Since contrast-induced nephropathy (CIN) was recognized more than 70 years ago, there have been continuous efforts to chemically modify iodine contrast media (CM) to become less nephrotoxic (1). Although CM have become safer, which reduces the likelihood of CIN per procedure, the indications for their use have dramatically increased. Over the last two decades, the utilization of computed tomography (CT) scanning and coronary angiograms (Cath) have increased by about 800 and 400%, respectively, with currently about 1.2 million Caths performed in the US annually and over 80 million CM doses delivered worldwide (2, 3). Furthermore, the number of patients with CIN risk factors, such as chronic renal insufficiency (CRI), diabetes, and congestive heart failure, has also grown. Currently, more than 27 million people are estimated to have CRI in the United States, and 200 million have diabetes worldwide (4, 5). The combination of increased CM administration frequency and greater prevalence of at-risk patients is likely to result in a continuing increase in CIN events. The incidence of CIN varies between studies, depending on risk factors of the cohort and definition of CIN, but figures have been reported to be as high as 50% in studies enriched with CRI and diabetic patients.

CIN is associated with a significant increase in mortality and morbidity in patients with native kidneys. After adjusting for comorbid factors, a retrospective study of 7,586 patients showed a significant increase in in-hospital and long-term mortality in patients who developed CIN (6). Another study of 1,826 patients, who underwent coronary artery intervention procedures, showed that 14% developed CIN and 1% required hemodialysis. Mortality was 1% in patients who did not develop CIN versus 7% in those with CIN, and 36% in the hemodialysis-treated CIN group (7). Moreover, studies by several other groups also support the position that CIN is associated with increased in-hospital and long-term mortality (8–10). Given the enhanced mortality and morbidity associated with CIN, several groups have been studying the pathophysiology of CIN, determining associated risk factors and investigating strategies for preventing it.

Although published papers studying CIN in native kidneys are abundant in the medical literature, data pertinent to CIN in renal allografts are relatively scarce (11–15). Moreover, it is plausible that renal transplant recipients is at a particularly higher risk for developing CIN due to aspects that are unique to renal allografts such as immunosuppression, lack of sympathetic innervation, glomerular hyperfiltration, and burden of cardiovascular disease. As a result, a better understanding of the incidence and predictors of CIN in renal transplant recipients is warranted.

In this retrospective study, we report the incidence of CIN in renal transplant recipients, its associated risk factors, and effect on long-term outcomes including allograft loss and death (16).

This is a retrospective observational study that was approved by the University of Cincinnati (UC) Institutional Review Board in April 2013. All angiograms and other CM-enhanced studies performed on renal transplant recipients hospitalized between January 1st of 2000 and March 31st of 2014 were considered for the final analysis.

Out of 161 CM exposures, 85 were excluded for not meeting inclusion/exclusion criteria. Fifty patients with 76 exposures (45 CT and 31 Cath) were analyzed. For 73 exposures, baseline SCr was established less than 4 months prior to exposure, while three baseline SCrs were established more than 4 months prior. Counting exposures (rather than patients), 50% were in male patients, 16% were in African-American patients, 9% were in smokers, 32% had diabetes, 78% had hypertension, 24% had coronary artery disease, 7% congestive heart failure, and 17% were on an ACE inhibitor. Seventy eight percent of exposures were in patients received living donor kidneys. Maintenance immunosuppression included tacrolimus in 70%, cyclosporine in 13%, and mycophenolate in 97% of the exposures (Table 1).

At the time of CM exposure, the (mean, ±SD) age of the patients was 53 ± 15 years, baseline SCr, 1.5 ± 0.9 mg/dl, hemoglobin 10.3 ± 2.3 g/dl, and albumin 3.5 ± 0.6 g/dl. Tacrolimus 12-h trough was 8.6 ± 5.2 ng/ml, cyclosporine 12-h trough was 79.1 ± 19.2 ng/ml, and 8% of the patients were hypotensive (SBP < 100 mm Hg). IV fluids and N-acetylcysteine were administered in 53 and 36% of the patients, respectively (Table 1). The overall incidence of CIN was 13% (10 out of 76 exposures), equally so in patients who underwent Cath (4 out of 31 exposures) and in patients who received CM-enhanced CT scans (6 out of 45 exposures) (Figure 1).

Significant simple bivariate predictors of CIN were IV fluid administration (p = 0.05), lower hemoglobin (p = 0.03), and lower albumin (p = 0.02). Female gender (p = 0.18) and N-acetylcysteine administration (p = 0.09) also made the cutoff to be included as candidate predictors in a multivariable model. After these five predictors were entered into a multivariable prediction model and subjected to backwards selection, lower hemoglobin (p = 0.01) and N-acetylcysteine (p = 0.03) were associated with CIN (Table 2).

