Long-term renal outcome of Cryopyrin-associated periodic syndrome (CAPS) under anti-Interleukin-1 therapy

Abstract

Cryopyrin-associated periodic syndromes (CAPS) are orphan hereditary auto-inflammatory diseases with various phenotypes, including chronic kidney disease (CKD). Current therapies inhibit interleukin-1 (IL-1) to achieve clinical and serological remission; however, the effect on kidney involvement remains unclear. The objective of this study was to investigate the long-term efficacy of anti-IL-1 treatment with special emphasis on renal outcome. We retrospectively analysed clinical, genetic and laboratory data of patients with CAPS under anti-IL-1 therapy from a single-centre university outpatient clinic. Patients with CAPS (n = 28) were followed for a median of 11 (IQR 8.5-13) years. Four patients at various ages (19%), bearing the most common CAPS mutation R260W, had significant CKD at presentation. All affected patients were related; however, other family members with the same genetic variant did not develop CKD. While anti-IL-1 therapy was effective in lowering symptom burden and inflammatory parameters in all CAPS patients, two of the four individuals with significant CKD had persistent proteinuria and worsening kidney function. None of the patients without renal affection at therapy initiation developed relevant CKD in the follow-up period. We showed that in patients with CAPS: (1) CKD is a common complication; (2) renal involvement shows familial predisposition beyond the mutational status and is independent of age; (3) anti-IL-1 therapy results in sustained improvement of inflammatory parameters and symptom load and (4) may prevent development of CAPS-associated CKD but not affect kidney involvement when already present. Overall, early therapy initiation might sufficiently prevent renal disease manifestation and attenuate progression.

Keywords: Anakinra; Anti-IL-1 therapy; CAPS; Canakinumab; Long-term; Renal outcome.

Figure 1

Renal disease in CAPS patients with respect to mutational status as well as clinical symptom load and inflammatory parameters under anti-IL1 therapy. (a) Overview of renal disease at start of anti-IL-1 therapy and at latest follow-up as defined per KDIGO stages of chronic kidney disease (CKD), with G signifying extent of eGFR (G1-G5) and A depicting amount of albuminuria (A1-A3). All patients are sorted by age at therapy initiation in descending order from top to bottom with the respective follow-up period. Additionally, individual age of symptom onset, agent and dose of anti-IL1 therapy and mutational status are depicted (please note that “E148Q” is a mutation of the MEFV gene); asterisks label the one family most frequently affected by CKD. Four patients with significant CKD are underlined and designated as pat 1 to pat 4. The fourth patient (pat 4) was in need of renal replacement therapy at therapy initiation, and received a renal transplant 3 years later. This patient was followed for 13 years after transplantation and constantly under anti-IL1 therapy additional to standard immunosuppressive therapy for allograft rejection prevention (cyclosporine, mycophenolate mofetil and low-dose steroids). Abbreviations: can/canakinumab, administered subcutaneously every 8 weeks; ana / anakinra, administered subcutaneously every day. (b) Symptom burden of CKD and non-CKD patients with CAPS under anti-IL-1 therapy as measured by clinical severity score (minimum 9, maximum 45): Specific treatment resulted in significant reduction of symptom load in both groups, which was maintained over time. The dashed line represents the lowest possible score value, signifying absence of any symptoms. (c) Course of serum amyloid A (SAA) concentrations in CKD and non-CKD patients at therapy initiation and during follow-up: Anti-IL-1 therapy significantly and permanently lowered SAA in both groups. (d) Albuminuria of CKD patients over time showing maintained improvement of urinary albumin excretion. Data of the pat 4 is not depicted because of renal replacement therapy prior to ant-IL-1-therapy. None of the other patients presented with or developed significant albuminuria. (e) Individual clinical severity score (minimum 9, maximum 45) measuring symptom load in CKD patients at start of anti-IL-1 therapy and during follow-up.