The Rare Kidney Stone Consortium’s (RKSC) goals are to advance the understanding of disease expression and the factors associated with renal injury in primary hyperoxaluria (PH), enteric hyperoxaluria (EH), cystinuria, adenine phosphoribosyltransferase (APRT) deficiency and dent disease with the overall goals of developing new treatments directed at protecting renal function and reducing nephrocalcinosis and stone formation.

Ready availability of diagnostic testing, pooling of data from patient experience in registries,  biobanks open to all investigators and the establishment of a consortium for cooperative exchange of information among investigators, clinicians and patients and a sharing of resources among researchers will improve care and outcomes for patients with the rare stone diseases and advance the science.

  • Primary Hyperoxaluria
  • Cystinuria
  • APRT Deficiency
  • Dent Disease
  • Lowe Disease

Primary Hyperoxaluria (PH)

What is Primary Hyperoxaluria?

Primary hyperoxaluria (PH) is the most severe of the hereditary causes of nephrolithiasis. Enzyme deficiency in the liver results in marked overproduction of oxalate that must be excreted by the kidneys. Oxalate in the urine in high concentrations is poorly soluble when combined with calcium and thus leads to calcium oxalate crystals and stones. Primary hyperoxalurias are autosomal recessive disorders of glyoxylate metabolism characterized by excessive production and urinary excretion of oxalate and glycolate (PH type 1),  oxalate and L-glycerate (PH type 2) and oxalate and hydroxyoxoglutarate (HOG) in PH type 3. The urine oxalate excretion rate in affected patients is typically 2 to 6 times normal with severe clinical consequences.The highest excretion rates are seen in PH1.

 Urolithiasis and/or nephrocalcinosis occur in childhood or adolescence. Renal injury due to oxalate and consequences of urinary tract stones leads to renal failure. Loss of renal function leads to markedly increased plasma concentrations of oxalate, and if not addressed promptly by transplantation, results in deposition of calcium oxalate in body tissue (oxalosis). Resulting organ system dysfunction including ischemic ulcers of the skin, metabolic bone disease, refractory anemia, cardiomyopathy and cardiac conduction system abnormalities are the cause of severe morbidity and mortality. These rare diseases can be caused by defects in at least three glyoxylate-metabolizing enzymes. Untreated, PH patient outcome is often poor, with death from renal failure and systemic oxalosis the norm in PH type 1,  Kidney failure is less often seen in PH types 2 and 3, though does occur and oxalosis can be severe. However, there is wide variability in outcome amongst patients, and with careful longterm clinical management patient survival with preserved renal function to middle age (or older) is possible in patients of all PH types. The important factors that influence improved patient survival are currently poorly understood.

Who gets Primary Hyperoxaluria?

Primary hyperoxaluria causes not only stones of the urinary tract, but also loss of renal function. Stones recur frequently, with most patients requiring many stone procedures over the course of a lifetime. By 20 years of age, end stage renal failure is observed in approximately 25% of patients with type 1 PH, and by 40 years of age, 55% have lost renal function. By contrast, in PH 2 at age 40 years approximately 20% have lost kidney function, and in PH3 5% have reached end stage kidney failure. Incidence and prevalence are unknown but have been estimated by surveys of nephrologists and urologists in France and Switzerland. Based on those studies, the incidence in central Europe is estimated at 1 in 120,000 live births and the prevalence at 1.05 to 2.9 per million population.  Observations of clinically diagnosed disease in North America are similar. However, examination of publically available genetic data from the NHLBI ESP suggests a higher prevalence of 1 in 58,000 among European and African Americans. This discrepancy may indicate milder forms of the disease or underdiagnosis. Some areas of the world, including Tunisia, the Canary Islands, and the Middle East appear to have a higher prevalence of PH.

What causes Primary Hyperoxaluria?

PH1,  PH2, and PH3 are autosomal recessive disorders. These three well-defined subtypes of primary hyperoxaluria are due to deficiencies of hepatic enzymes important in the metabolic disposition of glyoxylate. Type 1 (PH1) is due to deficiency or absence of alanine glyoxylate aminotransferase (AGT) enzyme and type 2 (PH2) is due to deficiency of glyoxylate reductase/hydroxypyruvate reductase (GRHPR) and type 3 (PH3) to deficiency of hydroxyoxoglutarate aldolase. A small number of patients have been identified with clinical characteristics indistinguishable from known PH types, but with normal AGT, GRHPR, and HOGA liver enzyme activity. The etiology of the marked hyperoxaluria in such patients remains to be elucidated.