Calcineurin inhibitor use was not associated with CIN. CIN was not associated with allograft loss or death on last follow-up, with last follow-up occurring (mean ± SD) 25 ± 24 months after exposure.

It is plausible that renal transplant recipients are at a particularly high risk for developing CIN. In addition to all the traditional risk factors associated with CIN in native kidneys, the following aspects are unique to renal allografts:

Immunosuppressive regimens often include calcineurin inhibitors, which harbor a significant risk of nephrotoxicity. Calcineurin inhibitor nephrotoxicity is mediated by several mechanisms including afferent arteriolar vasoconstriction, peripheral arteriolar hyalinosis, isometric vacuolization of tubular epithelial cells, stripped interstitial fibrosis, and thrombotic microangiopathy, all of which might predispose to CIN (17).

Although CIN in native kidneys has been studied extensively, only few small retrospective studies addressed CIN in renal allografts (11–15). In a retrospective study of 35 renal transplant recipients on cyclosporine, the incidence of CIN defined by a rise in SCr by >25% was 21% (12). This is higher than the 13% CIN incidence seen in native kidneys; however, six out of the seven patients developing CIN received 1/2 normal saline or no IV fluids for prophylaxis as opposed to standard of care isotonic fluid administration (23). In another paper of 57 patients undergoing coronary angiograms, CIN defined as a rise in SCr by >25% or 0.5 mg/dl within 3 days post-Cath occurred in 16% of the patients (11). Univariate comparisons showed that the use of N-acetylcysteine and isoosmolar CM were protective. Logistic regression analysis, however, revealed that only low osmolarity CM administration was associated with CIN compared to isoosmolar CM (odds ratio of ~7.7). Type of renal graft, preexisting comorbidities, and immunosuppressive medications were not associated with CIN. Neither of the two mentioned studies looked at hard outcomes such as death-censored allograft loss or death. More recently, three small studies reported a CIN incidence of 6–13% (13–15). In one study, CIN occurred in 13% of renal transplant recipients undergoing endovascular aortic aneurysm repair versus 5% in a non-transplanted comparison group (14).

In our study of transplant recipients receiving CT or Cath, the incidence of CIN was 13%, which is consistent with what was published and reproduced before in both native and transplant kidneys (11, 14, 23). Anemia was independently associated with CIN, which is consistent with previous reports (24). This is biologically plausible since anemia can exacerbate hemodynamic stress and ischemia reperfusion-related acute kidney injury particularly in solitary allografts whose hemodynamic compensatory mechanisms are already exhausted. N-acetylcysteine use positively correlated with CIN, which contradicts multiple previous studies that showed it had a protective effect (25, 26). This protective effect of N-acetylcysteine, however, could not be reproduced in multiple subsequent trials including a very well-designed randomized controlled trial. In this prospective trial of 2,308 patients with risk factors for CIN, N-acetylcysteine failed to have a protective effect (23). An alternative explanation for our finding could be that N-acetylcysteine was given to patients who were considered by the treating physician as high risk for developing CIN. Therefore, we should be cautious inferring that N-acetylcysteine use is a predictive marker of CIN given the possibility of indication bias that exists in retrospective analyses. We anticipated that intravenous fluid administration will have a protective effect, which would persist after multivariable modeling, but this did not occur. We attribute this to the small sample size and potential underlying bias that could not be accounted for in a retrospective design.

We did not observe any safety signal related to calcineurin inhibitor use, and we could not assess any potential protective effect of mycophenolate since 97% of patients were on it.

We acknowledge that our study has several limitations. First, it is a small and retrospective study. Second, we did not capture CM-enhanced studies done as outpatient procedures or at outside hospitals. Third, we did not exclude acute kidney injury episodes that occurred early after transplantation. This could overestimate the incidence of CIN since early acute allograft failure could be confounded by several factors including rejection.

In conclusion, CIN is common in renal transplant recipients receiving both intra-arterial and intravenous CM. Therefore, there is room for careful risk stratification, optimizing hemodynamics and avoiding further potential nephrotoxins in transplant recipients receiving CM-enhanced studies. Prospective controlled studies of CIN in transplant settings are warranted.

BA oversaw study design and conduction and wrote the manuscript. AL performed statistical analysis and wrote the statistics section of the manuscript. YS, SK, and AS performed data collection and helped with statistical analysis and writing of the manuscript. RA and EW helped with study design, access to transplant master database, and writing the manuscript. CT helped with study design and critical review of the manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.