M. Cazenave, V. Audard and J.P. Bertocchio, and P Bartolucci and M. Courbebaisse equally contributed to this work

Introduction: Metabolic acidosis is encountered in 42% of patients with sickle cell disease (SCD) (Maurel S, Clin J Am Soc Nephrol, 2014) but the pathophysiological processes remain largely unknown.

Patients and methods: We conducted a monocentric observational study including SCD patients, at steady state (>1 month of a vaso occlusive crisis and >3 months of a transfusion), with and without overt metabolic acidosis [HCO3-]<22 mmol/l and glomerular filtration rate estimated by CKD-EPI (eGFR)>60 ml/min/1.73 m2 The urinary acidification test was achieved by oral administration of furosemide and fludrocortisone, increasing distal tubular Na+ delivery, Na+ reabsorption via principal cells and H+ secretion via α-intercalated cells (Walsh SB, Kidney Int, 2007). An abnormal test was identified by a failure to lower urinary pH <5.3 and/or to increase urinary NH4+ excretion rate ≥33 µEq/min at least once within 6 hours.

Results: We evaluated 13 SCD patients with metabolic acidosis (4 males, 40.0 years [33.0-44.0], eGFR=114.0 ml/min/1,73m2 [95.0-126.0]) and 12 SCD patients without overt metabolic acidosis (4 males, 29.5 years [24,0.0-37.3], eGFR=128.5 ml/min/1,73m2 [124.8-140.0]).

During the test, among overt metabolic acidosis patients, urinary pH remained ≥5.3 in 7 patients and urinary NH4+ excretion remained <33 µEq/min in 9 patients. Only one patient had a normal test. In the control group, all of patients except one had a normal test. Maximum urinary NH4+ excretion was positively associated with fasting urine osmolality (r2 = 0.34, p=0.002).

Regarding hemolysis parameters, patients with overt metabolic acidosis had lower hemoglobin (7.7 [6.8-8.7] vs 9.2 [8.9-9.4] g/dl, p=0.02), higher lactate dehydrogenase (492 [455-636] vs 327 [256-458] IU/l, p=0.01) and a higher average red blood cell density (1.097 [1.096-1.097] vs 1.092 [1.091-1.094], p<0.01).

Discussion: Our study shows that SCD patients with overt metabolic acidosis have a defect in renal acidification process. The positive association between NH4+ excretion and fasting urine osmolality suggests that this metabolic acidosis is likely due to an impaired NH4+availability, probably secondary to the medullary ischemia seen in some SCD patients. This is supported by the fact that SCD patients with metabolic acidosis have a haematological phenotype of hyperhemolysis. Contrary to previous reports (Goossens JP, Clin Chim Act, 1972; Oster JR, Arch Intern Med, 1976), our results highlight that SCD patients with plasma bicarbonate within the normal range are not likely to exert incomplete tubular metabolic acidosis. Conclusion: In SCD patients, metabolic acidosis is related to a renal acidification defect, itself linked to the severity of hemolysis.


Bartolucci:Addmedica: Research Funding; Novartis US: Membership on an entity's Board of Directors or advisory committees; GBT: Membership on an entity's Board of Directors or advisory committees; Fondation Fabre: Research Funding.

Author notes


Asterisk with author names denotes non-ASH members.

Sign in via your Institution