TABLE 3.

Overarching questions & PICOs.

W&J criterium	Overarching question	PICO(s)
1	Does late rejection pose a health problem?	In renal transplant recipients (P), is late rejection (I) a significant contributor to allograft attrition rates compared to other factors (C)?
2	Do we understand the natural history of rejection sufficiently?	In renal transplant recipients with rejection (P), are DSA (I) a significant independent causative contributor to development of the rejection process (O) compared to those without DSA (C)?
		In renal transplant recipient with rejection (P), are other factors (I) determined as significant independent cause for the development of the rejection process (O) compared to those without those factors (C)?
3	Are we able to identify latent rejection through DSA screening before overt dysfunction occurs?	In renal transplant recipients (P), is development of dnDSA or prevalence of preformed DSA (I) associated with subclinical rejection (O) compared to those without DSA (C)?
		In renal transplant recipients with subclinical DSA (P), can allograft biopsy guided by DSA development/evolution (I) identify subclinical rejection in an earlier pathological stage (O) compared to biopsies in the event of more overt dysfunction (C)?
4,5,8	Are current DSA testing methods suitable for DSA screening and can certain DSA characteristics be used to further guide allograft biopsy decision making	In renal transplant recipients are current DSA assessment methods sufficient to reliably detect anti-HLA antibodies and their donor specificity?
		In renal transplant recipients with subclinical DSA (P), can DSA characteristics (MFI, class, IgG subclass, complement binding ability) (I), reliably be used to identify patients without rejection (O) compared to allograft biopsy (C)?
6–7	Is treatment for patients with subclinical DSA or subclinical rejection defined?	In renal transplant recipients with subclinical DSA who have not yet been biopsied (P), is treatment of any kind (I) compared to no treatment (C) beneficial for transplant outcome (O) (allograft loss, clinical rejection risk)?
		In renal transplant recipients with rejection (ABMR or TCMR) (P), is treatment in the subclinical phase (I) more beneficial to transplant outcome (O) (allograft loss/kidney function) compared to treatment in case of overt dysfunction (C)?
9	Is there any evidence of cost-effectiveness of standardized DSA monitoring and treatment of found cases?	In renal transplant recipients (P), has monitoring of DSA (I) been shown to be cost-effective compared to no monitoring of DSA (C)?
10	How frequent and until what time should DSA monitoring be conducted?	Is the incidence rate as a function of time post-transplant defined?
		In renal transplant recipients who have developed dnDSA (P), is development of additional dnDSA (I) associated with worse transplant outcome (O), compared to no additional dnDSA (C)?
		In renal transplant recipients who have developed dnDSA (P), is disappearance of the dnDSA (I) associated with better transplant outcomes (O) compared to persistence (C)?
		In renal transplant recipients (P), are clear risk categories (I) defined for the risk of development of dnDSA (O) compared to those without those risks (C)?
		In renal transplant recipients (P), are certain monitoring frequencies (annually, biannually, etc.) (I) associated with better transplant outcomes (O) compared to other monitoring frequencies (C)?