What is Calcium Deposition and Other Renal Crystal Diseases?
Crystals are tightly-packed structures made up of particles like ions, atoms, and molecules which form a regular, repeating pattern in a three-dimensional space. These crystal materials are filtered from a liquid part of the blood known as plasma by our kidneys, with the process taking place in the kidney tubes or “renal tubules”. The kidneys play a substantial role in this filtering process as they receive a significant 25% of the body’s total heart output.
Deposits of these crystals mainly happen in the renal tubules or kidney tubes, and also in the interstitium (the space around the body’s cells). The deposits can trigger the development of sudden (acute) or slowly-developing (chronic) kidney diseases. Symptoms might include the presence of blood in the urine that is only noticeable under a microscope (microscopic hematuria), urine containing crystals (crystalluria), and a moderately high level of protein in the urine, a condition known as sub-nephrotic range proteinuria.
What Causes Calcium Deposition and Other Renal Crystal Diseases?
Diseases related to crystals in the urinary system and kidneys are generally grouped into four main categories based on what causes them.
1. Crystalline diseases related to Calcium oxalate and Calcium phosphate.
2. Diseases due to crystal deposition related to Paraproteinemia, a condition where high levels of a certain protein are present in the blood.
3. Diseases due to crystal deposition caused by metabolic and inherited disorders.
4. Diseases due to crystal deposition caused by medication.
Risk Factors and Frequency for Calcium Deposition and Other Renal Crystal Diseases
There are several diseases related to autosomal recessive crystalline deposition. These conditions are more commonly seen in areas where marriages among relatives are prevalent. Some of these diseases include:
- Primary hyperoxaluria – contributes to 1% to 2% of severe kidney diseases in children, with an incidence of 1 in every 120,000 live births in Europe.
- cystinuria – responsible for about 1% to 2% of kidney stones in adults.
- cystinosis – happens about once in every 100,000 to 200,000 live births and contributes to 5% of severe kidney diseases in children.
- 2,8 dihydroxy adenine (2,8 DHA) crystalluria – caused by a deficiency in adenine phosphoribosyl transferase (APRT). It is extremely rare with around 400 cases globally, mostly found in France, Iceland, and Japan.
Multiple myeloma, a different type of disease, impacts an estimated 34,920 people in the US and about 588,161 people worldwide each year. It represents 1% of all cancers and 10% of all blood-related cancers. In patients with multiple myeloma, around half will develop kidney disease, with the most common cause of sudden kidney injury in these patients being myeloma cast nephropathy.
Signs and Symptoms of Calcium Deposition and Other Renal Crystal Diseases
When doctors suspect a patient might have kidney crystal disease, there are several key steps involved in their evaluation. This includes a detailed personal and family medical history, a physical examination, looking into their eating habits, reviewing any medications they’re taking, and checking whether they take any nutritional supplements.
People with a condition called primary hyperoxaluria often get recurrent kidney stones. These can lead to belly pain, blood in urine, difficulty passing urine, urinary tract infections and even developmental setbacks in kids.
- Children who have kidney stones or too much calcium in their kidneys, as well as adults who keep getting calcium oxalate kidney stones, should be tested for this condition. This is especially true if they excrete over 75mg of oxalate in their urine per day.
- Patients with primary hyperoxaluria experience repeated calcium oxalate kidney stones and rapidly worsening kidney disease, often leading to end-stage kidney failure.
- These people also often get calcium oxalate deposits in their eyes and skin, and can develop bone problems and blood issues. Extreme cases can lead to organ enlargement, and even heart and skin complications.
- Some patients with primary hyperoxaluria can have vascular deposition of
calcium oxalate. People with a condition called crystaloglobulinemia may have blood protein crystals deposited into their blood vessels, causing skin discolorations, blue discoloration of the skin due to inadequate circulation, the death of skin tissue, even ulcers.
People with other conditions that are grouped under renal crystal disease like secondary hyperoxaluria, 2,8 DHA crystalline nephropathy, PH2 disease, and cystinosis can also have recurring kidney stones, chronic kidney disease, calcium deposits in the kidneys and even require renal transplantation.
