Sickle Cell Nephropathy

A 15-year-old adolescent boy with sickle cell disease (hemoglobin SS) is referred to the nephrology clinic for elevated creatinine levels over the past few months. Over the past year, he has had multiple hospitalizations for pain crises. He has not needed any blood transfusions and has not had recent illnesses or gross hematuria. However, he has had microscopic blood in his urine for 1 year. His review of systems is negative. His only current medication is penicillin; he was prescribed additional medications that he does not take. His vitals are normal, with a blood pressure of 115/75 mm Hg. 

Laboratory data are shown, including results from his first morning urinalysis:

Laboratory Test

Result

Serum sodium

141 mEq/L (141 mmol/L)

Serum potassium

3.6 mEq/L (3.6 mmol/L)

Serum chloride

102 mEq/L (102 mmol/L)

Serum bicarbonate

20 mEq/L (20 mmol/L) 

Serum urea nitrogen

19 mg/dL (6.8 mmol/L)

Serum creatinine

1.2 mg/dL (106 μmol/L)

White blood cell count

5,000/µL (5 × 109/L)

Hemoglobin

7.4 g/dL (74 g/L)

Platelet count

300 × 103/µL (300 × 109/L)

Urine microalbumin

15 µg/mg creatinine

Urinalysis

Specific gravity

1.005

Blood

2+

Protein

Trace

f the following, the BEST medication to help slow the progression of his kidney disease is

A.

deferasirox

B.

folic acid

C.

hydroxyurea

D. lisinopril

Hydroxyurea is a strongly recommended medication for many patients with sickle cell disease. The reported renal benefits of hydroxyurea include improvement in glomerular filtration rate (GFR), less hyperfiltration, and lower rates of proteinuria. Of note, the medication can interfere with serum creatinine levels if measured by a point-of-care handheld blood analyzer device. The mechanism of hydroxyurea is not fully understood. The primary cellular target is ribonucleotide reductase enzyme, which is used in DNA synthesis and repair. By blocking the function of the enzyme, the drug causes arrest of the cell cycle and can lead to cell death. Other effects of hydroxyurea include increasing hemoglobin F production and nitric oxide, and reducing the proportion of reticulocytes and the number of white blood cells, leading to reduced vaso-occlusion. According to the National Heart, Lung, and Blood Institute guidelines, hydroxyurea is recommended for all infants older than 9 months, children, and adolescents. It should also be considered in infants younger than 9 months or adults with symptomatic disease. Hydroxyurea can help with many of the complications in sickle cell disease, including reducing the episodes of vaso-occlusive crises and kidney disease. In the long term, there can be improved survival and quality of life. The main adverse effect of hydroxyurea is myelosuppression. Clinically, patients may experience gastrointestinal toxicity.

The main site of injury in sickle cell nephropathy is the renal medulla, which receives blood supply from the vasa recta capillaries. Due to the relatively hypoxic conditions, these capillaries contribute to a favorable environment for sickling. As a result of the vascular effects, patients develop renal medullary ischemia and infarction. When sickling affects the concentration mechanisms in the medulla, there is impairment of the urinary concentrating ability. Often as infants, patients are found to have iso- or hyposthenuria, leading to polyuria and enuresis. As patients age, the renal involvement also progresses. In early childhood, there may be increased glomerular pressure and glomerular hyperfiltration. They can also develop a distal renal tubular acidosis with hyperkalemia. Acute kidney injury can occur and be multifactorial. These patients are often at increased risk due to hypovolemia, nephrotoxic medications, urinary obstruction, and complications from iron overload. Older children are more likely to start developing microalbuminuria and hematuria. In later adulthood, patients can develop worsening renal disease with a small percentage progressing to end-stage renal disease. 

Sickle cell nephropathy is a term used to describe the wide range of renal pathology seen in patients with sickle cell disease and is associated with an increased risk of morbidity and mortality. Hematuria remains one of the most common renal findings in sickle cell disease. Microscopic hematuria occurs in approximately 30% of patients. Gross hematuria raises concern for more serious complications. Infarction along with papillary necrosis can be common in patients with sickle cell disease and is often associated with additional risk factors, including infection, obstructive uropathy, diabetes mellitus, and analgesic use. For diagnosis of papillary necrosis, a definitive diagnosis often requires a computed tomography scan but is not always necessary. Management depends on the degree of hematuria.

Proteinuria, which often develops later in life, can be related to tubular dysfunction, focal and segmental glomerulosclerosis, and membranoproliferative glomerulonephritis. According to Kidney Disease Improving Global Outcomes (KDIGO), 16% to 27% of children with sickle cell nephropathy have chronic kidney disease. The Table includes a complete list of clinical manifestations in sickle cell nephropathy.

Folic acid is also a common medication used in sickle cell disease but would not help with his sickle cell nephropathy. Deferasirox is indicated in sickle cell disease to treat iron overload related to transfusions. This drug has a large number of adverse effects, including rash, gastrointestinal toxicity, proteinuria, and increased creatinine levels. However, in the vignette, the patient did not have a history of any recent transfusions, so this drug would unlikely be indicated. Finally, renin-angiotensin-aldosterone inhibition is recommended in patients with sickle cell disease with persistent proteinuria. The most common adverse effects are increased creatinine levels, hypotension, dizziness, cough, and hyperkalemia. In the vignette, the patient has normal blood pressure and no microalbuminuria (despite trace protein on urine strip testing), suggesting that lisinopril is not indicated.

PREP Pearls

• Hematuria is the most common renal finding in sickle cell disease, and gross hematuria is concerning for more serious complications.

• The main site of injury in sickle cell nephropathy is the renal medulla.

• Hydroxyurea can be beneficial in patients with sickle cell disease and sickle cell nephropathy, and it can improve survival and quality of life.