Early Recognition and Management of Rare Kidney Stone Disorders

Ross Goldstein, MD, MBA; David S. Goldfarb, MD


Urol Nurs. 2017;37(2):81-89. 

In This Article

Dent Disease

Dent disease is a very rare X-linked disorder of proximal tubule dysfunction due to mutations in the CLCN5 chloride/protein exchanger gene (Dent disease 1, accounting for 60% of cases) or in the OCRL1 gene (Dent disease 2, accounting for 15% of cases) (Devuyst & Thakker, 2010; Edvardsson et al., 2013; Lieske et al., 2014). These mutations result in defective receptor-mediated endocytosis, causing generalized dysfunction of proximal tubule cells (Devuyst, 2010; Devuyst & Thakker, 2010). Exactly how this dysfunction produces the phenotype of hyper calciuria remains uncertain.

Dent disease is characterized by low-molecular-weight (LMW) proteinuria, hypercalciuria, nephrolithiasis, nephrocalcinosis, and progressive renal failure (Devuyst & Thakker, 2010; Lieske et al., 2014). To date, approximately 250 families with Dent disease have been identified (Devuyst & Thakker, 2010; Lieske et al., 2014).

Clinical Presentation of Dent Disease

Dent disease generally presents in childhood or early adulthood, with males more severely affected than females. A universal feature is LMW proteinuria (pathognomonic feature). Other features include hypercalciuria, stone disease, rickets, nephrocalcinosis, and renal failure, with possible foamy urine and bone pain. Dent disease may also be accompanied by short stature and growth retardation. In males younger than 10 years, the only manifestation of the disease may be asymptomatic LMW proteinuria and/or hypercalciuria. Up to 80% of affected males may develop ESRD between the third and fifth decades of life (Devuyst & Thakker, 2010; Lieske et al., 2014). Patients with Dent disease 2, caused by OCRL mutations, have Lowe syndrome, an "oculocerebral" syndrome. Their phenotype includes reduced cognitive function, bone disease, cataracts, and growth retardation.

Diagnosis of Dent Disease

Clinical diagnosis of Dent disease is based on the presence of all three of the following criteria: a) LMW proteinuria (elevation of urinary excretion of 2-micro globulin or retinol binding protein (RBP) by at least 5-fold above the upper limit of normality); b) hypercalciuria (> 4 mg/kg in a 24 h-hour collection or > 0.25 mg Ca2+ per mg creatinine on a spot sample); and c) at least one of the following: nephrocalcinosis, kidney stones, hematuria, hypo phosphatemia, renal insufficiency, or a family history consistent with X-linked inheritance (Devuyst & Thakker, 2010; Lieske et al., 2014). Genetic screening for either of the two implicated genes (CLCN5 and OCRL1) can be used to confirm the diagnosis (Edvardsson et al., 2013; Lieske et al., 2014).

A typical urinary total protein screen can detect LMW proteinuria. However, these LMW proteins are not detected by dipstick. Stone analysis will reveal calcium oxalate and/or calcium phosphate stones (Edvardsson et al., 2013). Some patients with Dent disease not only have LMW proteinuria, but albuminuria as well; occasionally, they may present with the nephrotic syndrome. Kidney biopsy in such patients may demonstrate focal segmental glomerulosclerosis (Copelovitch, Nash, & Kaplan, 2007). Some patients have unnecessarily been subjected to treatment with glucocorticoids or cytotoxic therapy, treatments that will not be effective for Dent disease.

Management of Dent Disease

Goals of management are to decrease hypercalciuria, prevent kidney stones and nephrocalcinosis, and delay the progression of CKD. However, no specific treatments have been evaluated in randomized clinical trials (Lieske et al., 2014).

Thiazide diuretics, chlorthalidone, hydrochlorothiazide, and indapamide have been used to reduce urinary calcium excretion. At doses greater than 0.4 mg/kg/day, thiazide diuretics are shown to reduce urinary calcium excretion by more than 40% (Blanchard et al., 2008; Raja et al., 2002). However, these agents should be dosed with caution, and patients need to be monitored for side effects, such as hypokalemia, hyponatremia, hy per uricemia, and cramping (Blan chard et al., 2008). Angiotensin-converting en zyme (ACE) inhibitors and angiotensin receptor blockers have been used to stabilize kidney function in children with proteinuria (Lieske et al., 2014).