How is Primary Hyperoxaluria diagnosed?

All the pathological sequelae of the primary hyperoxalurias are related to the increased synthesis and excretion of oxalate. Marked hyperoxaluria is present from birth on, with 2 to 8 times the upper limit of normal urine oxalate being characteristic. Blood in the urine or pain related to stones, stone passage, or urinary tract infection are the most common symptoms of the disease. Over time, frequent stone recurrences and the need for multiple stone removal procedures are typical. The majority of patients are symptomatic before 10 years of age. In some cases, however, the disease may go unrecognized either due to the absence of symptoms or to incorrect diagnosis, until patients reach 30 to 50 years of age.

Oxalate at high concentrations with calcium in the urine forms crystals that form in the urinary tract leading to stones, and also deposit in kidney tissue causing nephrocalcinosis. Calcium oxalate crystals are also directly injurious to renal cells and incite a granulomatous reaction in the renal interstitium. Over time the effects of such injury, often combined with intermittent obstruction or infection related to stones, lead to kidney failure. However, some patients present with kidney failure as the first manifestation of the disease, as early as 4 months of age. Patients with types 2 and 3 disease appear to have a milder course overall than those with type 1, including better preservation of renal function. The reasons for such variation in clinical expression are poorly understood, and if elucidated may provide valuable insights as to potentially remediable factors that can be exploited for therapeutic benefit. Once renal function declines to less than 30-40 ml/min/1.73 m2, plasma oxalate concentration rises, exceeding the supersaturation threshold for calcium oxalate and systemic oxalosis with associated morbidity and death result. Transplantation is required for satisfactory long term outcomes. Early diagnosis of primary hyperoxaluria is of vital importance so that treatment can be initiated as soon as possible. While molecular genetics can now provide definitive diagnosis for most patients, the lack of familiarity with the disease can result in delays of many years from onset of symptoms until diagnosis.

What is the treatment for Primary Hyperoxaluria?

Treatment strategies include maximizing oral fluid intake, carefully titrated doses of pyridoxine for those PH type 1 patients in whom it is effective and citrate or neutral phosphate to reduce calcium oxalate crystal formation in the urine. Renal function must be monitored vigilantly and renal replacement therapy should be initiated promptly if renal clearance falls below a critical threshold, in order to prevent body-wide deposition of calcium oxalate. Kidney transplantation alone or combined kidney-liver transplantation is clearly the preferred treatment of renal failure for PH patients. If transplantation is not possible, patients must be aggressively dialyzed, often 6 or 7 days per week and/or using a combination of modalities, in order to remove enough oxalate to prevent body-wide oxalosis. The only definitive treatment for type 1 PH is liver transplantation to replace the missing AGT enzyme. All of these modalities have been in use for more than 20 years. Though long term outcomes have improved with earlier diagnosis and currently available treatment, more effective treatments are urgently needed. Promising new directions using molecular  therapeutics with siRNA techniques and chaperone molecules, oxalate degrading bacteria, and exploitation of oxalate transport physiology are in various stages of investigation.


Please see Cystinuria for patients.

Adenine Phosphoribosyltransferase (APRT) Deficiency

What is Adenine Phosphoribosyltransferase Deficiency?

Adenine phosphoribosyltransferase (APRT) deficiency is a rare, autosomal recessive disorder of adenine metabolism, leading to 2,8-dihydroxyadeninuria that causes radiolucent kidney nephrolithiasis and chronic kidney failure in a significant proportion of untreated patients. A minority of patients may, however, be asymptomatic. APRT deficiency occurs in both men and women and affects both children and adults. Most reported cases come from Japan, France and Iceland but an increasing number of patients are being identified in other countries, including the United States.

Epidemiology of Adenine Phosphoribosyltransferase Deficiency

The estimated prevalence is 0.5 to 1 per 100,000 in the Caucasian population, 0.25 to 0.5 per 100,000 in the Japanese population and in Iceland the estimated point prevalence is 8.9/100,000. Likely explanations for the low prevalence in other countries include lack of awareness of the disorder, inadequate evaluation of patients with kidney stones, and erroneous diagnosis of 2,8-dihydroxyadenine (2,8-DHA) stones as uric acid or xanthine stones as they are all radiolucent.

How is Adenine Phosphoribosyltransferase Deficiency diagnosed?

