QUIZ PAGE MAY 2014 Acute Kidney Injury With Red Urine CLINICAL PRESENTATION
Am J Kidney Dis. 2014;63(5):xxi-xxiv
Figure 1.
Peripheral blood smear.
- What is the evaluation of red urine? - How does the blood smear help differen-
tiate between various causes of hemolytic anemia and acute kidney injury? - What could be the mechanism by which
this patient developed pulmonary emboli? - How should this patient be treated?
xxi
QUIZ PAGE
A 56-year-old woman of Iranian descent with rheumatoid arthritis and hypertension presented with 1 day of malaise, nausea, vomiting, dyspnea, and red urine. She was otherwise comfortable and denied flank pain. Her medications included methotrexate, folic acid, celecoxib, atenolol, and hydrochlorothiazide. On examination, the patient was not acutely ill and was alert and responsive. Blood pressure was 155/90 mm Hg, heart rate was 90 beats/min, and oxygen saturation was 92% while breathing room air. She had dry mucous membranes. Breath sounds were normal. The abdomen was tender on deep palpation. During her stay in the emergency department, the patient developed a fever (temperature, 38.5 C) and oxygen saturation decreased further. Laboratory results showed a serum creatinine level of 1.8 mg/dL corresponding to an estimated glomerular filtration rate of 29 mL/min/1.73 m2 using the 4-variable MDRD (Modification of Diet in Renal Disease) Study equation. The patient’s serum creatinine level measured 3 months earlier was 0.75 mg/dL (estimated glomerular filtration rate, 81 mL/min/1.73 m2). Further laboratory testing showed the following values: hemoglobin, 8.06 g/dL; hematocrit, 24%; total bilirubin, 6.84 mg/dL; direct bilirubin, ,0.06 mg/dL; lactate dehydrogenase, 2,390 IU/L; undetectable haptoglobin, and negative results for a Coombs test. Platelet count was 221 3 109/L and D-dimer level was 39,714 ng/mL. Creatine kinase (CK) level was normal at 155 U/L. Arterial blood analysis showed pH of 7.47, PCO2 of 35 mm Hg, and PO2 of 57 mm Hg. Peripheral-blood smear showed blister cells and irregularly contracted cells (Fig 1). Urinalysis showed heme (31) and protein (31), with sediment evaluation showing more than 100 erythrocytes per high-power field with no dysmorphic cells or acanthocytes, 5 leukocytes, 2-3 detached tubular cells, and occasional granular casts without cellular or pigmented casts. Kidney ultrasonography produced unremarkable results. Computed tomography with iodinated contrast showed extensive pulmonary embolism.
QUIZ PAGE MAY 2014
ANSWERS
DISCUSSION
QUIZ PAGE
- What is the evaluation of
red urine? The first step in evaluating red urine should be a urine dipstick test (Fig 2). Heme-negative red urine is caused by foods or medication. Heme-positive red urine is caused by red blood cells (hematuria), myoglobin, or free hemoglobin. In heme-positive urine, the second step should be to centrifuge the urine, thereby differentiating hematuria from myoglobinuria and hemoglobinuria. In hematuria, erythrocytes remain in the sediment and the supernatant appears straw-colored. Red supernatant suggests hemoglobinuria or myoglobinuria. Although centrifugation of plasma can further differentiate hemoglobinuria (red supernatant) from myoglobinuria (clear supernatant), blood laboratory results usually point to either one or the other. A low haptoglobin level is typical for hemolysis, while an elevated CK level often is seen in rhabdomyolysis. In our patient, urine dipstick was positive for heme and the supernatant was red after centrifuging, indicating hemoglobinuria or myoglobinuria. Taken together with the blood test results showing a normal CK level and signs of hemolysis with a low haptoglobin level, this suggests that hemoglobinuria caused the red urine. However, microscopic examination of the urine also revealed erythrocytes, indicating a combination of hemoglobinuria and hematuria. xxii
- How does the blood
smear help differentiate between various causes of hemolytic anemia and acute kidney injury? The combination of Coombsnegative hemolysis and acute kidney injury (AKI) can have various causes, including thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome, erythrocyte enzyme deficiencies
such as glucose-6-phosphate dehydrogenase (G6PD) deficiency, hemoglobinopathies, and paroxysmal nocturnal hemoglobinuria. Recognizing TTP quickly is essential for reducing mortality and morbidity. In TTP and hemolytic uremic syndrome, schistocytes and thrombocytopenia are seen in the blood smear. However, our patient’s blood smear showed blister cells (Fig 1,
a Figure 2. Algorithm for the evaluation of red urine. Hemoglobinuria is accompanied by a red supernatant, whereas myoglobinuria is accompanied by a clear supernatant. b Blood results usually are indicative of either hemolysis with decreased haptoglobin or rhabdomyolysis with elevated creatine kinase levels.
