Immune Glomerulopathies

Presentation and early outcome in juvenile Lupus nephritis

Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease of unclear etiology, which can affect all organ systems, mostly through autoantibody-driven immune complex deposition and vasculitis. Childhood-onset SLE (juvenile SLE) has a higher disease severity and higher mortality compared with adult-onset SLE (1). Kidney involvement, i.e. lupus nephritis (LN), occurs in 60- 80% of pediatric SLE patients and plays a decisive role in the prognosis of the disease. The most common symptoms of LN are proteinuria in 90% of patients and microhematuria in 80%. Other symptoms include edema, hypertension (30- 50%), impaired renal function (50%) and even acute renal failure (17%) (3,4). Data on renal outcome in juvenile LN are few, with small patient cohorts and usually retrospective data only. Chronic kidney disease CKD stage 5 or kidney failure was described in 1%-15% of patients in a follow up time of 4-20 years (5-10).

Patients with juvenile LN are treated with various immunosuppressive protocols including long-term steroid treatment (11-13). Pediatric patients are mostly treated off-label since data on renal outcome and treatment toxicity are scarce. Due to the lack of data, specific requirements of pediatric patients are not taken into account. Not only growth and development, but also psychological factors such as puberty and family structures differentiate this group of patients from adults and make extrapolation from adult data or classifiers difficult. This was highlighted by our results of the analysis of the German Lupus Nephritis Registry (14). With the dataset stemming collected in between 1997 and 2015 an update of the German registry was inevitable and in a common endeavor the ESPN/ERKNet-ERKReg LN subregistry, one of the first subregistries of ERKReg was initiated and went online in April 2021. This expansion would allow the collection of data from 70+ expert centres (including affiliated centers) throughout the European Union, allowing to connect a large European mostly prospective cohort in order to analyze disease course, treatment protocols, comorbidities and long-term renal outcome. This is essential for improving childhood-specific treatment.

REFERENCES:
(1) Oni L, Wright RD, Marks S et al. Kidney outcomes for children with lupus nephritis. Pediatr Nephrol 2020; doi: 10.1007/s00467-020-04686-1).
(2) Selcan Demir, Bora Gülhan et al. Long-term renal survival of paediatric patients with lupus nephritis, Nephrology Dialysis Transplantation, Volume 37, Issue 6, June 2022, Pages 1069–1077, doi.org/10.1093/ndt/gfab152
(3) Moroni G, Quaglini S, Gallelli B, Banfi G, Messa P, Ponticelli C (2007) The long-term outcome of 93 patients with proliferative lupus nephritis. Nephrol Dial Transplant 22:2531–2539
(4) Lee BS, Cho HY, Kim EJ, Kang HG, Ha IS, Cheong HI, Kim JG, Lee HS, Choi Y (2007) Clinical outcomes of childhood lupus ne- phritis: a single center's experience. Pediatr Nephrol 22:222–231
(5) Qiu, S., Zhang, H., Yu, S. et al. Clinical manifestations, prognosis, and treat-to-target assessment of pediatric lupus nephritis. Pediatr Nephrol 37, 367–376 (2022). doi.org/10.1007/s00467-021-05164-y
(6) Groot N, Shaikhani D, Teng YKO, de Leeuw K, Bijl M, Dolhain R et al (2019) Long-term clinical outcomes in a cohort of adults with childhood-onset systemic lupus erythematosus. Arthritis Rheum 71(2):290–301
(7) Hari P, Bagga A, Mahajan P, Dinda A (2009) Outcome of lupus nephritis in Indian children. Lupus. 18(4):348–354
(8) Taheri S, Beiraghdar F (2011) Lupus nephritis in Iranian children: a review of 60 patients. Ren Fail 33(5):499–505
(9) Wong SN, Tse KC, Lee TL, Lee KW, Chim S, Lee KP et al (2006) Lupus nephritis in Chinese children--a territory-wide cohort
study in Hong Kong. Pediatr Nephrol 21(8):1104–1112
(10) Vachvanichsanong P, Dissaneewate P, McNeil E (2009) Diffuse proliferative glomerulonephritis does not determine the worst outcome in childhood-onset lupus nephritis: a 23-year experience in a single centre. Nephrol Dial Transplant 24(9):2729–2734
(11) Bertsias GK, Tektonidou M, Amoura Z, Aringer M, Bajema I, Berden JH, Boletis J, Cervera R, Dorner T, Doria A, Ferrario F, Floege J, Houssiau FA, Ioannidis JP, Isenberg DA, Kallenberg CG, Lightstone L, Marks SD, Martini A, Moroni G, Neumann I, Praga M, Schneider M, Starra A, Tesar V, Vasconcelos C, van Vollenhoven RF, Zakharova H, Haubitz M, Gordon C, Jayne D, Boumpas DT, European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (2012) Joint european league against rheumatism and european renal association-european dialysis and transplant associ- ation (EULAR/ERA-EDTA) recommendations for the manage- ment of adult and paediatric lupus nephritis. Ann Rheum Dis 71: 1771–1782
(12) Hahn BH, MA MM, Wilkinson A, Wallace WD, Daikh DI, Fitzgerald JD, Karpouzas GA, Merrill JT, Wallace DJ, Yazdany J, Ramsey-Goldman R Singh K Khalighi M Choi SI Gogia M Kafaja S Kamgar M Lau C Martin WJ Parikh S Peng J Rastogi
A, Chen W, Grossman JM, American College of Rheumatology (2012) American college of rheumatology guide- lines for screening, treatment, and management of lupus nephritis. Arthritis Care Res 64:797–808
(13) Groot N, de Graeff N, Marks SD, et al European evidence-based recommendations for the diagnosis and treatment of childhood-onset lupus nephritis: the SHARE initiative Annals of the Rheumatic Diseases 2017;76:1965-1973.
(14) Suhlrie A, Hennies I, Gellermann J, et al. Twelve-month outcome in juvenile proliferative lupus nephritis: results of the German registry study. Pediatr Nephrol. 2020;35(7):1235-1246. doi:10.1007/s00467-020-04501-x