The diagnosis of APRT deficiency is simple because the typical 2,8-DHA crystals are readily detected by urine microscopy. All patients with radiolucent kidney stones and patients with presumed uric acid stones, who do not respond to alkali therapy but improve with allopurinol treatment, should be screened for APRT deficiency. The diagnosis can also be made with APRT mutation analysis of or measurement of APRT enzyme activity in red cell lysates. Analysis of 2,8-DHA crystals and stone material with infrared and ultraviolet spectrophotometry and/or x-ray crystallography easily differentiates 2,8-DHA from uric acid.

How is Adenine Phosphoribosyltransferase Deficiency treated?

Allopurinol, when administered in the dose of 5-10 mg/kg/day (maximum suggested daily dose 600-800 mg) effectively prevents 2,8-DHA crystalluria and new stone formation and significantly improves kidney function in most patients with reduced renal function. In patients who do not tolerate allopurinol, treatment with febuxostat (Uloric®) should be considered. The treatment should be monitored by urine microscopy at follow-up visits. The prognosis of adequately treated patients is excellent.

Why is Adenine Phosphoribosyltransferase Deficiency underdiagnosed?

Lack of recognition of the disorder by clinicians is likely to remain a problem leading to unnecessary morbidity and mortality in affected patients. Increased awareness of APRT deficiency among physicians is needed to improve the outcome of this group of patients.

Dent Disease

What is Dent Disease?

Dent disease is a rare X-linked kidney disorder characterized by hypercalciuria and low molecular weight proteinuria, and is often accompanied by nephrolithiasis and nephrocalcinosis that can lead to renal failure. Other common manifestations are hypophosphatemia and osteomalacia.

How is Dent disease diagnosed?

Laboratory Findings

  1. Proteinuria usually in the range of 1-2 gm/day, half of which is low molecular weight (LMWP) (<30,000 Da). Low molecular weight proteins that can be clinically measured include alpha 1 microglobulin and retinol binding protein. ß2 microglobulin is another low molecular weight protein that is often measured, but it is not stale in acidic urine and therefore not recommended for this purpose.
  2. Hypercalciuria in the range of 4-6 mg/kg body weight if kidney function is preserved
  3. Low levels of parathyroid hormone
  4. Increased levels of 1,25 vitamin D
  5. Hypophosphatemia and relative hyperphosphaturia with normal serum calcium levels
  6. Aminoaciduria, glycosuria, hypokalemia

Radiologic findings
Patients can have presence of kidney stones or nephrocalcinosis. When analyzed stones are made of calcium oxalate or calcium phosphate.

Genetic screening/testing
Testing for the genes that cause Dent disease 1 (CLCN5) or Dent disease 2 (ORCL1) can be obtained through commercial laboratories, although many insurance companies will not pay for this testing.

Treatment of Dent disease

Hypercalciuria is thought to be the major factor that causes kidney stones and nephrocalcinosis in patients with Dent disease. Therefore it is reasonable to attempt to reduce urinary calcium by restricting dietary sodium intake and prescribing a thiazide diuretic. Caution has to be applied in young patients who might develop volume depletion and hypokalemia. Recently, animal studies in a model of Dent Disease have suggested that a high citrate diet may delay the loss of kidney function. Therefore some clinicians recommend a high citrate diet or prescribe potassium citrate. No studies are yet available to support the efficacy of either approach in humans with Dent disease.

Lowe Syndrome (LS)

Lowe syndrome was first recognized as a distinctive disease in 1952 by Drs. Lowe, Terrey, and MacLachlan at the Massachusetts General Hospital in Boston. They described three male children who had a similar set of problems that had not been previously associated with each other. Although they could not determine the cause of the disorder, they recognized a pattern to the symptoms and features and therefore described it as a "syndrome" a set of symptoms which occur together. The condition became known as "Lowe syndrome" named after Dr. Charles Lowe, the senior member of the group that described it. Lowe syndrome is also known as the "oculo cerebro renal" syndrome of Lowe (OCRL), reflecting the three major organ systems involved in the disorder (eyes, brain, and kidney). In subsequent years, doctors learned that Lowe syndrome is a hereditary condition that affects mostly males. It is caused by a single defective gene on the X-chromosome, one of the two sex determining chromosomes. Normally, this gene produces a specific enzyme that is essential to inositol metabolism. Because the gene is defective in Lowe syndrome, the enzyme cannot be produced. Therefore, the underlying cause of Lowe syndrome and its numerous features is the deficiency of this enzyme.