Am J Kidney Dis. 2014;63(5):xxi-xxiv
arrow) and irregularly contracted cells, which indicate oxidative stress, as seen in G6PD deficiency.1 G6PD is the first enzyme of a metabolic pathway that produces NADPH (the reduced form of NADP [nicotinamide adenine dinucleotide phosphate]), which itself is essential for the function of enzymes counterbalancing oxidative stress. In erythrocytes, this G6PD-dependent pathway is the only source of NADPH. Therefore, patients with G6PD deficiency are at risk for hemolytic anemia in circumstances of oxidative stress. Upon inquiry, our patient revealed that she had eaten fava beans 1 day before her symptoms started. Fava beans contain strong oxidants. Therefore, patients with G6PD deficiency are at risk for developing severe acute hemolysis after eating fava beans, a condition called favism. Our patient’s G6PD enzyme level proved to be undetectable (,0.1 U/g of hemoglobin), confirming the diagnosis of favism. - What could be the
Am J Kidney Dis. 2014;63(5):xxi-xxiv
- How should this patient
be treated? Avoiding oxidative stressors (eg, fava beans, infections, and oxidative drugs and chemicals) is important to prevent hemolysis in a patient with G6PD deficiency. See Box 1 for a list of oxidative agents. Most episodes of G6PD-related hemolytic anemia are mild. However, especially in favism, hemolysis can be severe and complicated by AKI. Conservative treatment of AKI with fluid administration may attenuate kidney damage4; nevertheless, hemodialysis may be necessary. Complete recovery of kidney function seems to be the rule.5 In our patient, the nephrotoxic effects of free hemoglobin and Box 1. Oxidative Drugs and Chemicals to be Avoided by Persons With G6PD Deficiency Acetanalida Diaminodiphenyl sulfone Furazolidone Glibenclamide Henna Isobutylnitrite (poppers) Methylene blue Naphtalene (in naphtalene balls) Niridazolea Nitrofurantoine Phenazopyridine Phenylhydrazinea Primaquine Sulfacetamide Sulfanilamide Sulfapyridinea Thiazolesulfone Trinitrotoluene Urate oxidase/rasburicase a
No longer in clinical use in most countries. Reproduced in modified form from Beutler6 with permission of American Society of Hematology; permission conveyed through Copyright Clearance Center, Inc.
bilirubin were compounded by hypovolemia, celecoxib treatment, and iodinated contrast. Because of progressive kidney failure complicated by fluid overload, hemodialysis therapy was initiated. After 3 sessions, kidney function improved gradually and recovered completely after 3 months.
FINAL DIAGNOSIS Favism complicated by AKI and pulmonary embolism.
