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Managing chronic complications of sickle cell disease: renal complications

Chronic kidney disease ( CKD ) is defined as either having a glomerular filtration rate ( GFR ) of less than 60 mL/min/1.73 mL for more than 3 months with or without kidney damage or having evidence of kidney damage for more than 3 months, with or without decreased GFR.

Evidence of kidney damage includes pathologic abnormalities or markers of kidney damage ( i.e., proteinuria ) independent of cause.
Kidney disease severity is classified into five stages according to the level of GFR: Stage 1: kidney damage with normal or increased GFR ( greater than or equal to 90 mL/min/1.73 m2 ); Stage 2: kidney damage with mildly decreased GFR ( 60–89 mL/min/1.73 m2 ); Stage 3: moderately decreased GFR ( 30–59 mL/min/1.73 m2 ); Stage 4: severely decreased GFR ( 15–29 mL/min/1.73 m2 ); Stage 5: kidney failure ( ESRD ); GFR less than 15 mL/min/1.73 m2 or on dialysis ( source: Levey AS et al, Kidney Int 2005;67:2089–2100 ).

An estimated 23 million Americans have chronic kidney disease including 4–18% of people with sickle cell disease ( SCD ).

In one study, renal failure was seen in 4.2% of people with sickle-cell anaemia ( SCA ). In this study, 68% of people had proteinuria ( defined as any abnormal urinary protein ), 40% had nephrotic syndrome, and 33% had hypertension ( HTN ) prior to developing renal failure.

In another study, Falk et al. evaluated all people with sickle cell disease, including both children and adults, followed at the University of North Carolina and Duke University; 26% had proteinuria on urine dipstick.

Finally, in a study of 300 adults with sickle cell disease, the prevalence of any albuminuria in people with sickle-cell anaemia was 68%, and the prevalence in other genotypes was 32%.

Identification of early renal disease in people with sickle cell disease is important, as these individuals hypersecrete creatinine through the proximal tubules, thus masking significant renal impairment before the serum creatinine rises.

Microalbuminuria is defined as urinary albumin excretion greater than 30 mg albumin per gram urine creatinine in two of three spot urine specimens or 30–299 mg albumin in 24-hour urine collection.

Macroalbuminuria ( proteinuria ) is defined as urinary albumin excretion of 300–3,500 mg albumin in 24-hour urine collection.

Microalbuminuria is most often the first manifestation of chronic kidney disease in sickle cell disease. One study showed a prevalence of 16% in affected children, and another study showed a prevalence of 32.9% in adults with sickle cell disease.

Spot urine protein/creatinine ratio has not been validated in sickle cell disease because creatinine is hyperexcreted.

The most common renal complication in people with sickle cell disease is hyposthenuria, or the inability to concentrate the urine, which is progressive with age. This is due to the loss of deep juxtamedullary nephrons.
Frequent urination is common in people with SCD and is usually due to hyposthenuria.
Because of their hyposthenuria, individuals with SCD are also at higher risk for intravascular volume depletion, as they cannot respond to decreased oral fluid intake by concentrating their urine.
In addition, hyposthenuria also causes enuresis, which is prevalent among individuals with sickle-cell anaemia, with up to 42% of children ages 6 to 8 and 9% of adults ages 18 to 20 experiencing this complication.

Renal papillary necrosis, which often causes hematuria, is thought to be due to medullary infarction from obstruction of the vessels supplying the vasa recta. The prevalence of renal papillary necrosis was found to be as high as 23% in asymptomatic people with SCA undergoing urography.

Proteinuria due to glomerular injury is also common, but both microalbuminuria and macroalbuminuria are typically asymptomatic. Other early manifestations that should lead providers to investigate people for renal disease include HTN and gout. <
Joint pain due to gout can often be mistaken for vaso-occlusive episode pain.
Diagnosis and management of gout in individuals with sickle cell disease is the same as in other populations.

There have not been any studies looking at the utility of renal biopsy in individuals with sickle cell disease. One study that examined 18 renal biopsy specimens found four histopathologic variants: focal segmental glomerulosclerosis ( FSGS ) ( 39% ), membranoproliferative glomerulonephritis ( 28% ), thrombotic microantigopathy glomerulopathy ( 17% ), and specific sickle cell disease glomerulopathy ( 17% ).
The authors of this study note that the long-term outcomes were not different according to the histologic lesions that were identified, with 50% of cases having chronic renal failure after a mean follow-up of 28 months.
The decision to perform renal biopsy should be individualized for each patient. ( Xagena )

NIH - Evidence-Based Management of Sickle Cell Disease - Expert Panel Report, 2014