Medical Features

Living with Lowe Syndrome

III. Medical Features, cont'd.

D. Kidneys

1. Kidney "wasting" and replacement therapy. The primary kidney problem in Lowe syndrome is the abnormal "wasting," or loss, of certain substances into the urine, including bicarbonate, sodium, potassium, amino acids, organic acids, albumin and other small proteins, calcium, phosphate, glucose, and L-carnitine. In a normal kidney, these substances are usually filtered and then either excreted in the urine or reabsorbed as needed back into the body. Filtering is done by tiny filters called glomeruli. Reabsorption occurs in the kidney's tubules which are attached to each glomerulus. In kidneys affected by Lowe syndrome, the tubules are abnormal. As a result, substances are filtered out and excreted rather than reabsorbed as needed. This problem is known as Fanconi-type renal tubular dysfunction and can also be seen in certain other diseases and syndromes. In Lowe syndrome, the Fanconi syndrome may be mild and involve only a few substances or may be severe and involve large losses of many substances.

The clinical signs of kidney abnormalities in Lowe syndrome are often not present at birth, but usually become apparent by one year of age. Physicians who are not aware of this delay may be reluctant to diagnose Lowe syndrome during the first year if the blood and urine tests of kidney function are normal. In a child suspected to have Lowe syndrome, screening tests for kidney abnormalities should be done about every three months in the first year of life, then at least yearly thereafter until the Fanconi syndrome becomes apparent.

Some of the substances lost in the urine, such as organic acids, small proteins, and glucose, do not need to be replaced. A generalized loss of amino acids in the urine usually causes no clinical problem and needs no treatment. However, this finding is helpful in establishing the nature of the kidney problem and in diagnosing Lowe syndrome. Albumin loss in the urine may be large in some patients, but even in those patients is usually not severe enough to lower the blood albumin level and cause body swelling typical of the clinical nephrotic syndrome.

On the other hand, some of the substances lost in the urine, like bicarbonate, sodium, potassium, phosphorus, and carnitine, are essential to normal body chemistry. Excessive loss of these substances may result in serious metabolic problems (see Table 1 below). Most individuals respond to replacement therapy in which medication is given to replace the lost substances. The type of medication and dosage must be individualized for each patient by his physician. Blood and urine testing is done at intervals to monitor the benefits of therapy and to determine the appropriate doses of replacement medication. In addition, because the kidneys are often not able to conserve water and concentrate urine normally, a larger than normal intake of fluids may be needed to prevent dehydration.

Table 1. Substances Lost in the Urine Which May Require Replacement

Bicarbonate. The loss of bicarbonate into the urine results in a state of acid-base imbalance called acidosis, which is characterized by a body pH level that is lower than normal. Physical symptoms of acidosis include lethargy, poor appetite, and poor growth. If left untreated, severe acidosis may become life-threatening. In about two-thirds of the individuals with Lowe syndrome, acidosis is a long-term problem and requires replacement therapy. Oral preparations containing bicarbonate, or substances changed to bicarbonate in the body, such as citrate, may be given. Bicarbonate or citrate are usually given as the sodium or sodium and potassium-containing salts, which help replace the sodium and potassium which are also lost in the urine.

L-Carnitine. L-carnitine is a small protein molecule that is needed for our cells to produce energy from fats. Low blood levels of L-carnitine have been associated with a decreased ability to tolerate fasting, with symptoms of hypotonia, an enlarged or dysfunctional liver, low blood sugar and changes in awareness and consciousness. Replacement therapy with L-carnitine supplements may be needed in some patients.

Potassium. Excessive loss of potassium in the urine leads to hypokalemia, or low levels of potassium in the blood and the body. Symptoms of hypokalemia include muscle weakness, fatigue, excessive urination, and thirst. Oral potassium supplements are often given with citrate.

Phosphate. Loss of phosphate in the urine may lead to hypophosphatemia, or low blood phosphate levels in about one-third of the cases. This may lead to serious bone problems such as rickets or soft bones. Oral neutral phosphate supplements may be given if indicated to maintain the blood level of phosphate in the normal range.

2. Other abnormal lab findings. The kidney abnormality in Lowe syndrome may also cause other abnormal laboratory findings, including high cholesterol levels. Increased levels of cholesterol, particularly high-density-lipoprotein cholesterol, are common. Generally, this is the result of the renal Fanconi syndome (see Kidney "wasting," above) and should not be a cause for concern. Other laboratory abnormalities that are common in Lowe syndrome include high levels of liver function enzymes SGOT and LDH. In most cases, these findings are not the result of liver problems, but rather the result of impaired muscle integrity. Generally, these lab findings are not a cause for concern.

3. Nephrocalcinosis. Excessive loss of calcium in the urine can be part of the Fanconi syndrome. If the calcium does not remain in solution in the urine, calcium can be deposited in the kidney tissue, a condition called nephrocalcinosis, or form stones in the urine collecting system of the kidney, which is called nephrolithiasis. Patients with Lowe syndrome appear more likely to develop these conditions than other children with diseases associated with Fanconi syndrome. Calcium is more likely to cause nephrocalcinosis or nephrolithiasis when acidosis occurs and is untreated for prolonged periods. Extra citrate in the urine can combine with calcium to help keep the calcium in solution and prevent nephrocalcinosis and nephroliathiasis. Vitamin D metabolite therapy for treatment of rickets (see Rickets and Soft Bones) should be carefully monitored in patients with Lowe syndrome to try to prevent the occurrence or worsening of nephrocalcinosis. Calcium supplements should probably be avoided, unless the blood calcium is low.

When nephrocalcinosis or nephrolithiasis occur, they may also cause microscopic amounts of blood to appear in the urine. Nephrocalcinosis is best diagnosed by renal ultrasound. If a patient is suspected of having a kidney stone, a contrast X-ray study of the kidneys, like a CT scan (computed tomography) or intravenous pyelogram, may be needed to identify the exact position of the stone. A spot "urine calcium to creatinine ratio" or a 24-hour urine calcium measurement may be needed to determine the extent of calcium wasting and its subsequent response to any therapy. The use of chlorothiazide diuretics may be useful in some patients with nephrocalcinosis or stones. Diuretics can increase the amount of fluid filtered from the blood and therefore increase the amount of fluid in the kidneys. This in turn allows more calcium to dissolve (since there is more fluid for it to dissolve in). Diuretic therapy must be carefully monitored by a physician to prevent dehydration.

4. Kidney failure. Later in life, usually starting after the age of 10 years, the tiny filters of the kidney (the glomeruli) may start to fail. The exact cause of the filtration failure in Lowe syndrome is unknown. Kidney failure is diagnosed when waste products, like creatinine and urea nitrogen, begin to accumulate in the blood instead of being filtered out. This may begin to happen even before any physical symptoms occur. Creatinine and urea nitrogen are made every day by normal body metabolism and are good markers for kidney filtration. Creatinine is made by the muscles, so blood levels of creatinine may be lower than expected for a given degree of kidney failure if the muscle mass is decreased in Lowe syndrome. In that case, a 24-hour urine creatinine clearance gives a more accurate estimate of the kidney function than the blood creatinine alone. Symptoms of fatigue, decreased appetite, nausea, and vomiting may occur when kidney function is less than 20% of normal.

Kidney failure usually progresses slowly and is not complete until age 30 or 40 years. Since few patients are older than 40, it is difficult to know what the late renal history of most patients will be and whether chronic dialysis or kidney transplant would be a good therapy for patients whose kidneys completely fail.