Coexistence of autosomal dominant polycystic kidney disease type 1 and hereditary renal hypouricemia type 2: A model of early‐onset and fast cyst progression

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is a heterogeneous inherited disease characterized by renal and extrarenal manifestations with progressive fluidfilled cyst development leading to end-stage renal disease. The rate of disease progression in ADPKD exhibits high inter-and intrafamilial variability suggesting involvement of modifier genes and/or environmental factors. Renal hypouricemia (RHUC) is an inherited disorder characterized by impaired tubular uric acid transport with severe complications, such as acute kidney injury and chronic kidney disease (CKD).However, the two disorders have distinct and well-delineated genetic, biochemical, and clinical findings. Only a few cases of coexistence of ADPKD and RHUC (type 1) in a single individual have been reported. We report a family with two members: an ADPKD 24-year-old female which presented bilateral renal cysts in utero and hypouricemia since age 5, and her mother with isolated hypouricemia. Next-generation sequencing identified two mutations in two genes PKD1 and SLC2A9 in this patient and one isolated SLC2A9 mutation in her mother, showing RHUC type 2, associated to CKD. The coexistence of these two disorders provides evidence of SLC2A9 variant could act as a modifier change, with synergistic actions, that could promote cystogenesis and rapid ADPKD progression. This is the first case of coexistence of PKD1 and SLC2A9 mutations treated with tolvaptan.

Rapidly Progressing to ESRD in an Individual with Coexisting ADPKD and Masked Klinefelter and Gitelman Syndromes

“…Then, the progression of ADPKD is highly variable, in part because of the gene affected [ 1 , 2 , 3 , 4 , 5 , 6 , 7 ], as well as the presence of other variants modifying its effect. In fact, how environmental factors and/or modifier genes/variants may modulate ADPKD, involving a rapid progression of the disease [ 6 , 7 , 8 , 13 , 44 , 45 ], is still unknown. Indeed, the presence of additional gene variants may promote cystogenesis and/or fibrosis, and potentiate the advancement toward ESRD [ 4 , 5 , 6 , 7 , 8 , 14 ].…”

“…The clinical progression to ESRD and disease prognosis in this patient with ADPKD, KS, and GS (isolated KS or GS not producing CRF) could be potentially synergistic and comparable to individuals with variants in both PKD1 and PKD2 [ 6 , 7 ], hypomorphic PKD1 variants and likely biallelic disease [ 12 ], the contiguous gene syndrome TSC2-PKD1 [ 8 ], co-occurrence of ADPKD and hereditary renal hypouricemia [ 45 ], or dual sequence variants in PKD2 and COL4A1 [ 63 ]. In fact, our patient with an LP variant in PKD1 , KS, and a compound heterozygous GS-associated variant showed a severe phenotype of ADPKD, characterized by the development of early CRF (at 27 years old) and rapid evolution to ESRD (at 40 years old) ( Table 1 ), associated with an intracranial aneurysm ( Figure 1 C).…”