REFERENCES 1. Bain BJ. Diagnosis from the blood smear. N Engl J Med. 2005;353(5):498-507. 2. Rother RP, Bell L, Hillmen P, Gladwin MT. The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: a novel mechanism of human disease. JAMA. 2005;293(13):1653-1662. 3. Villagra J, Shiva S, Hunter LA, Machado RF, Gladwin MT, Kato GJ. Platelet activation in patients with sickle disease, hemolysisassociated pulmonary hypertension, and nitric oxide scavenging by cellfree hemoglobin. Blood. 2007;110(6): 2166-2172. 4. Garcia-Camin RM, Goma M, Osuna RG, et al. Molecular mediators of favism-induced acute kidney injury. Clin Nephrol. 2014;81(3): 203-209. 5. Fauci AS, Braunwald E, Kasper DL, et al, eds. Hemolytic anemias and anemias due to blood loss. G6PD deficiency. In: Fauci AS, Braunwald E, Kasper DL, et al, eds. Harrison’s Principles of Internal Medicine. 17th ed. New York, NY: McGraw-Hill Companies Inc; 2008: 652-662. 6. Beutler E. Glucose-6-phosphate dehydrogenase deficiency: a historical perspective. Blood. 2008;111(1): 16-24. xxiii
QUIZ PAGE
mechanism by which this patient developed pulmonary emboli? In massive hemolysis, the degradation mechanisms for hemoglobin are overwhelmed, resulting in free hemoglobin in plasma. This free hemoglobin acts as a nitric oxide (NO) scavenger. NO depletion can cause vascular dysfunction, impaired regulation of smooth muscle tone, vasoconstriction, enhanced platelet adhesion and aggregation, and disrupted coagulation promoting intravascular thrombosis.2,3 Pulmonary embolism might have been evoked by the NO-depleting effects of free hemoglobin, and hypovolemia and inflammation related to the
patient’s rheumatoid arthritis likely contributed.
QUIZ PAGE
CASE PROVIDED AND AUTHORED BY Daniëlle E.P. Verbeek, MD,1 Femke Waanders, MD, PhD,2 André B. Mulder, MD, PhD,3 Wouter F.W. Bierman, MD, PhD,1 and F. Nanne Croles, MD,4 Departments of 1Internal Medicine, 2 Nephrology, 3Laboratory Medicine, and 4Hematology, University
xxiv
Medical Center Groningen, University of Groningen, Groningen, the Netherlands. Address correspondence to Daniëlle E.P. Verbeek, MD, University Medical Center Groningen, Department of Internal Medicine, PO Box 30.001, 9700 RB Groningen, the Netherlands. E mail: [email protected]
Ó 2014 by the National Kidney Foundation, Inc. http://dx.doi.org/10.1053/j.ajkd.2013. 09.024 SUPPORT: None. FINANCIAL DISCLOSURE: The authors declare that they have no relevant financial interests.
Am J Kidney Dis. 2014;63(5):xxi-xxiv
Am J Kidney Dis. 2014;63(5):xxi-xxiv
Figure 1.
Peripheral blood smear.
- What is the evaluation of red urine? - How does the blood smear help differen-
tiate between various causes of hemolytic anemia and acute kidney injury? - What could be the mechanism by which
this patient developed pulmonary emboli? - How should this patient be treated?
xxi
QUIZ PAGE
A 56-year-old woman of Iranian descent with rheumatoid arthritis and hypertension presented with 1 day of malaise, nausea, vomiting, dyspnea, and red urine. She was otherwise comfortable and denied flank pain. Her medications included methotrexate, folic acid, celecoxib, atenolol, and hydrochlorothiazide. On examination, the patient was not acutely ill and was alert and responsive. Blood pressure was 155/90 mm Hg, heart rate was 90 beats/min, and oxygen saturation was 92% while breathing room air. She had dry mucous membranes. Breath sounds were normal. The abdomen was tender on deep palpation. During her stay in the emergency department, the patient developed a fever (temperature, 38.5 C) and oxygen saturation decreased further. Laboratory results showed a serum creatinine level of 1.8 mg/dL corresponding to an estimated glomerular filtration rate of 29 mL/min/1.73 m2 using the 4-variable MDRD (Modification of Diet in Renal Disease) Study equation. The patient’s serum creatinine level measured 3 months earlier was 0.75 mg/dL (estimated glomerular filtration rate, 81 mL/min/1.73 m2). Further laboratory testing showed the following values: hemoglobin, 8.06 g/dL; hematocrit, 24%; total bilirubin, 6.84 mg/dL; direct bilirubin, ,0.06 mg/dL; lactate dehydrogenase, 2,390 IU/L; undetectable haptoglobin, and negative results for a Coombs test. Platelet count was 221 3 109/L and D-dimer level was 39,714 ng/mL. Creatine kinase (CK) level was normal at 155 U/L. Arterial blood analysis showed pH of 7.47, PCO2 of 35 mm Hg, and PO2 of 57 mm Hg. Peripheral-blood smear showed blister cells and irregularly contracted cells (Fig 1). Urinalysis showed heme (31) and protein (31), with sediment evaluation showing more than 100 erythrocytes per high-power field with no dysmorphic cells or acanthocytes, 5 leukocytes, 2-3 detached tubular cells, and occasional granular casts without cellular or pigmented casts. Kidney ultrasonography produced unremarkable results. Computed tomography with iodinated contrast showed extensive pulmonary embolism.
