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

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1 Nephrol Dial Transplant (2006) 21: doi: /ndt/gfl203 Advance Access publication 5 August 2006 Original Article Early assessment of renal resistance index after kidney transplant can help predict long-term renal function Angelo Saracino 1, Giovanni Santarsia 2, Angela Latorraca 1 and Vito Gaudiano 1 1 Basilicata Referral Centre for Transplantation and 2 Division of Nephrology and Dialysis, Hospital of Matera, Italy Abstract Background. Color Doppler ultrasonography of intrarenal arterial resistance index (), 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 longterm renal function. Methods. We retrospectively analysed 76 kidney transplant patients who underwent assessment within 1 month after the transplant, subdivided into two groups according to values, lower (group A) or higher (group B) than its median value (35). 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 ¼ 0.001), the donor age was also older (41 16 vs years; P ¼ 0.02) and had a slightly higher proteinuria (4 vs g/24 h; P ¼ 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, turned out to directly correlate with the recipient age, donor age and daily proteinuria (P ¼ 0.007, P ¼ and P ¼ 0.02, respectively). Multivariate analysis showed that only donor and recipient age maintained their independent predictive value on. 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 ¼ 5.489; P ¼ 0.01). The univariate relative risk of deterioration of graft function among patients with higher was Proteinuria and recipient age increased the risk as well. Conclusions. Our data seem to suggest that early determination of can help predict long-term graft function in kidney transplant recipients. Correspondence and offprint requests to: Dr Angelo Saracino, Centro Regionale Trapianti, Ospedale Madonna delle Grazie, Contrada cattedra ambulante, 75100, Matera, Italia. asaracino@inwind.it Keywords: color Doppler ultrasonography; graft survival; intrarenal arteries; renal resistance index Introduction 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 () is a haemodynamic index, which is particularly affected by the vascular compliance of the recipient [7], and that an increase of is observed in the presence of acute rejection and acute tubular necrosis [8]. Previously, the assessment of, 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 could also help predict long-term renal function. Patients and methods We conducted a retrospective study on all patients of our centre who had received a kidney transplant from a cadaveric donor between 1994 and ß The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please journals.permissions@oxfordjournals.org

2 Early assessment of renal resistance index after kidney transplant 2917 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 ¼ 31), or because they had been transplanted for <6 months (n ¼ 4), or owing to the presence of interfering factors at the time of US examination that may have influenced the values. Such factors included clinical signs of acute rejection (n ¼ 1) or rapid deterioration of the renal function for other reasons (n ¼ 2), as well as a stenosis of the transplanted renal artery (by Doppler US; n ¼ 1) or evidence of obstruction of the urinary tract (by standard US; n ¼ 2). Thus, a total of 76 patients (18 females, 58 males), aged 38 9 years (range 21 58), followed-up for a period of 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 ¼ 62 or tacrolimus: n ¼ 14) and methylprednisolone; 66 patients were also taking a third immune suppressive drug: mycophenolate mofetil (n ¼ 44), azathioprine (n ¼ 21) or rapamycin (n ¼ 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 þ 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. 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 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, was calculated from the Doppler spectra using the system software, according to the following formula: ¼ (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 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 value, the patient sample was subdivided into two groups: group A ( < median) and group B ( 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 (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 Mean was (range ), with a median value of 35. The clinical features of the patients, divided into two groups according to the median value: [group A ( < 35): n ¼ 37; group B ( 35): n ¼ 39], are shown in Table 1. 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 ¼ 0.001), the donor age was higher (41 16 vs years; P ¼ 0.02), and they had more severe proteinuria (4 vs g/24 h; P ¼ 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 and recipient age (A), donor age (B) and proteinuria (C) (P ¼ 0.007, P ¼ and P ¼ 0.02, respectively). Multivariate analysis showed that only donor and recipient age maintained their independent predictive value (Table 2). The endpoint (increase of serum creatinine >50%) was reached by 13 patients: four in group A (10%) and nine in group B (24%).

3 2918 A. Saracino et al. Table 1. Clinical characteristics of the two groups: group A ( <35), group B ( 35) Group A <35 Group B >35 P-value n ¼ 37 n ¼ 39 Recipient age (years) Donor age (years) Serum creatinine (mg/dl) Proteinuria (g/day) Pre-transplant dialysis duration (months) Ciclosporin (n patients/%) 34/91% 28/71% Tacrolimus (n patients/%) 4/10% 10/25% Immunosuppressive drugs (n/day) Systolic blood pressure (mmhg) Diastolic blood pressure (mmhg) Pulse pressure (mmhg) Mean arterial pressure (mmhg) HLA mismatches Ciclosporin trough level (ng/ml) Tacrolimus trough level (ng/ml) Delayed graft function >6 days (n/%) 6/16% 3/8% Anti-hypertensive drugs (n/day) A C 5 5 Y = X Recipient age (years) B 5 5 Y = X Donor age (years) Y = X Proteinuria (g/day) Fig. 1. Correlation between and recipient age (A), donor age (B) and daily proteinuria (C). 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 was 3.77 (95% confidence interval, ). Proteinuria and recipient age also increased the risk, as shown in Table 3. Kaplan Meier analysis demonstrated a statistically significant difference in graft survival between the two groups: log-rank test ¼ 5.489; P ¼ 0.01 (Figure 2).

