Diagnosis, management, and prognosis of HNF1B nephropathy in adulthood

Abstract

Mutations in HNF1B are responsible for a dominantly inherited disease with renal and nonrenal consequences, including maturity-onset diabetes of the young (MODY) type 5. While HNF1B nephropathy is typically responsible for bilateral renal cystic hypodysplasia in childhood, the adult phenotype is poorly described. To help define this we evaluated the clinical presentation, imaging findings, genetic changes, and disease progression in 27 adults from 20 families with HNF1B nephropathy. Whole-gene deletion was found in 11 families, point mutations in 9, and de novo mutations in half of the kindred tested. Renal involvement was extremely heterogeneous, with a tubulointerstitial profile at presentation and slowly progressive renal decline throughout adulthood as hallmarks of the disease. In 24 patients tested, there were cysts (≤5 per kidney) in 15, a solitary kidney in 5, hypokalemia in 11, and hypomagnesemia in 10 of 16 tested, all as characteristics pointing to HNF1B disease. Two patients presented with renal Fanconi syndrome and, overall, 4 progressed to end-stage renal failure. Extrarenal phenotypes consisted of diabetes mellitus in 13 of the 27 patients, including 11 with MODY, abnormal liver tests in 8 of 21, diverse genital tract abnormalities in 5 of 13 females, and infertility in 2 of 14 males. Thus, our findings provide data that are useful for recognition and diagnosis of HNF1B disease in adulthood and might help in renal management and genetic counseling.

Hepatocyte Nuclear Factor 1β–Associated Kidney Disease

“…12 Renal phenotype appeared to be extremely heterogenic, with 62% of patients having one or more renal cysts. These cysts may be apparent on a renal ultrasound, mostly in the cortex, but they sometimes require magnetic resonance imaging to be detected.…”

“…15 Faguer et al reported a renal function decline of 22.45 ml/min per 1.73 m 2 per year over a median followup of 5.5 years in their cohort of HNF1b patients. 12 About 13%-15% of patients eventually develop ESRD. 16 In a retrospective study of 377 patients with HNF1b mutations, no correlation was found between the type and location of the genetic mutation and severity of kidney failure.…”

Mutations in PCBD1 Cause Hypomagnesemia and Renal Magnesium Wasting

“…1,2 Hypomagnesemia (plasma Mg 2+ levels,0.7 mmol/L) with hypermagnesuria affects up to 50% of the HNF1B patients. 1,3 In adult kidney, HNF1B is expressed in epithelial cells along all segments of the nephron. The role of HNF1B in renal Mg 2+ handling was, however, pinpointed to the distal convoluted tubule (DCT), where the final urinary Mg 2+ excretion is determined.…”

Hepatocyte Nuclear Factor 1-β Gene Mutation: Brief Report and Review of Hepatic Involvement

“…To date, 47 individuals have been reported with liver disease associated with HNF1β gene defects, 25 as case reports [6,[8][9][10][11][12][13][14] and 22 identified in patients with the known renal disease being screened for HNF1β defects [15][16][17]. Liver involvement may present as cholestasis, elevated liver enzyme levels (ALT and/or GGT), hepatomegaly, or steatosis.…”

“…This is probably an over-representation as these patients had known liver disease and were subsequently found to harbor a defect in HNF1β. When searching for hepatic injury in patients with known HNF1β defects, the percentages are lower, ranging from 17% to 56% for GGT and 12% to 56% for ALT [14][15][16][17][18]. The degree of enzyme elevation varies from mild (twice the upper limit of normal) to severe (10-times the upper limit CASE REPORT of normal).…”