LAUSR

Familial IgA nephropathy (IgAN) has been widely reported around the world. However, it's clinico-histological characteristics and long-term prognosis are not clear. In this study, 348 familial IgAN cases from167 independent IgAN families were recruited and their clinico-histological characteristics were compared to 1,116 sporadic IgAN patients from the same geographic region. Inheritance patterns, clinical features, and treatment regimens of all recruited patients were recorded and lifetime risk of end-stage renal disease (ESRD) was compared between familial and sporadic cases. Of all familial IgAN patients, 60 (17%) came from 32 single-generation (SG, defined as all affected individuals are siblings) families, while 286 (82%) came from 134 multiple-generation (MG, affected individuals were present in at least two consecutive generations) families. There’re totally 178 transmissions, 79 of which (44%) were paternal transmission and 99 (56%) were maternal transmissions. We observed evidence for incomplete penetrance in 30 (22%) MG families. The lifetime risk of progression to ESRD was significantly higher in familial IgAN patients than sporadic patients after adjusted by gender [HR=1.40, 95%CI: 1.12-1.74, P=0.004], with 5-year younger in median ESRD onset age [median ESRD-free survival of 60 years vs. 65 years in familial and sporadic cases separately]. As expected, compared to the ones without progressive renal failure at disease onset (eGFR≥60ml/min), familial cases with progressive renal failure (eGFR<60ml/min) had higher risk of lifetime ESRD [HR=6.32, 95%CI: 3.73-10.72, P<0.001]. Interestingly, among familial cases, we found cases from SG families [vs MG families: HR=2.62, 95%CI: 1.59-4.31, P<0.001] or with early onset (onset age <30yrs) [vs late onset: HR=4.79, 95%CI: 3.16-7.26, P<0.001] had higher lifetime risk of ESRD. Furthermore, among sporadic patients, compared to females, males had lower eGFR, higher urine protein, higher Oxford T score and resulted in a higher risk for lifespan ESRD (male vs female, 25% vs 17%, P=0.003) while these gender difference was not seen in familial patients. In conclusion, familial IgAN cases had poorer renal outcomes and less gender differences compared to sporadic cases. These findings provide evidence that familial disease represent a distinct subtype of more progressive IgAN.