However, it’s worth noting that the progression to chronic kidney failure in people with PH3 hasn’t been documented yet.
- Patients with cystinosis, have an accumulation of a chemical called cystine in the kidney tubes, which causes gradual kidney damage and can lead to end-stage kidney failure. There can also be a buildup of cystine in the eyes, thyroid gland, pancreas, reproductive organs, liver, muscles, and even brain leading to a variety of complications.
- People with bone disorders due to abnormal proteins in their blood can experience fatigue, bone ache, anemia, kidney dysfunction, too much calcium in the blood, increased protein levels in their blood, bone destruction and fractures.
- Patients presenting with Fanconi syndrome due to issues linked to abnormal proteins in the blood, cystinosis, Dent disease types 1 and 2, and Lowe syndrome, may also have excess calcium in their kidneys and pass too much calcium in their urine.
Lastly, some patients with kidney tubule dysfunction might experience dehydration, electrolyte imbalances, metabolic acidosis, low levels of phosphate in their blood, and acute kidney injury. Small kids with this condition may show poor growth, softening or weakening of bones and possibly fractures. Patients with a condition called crystaloglobulinemia can experience skin purpura (small, red or purple spots on the skin), painful ulcers on the skin, joint inflammation and destruction, nerve damage, poor blood flow in the extremities, kidney dysfunction and even compromised blood supply to the internal organs.
Testing for Calcium Deposition and Other Renal Crystal Diseases
If your doctor thinks you might have a condition called primary hyperoxaluria, they will need to test your urine for substances such as calcium, phosphorus, magnesium, uric acid, oxalate, citrate, and cystine over a 24-hour period. If you pass any kidney stones during this time, these will also be collected and tested.
Patients with high levels of oxalate in their urine will need further tests to rule out other potential causes. For those with particularly high levels (more than 75mg a day), genetic testing is carried out to confirm the diagnosis of primary hyperoxaluria. In some cases, this condition has been linked with high calcium levels in the blood.
Doctors will also measure oxalate levels in your blood if your kidneys are not working well, especially if your glomerular filtration rate (GFR) – a test that measures how well your kidneys are cleaning your blood – is less than 30 mL/min. This is because the usual measure of oxalate levels in the urine can’t be relied on in this situation. If your kidneys aren’t working at all (known as ESRD), blood oxalate levels are usually more than 80 μmol/L. In patients with high oxalate levels but not primary hyperoxaluria, these levels may range from 30 to 80 μmol/L.
Quick urine tests for substances like glycolate, glycerate, and 4-hydroxy-2-oxoglutarate can also be very helpful, especially for types 2 and 3 primary hyperoxaluria. However, the best way to confirm a diagnosis of all types of primary hyperoxaluria is genetic testing. These tests also help predict how well you might respond to a treatment called pyridoxine if you have type 1 primary hyperoxaluria.
If your GFR drops below 30 mL/min, oxalate levels in your blood can increase and can cause calcium oxalate deposits in other parts of your body, such as your bones, skin, the nervous system in your brain and spine, your retina (back of your eye), and your cardiovascular organs. This condition is known as systemic oxalosis. If you have this, your doctor may ask for an electrocardiogram, echocardiogram, thyroid function tests, and x-rays of your long bones.
If Fanconi syndrome is suspected, your doctor will test your urine microscopically and measure the levels of glucose, amino acids, and uric acid in your urine and blood. Cystinosis can be diagnosed by high cystine levels in your blood cells. Or, the doctor might look for cystine crystals in your eyes with a special lamp or perform genetic testing. Other conditions including Dent disease types 1 and 2, and Lowe’s syndrome can also be confirmed by genetic testing.
If your doctor suspects you have a condition caused by abnormal protein in your blood (paraproteinemia), they will take a full blood count, test your blood for specific proteins and other substances, check your kidney function, and scan your entire skeleton. Depending on the results, your doctor may also request a test to measure the amount of protein in your urine. Depending on the type of protein detected in your urine, you may have a higher likelihood of certain diseases, such as myeloma cast nephropathy, myeloma-induced amyloidosis, light chain deposition disease, and heavy chain deposition disease.
