What is sickle cell nephropathy (SCN)?

What is sickle cell nephropathy (SCN)?

In this article, we will describe what is sickle cell nephropathy (SCN).

Sickle cell nephropathy (SCN) is a group of renal complications of sickle cell disease (SCD) that include: haematuria, proteinuria, renal papillary necrosis, renal tubular disorders, acute kidney injury (AKI), chronic kidney disease (CKD), sickle cell glomerulopathy, and renal medullary carcinoma.

“SCN can affect the whole of the nephron from the glomerulus to the papillary tip”

1. Prevalence

SCN is a common complication in individuals with SCD, with up to 50% of patients developing some form of kidney involvement during their lifetime.

2. Pathophysiology

SCN results from sickling of red blood cells in the renal microcirculation, leading to vaso-occlusion, ischaemia, and subsequent damage to renal tissue.

The hypertonic and relatively hypoxic environment in the renal medulla, along with slow blood flow, causes sickling of red blood cells. This leads to local infarction (papillary necrosis) and functional tubule defects.

Chronic hypoxia and haemolysis also play a role.

Note. Genetic factors: co-inheritance of microdeletions in the β-globin gene (thalassemia) appears to protect against nephropathy. These individuals have lower mean arterial pressure and less proteinuria.

3. Early signs

The earliest signs of SCN often include microalbuminuria or proteinuria, indicating early kidney damage.

4. Later signs

Haematuria. Macroscopic haematuria (visible blood in urine) can occur, typically resulting from papillary necrosis, or infarction of the renal medulla.

Proteinuria. By age 40 years, 80% of people with SCD have a raised uACR, and 40% have overt proteinuria (5% develop nephrotic syndrome, which carries a poor prognosis).

Chronic kidney disease (CKD). CKD occurs and can progress to ESRF in 10% of cases.

Note. Hypertension is common in patients with SCN and can exacerbate kidney damage. Blood pressure control is crucial in managing SCN.

5. Pathology

No specific pathognomonic lesion defines SCN, but glomerular hypertrophy, leading to hyperfiltration, is universal – and is seen in children as young as 1 to 3 years of age.

Glomerular damage. In SCN, progressive damage to the glomeruli can occur. FSGS is the most common lesion in SCN and is associated with proteinuria. Collapsing pattern and ‘normal’ patterns of FSGS can be observed. Other renal biopsy lesions that have been reported in SCD, including thrombotic microangiopathy (TMA) and mesangiocapillary glomerulonephritis – though neither are limited to SCN.

6. Tubular dysfunction

Individuals with SCN may also have tubular dysfunction, leading to impaired ability to concentrate urine; resulting in polyuria, nocturia and volume depletion (and enuresis in children).

In fact hyposthenuria (an abnormally low urinary specific gravity) is almost universal in SCN. Urine osmolality usually does not exceed 450 mosm/Kg.

Hyperkalaemia and mild hyperchloraemic metabolic acidosis (type IV renal tubular acidosis) also occur.

7. Investigation

Diagnosis of SCN involves :

• Blood tests – FBC, U+E, including creatinine and eGFR
• Urine tests for proteinuria (uACR) and haematuria (MSU)
• Imaging studies such as ultrasound, CT or MRI.

Note 1. Diagnosis of SCN is primarily based on clinical manifestations and is essentially a diagnosis of exclusion (i.e of other renal diseases)
Note 2. If in doubt (i.e. other diagnoses are being considered), a renal biopsy is indicated.

8. Complications

Renal papillary necrosis. Renal papillae are especially susceptible to damage, eventually causing papillary necrosis due to insufficient blood supply from the vasa recta. This can present as macrohaematuria, abdominal/loin pain and/or renal (‘clot’) colic.

80% of bleeds come from the left kidney. This anomaly is thought to be due to increased venous pressure within the longer left vein (that is compressed between the aorta and the superior mesenteric artery). This is known as the ‘nutcracker phenomenon’.

Other complications. These include:

• Renal medullary carcinoma. This typically presents in young patients (20 to 30 years old) as an aggressive metastatic disease at the time of diagnosis. Median survival is 3 months following diagnosis. Affected individuals may present with haematuria, flank pain, and/or abdominal mass
• Rhabdomyolysis
• Renal vein thrombosis
• Renal infarction – presenting with flank or abdominal pain, nausea, vomiting, and fever
• Urinary tract infections (UTIs) and pyelonephritis
• Nephrogenic diabetes insipidus.

9. Treatment and management

Management of SCN includes controlling sickle cell disease with hydroxyurea or chronic transfusion therapy, managing blood pressure, using ACE inhibitors or ARBs for proteinuria, and monitoring kidney function regularly. In advanced cases, renal replacement therapy (RRT; dialysis or transplantation) may be necessary.

Higher doses of ESAs are usually required, with a lower target Hb of 80-100 g/L.

Transplantation is possible though less successful than normal, with reduced graft (kidney) and patient survival.

10. End-Stage Renal Failure (ESRF)

Sickle cell nephropathy can progress to end-stage renal failure (ESRF). Median survival for patients with ERSF is 4 years. Proteinuria/nephrotic syndrome and ESRF is rare in sickle cell trait (SCT).

Summary

We have described what is sickle cell nephropathy (SCN). We hope it has been helpful.

Other resources

10 sickle cell disease (SCD) facts
Review article: Aeddula, 2023

Last Reviewed on 28 June 2024