- Email: [email protected]
Quiz Page MAY 2013
QUIZ PAGE MAY 2013 A Case of Postpartum Acute Kidney Injury CLINICAL PRESENTATION A 30-year-old Asian woman presented with oliguria, edema, and breathlessness for the previous 10 days and was found to have severe acute kidney injury. She was gravida 2, para 2 and had undergone lower segment caesarean section at term 1 month earlier. Her pregnancy was uncomplicated: she had normal kidney function and no preeclampsia. Her previous pregnancy also was uneventful and delivered by lower segment caesarean section by choice. On evaluation, blood pressure was high at 150/90 mm Hg and urinalysis showed proteinuria and hematuria. She had no evidence of hypertensive retinopathy. Blood work showed a creatinine level of 13.2 mg/dL (corresponding to an estimated glomerular filtration rate of 3 mL/min/ 1.73 m2 using the 4-variable Modification of Diet in Renal Disease [MDRD] Study equation), a hemoglobin level of 6.4 g/dL, and a platelet count of 2,700,000/L. Peripheral smear showed normocytic normochromic anemia with occasional spherocytes, teardrop cells, target cells, acanthocytes, and no evidence of significant red blood cell fragmentation. Liver function and coagulation profile results were normal, and lactate dehydrogenase level was mildly elevated at 730 U/L (reference range, 240480 U/L). Results of C3, antinuclear antibody, proteinase 3 and myeloperoxidase antinuclear cytoplasmic antibody, and antiphospholipid antibody screens were negative. A kidney ultrasound showed normal-sized kidneys with increased echogenicity in the renal cortex. She was oligoanuric, and hemodialysis treatment was initiated. A kidney biopsy was performed (Figs 1-3).
Figure 1. Moderate degree of multilayering of the intima of small arteries with reactive endothelium. Red blood cells are present between the hyperplastic intimal layers (trichrome stain).
Figure 2. Preglomerular arterioles show hyperplasia of the intima with
swollen endothelium. The glomerulus shows congestion of the capillaries without inflammation (Jones silver methenamine stain).
What does the biopsy show? What diseases cause these pathologic findings? How should this patient be treated?
Am J Kidney Dis. 2013;61(5):xxv-xxvii
xxv
QUIZ PAGE
Figure 3. The glomerulus shows focal wrinkling of the capillary basement membranes with occasional double contours (Jones silver methenamine stain).
QUIZ PAGE MAY 2013 ANSWERS DISCUSSION
QUIZ PAGE
f What does the biopsy show? Figure 1 shows a moderate degree of multilayering of the intima of small arteries with reactive endothelium. Red blood cells are present between the hyperplastic intimal layers. Figure 2 shows preglomerular arterioles with hyperplasia of the intima with swollen endothelium. The glomerulus shows congestion of the capillaries without inflammation. Figure 3 shows a glomerulus with focal wrinkling of the capillary basement membranes and occasional double contours. Thrombotic microangiopathy (TMA) is the pathologic lesion characterized by occluded microvessels due to swollen endothelial cells and subendothelial aggregation of platelets, proteins, and debris. All diseases associated with TMA are characterized by kidney biopsy findings of endothelial injury and thrombus formation.1 The pathologic findings primarily involve glomeruli and vessels, can be divided into acute and chronic lesions, and do not distinguish between the multiple disease entities associated with TMA. f What diseases cause these pathologic findings? The way TMA disorders are classified has fluctuated over time, and even now the term TMA is inappropriately treated as if it were synonymous with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTPxxvi
Table 1. Features and Treatments of Various Causes of TMA Causes of TMA
Features
Treatment
D⫹ HUS
Cause of childhood HUS in 90% of cases; caused by verocytotoxinproducing Escherichia coli
Treatment is supportive, but plasma exchange may be used in patients with significant neurologic symptoms; eculizumab may be helpful
D⫺ HUSa
Cause of childhood HUS in 10% of cases; disease of alternate complement pathway, may be familial
Plasma exchange is the first-line therapy; eculizumab may be helpful
TTP
Severe deficiency of ADAMTS13 (genetic or acquired) commonly is observed, no other obvious cause has been found
Plasma exchange is the treatment of choice; in resistant cases, glucocorticoids, rituximab, or cyclosporine may be helpful
Pregnancy or postpartum HUS
Risk of recurrence with subsequent pregnancies; can be difficult to differentiate clinically and histologically from HELLP syndrome; progression past 3 d postpartum can help differentiate from HELLP syndrome