Treatment Options for Calcium Deposition and Other Renal Crystal Diseases
Primary hyperoxaluria type 1 (PH1) is a medical condition that can be treated with different therapies. One of these is hyperhydration, but there are also several medications and therapies that are used to help control the symptoms. Pyridoxine, for example, can be used to lower oxalate levels in some patients.
A patient will typically start off with a small dose of Pyridoxine, and then doctors will measure their urinary oxalate levels to determine if the medicine is working. It’s expected that urinary oxalate levels should reduce by at least 30% after three months of treatment for the treatment to be considered effective. However, if there’s no response, the treatment will usually be stopped. Around 30% of patients with PH1 respond to this treatment.
Lumasiran, which was approved by the FDA in 2020, is another drug used to treat PH1. It works by targeting and reducing the amount of a specific type of chemical called glycolate oxidase, which is involved in the process of producing oxalate. It has been shown to decrease urinary oxalate excretion significantly.
For end-stage kidney disease (CKD stage IV and stage V) patients, aggressive hemodialysis should be done to decrease the systemic oxalate load. Liver transplantation is the only current curative treatment for PH1, and patients who progress to CKD require combined liver and kidney transplantation.
It is also important for patients to maintain sufficient hydration and follow a diet that is low in oxalate, high in calcium, and low in fat. The use of calcium citrate supplements can help decrease the absorption of oxalate in the body. There are also certain probiotics that have been tested, but so far, they have not shown improved outcomes.
On the other hand, treatment for cystinosis includes life-long oral cysteamine therapy. The drug helps to break down cystine into smaller particles, which can then be removed from the body. However, the treatment may not cure the disease and patients may have progressive renal failure even with long-term therapy.
The treatment considers various factors such as the symptoms presented by the patients, their general health and lifestyle, as well as any other underlying health conditions that may affect the progression of the disease. Patient-specific factors and clinical guidelines then guide the choice of treatment for each individual patient.
In conclusion, these treatments aim to manage the symptoms and slow the progression of these conditions, while research is ongoing to discover more efficient treatments.
What else can Calcium Deposition and Other Renal Crystal Diseases be?
When a doctor suspects primary hyperoxaluria, they have to rule out a number of other conditions that can present similarly. Some of these include:
- PH2 and PH3 – different types of primary hyperoxaluria
- Hyperparathyroidism – overactive parathyroid glands
- Nephrocalcinosis – too much calcium deposited in the kidneys
- Various causes of secondary hyperoxaluria
There are also conditions with symptoms that can be confused with diseases like cystinosis, Dent disease, and Lowe’s syndrome. To ensure an accurate diagnosis, other diseases to consider include:
- Fanconi syndrome, either due to known underlying causes or drug-induced
- Disorders such as tyrosinemia, galactosemia, glycogen storage diseases, Wilsons disease, hereditary fructose intolerance
- Mitochondrial disorders that cause kidney malfunction
- Heavy metal poisoning (lead, cadmium) or Sjögren syndrome
- Certain medications, including aminoglycoside antibiotics, sodium valproate, and carbonic anhydrase inhibitors
When it comes to myeloma cast nephropathy, physicians have to rule out:
- Amyloidosis and light chain deposition disease
- Heavy chain deposition disease
- Membranoproliferative glomerulonephritis – a type of kidney disease
- Hypercalcemia-induced acute kidney injury
Finally, with drug-induced crystalline nephropathy, a doctor needs to consider other possibilities like:
- Drug-induced interstitial nephritis – a type of kidney inflammation
- Drug-induced tubular toxicity – damage to the kidney tubules caused by drugs
- Acute tubular necrosis – severe kidney injury due to damage to the kidney tubule cells
What to expect with Calcium Deposition and Other Renal Crystal Diseases
Primary hyperoxaluria is a condition that can cause serious health problems and even death in infants, but the overall death rate has been decreasing recently. However, it can still lead to serious kidney issues like CKD and ESRD, which stand for chronic kidney disease and end-stage renal disease respectively. Unfortunately, it’s common for this condition to be detected late or even missed entirely. In some cases, it’s only identified when the patient’s new kidney (allograft) starts to fail.
