This study presents a novel standardized immunosuppressive adverse effects scoring system for renal transplant recipients with validation and inter-rater reliability demonstrated. Multidisciplinary development of this scoring system with successful application to the intended population provides face validity . The heterogeneous nature of the individual adverse effects depicted in Table 3 emphasizes varying degrees of severity and frequency among stable renal transplant recipients receiving calcineurin inhibitor based immunosuppressive regimens. Severity assessment of a 3+ score for any adverse effect was less than 1% of all adverse effects during this study since clinically stable patients were targeted for enrollment. Identifying transplant patients with mild to moderate adverse effects may have important clinical impact since drug regimen adjustments during maintenance immunosuppression may improve or eliminate these manifestations. Renal transplant recipients with numerous mild to moderate adverse effects also have increased risk for medication non-adherence as time post-transplant increases which may impact long-term allograft survival [16, 17]. Therefore, prospective, standardized monitoring of immunosuppressive adverse effects may reduce medication non-adherence, improve patient tolerability of immunosuppressive regimens and may improve renal allograft survival [16, 17]. In addition, this adverse effects evaluation system provides an objective approach to document and rank severity of medication related effects in patients during clinic visits. Differences in the rating scales for the individual adverse effects are present (i.e. 0-2+, 0-3+) based on the smallest detectable incremental change in manifestation clinically observed by the physician. This rating is adjusted by using the cumulative and organ system specific adverse effect ratios which incorporates internal normalization in order to compare patients. This approach documents adverse effect frequency and severity which is rarely verified in clinical studies .
Nephrologists as subject matter experts verified moderate to significant clinical importance for the individual adverse effects to be used in the scoring system and substantiated content validity . Some limitations exist with this evaluation including physician bias with current prescribing trends for low glucocorticoid doses or steroid-free immunosuppressive regimens post-transplant. These prescribing trends may account for lower clinical importance scores of steroid associated adverse effects. Since interpatient variation in clinical response, drug exposure, and adverse effect manifestations to steroid therapy post-transplant exists, these adverse effects will remain in the scoring system to guide maintenance immunosuppression [25–27]. Tailoring the specific adverse effects scoring system to reflect the inclusion or exclusion of glucocorticoids (i.e. prednisone) in the immunosuppressive regimen provides a practical and flexible objective monitoring alternative for transplant recipients.
The adverse effect ratios documented that renal transplant recipients receiving tacrolimus and EC-MPS regimen had greater gastrointestinal and CNS adverse effects compared to patients stabilized on the cyclosporine and MMF regimen. These findings are consistent with previous clinical reports [7, 22]. Aesthetic adverse effects such as gingival hyperplasia, hirsutism, acne, and skin changes are more frequent in cyclosporine treated patients, but was not observed in this study for the aesthetic adverse effect ratio [7, 21]. This finding may be attributed to sample size or the male predominance in the cyclosporine group. Additionally, individual aesthetic adverse effects such as gingival hyperplasia was more frequent in the cyclosporine treated patients and confirms adverse effect patterns observed in renal transplant recipients participating in comparative efficacy studies between these two immunosuppressive regimens. This finding further verifies construct validity [19, 20, 22]. The cumulative adverse effect ratio was created a priori with incorporation of the normalization for purpose of interpatient comparison. No differences were noted in the cumulative ratio between regimens. However, gastrointestinal, central nervous system (CNS), and aesthetic adverse effect ratios were generated a posteriori to further quantitate organ system specific adverse effects and interpatient differences of these manifestations were successfully demonstrated. Potential construct limitations include confounding factors such as concomitant medications with overlapping adverse effect profiles and the inability to distinguish causative relationships to individual medications. Since this scoring system provides a composite of adverse effects manifested by common immunosuppression regimens, additional factors such as concomitant medications or co-morbidities should also be considered during routine clinical assessment.
Inter-rater reliability of the scoring system was substantial based on intra-class correlation and Kappa analyses documenting agreement between raters [23, 24]. The overall scoring system and each organ system adverse effect ratio achieved the a priori endpoint for intra-class correlation ≥ 0.7. Qualitative assessment of specificity was observed through rigorous patient assessment methodologies to characterize the adverse effects, the significant inter-rater reliability, and calcineurin inhibitor specific differences in adverse effect profiles observed.
The adverse effects scoring system administered by a clinician provides a time efficient, standardized clinical approach to assess the frequency and severity of these manifestations in renal transplant recipients. In contrast, the Memphis survey provides a patient completed questionnaire with comprehensive evaluation of symptoms and quality of life post-transplant, but does not provide succinct, efficient, objective adverse effects evaluation completed by the practitioner . In addition, the patient completed gastrointestinal symptom rating scale validated for renal transplant recipients does not include physician verification or other organ-specific adverse effects . Therefore, routine clinical application of these patient rating scales may be limited for objective immunosuppressive monitoring.
This is a single-center experience in stable renal transplant recipients receiving maintenance immunosuppression according to pre-established protocols. Therefore, variability observed in adverse effect manifestations as detected by the scoring system supports internal validity. As a single center experience, consideration of scoring bias by participating nephrologists who may provide routine medical care to some of these patients was possible. Due to the high inter-rater reliability, this type of bias was minimized. The novelty of the scoring system is the utilization of clinician directed evaluation of common adverse effects using a systematic, objective approach instead of a reactive response to these manifestations. A few infrequent adverse effects (e.g. alopecia) were not included and may be considered a study limitation.
Future research using this validated adverse effect rating system may include longitudinal evaluation of immunosuppressive adverse effects during the acute and chronic post-transplant periods and relationships to medication adherence, physician evaluation and allograft outcomes. This preliminary report provides a novel standardized adverse effect assessment which may benefit other solid organ transplant populations through prospective evaluations.