Treatment is the same as adult TTP-HUS; during pregnancy, if distinction from HELLP syndrome is difficult, delivery is indicated
Drugsb
Quinine is the most common cause and the only drug with documented drug-dependent antibodies; often presents with slowly progressive kidney failure, new/accelerated hypertension, and bland urinary sediment
Often reversible with discontinuation of the offending drug; plasma exchange ineffective; may respond to rituximab
Disseminated malignancy
Normal or slightly reduced ADAMTS13 levels; high LDH; often occurs with mucin-producing adenocarcinoma
Plasma exchange ineffective
Transplantassociated TMA
Schistocytes ⬎4% of RBCs; de novo prolonged or progressive thrombocytopenia; high serum LDH and low haptoglobin
No role for plasma exchange; may respond to rituximab
APS
Kidney involvement in 25% of primary APS patients; clinical spectrum varies from mild proteinuria to acute/ subacute kidney failure and often marked hypertension
May respond to either plasmapheresis or corticosteroids and maintenance anticoagulation
Scleroderma kidney
Abrupt onset of severe hypertension; bland urine sediment with progressive kidney failure
ACE inhibitors are the drugs of choice; may progress to ESRD in 20%-50% despite treatment
Note: Apart from the causes listed here, TMA also can be caused by malignant nephrosclerosis, radiation nephritis, and human immunodeficiency virus infection. Abbreviations: ACE, angiotensin-converting enzyme; APS, antiphospholipid syndrome; D⫹ HUS, diarrhea-positive hemolytic uremic syndrome; D⫺ HUS, diarrhea-negative hemolytic uremic syndrome; ESRD, end-stage renal disease; HELLP, hemolysis, elevated liver enzymes, low platelet count; HUS, hemolytic uremic syndrome; LDH, lactate dehydrogenase; RBC, red blood cell; TMA, thrombotic microangiopathy; TTP, thrombotic thrombocytopenic purpura. a Also known as atypical HUS. b Drugs include mitomycin C, cisplatin, gemcitabine, vascular endothelial growth factors (bevasizumab), immunosuppressives (cyclosporine, tacrolimus), and other drugs such as quinine and ticlopidine.
Am J Kidney Dis. 2013;61(5):xxv-xxvii
HUS).2 Although one can be confident of the diagnosis of postpartum HUS in the clinical setting described, the morphologic findings are not specific to this condition and many diseases centered around the endothelium-platelet interaction will manifest the same structural lesions. These include diarrhea-positive HUS, which accounts for 90% of HUS in children, and diarrhea-negative HUS, or atypical HUS, which is a disease of the alternative complement pathway. TTP, which should be reserved for genetic or acquired deficit of the enzymatic activity of ADAMTS13, will show the same histologic features. When other precise causes or mechanisms of the process are known, it is called secondary TMA. Processes that can induce these changes include malignant hypertension, antiphospholipid syndrome, radiation exposure, bone marrow transplantation, scleroderma, medication (calcineurin inhibitors, clopidogrel, mitomycin C, gemcitabine, cisplatin, anti–vascular endothelial growth factor agents, etc), and neoplasias. Table 1 lists the diseases responsible for TMA, their key features, and the appropriate treatment for each condition. f How should this patient be treated? Maternal mortality was as high as 55% in cases of postpartum HUS
FINAL DIAGNOSIS Postpartum HUS.
REFERENCES 1. Halevy D, Radhakrishnan J, Glen Markowitz G, Appel G. Thrombotic microangiopathies. Crit Care Clin. 2002;18:309-320. 2. De Serres S, Isenring P. Renal thrombotic microangiopathy revisited: when a lesion is not a clinical finding. Saudi J Kidney Dis Transplant. 2010; 21:411-416.
3. Weiner CP. Thrombotic microangiopathy in pregnancy and the postpartum period. Semin Hematol. 1987;24:119-129. 4. Egerman RS, Witlin AG, Friedman SA, Sibai BM. Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome in pregnancy: review of 11 cases. Am J Obstet Gynecol. 1996;175:950-956. CASE PROVIDED AND AUTHORED BY Shashidhar Baikunje, MD, FRCP(UK),1 Mahesha Vankalakunti, MD,2 and Rama Prakasha Saya, MD,3 1Department of Nephrology, K.S. Hegde Medical Academy, Deralakatte, Mangalore; 2Department of Nephropathology, Manipal Hospital, Bengaluru; and 3Department of Medicine, K.S. Hegde Medical Academy, Deralakatte, Mangalore, Karnataka, India. Address correspondence to Shashidhar Baikunje, MD, FRCP(UK), Department of Nephrology, K.S. Hegde Medical Academy, Deralakatte, Mangalore, Karnataka, India. E mail: baikunje@hotmail. com © 2013 by the National Kidney Foundation, Inc. http://dx.doi.org/10.1053/j.ajkd. 2012.12.032 SUPPORT: None. FINANCIAL DISCLOSURE: The authors declare that they have no relevant financial interests.
