Phenotype and outcome in hereditary tubulointerstitial nephritis secondary to UMOD mutations

Abstract

Background: UMOD mutations cause familial juvenile hyperuricemic nephropathy (FJHN) and medullary cystic kidney disease (MCKD), although these phenotypes are nonspecific.

Design, setting, participants, & measurements: We reviewed cases of UMOD mutations diagnosed in the genetic laboratories of Necker Hospital (Paris, France) and of Université Catholique de Louvain (Brussels, Belgium). We also analyzed patients with MCKD/FJHN but no UMOD mutation. To determine thresholds for hyperuricemia and uric-acid excretion fraction (UAEF) according to GFR, these parameters were analyzed in 1097 patients with various renal diseases and renal function levels.

Results: Thirty-seven distinct UMOD mutations were found in 109 patients from 45 families, all in exon 4 or 5 except for three novel mutations in exon 8. Median renal survival was 54 years. The type of mutation had a modest effect on renal survival, and intrafamilial variability was high. Detailed data available in 70 patients showed renal cysts in 24 (34.3%) of nonspecific localization in most patients. Uricemia was >75th percentile in 31 (71.4%) of 42 patients not under dialysis or allopurinol therapy. UAEF (n = 27) was <75th percentile in 70.4%. Among 136 probands with MCKD/FJHN phenotype, UMOD mutation was found in 24 (17.8%). Phenotype was not accurately predictive of UMOD mutation. Six probands had HNF1B mutations.

Conclusions: Hyperuricemia disproportionate to renal function represents the hallmark of renal disease caused by UMOD mutation. Renal survival is highly variable in patients with UMOD mutation. Our data also add novel insights into the interpretation of uricemia and UAEF in patients with chronic kidney diseases.

Figure 1.

Representation of UMOD gene and uromodulin protein and radiological features associated to UMOD or HNF1B mutation. (A) Schematic representation of UMOD gene and uromodulin protein. The shaded boxes represent the exons of UMOD gene encoding uromodulin (4,5). The number of the first codon of each exon is indicated. The codon that initiates traduction is in exon 3 (nucleotide 106). More than 80% of mutations are in exon 4 (arrow) (upper panel). Uromodulin protein is a 640-amino acid glycoprotein. The N-terminal region (mainly exon 4) contains three calcium-binding EGF domains followed by a highly conserved cysteine-rich sequence of 166 residues. The C-terminal region contains the zona pellucida (ZP) domain and a phosphatidylinositol anchor (lower panel) (4,5). (B) Injected computed tomography (CT) in two patients with UMOD and HNF1B mutation, respectively. CT in one patient with UMOD mutation showed bilateral corticomedullary cysts (5 mm on the right kidney and 20 mm on the left kidney) (arrows), and kidneys were of normal size (left panel). CT in one patient with HNF1B mutation showed normal kidney size with multiple bilateral medullary cysts (arrows), predominantly on the left kidney (right panel).

Figure 2.

Serum uric acid levels and uric acid excretion fraction (UAEF) in chronic kidney disease population and in patients with UMOD mutation. Median and 10th, 25th, 75th, and 90th percentile values for uricemia in men (A), uricemia in women (B), and UAEF (C) according to GFR are provided. Circles indicate values observed in patients with UMOD mutation.

Figure 3.

Renal survival and renal function at last follow-up. (A) Kaplan–Meier curve of renal survival in 107 patients with UMOD mutation. (B) Estimated GFR (eGFR) estimated by MDRD formula was available in 93 patients with UMOD mutation.

Figure 4.

Intrafamilial variability and renal survival according to the type of mutation. (A) Age at onset of ESRD was analyzed in 12 families with at least two members reaching ESRD. Type of mutation as stated in Table 1 is provided. (B) Renal survival in probands was analyzed according to the type of mutation in UMOD gene. AA, amino acid.

Figure 5.

Screening for UMOD and HNF1B mutation at Necker Hospital in probands with FJHN or MCKD phenotype.