Tuesday, 12 April 2016

A few notes on "Dent’s disease"

Inheritance:
X-linked recessive, with a wide range of severity of phenotype (the gene CLCN5.) Of patients with Dent’s disease but lacking mutation in CLCN5, OCRL1 is mutated in a proportion, though not all, of the remainder.

Pathogenesis:
Both CLC-5 and ORL1 are strictly related to endosomal membrane trafficking and function.

Clinical features:
Proximal tubular solute loss,
LMW proteinuria;
hypercalciuria;
nephrocalcinosis and kidney stones; and
progressive renal insufficiency.
(rickets)

LMW proteinuria is the most consistent finding in patients with Dent’s disease, and the degree of protein loss is extreme
From childhood, the degree of albuminuria ranges 1–2 grams per day, representing about half of the proteinuria in these patients..
Other clinical signs of proximal reabsorptive dysfunction, such as glycosuria, aminoaciduria, and hypophosphatemia,
are common but not universal. When hypophosphatemia and hypokalemia occur, they can be severe and may require replacement.
Kidney stones occur in only half of patients. Hypercalciuria is an early finding, almost universal. In young adults with Dent’s disease, it ranges from 4 to 6 mg/kg body Weight. Nephrocalcinosis develops in a majority of patients with
Dent’s disease
Serum levels of PTH are consistently below the mean of the normal range in patients with Dent’s disease, and often
frankly low. Conversely, levels of 1,25-dihydroxyvitamin D are often elevated.
Renal failure develops in two-thirds of patients, but variably, and some patients reach an advanced age with little or only modest renal impairment. The mechanism of the renal failure is unknown.
Patients with clinical bone disease have elevated serum levels of alkaline phosphatase, but those without clinical
rickets have normal alkaline phosphatase levels and normal bone density.
One remarkable feature of Dent’s disease is the absence of systemic acidosis, except in the presence of renal insufficiency or nephrocalcinosis.
Nocturia is often the first symptom in affected boys, and moderate polyuria in the range of 1–3 liters per day is common.

Therapy:
Patients with recurrent stones and hypercalciuria may benefit from treatment with a thiazide diuretic. In view of one report of a dramatic natriuretic and kaliuretic response to a large dose of hydrochlorothiazide, patients should be followed closely when starting the diuretic.
Dietary sodium restriction may reduce calcium excretion,.
Vitamin D should only be considered in patients with clinical bone disease.