xxvii
QUIZ PAGE
Am J Kidney Dis. 2013;61(5):xxv-xxvii
in the pre–plasma exchange era, as reported in a series by Weiner.3 Since the introduction of plasma exchange, the outcome has improved significantly, as shown in a more recent series of 11 patients in which 9 survived.4 Although there was no evidence of significant red blood cell fragmentation in the peripheral smear, which often is considered the hallmark of the disease, this patient was treated successfully with 6 sessions of plasma exchange using fresh frozen plasma as the replacement fluid. There was gradual improvement in kidney function over the next 4 months, with serum creatinine level decreasing to 1.9 mg/dL (estimated glomerular filtration rate, 31 mL/min/1.73 m2). This case emphasizes the importance of initiating plasma exchange in patients with postpartum HUS even if there is some uncertainty about the diagnosis.
Figure 1. Moderate degree of multilayering of the intima of small arteries with reactive endothelium. Red blood cells are present between the hyperplastic intimal layers (trichrome stain).
Figure 2. Preglomerular arterioles show hyperplasia of the intima with
swollen endothelium. The glomerulus shows congestion of the capillaries without inflammation (Jones silver methenamine stain).
What does the biopsy show? What diseases cause these pathologic findings? How should this patient be treated?
Am J Kidney Dis. 2013;61(5):xxv-xxvii
xxv
QUIZ PAGE
Figure 3. The glomerulus shows focal wrinkling of the capillary basement membranes with occasional double contours (Jones silver methenamine stain).
QUIZ PAGE MAY 2013 ANSWERS DISCUSSION
QUIZ PAGE
f What does the biopsy show? Figure 1 shows a moderate degree of multilayering of the intima of small arteries with reactive endothelium. Red blood cells are present between the hyperplastic intimal layers. Figure 2 shows preglomerular arterioles with hyperplasia of the intima with swollen endothelium. The glomerulus shows congestion of the capillaries without inflammation. Figure 3 shows a glomerulus with focal wrinkling of the capillary basement membranes and occasional double contours. Thrombotic microangiopathy (TMA) is the pathologic lesion characterized by occluded microvessels due to swollen endothelial cells and subendothelial aggregation of platelets, proteins, and debris. All diseases associated with TMA are characterized by kidney biopsy findings of endothelial injury and thrombus formation.1 The pathologic findings primarily involve glomeruli and vessels, can be divided into acute and chronic lesions, and do not distinguish between the multiple disease entities associated with TMA. f What diseases cause these pathologic findings? The way TMA disorders are classified has fluctuated over time, and even now the term TMA is inappropriately treated as if it were synonymous with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTPxxvi
Table 1. Features and Treatments of Various Causes of TMA Causes of TMA
Features
Treatment
D⫹ HUS
Cause of childhood HUS in 90% of cases; caused by verocytotoxinproducing Escherichia coli
Treatment is supportive, but plasma exchange may be used in patients with significant neurologic symptoms; eculizumab may be helpful
D⫺ HUSa
Cause of childhood HUS in 10% of cases; disease of alternate complement pathway, may be familial
Plasma exchange is the first-line therapy; eculizumab may be helpful
TTP
Severe deficiency of ADAMTS13 (genetic or acquired) commonly is observed, no other obvious cause has been found
Plasma exchange is the treatment of choice; in resistant cases, glucocorticoids, rituximab, or cyclosporine may be helpful
Pregnancy or postpartum HUS
Risk of recurrence with subsequent pregnancies; can be difficult to differentiate clinically and histologically from HELLP syndrome; progression past 3 d postpartum can help differentiate from HELLP syndrome
Treatment is the same as adult TTP-HUS; during pregnancy, if distinction from HELLP syndrome is difficult, delivery is indicated
Drugsb
Quinine is the most common cause and the only drug with documented drug-dependent antibodies; often presents with slowly progressive kidney failure, new/accelerated hypertension, and bland urinary sediment
Often reversible with discontinuation of the offending drug; plasma exchange ineffective; may respond to rituximab
Disseminated malignancy
Normal or slightly reduced ADAMTS13 levels; high LDH; often occurs with mucin-producing adenocarcinoma
Plasma exchange ineffective
Transplantassociated TMA
Schistocytes ⬎4% of RBCs; de novo prolonged or progressive thrombocytopenia; high serum LDH and low haptoglobin
No role for plasma exchange; may respond to rituximab
APS
Kidney involvement in 25% of primary APS patients; clinical spectrum varies from mild proteinuria to acute/ subacute kidney failure and often marked hypertension
May respond to either plasmapheresis or corticosteroids and maintenance anticoagulation
Scleroderma kidney
Abrupt onset of severe hypertension; bland urine sediment with progressive kidney failure
ACE inhibitors are the drugs of choice; may progress to ESRD in 20%-50% despite treatment
Note: Apart from the causes listed here, TMA also can be caused by malignant nephrosclerosis, radiation nephritis, and human immunodeficiency virus infection. Abbreviations: ACE, angiotensin-converting enzyme; APS, antiphospholipid syndrome; D⫹ HUS, diarrhea-positive hemolytic uremic syndrome; D⫺ HUS, diarrhea-negative hemolytic uremic syndrome; ESRD, end-stage renal disease; HELLP, hemolysis, elevated liver enzymes, low platelet count; HUS, hemolytic uremic syndrome; LDH, lactate dehydrogenase; RBC, red blood cell; TMA, thrombotic microangiopathy; TTP, thrombotic thrombocytopenic purpura. a Also known as atypical HUS. b Drugs include mitomycin C, cisplatin, gemcitabine, vascular endothelial growth factors (bevasizumab), immunosuppressives (cyclosporine, tacrolimus), and other drugs such as quinine and ticlopidine.
