From juvenile hyperuricaemia to dysfunctional uromodulin: an ongoing metamorphosis

Abstract

Familial juvenile hyperuricaemic nephropathy (FJHN) is a diagnosis that is easily missed. It has taken a long time to clarify the pathophysiology and prevalence of this disease entity which has been shown to be genetically identical to medullary cystic kidney disease (MCKD) type II. The initial suspicion that uric acid was the noxious agent has been replaced by the recognition that a mutant uromodulin (UMOD) is the real culprit-although the exact mechanisms of pathogenicity remain uncertain. The mutation has been traced to the UMOD gene in chromosome 16. The disease is characterised by the classic triad of autosomal dominant inheritance, progressive renal failure beginning in the third to fifth decade of life and gout. Phenotypically similar but genotypically distinct entities have been described over the last 10 years, making a clinical diagnosis difficult. These include mutations in the renin, hepatocyte nuclear factor 1-β and mucin 1 genes. UMOD-associated kidney disease has been proposed as a logical diagnostic label to replace FJHN, but given all these other mutations, an over-arching diagnostic term of 'autosomal dominant tubulointerstitial kidney disease' (ADTKD) has been recently adopted. Allopurinol has been suggested as a therapeutic agent, but unfortunately this was based on non-randomised uncontrolled trials with small patient numbers.

Autosomal dominant tubulointerstitial kidney disease-UMOD is the most frequent non polycystic genetic kidney disease

“…Apart from incomplete and inadequate coding, the reason for the low published prevalence rates appears to be that genetic kidney diseases often go unrecognized [ 21 ]. This is especially true for ADTKD which has subtle phenotypic characteristics that can easily be missed [ 15 ]. While genetic tests are available for many genetic kidney diseases, they have not been commonly performed historically, because of their cost and the limited availability of diagnostic centres.…”

“…Despite hyperuricaemia and gout being considered hallmarks of ADTKD-UMOD, there was no significant association with the disease, reflecting how common both are in a general CKD population and that they can be absent in ADTKD-UMOD [ 9 ]. Hyperuricaemia and/or gout can still be helpful when present in patients with normal renal function, especially in females and young patients [ 15 ].…”

“…Inherited interstitial kidney diseases are underrecognised and underreported due to their lack of distinctive clinical or diagnostic histological features, lack of physician awareness and incomplete acquisition of family histories [ 15 ]. Registry data reliant on accurate diagnostic coding is known to be incomplete [ 16 ], and there is a paucity of information on the prevalence of genetic kidney diseases.…”

Potential serum and urine biomarkers in patients with lupus nephritis and the unsolved problems

“…In physiological and certain pathological conditions, the sugar moieties in THP side chains are altered, or the amount in urine excretion is reduced 118–123. Evidence suggests that mutations in THP gene may lead to congenital cystic kidney diseases or familial juvenile hyperuricemic nephropathy 124–127Table 8 lists the alterations in THP glycosylation or defective production in different pathological conditions.…”

Identification of a novel UMOD mutation (c.163G>A) in a Brazilian family with autosomal dominant tubulointerstitial kidney disease

“…Patients with this condition may have anemia, developmental delay, and/or leukopenia. Of all the subtypes of ADTKD, ADTKD- UMOD is the most common ( 6 , 7 ).…”