Predictive Value of Gradual Change in Renal Function on Vasculopathy Related Complications and Mortality in Patients with Sickle Cell Disease

Introduction:

For a long time sickle cell disease (SCD) was mainly prevalent in children and young adults, but due to improved prevention of (fatal) complication in early life, SCD patients become older. However, with the rising age of these patients more complications are observed including cumulating organ damage, which plays an important role in the limited life expectancy of adult sickle cell patients. In the general population, change in renal function over time is related to cardiovascular mortality and is considered to be a reflection of general microvascular damage. By the use reciprocal serum creatinine values over time the subclinical decline in renal function is linear in time. Given the fact that most forms of organ damage in SCD are related to vasculopathy, the gradual change in renal function in the SCD population may have a predictive value for developing organ damage. In this study, we assessed the relation between the slope in renal deterioration (plotted by linear regression) with organ damage and several laboratory values in a cohort of sickle cell patients in a single tertiary hospital.

Methods:

All SCD patients (HbSS, HbSC and HbSβ-thalassemia) at the out-patient clinicin the period from 2006 until 2016 were included and their gradual change in renal function over this period was determined and the slope of renal deterioration was plotted. Only creatinine values assessed in steady state conditions were included in the analysis. Patients with less than 3 creatinine measurements over this period or missed their regular outpatient appointments in the last three years were excluded. Patients were divided into three tertiles according to the slope of renal decline and the development of organ damage (i.e., microalbuminuria, chronic kidney disease (CKD; eGFR<60 ml/min/1.73m2), retinopathy, avascular necrosis (AVN), CVA and elevated tricuspid regurgitation velocity (TRV)), mortality rate, various laboratory values (i.e., Hb, LDH, reticulocyte count, leukocyte count, HbF, NT-proBNP, creatinine and eGFR) and patient characteristics (i.e., age, gender, genotype groups) were related to these tertiles.

Results:

In total 167 patients were included in the study and divided in tertiles according to the slope of renal function (ie. Tertile 1 representing the fastets detertioration in renal function over time and tertile 3 the slowest decline in renal function). Patients with the more severe genotype (HbSS/HbSβ⁰) were significantly more present in tertile 1 as compared to the other tertiles (83.9%, 55.4% and 52.7%, respectively (p=0.001)) indicating that the decline in renal function was significantly faster in patients with HbSS/HbSβ⁰. The slope of renal function decline was also significantly associated with occurrence of microalbuminuria (59.3% , 32.1% and 15.1% for tertile 1-3, respectively (p<0.001)). Mortality (10.7%, 3.6% and 1.8% , respectively) and CKD (7.1%, 1.8% and 0.0%, respectively) showed the same trend but did not reach statistical significance. Other forms of organ damage, i.e., retinopathy, AVN, CVA and increased TRV were not associated with the slope in renal deterioration. (Table 1) Hemolysis (LDH, Hb, reticulocytes) was significantly more prevalent in tertile 1 as compared to the other tertiles whereas leukocyte count, HbF or NT-proBNP were not related to the decline in renal function.

Conclusion:

This study demonstrates that long-term subclinical renal deterioration determined in a population of patients with SCD is faster in patients with the severe genotype (HbSS/HbSβ⁰) and is associated with microalbuminuria while a trend towards correlation with mortality and renal failure was observed. The slope in renal decline appeared to be related with hemolytic rate while no association with other forms of organ damage or laboratory values was found.

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