Am J Kidney Dis. 2013;61(5):xxv-xxvii
HUS).2 Although one can be confident of the diagnosis of postpartum HUS in the clinical setting described, the morphologic findings are not specific to this condition and many diseases centered around the endothelium-platelet interaction will manifest the same structural lesions. These include diarrhea-positive HUS, which accounts for 90% of HUS in children, and diarrhea-negative HUS, or atypical HUS, which is a disease of the alternative complement pathway. TTP, which should be reserved for genetic or acquired deficit of the enzymatic activity of ADAMTS13, will show the same histologic features. When other precise causes or mechanisms of the process are known, it is called secondary TMA. Processes that can induce these changes include malignant hypertension, antiphospholipid syndrome, radiation exposure, bone marrow transplantation, scleroderma, medication (calcineurin inhibitors, clopidogrel, mitomycin C, gemcitabine, cisplatin, anti–vascular endothelial growth factor agents, etc), and neoplasias. Table 1 lists the diseases responsible for TMA, their key features, and the appropriate treatment for each condition. f How should this patient be treated? Maternal mortality was as high as 55% in cases of postpartum HUS
FINAL DIAGNOSIS Postpartum HUS.
REFERENCES 1. Halevy D, Radhakrishnan J, Glen Markowitz G, Appel G. Thrombotic microangiopathies. Crit Care Clin. 2002;18:309-320. 2. De Serres S, Isenring P. Renal thrombotic microangiopathy revisited: when a lesion is not a clinical finding. Saudi J Kidney Dis Transplant. 2010; 21:411-416.
3. Weiner CP. Thrombotic microangiopathy in pregnancy and the postpartum period. Semin Hematol. 1987;24:119-129. 4. Egerman RS, Witlin AG, Friedman SA, Sibai BM. Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome in pregnancy: review of 11 cases. Am J Obstet Gynecol. 1996;175:950-956. CASE PROVIDED AND AUTHORED BY Shashidhar Baikunje, MD, FRCP(UK),1 Mahesha Vankalakunti, MD,2 and Rama Prakasha Saya, MD,3 1Department of Nephrology, K.S. Hegde Medical Academy, Deralakatte, Mangalore; 2Department of Nephropathology, Manipal Hospital, Bengaluru; and 3Department of Medicine, K.S. Hegde Medical Academy, Deralakatte, Mangalore, Karnataka, India. Address correspondence to Shashidhar Baikunje, MD, FRCP(UK), Department of Nephrology, K.S. Hegde Medical Academy, Deralakatte, Mangalore, Karnataka, India. E mail: baikunje@hotmail. com © 2013 by the National Kidney Foundation, Inc. http://dx.doi.org/10.1053/j.ajkd. 2012.12.032 SUPPORT: None. FINANCIAL DISCLOSURE: The authors declare that they have no relevant financial interests.
xxvii
QUIZ PAGE
Am J Kidney Dis. 2013;61(5):xxv-xxvii
in the pre–plasma exchange era, as reported in a series by Weiner.3 Since the introduction of plasma exchange, the outcome has improved significantly, as shown in a more recent series of 11 patients in which 9 survived.4 Although there was no evidence of significant red blood cell fragmentation in the peripheral smear, which often is considered the hallmark of the disease, this patient was treated successfully with 6 sessions of plasma exchange using fresh frozen plasma as the replacement fluid. There was gradual improvement in kidney function over the next 4 months, with serum creatinine level decreasing to 1.9 mg/dL (estimated glomerular filtration rate, 31 mL/min/1.73 m2). This case emphasizes the importance of initiating plasma exchange in patients with postpartum HUS even if there is some uncertainty about the diagnosis.