QUIZ PAGE MAY 2014
ANSWERS
DISCUSSION
QUIZ PAGE
- What is the evaluation of
red urine? The first step in evaluating red urine should be a urine dipstick test (Fig 2). Heme-negative red urine is caused by foods or medication. Heme-positive red urine is caused by red blood cells (hematuria), myoglobin, or free hemoglobin. In heme-positive urine, the second step should be to centrifuge the urine, thereby differentiating hematuria from myoglobinuria and hemoglobinuria. In hematuria, erythrocytes remain in the sediment and the supernatant appears straw-colored. Red supernatant suggests hemoglobinuria or myoglobinuria. Although centrifugation of plasma can further differentiate hemoglobinuria (red supernatant) from myoglobinuria (clear supernatant), blood laboratory results usually point to either one or the other. A low haptoglobin level is typical for hemolysis, while an elevated CK level often is seen in rhabdomyolysis. In our patient, urine dipstick was positive for heme and the supernatant was red after centrifuging, indicating hemoglobinuria or myoglobinuria. Taken together with the blood test results showing a normal CK level and signs of hemolysis with a low haptoglobin level, this suggests that hemoglobinuria caused the red urine. However, microscopic examination of the urine also revealed erythrocytes, indicating a combination of hemoglobinuria and hematuria. xxii
- How does the blood
smear help differentiate between various causes of hemolytic anemia and acute kidney injury? The combination of Coombsnegative hemolysis and acute kidney injury (AKI) can have various causes, including thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome, erythrocyte enzyme deficiencies
such as glucose-6-phosphate dehydrogenase (G6PD) deficiency, hemoglobinopathies, and paroxysmal nocturnal hemoglobinuria. Recognizing TTP quickly is essential for reducing mortality and morbidity. In TTP and hemolytic uremic syndrome, schistocytes and thrombocytopenia are seen in the blood smear. However, our patient’s blood smear showed blister cells (Fig 1,
a Figure 2. Algorithm for the evaluation of red urine. Hemoglobinuria is accompanied by a red supernatant, whereas myoglobinuria is accompanied by a clear supernatant. b Blood results usually are indicative of either hemolysis with decreased haptoglobin or rhabdomyolysis with elevated creatine kinase levels.
Am J Kidney Dis. 2014;63(5):xxi-xxiv
arrow) and irregularly contracted cells, which indicate oxidative stress, as seen in G6PD deficiency.1 G6PD is the first enzyme of a metabolic pathway that produces NADPH (the reduced form of NADP [nicotinamide adenine dinucleotide phosphate]), which itself is essential for the function of enzymes counterbalancing oxidative stress. In erythrocytes, this G6PD-dependent pathway is the only source of NADPH. Therefore, patients with G6PD deficiency are at risk for hemolytic anemia in circumstances of oxidative stress. Upon inquiry, our patient revealed that she had eaten fava beans 1 day before her symptoms started. Fava beans contain strong oxidants. Therefore, patients with G6PD deficiency are at risk for developing severe acute hemolysis after eating fava beans, a condition called favism. Our patient’s G6PD enzyme level proved to be undetectable (,0.1 U/g of hemoglobin), confirming the diagnosis of favism. - What could be the
Am J Kidney Dis. 2014;63(5):xxi-xxiv
- How should this patient
be treated? Avoiding oxidative stressors (eg, fava beans, infections, and oxidative drugs and chemicals) is important to prevent hemolysis in a patient with G6PD deficiency. See Box 1 for a list of oxidative agents. Most episodes of G6PD-related hemolytic anemia are mild. However, especially in favism, hemolysis can be severe and complicated by AKI. Conservative treatment of AKI with fluid administration may attenuate kidney damage4; nevertheless, hemodialysis may be necessary. Complete recovery of kidney function seems to be the rule.5 In our patient, the nephrotoxic effects of free hemoglobin and Box 1. Oxidative Drugs and Chemicals to be Avoided by Persons With G6PD Deficiency Acetanalida Diaminodiphenyl sulfone Furazolidone Glibenclamide Henna Isobutylnitrite (poppers) Methylene blue Naphtalene (in naphtalene balls) Niridazolea Nitrofurantoine Phenazopyridine Phenylhydrazinea Primaquine Sulfacetamide Sulfanilamide Sulfapyridinea Thiazolesulfone Trinitrotoluene Urate oxidase/rasburicase a
No longer in clinical use in most countries. Reproduced in modified form from Beutler6 with permission of American Society of Hematology; permission conveyed through Copyright Clearance Center, Inc.
