance of the recipient, which is, in turn, affected by age-dependent atherosclerosis phenomena. Similar results were reported by Heine et al. [8]. Recently, in a population of 33 patients who underwent renal biopsy, Ikee et al. [17] demonstrated that RI correlated both with patient's age and with histologically proven arteriolosclerosis of the intrarenal vessels. Altogether, the above studies would demonstrate that intrarenal RI measurement early after engraftment reflects both donor-related compliance of the intrarenal vessels as well as the compliance of the recipient's arterial tree, from the heart (site of origin of the sphygmic wave) up to the iliac arteries.

Finally, previous research found a correlation between RI and arterial pulse pressure, which apparently confirmed the dependence of RI from age-related vascular compliance of the recipient [7]. We were unable to confirm this correlation, possibly due to the high dosage of anti-hypertensive drugs taken by most of the patients in our cohort.

In conclusion, our findings suggest that early RI determination can represent a useful and feasible predictor of long-term graft function. We are aware that only future multicentre trials conducted in larger patients samples and in which RI is determined by several different operators, can definitively prove the predictive power of early RI determination as a marker of long-term renal function.



   Acknowledgements
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
References
 
The authors would like to thank Dr Salvatore Di Paolo for his technical assistance.

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 

  1. Wolfe RA, Ashby VB, Milford EL, et al. (1999) Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. N Engl J Med 341:1725–1730.[Abstract/Free Full Text]
  2. Kasiske BL. (1997) Clinical correlates to chronic renal allograft rejection. Kidney Int 63:S71–S74.
  3. Tilney NL and Guttmann RD. (1997) Effects of initial ischemia/reperfusion injury on the transplanted kidney. Transplantation 64:945–947.[CrossRef][Web of Science][Medline]
  4. Hariharan S, Johnson CP, Bresnahan BA, Taranto SE, McIntosh MJ, Stablein D. (2000) Improved graft survival after renal transplantation in the United States, 1988 to 1996. N Engl J Med 342:605–612.[Abstract/Free Full Text]
  5. Allen KS, Jorkasky DK, Arger PH, et al. (1988) Renal allografts: prospective analysis of Doppler sonography. Radiology 169:371–376.[Abstract/Free Full Text]
  6. Meyer M, Paushter D, Steinmuller DR. (1990) The use of duplex Doppler ultrasonography to evaluate renal allograft dysfunction. Transplantation 50:974–978.[Web of Science][Medline]
  7. Krumme B, Grotz W, Kirste G, Schollmeyer P, Rump LC. (1997) Determinants of intrarenal Doppler indices in stable renal allografts. J Am Soc Nephrol 8:813–816.[Abstract]
  8. Heine GH, Girndt M, Sester U, Kohler H. (2003) No rise in renal Doppler resistance indices at peak serum levels of cyclosporin A in stable kidney transplant patients. Nephrol Dial Transplant 18:1639–1643.[Abstract/Free Full Text]
  9. Kahraman S, Genctoy G, Cil B, et al. (2004) Prediction of renal allograft function with early Doppler ultrasonography. Transplant Proc 36:1348–1351.[CrossRef][Web of Science][Medline]
  10. Radermacher J, Mengel M, Ellis S, et al. (2003) The renal arterial resistance index and renal allograft survival. N Engl J Med 349:115–124.[Abstract/Free Full Text]
  11. Takano R, Ando Y, Taniguchi N, Itoh K, Asano Y. (2001) Power Doppler sonography of the kidney: effect of Valsalva's maneuver. J Clin Ultrasound 29:384–388.[CrossRef][Web of Science][Medline]
  12. Schwerk WB, Restrepo IK, Prinz H. Semiquantitative analysis of intrarenal arterial Doppler flow spectra in healthy adults. Ultraschall Med (1993) 14:117–122 (in German).[Web of Science][Medline]
  13. Boddi M, Sacchi S, Lammel RM, Mohseni R, Serneri GG. (1996) Age-related and vasomotor stimuli-induced changes in renal vascular resistance detected by Doppler ultrasound. Am J Hypertens 9:461–466.[CrossRef][Web of Science][Medline]
  14. Perrella RR, Duerinckx AJ, Tessler FN, et al. (1990) Evaluation of renal transplant dysfunction by duplex Doppler sonography: a prospective study and review of the literature. Am J Kidney Dis 15:544–550.[Web of Science][Medline]
  15. Kelcz F, Pozniak MA, Pirsch JD, Oberly TD. (1990) Pyramidal appearance and resistive index: insensitive and nonspecific sonographic indicators of renal transplant rejection. AJR 155:531–535.[Abstract/Free Full Text]
  16. Berland LL, Lawson TL, Adams MB, Melrose BL, Foley WD. (1982) Evaluation of renal transplants with pulsed Doppler duplex sonography. J Ultrasound Med 1:215–222.[Abstract]
  17. Ikee R, Kobayashi S, Imakiire T, et al. (2005) Correlation between the resistive index by Doppler ultrasound and kidney function and histology. Am J Kidney Dis 46:603–609.[CrossRef][Web of Science][Medline]
Received for publication: 3.12.05
Accepted in revised form: 21. 3.06


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