Renal Complications

Background
Chronic kidney disease (CKD) is defined as either having a glomerular filtration rate (GFR) of
<60 mL/min/1.73 mL for 2:3 months with or without kidney damage or having evidence of kidney damage for 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.

An estimated 23 million Americans have CKD including 4-18 percent of people with SCD. In one study, renal failure was seen in 4.2 percent of people with SCA. In this study, 68 percent of people had proteinuria (defined as any abnormal urinary protein), 40 percent had nephrotic syndrome, and 33 percent had hypertension (HTN) prior to developing renal failure.346 In another study, Falk et al.347 evaluated all people with SCD, including both children and adults, followed at the University of North Carolina and Duke University; 26 percent had proteinuria on urine dipstick. Finally, in a study of 300 adults with SCD, the prevalence of any albuminuria in people with SCA was 68 percent, and the prevalence in other genotypes was 32 percent. Identification of early renal disease in people with SCD 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 ofCKD in SCD. One study showed a prevalence of 16 percent in affected children, and another study showed a prevalence of 32.9 percent in adults with SCD. Spot urine protein/creatinine ratio has not been validated in SCD because creatinine is hypersecreted. The most common renal complication in people with SCD 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 SCA, with up to 42 percent of children ages 6 to 8 and 9 percent 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 percent 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 SCD is the same as in other populations. There have not been any studies looking at the utility of renal biopsy in individuals with SCD. One study that examined 18 renal biopsy specimens found four histopathologic variants: focal segmental glomerulosclerosis (FSGS) (39 percent), membranoproliferative glomerulonephritis (28 percent), thrombotic microangiopathy glomerulopathy(17 percent), and specific sickle cell disease glomerulopathy(17 percent).

The authors of this study note that the long-term outcomes were not different according to the histologic lesions that were identified, with 50 percent of cases having chronic renal failure after a mean followup of 28 months. The decision to perform renal biopsy should be individualized for each patient. Key Question Summary of the Evidence One RCT, 5 observational studies, and 10 case reports examined the management of several acute and chronic renal complications of SCD. Although numerous SCD-related renal abnormalities have been described in the literature (e.g., hyposthenuria, hematuria, impaired urinary potassium excretion and acidification, tubular and glomerular dysfunction, infection, medullary carcinoma, and acute necrosis and renal failure), most were without effective therapeutic approaches or clear prognosis.

The overall quality of the evidence was low. A double-blind, placebo-controlled randomized trial of 22 normotensive adults with SCA and persistent microalbuminuria found that captopril (25 mg/day) for 6 months significantly reduced albuminuria. One observational study included more than 300 individuals with SCD and evaluated them for renal dysfunction.347 Ten people were found to have proteinuria (urinary protein, :::0.5 g per day) and serum creatinine concentrations of <2.0 mg/dL. They underwent treatment with enalapril for 2 weeks and had a decrease in proteinuria with a mean decrement of 57 percent below baseline. An observational study of 191 patients with SS with a mean followup of 2.19 years demonstrated that microalbumin excretion normalized in 44 percent of patients treated with hydroxyurea and 56 percent of patients treated with ACEI. One observational study looked at the prevalence of microalbuminuria in children and found it in 19 of 120 children with SCD.

Two observational studies enrolled 91 people and evaluated the role of renal transplant in end-stage renal disease. The larger study was a retrospective study comparing patient and renal allograft outcomes for individuals with SCD (n=82) compared to those without SCD (n=22, 565) who were transplanted and compared to those with SCD who did not undergo transplant.170 The study reported incidence rates of 26 percent and 24 percent for delayed predischarge and acute graft rejection, respectively. There was a trend towards improved survival in the transplant group compared to waitlisted individuals. The second smaller study reported a survival rate of 89 percent in the recipient of the graft, but the study did not have a comparison arm.

Recommendations

If microalbuminuria is identified, order a 24-hour urine test for protein. (Consensus-Pane/Expertise)

Refer people with proteinuria (>300 mg/24 hours) to a neurologist for further evaluation.
(Strong Recommendation, Low-Quality Evidence)

For adults with microalbuminuria without other apparent cause, initiate ACE inhibitor therapy.
(Moderate Recommendation, Moderate-Quality Evidence)

For adults with proteinuria without other apparent cause,initiate ACE inhibitor therapy.
(Moderate Recommendation, Low-Quality Evidence)

For children with microalbuminuria or proteinuria, consult a nephrologist. (Consensus-Panel Expertise)

Consider patients with SCD with modest elevations of serum creatinine (>0.7 mg/dl in children, >1.0mg/dl in adults) to have renal impairment and refer to nephrologist for further evaluation.
(Consensus-Panel Expertise)

Give ACE inhibitor therapy for renal complications when indicated even in the presence of normal blood pressure.

(Moderate Recommendation, Low-Quality Evidence)

Renal replacement therapy (e.g. hemodialysis,peritoneal dialysis, and renal transplantation) should be used in people with SCD if needed.
(Strong Recommendation, Low-Quality Evidence)

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