What is Sickle Cell Nephropathy?
Sickle cell disease (SCD), originally discovered in West Africa, is a genetic blood disorder predominantly found in people of African, Mediterranean, Indian, and Middle Eastern ancestry. This disorder results from an alteration in the blood’s hemoglobin, caused by a swap in two amino acids in the structure of the hemoglobin. This alteration leads to the formation of an unusual type of hemoglobin called hemoglobin S.
When the body is under stress, low in oxygen, or dehydrated, this different hemoglobin can cause red blood cells to form a sickle shape. Resulting in their premature destruction and leading to blockages within blood vessels. This can result in damage to various organs. Some of the kidney complications related to this condition, collectively known as sickle cell nephropathy, include blood in urine, reduced urine concentration, kidney damage, and even kidney cancer. The kidney complications are more common in individuals with sickle cell disease rather than sickle cell trait or other combined blood disorders, except for kidney cancer, which is reportedly more common among individuals with sickle cell trait.
The progression of SCD is quite unpredictable. People with this disease generally tend to have a shorter lifespan. In the United States and Jamaica, the median survival is reported to be around 45 to 55 years. Here is how the disease generally presents at different ages:
- Infants in their early months do not show any symptoms due to the predominance of a special kind of hemoglobin (HbF).
- During early childhood, several conditions such as finger inflammation, chest disorders, infections, spleen problems, and strokes might occur. Also, an infection known as human parvovirus B19, can destroy red blood cells leading to severe and sudden anemia in children and teenagers with SCD.
- Around the age of 5 and onwards, painful blockages in the blood vessels begin to occur, increasing in frequency with age.
- Adolescents may experience bedwetting, hip joint problems, leg ulcers, delayed puberty and long-lasting, unwelcome erections.
After the age of 25 to 30, the frequency of these painful blockages begins to decrease but is replaced by symptoms of chronic organ damage, such as heart failure, lung disease, liver disease, and kidney disease. Infections are the common causes of death in younger patients, while irreversible organ damage is the primary cause of death in older patients.
What Causes Sickle Cell Nephropathy?
Sickle cell disease (SCD) is caused by a mutation in the hemoglobin, the protein in red blood cells that carries oxygen. This mutation, known as hemoglobin S or HbS, swaps out one protein building block (amino acid) for another in a particular spot on the hemoglobin molecule. This causes the hemoglobin to behave differently and form a different shape.
SCD can occur in two ways. One type, known as sickle cell anemia, occurs when a person has two copies of the HbS mutation. Another type occurs when a person has one copy of the HbS mutation along with another abnormal or missing part of the hemoglobin. For example, this can include when HbS is paired with HbC or HbS beta-thalassemia.
Sickle cell trait is a milder form of the condition where a person has one copy of the HbS mutation and one normal copy of hemoglobin (HbAS).
There are several factors that can make sickle cell nephropathy (SCN), a type of chronic kidney disease associated with SCD, get worse over time. These risk factors include certain genetic variants, infection with a specific virus (parvovirus B19), repeated episodes of a lung condition called acute chest syndrome and episodes of blood vessel blockage, a condition known as heavy protein loss in the urine (nephrotic range proteinuria), high blood pressure, and severe anemia.
Having another genetic condition called alpha-thalassemia or higher levels of fetal hemoglobin can actually protect against SCN.
Risk Factors and Frequency for Sickle Cell Nephropathy
Sickle Cell Disease (SCD) is highly prevalent in West Africa and parts of Asia as having the sickle cell gene can help protect against malaria. The carrier state has expanded globally, making SCD a worldwide health issue, affecting regions like Africa, the Mediterranean, the Middle East, South Asia, the Caribbean, North America, and Northern Europe.
- In the United States alone, SCD affects between 70,000 to 100,000 people.
- It accounts for less than 1% of all new cases of end-stage kidney disease, also known as ESRD.
- In a long-term study conducted over 25 years, 4% of the 725 SCD patients monitored developed chronic kidney disease (CKD), with the average age of onset being 23 years.
- Most of these patients required dialysis within a few years.
- When the study length was extended by another 15 years, the rate of incidence increased to 12% with the median age of onset being 37 years.
Proteinuria, where an excess of protein is found in urine, is common amongst SCD patients, affecting about 30% of them. The sickle cell gene is found in about 8% of African Americans and 25% of adult Nigerians.
Signs and Symptoms of Sickle Cell Nephropathy
People with sickle cell nephropathy, a kidney condition related to sickle cell disease, often have several common symptoms. These include:
- Hyperfiltration, in which the kidneys filter blood at an unusually high rate. This is seen in 51% of patients with HbSS, a severe form of sickle cell disease.
- Self-limiting microhematuria, or small amounts of blood in the urine. This can range from painless and barely noticeable to visible, painful, and requiring transfusions.
- Microalbuminuria and proteinuria, which are conditions where too much protein is lost in the urine. These conditions become more common with age, affecting more than 60% of people with sickle cell disease by the time they turn 45.
- Nephrotic syndrome, a condition that causes your body to excrete too much protein in your urine, is experienced by up to 4% of patients.
- Hyposthenuria, an inability to concentrate urine, is nearly universal in people with sickle cell disease.
- Renal infarction, a condition where part of the kidneys lose blood flow. This can cause symptoms like flank or abdominal pain, nausea, vomiting, and fever.
- Hyperkalemia and mild hyperchloremic metabolic acidosis (type IV renal tubular acidosis), which are imbalances in the blood’s levels of potassium and acid, respectively.
Additional problems that can occur include urinary tract infections, kidney inflammation called pyelonephritis, a type of excessive urination called nephrogenic diabetes insipidus, acute kidney injury, and progressive chronic kidney disease.