bilirubin were compounded by hypovolemia, celecoxib treatment, and iodinated contrast. Because of progressive kidney failure complicated by fluid overload, hemodialysis therapy was initiated. After 3 sessions, kidney function improved gradually and recovered completely after 3 months.
FINAL DIAGNOSIS Favism complicated by AKI and pulmonary embolism.
REFERENCES 1. Bain BJ. Diagnosis from the blood smear. N Engl J Med. 2005;353(5):498-507. 2. Rother RP, Bell L, Hillmen P, Gladwin MT. The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: a novel mechanism of human disease. JAMA. 2005;293(13):1653-1662. 3. Villagra J, Shiva S, Hunter LA, Machado RF, Gladwin MT, Kato GJ. Platelet activation in patients with sickle disease, hemolysisassociated pulmonary hypertension, and nitric oxide scavenging by cellfree hemoglobin. Blood. 2007;110(6): 2166-2172. 4. Garcia-Camin RM, Goma M, Osuna RG, et al. Molecular mediators of favism-induced acute kidney injury. Clin Nephrol. 2014;81(3): 203-209. 5. Fauci AS, Braunwald E, Kasper DL, et al, eds. Hemolytic anemias and anemias due to blood loss. G6PD deficiency. In: Fauci AS, Braunwald E, Kasper DL, et al, eds. Harrison’s Principles of Internal Medicine. 17th ed. New York, NY: McGraw-Hill Companies Inc; 2008: 652-662. 6. Beutler E. Glucose-6-phosphate dehydrogenase deficiency: a historical perspective. Blood. 2008;111(1): 16-24. xxiii
QUIZ PAGE
mechanism by which this patient developed pulmonary emboli? In massive hemolysis, the degradation mechanisms for hemoglobin are overwhelmed, resulting in free hemoglobin in plasma. This free hemoglobin acts as a nitric oxide (NO) scavenger. NO depletion can cause vascular dysfunction, impaired regulation of smooth muscle tone, vasoconstriction, enhanced platelet adhesion and aggregation, and disrupted coagulation promoting intravascular thrombosis.2,3 Pulmonary embolism might have been evoked by the NO-depleting effects of free hemoglobin, and hypovolemia and inflammation related to the
patient’s rheumatoid arthritis likely contributed.
QUIZ PAGE
CASE PROVIDED AND AUTHORED BY Daniëlle E.P. Verbeek, MD,1 Femke Waanders, MD, PhD,2 André B. Mulder, MD, PhD,3 Wouter F.W. Bierman, MD, PhD,1 and F. Nanne Croles, MD,4 Departments of 1Internal Medicine, 2 Nephrology, 3Laboratory Medicine, and 4Hematology, University
xxiv
Medical Center Groningen, University of Groningen, Groningen, the Netherlands. Address correspondence to Daniëlle E.P. Verbeek, MD, University Medical Center Groningen, Department of Internal Medicine, PO Box 30.001, 9700 RB Groningen, the Netherlands. E mail: [email protected]
Ó 2014 by the National Kidney Foundation, Inc. http://dx.doi.org/10.1053/j.ajkd.2013. 09.024 SUPPORT: None. FINANCIAL DISCLOSURE: The authors declare that they have no relevant financial interests.
Am J Kidney Dis. 2014;63(5):xxi-xxiv