4 Early assessment of renal resistance index after kidney transplant 2919 Table 2. Multiple linear regression analysis of and clinical parameters 1 Parameter Table 3. Univariate relative risk of a 50% creatinine increase associated with selected variables Risk factor Discussion Relative risk 95% Confidence Interval P-value Recipient age 0.02 Pre-transplant dialysis duration Donor age 0.05 Serum creatinine Daily proteinuria Systolic blood pressure Diastolic blood pressure Pulse pressure Mean arterial pressure P-value Recipient age Donor age Resistive index > Serum creatinine concentration Daily proteinuria Pre-transplant dialysis duration Systolic blood pressure Diastolic blood pressure Pulse pressure Mean arterial pressure HLA mismatches Ciclosporin trough level Tacrolimus trough level Delayed graft function >6 days Anti-hypertensive drugs 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, performed within 4 weeks from the transplant. Our findings show that kidney transplant recipients with an >35 have a 3.77-fold increase in the relative risk of graft function deterioration (i.e. serum creatinine increase >50%). Then, 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 values, higher or lower than 35. 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 [10]. Cum. survival Group A ( <35) Group B ( >35) Time (months) Number at risk Group A Group B Fig. 2. Kaplan Meyer analysis of time to the endpoint (serum creatinine increase >50%). 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 makes it possible to estimate diastolic perfusion in relation to systolic perfusion: an increase in 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 in nephroangiosclerosis due to hypertension or diabetes mellitus. Moreover, intrarenal 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. 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 determination in renal grafts. Kahraman et al. [9] showed that, 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 in a very large cohort of renal transplanted patient s and showed that 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 <0 [10]. At variance from the

5 2920 A. Saracino et al. 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 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 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 and proteinuria observed at univariate analysis. Normal 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 and age of the recipient, and concluded that the main factor influencing 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 correlated both with patient s age and with histologically proven arteriolosclerosis of the intrarenal vessels. Altogether, the above studies would demonstrate that intrarenal 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 and arterial pulse pressure, which apparently confirmed the dependence of 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 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 is determined by several different operators, can definitively prove the predictive power of early determination as a marker of long-term renal function. Acknowledgements. The authors would like to thank Dr Salvatore Di Paolo for his technical assistance. Conflict of interest statement. None declared. References 1. Wolfe RA, Ashby VB, Milford EL et al. Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. N Engl J Med 1999; 341: Kasiske BL. Clinical correlates to chronic renal allograft rejection. Kidney Int 1997; 63: S71 S74 3. Tilney NL, Guttmann RD. Effects of initial ischemia/ reperfusion injury on the transplanted kidney. Transplantation 1997; 64: Hariharan S, Johnson CP, Bresnahan BA, Taranto SE, McIntosh MJ, Stablein D. Improved graft survival after renal transplantation in the United States, 1988 to N Engl J Med 2000; 342: Allen KS, Jorkasky DK, Arger PH et al. Renal allografts: prospective analysis of Doppler sonography. Radiology 1988; 169: Meyer M, Paushter D, Steinmuller DR. The use of duplex Doppler ultrasonography to evaluate renal allograft dysfunction. Transplantation 1990; 50: Krumme B, Grotz W, Kirste G, Schollmeyer P, Rump LC. Determinants of intrarenal Doppler indices in stable renal allografts. J Am Soc Nephrol 1997; 8: Heine GH, Girndt M, Sester U, Kohler H. No rise in renal Doppler resistance indices at peak serum levels of cyclosporin A in stable kidney transplant patients. Nephrol Dial Transplant 2003; 18: Kahraman S, Genctoy G, Cil B et al. Prediction of renal allograft function with early Doppler ultrasonography. Transplant Proc 2004; 36: Radermacher J, Mengel M, Ellis S et al. The renal arterial resistance index and renal allograft survival. N Engl J Med 2003; 349: Takano R, Ando Y, Taniguchi N, Itoh K, Asano Y. Power Doppler sonography of the kidney: effect of Valsalva s maneuver. J Clin Ultrasound 2001; 29: Schwerk WB, Restrepo IK, Prinz H. Semiquantitative analysis of intrarenal arterial Doppler flow spectra in healthy adults. Ultraschall Med 1993; 14: (in German) 13. Boddi M, Sacchi S, Lammel RM, Mohseni R, Serneri GG. Age-related and vasomotor stimuli-induced changes in renal vascular resistance detected by Doppler ultrasound. Am J Hypertens 1996; 9: Perrella RR, Duerinckx AJ, Tessler FN et al. Evaluation of renal transplant dysfunction by duplex Doppler sonography: a prospective study and review of the literature. Am J Kidney Dis 1990; 15: Kelcz F, Pozniak MA, Pirsch JD, Oberly TD. Pyramidal appearance and resistive index: insensitive and nonspecific sonographic indicators of renal transplant rejection. AJR 1990; 155: Berland LL, Lawson TL, Adams MB, Melrose BL, Foley WD. Evaluation of renal transplants with pulsed Doppler duplex sonography. J Ultrasound Med 1982; 1: Ikee R, Kobayashi S, Imakiire T et al. Correlation between the resistive index by Doppler ultrasound and kidney function and histology. Am J Kidney Dis 2005; 46: Received for publication: Accepted in revised form:

Reduced graft function (with or without dialysis) vs immediate graft function a comparison of long-term renal allograft survival

Nephrol Dial Transplant (2006) 21: 2270 2274 doi:10.1093/ndt/gfl103 Advance Access publication 22 May 2006 Original Article Reduced graft function (with or without dialysis) vs immediate graft function