Testing for Sickle Cell Nephropathy
If someone is showing signs of Sickle Cell Disease (SCD), which can include symptoms like blood in the urine or high levels of protein in the urine, a doctor will perform various tests. They might first rule out other possible diseases. The tests often include:
- Basic metabolic panel, to measure your body’s metabolism and energy production
- Urine analysis, to check for problems that can appear in your urine
- Renal ultrasound, to have a detailed look at the kidneys
- Intravenous pyelogram, to screen for a specific type of kidney disorder (papillary necrosis)
- CT scan, to help rule out a specific type of kidney cancer, especially when dealing with sickle cell trait patients
- Serum albumin levels, to measure the amount of albumin (a protein) in your blood
- Autoantibodies and complement levels, to test for certain autoimmune diseases
- Tests for HIV, hepatitis B and C virus infection
- Serum electrophoresis, a blood test that separates your proteins
- Renal biopsy when clinically indicated, to gather a small sample of kidney tissue to better understand any possible kidney disease
- Review of the current and previous medication history, to check for possible side effects or interactions
If patients have a specific level of kidney function as measured by the estimated Glomerular Filtration Rate (eGFR) of less than 60 ml/mt/1.73mt2 or a rapid decline in this rate, or if protein in the urine persists, they need to be referred to a kidney specialist. Particularly, SCD patients with a urinary protein to creatinine ratio (UPCR) greater than 300 mg/gm should be evaluated for other possible causes of Chronic Kidney Disease (CKD).
Treatment Options for Sickle Cell Nephropathy
Rest, oral hydration (drinking fluids), is still the primary steps in managing gross hematuria (blood in urine).
In severe cases, treatments might include making the urine more alkaline (less acidic), using loop diuretics (medications that increase urine output), and blood transfusions.
A drug called hydroxyurea has been shown to be successful in managing SCD (a genetic disorder affecting red blood cells). It works by increasing the levels of healthy hemoglobin (HbF) to dilute the amount of unhealthy hemoglobin (HbS), thus reducing the risk of blood cells sticking together. Although there is no randomized adult trial, the drug has proven to be effective in observational studies in children and adolescents. It is particularly beneficial for patients showing early symptoms of kidney disease.
There is an ongoing debate about the use of renin-angiotensin system (RAS) blockage in SCN (a disorder causing protein leakage in urine). Some experts believe it’s beneficial when the urine protein-creatinine ratio (UPCR) is higher than 300 mg/gm based on its effectiveness in other kidney diseases. But patients need to be careful if they have normal or low blood pressure and need to stop the medication during acute illness. A good goal for blood pressure in these patients is under 130/80 mm Hg.
For proteinuria (excess proteins in urine), patients with high blood pressure should aim for a blood pressure less than 130/80 mm Hg. In children under nine with SCN, transfusions can be helpful, but they may lead to iron overload which is a challenge to manage.
Erythropoiesis-stimulating agents (ESAs) can be handy with hydroxyurea. ESAs should be started when a patient’s hemoglobin (the protein that carries oxygen in the blood) drops 10-15% below the normal range. However, the target for hemoglobin should be lower in SCD patients due to the risk of vaso-occlusive episodes (blockages of blood vessels). The ideal hemoglobin level for SCN patients should be no more than 10 to 10.5 g/dL. They should also avoid increasing their hemoglobin level by more than 1-2% per week to avoid the risk of a vaso-occlusive crisis (painful blockages of blood vessels). Sometimes, they might need intermittent intravenous iron supplementation due to long-term minor gastrointestinal bleeding.
For patients with intense bleeding due to papillary necrosis (destruction of kidney tissue), medications like aminocaproic acid or desmopressin acetate can be used. These medicines can help improve blood clotting.
High doses of urea can be used for persistent cases. Urea can prevent the bonding of sickle hemoglobin (the defective form of hemoglobin in SCD patients). Hemopoietic stem cell transplantation (HSCT), a potentially curative procedure, is mainly used in children resistant to hydroxyurea and suffering from severe complications. For SCN patients needing kidney replacement therapy, kidney transplantation has been shown to offer the best survival outcomes.
What else can Sickle Cell Nephropathy be?
- Lupus affecting the kidneys (Lupus nephritis)
- Different types of inflammation of small blood vessels in the kidneys (Glomerulonephritis)
- Bone marrow cancer (Multiple myeloma)
- Kidney cancer (Renal cell carcinoma)
- Kidney stones (Nephrolithiasis)
- Kidney disease caused by viral infections (Viral nephropathy)
What to expect with Sickle Cell Nephropathy
In the United States, less than 1% of people suffering from End-Stage Renal Disease (ESRD) have Sickle Cell Nephropathy (SCN), a type of kidney disease. These patients have a higher mortality rate than those with other causes of ESRD. On average, patients with this condition tend to live about 29 years, compared to 51 years for those without kidney failure.
A US study found that the average age of patients with SCN who reach a stage requiring dialysis is around 23 years. On average, these patients tend to die roughly 4 years after they start dialysis. Also, it was found that those with SCN are more likely to die while undergoing hemodialysis and less likely to have a kidney transplant.
A French study, on the other hand, looked at patients with ESRD who were undergoing dialysis due to SCN and compared their mortality rates to patients with ESRD caused by other conditions. They found that over a five year period, 46.3% of those with SCN died compared to just 6.4% of patients with other causes. Furthermore, SCN patients were much less likely to receive a kidney transplant, with only 26% receiving one compared to 53.5% of other patients. While recurrence of SCN has been reported in the past, recent literature suggests that SCN patients who receive transplants have better outcomes than those with diabetic kidney disease.