The objective of ERKNet Lupus nephritis registry is to collect data on renal outcome and its determining factors in juvenile LN (including transition) and detect disease and treatment associated comorbidities in order to allow benchmarking, develop research hypothesis, improve treatment and outcome. With an interim analysis of the dataset in the Pediatric LN Registry of ERReg, we aim to gain epidemiological insights into the course of pediatric LN of a large European cohort and will be able to lay the groundwork for prognostic and therapeutic classifiers in juvenile LN.

The LN Registry went online in April 2021. Inclusion criteria are diagnosis of LN under the age of 18 years and biopsy proven LN. This sub-registry not only collects parameters from ERKReg’s basic module, but also SLE-specific parameters as described in “Data elements”.
Since its launch in April 2021, a total of n=114 patients from 15 European centers have been entered to the ERKReg the Pediatric SLE Sub-Registry. With the Registry still growing, so far 94 patients have documented more than one annual visit. The median follow-up time is 2 years with the registry aiming for a median follow-up of 5 years.

Data Sources: Other registries (please specify): Pediatric SLE Sub-registry

Data Elements:
Basic data of the 114 patients include more than 70 parameters including age at first symptoms, gender, age, ethnicity and anthropometic data. Lupusnephritis specific data include renal function- and immunological parameters (blood: creatinine, cystatin c, albumin, urea, blood count, immunological parameters: ANA, ANCA, dsDNA-antibody, C3, C4; urine : albumin, protein, hematuria, erythrocyte casts), as well as symptoms at diagnosis based on the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Kidney biopsy results and histological classification according to WHO and ISN/RPS classification are documented.
Data for annual visits include data on anthropometrics and kidney function (eGFR) and immunological parameters, detailed medication overview, extracorporal therapy such as dialysis, plasmapheresis, and transplantation. Complications including steroid associated and disease associated comorbidity including high blood pressure, left ventricular hypertrophy, fever, diarrhea, gingival hyperplasia, menstrual disorder, anemia, thrombocytopenia, leukocytopenia and clearly steroid associated complications e.g. cushingoid appearance, striae distensae, cataract, osteonecrosis are queried.

The aim of this fellowship is the descriptive evaluation of the LN-Registry to describe this large international European patient cohort. This includes kidney function, histological classification and clinical symptoms at diagnosis. Furthermore, the clinical course after 1 to 5 years will be described. Response to therapy and renal flares based on creatinine progression, eGFR and proteinuria are to be worked out. The evaluation would provide a detailed overview of a large European cohort of childhood onset LN of 14 different centers regarding course of disease, therapy regimens, comorbidities and complications with the background of histological impairment.

The development of a prognostic model for poor renal outcome in terms of chronic/terminal renal insufficiency/transplantation is strived for.