Patients who have kidney issues due to swallowing too much calcium oxalate typically recover well. On the other hand, individuals who have high levels of oxalate in the intestines (enteric hyperoxaluria) usually develop advanced kidney disease that progresses over time.
2,8 dihydroxyadeninuria is a condition usually diagnosed late, leading to repeated cases of kidney stones, kidney failure, and ESRD without proper diagnosis and treatment. Sometimes this condition is initially misdiagnosed based on the appearance of its crystals in urine tests or x-ray results. Early and accurate diagnosis and aggressive treatment with a type of medicine called xanthine oxidase inhibitors can help these patients to improve and even avoid progressing to ESRD.
Long-term treatment for cystinosis with a drug called cysteamine has shown marked improvement in growth and other hormonal disorders. Cystinosis can cause a build-up of cystine in the brain, leading to various physical abnormalities, cognitive impairment, and learning difficulties. Treatment with cysteamine also helps to alleviate many neurological symptoms and muscle weakness. Starting treatment early and sticking to the treatment plan are crucial to the best outcome.
Patients with a disease linked to multiple myeloma known as proximal tubular crystalline nephropathy and crystalline histiocytosis usually have a mild form kidney disease and an overall good outlook. These patients tend to have a less aggressive form of multiple myeloma, a type of blood cancer that has seen improved prospects over the years.
However, patients with myeloma cast nephropathy and crystalglobulinemia, other conditions associated with multiple myeloma, usually have worse kidney outcomes and may ultimately need long-term kidney replacement therapy.
Lastly, patients with drug-induced crystalluria, which is a high level of crystals in urine due to medication, usually recover well if the problematic drug is identified and stopped early. However, a delay in diagnosis and treatment of this condition can lead to irreversible kidney dysfunction.
Possible Complications When Diagnosed with Calcium Deposition and Other Renal Crystal Diseases
Patients prone to increased kidney stone formation include those with primary hyperoxaluria, secondary hyperoxaluria, and 2,8 DHA crystalluria. These individuals may suffer from sudden kidney damage, obstruction of urinary flow resulting in severe infection, worsening chronic kidney disease, and even end-stage kidney disease (ESRD).
People with the condition PH1 often experience frequent kidney stones made up of calcium oxalate and they are at increased risk of a fast-paced decline in kidney health which may lead to ESRD. The average onset age for ESRD is 5.5 years, and most people experience kidney failure within their first thirty years of life. Children with this condition can have complications such as slow growth, failure to grow properly, higher risk of fractures, a decrease in all types of blood cells, underactive thyroid, and hardening of the arteries, which can lead to insufficient blood flow and heart complications. Heart and blood vessel complications are more commonly observed in adults.
Diseases such as cystinosis, Dent Disease types 1 and 2, Lowe Syndrome, and paraproteinemia-associated proximal tubular dysfunction can cause the development of Fanconi syndrome. This condition leads to several complications like metabolic acidosis, low phosphate levels, dehydration, sudden kidney damage, and increased kidney stones formation. Children with Fanconi syndrome may develop bone softening and growth retardation.
People with cystinosis can progress to severe kidney failure, ESRD, underactive thyroid, and vacuolar myopathy, which is muscle weakness that can lead to restrictive lung disease and a higher likelihood for aspiration pneumonia. They also risk slowed growth, fractures, light sensitivity, reduced sexual development, blindness, and defective pancreatic function.
Myeloma cast nephropathy, a condition linked to multiple myeloma, can lead to complications such as progressive kidney failure, dangerously high levels of calcium, anemia, spinal compression fractures, spinal cord compression, nerve root compression, peripheral neuropathy, blood clots in the veins, and an increased risk of infection.
Preventing Calcium Deposition and Other Renal Crystal Diseases
Educating patients is really important to get the best possible results from treatments. Following treatments correctly, keeping track of your health, and regular check-ups are key in preventing damage to your kidneys. For many kidney diseases that are known to run in families, genetic counseling can provide useful information. This is a process where experts explain how these diseases can be passed down through family lines.
