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Quiz Page December 2007
QUIZ PAGE DECEMBER 2007 Diarrhea and Anuria in a Recipient of an En Bloc Infant Kidney Transplant
BRIEF CLINICAL PRESENTATION A 66-year-old man presented with sudden loss of kidney allograft function and anuria after a short episode of diarrhea. Function of the en bloc infant kidneys had been excellent since transplantation 10 years ago. Duplex sonography and a kidney biopsy were performed.
f What is your differential diagnosis? f What do you see by means of (A, C) duplex sonography in comparison to (B) a normal allograft?
f What is your interpretation of the light microscopy pictures? f What is your clinicopathologic diagnosis?
Figure 1. Duplex sonography shows kidney allograft from (A, C) this patient and (B) a healthy control patient.
Figure 2. Kidney biopsy specimen shows tissue from (A) the upper pole and (B, C) lower pole ([A, B] hematoxylin and eosin stain, [C] periodic acid– Schiff stain; original magnification ⫻100).
American Journal of Kidney Diseases, Vol 50, No 6 (December), 2007: pp xli-xliii
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QUIZ PAGE DECEMBER 2007 ANSWERS DISCUSSION f What is your differential diagnosis? The differential diagnosis includes prerenal, renal, and postrenal causes of acute anuric renal failure. Prerenal: hypovolemia caused by lack of intravascular volume because of watery diarrhea or third spacing. In the early posttransplantation period, arterial or venous thrombosis caused by small vessel size in en bloc infant kidneys may cause anuric renal failure. Renal: acute tubular necrosis, cytomegalovirus infection, acute rejection, hemolytic uremic syndrome, thrombophilia, antiphospholipid syndrome, and scleroderma. Postrenal: urinary tract obstruction.
either kidney. The differential diagnosis includes acute rejection, calcineurin-inhibitor toxicity, and microvascular thrombi, as in disseminated intravascular coagulation in hemolytic uremic syndrome. Figure 1B shows an unremarkable allograft with normal resistive index values and good perfusion in all areas, including the cortical region. f What is your interpretation of the light microscopy pictures?
other types of thrombosis or thromboembolism. Moreover, in this scenario, kidney involvement is often bilateral, whereas arterial occlusion usually affects only 1 kidney or part of 1 kidney. Renal vein thrombosis is difficult to see morphologically, offering only minor changes that are not pathognomonic for this entity. Sometimes a hemorrhagic component may point in this direction. f Full clinical presentation
f What do you see in (A, C) duplex sonography in comparison to (B) a normal control allograft? As shown in Fig 1A, perfusion of the allograft cortex is severely diminished in power-mode depiction. Intrarenal resistive index values are very high (Fig 1C) measured on a level of segmental and interlobular arteries in the upper, middle, and lower third of both kidneys. At 10.3 ⫻ 6.6 and 11.4 ⫻ 6.0 cm, both kidneys are normal size. There is no urinary obstruction. The diameter of the renal arteries and veins in these en bloc infant kidneys is within the normal range because of growth within the recipient’s body during several years. There are no signs of renal artery stenosis or renal vein thrombosis in
The kidney biopsy specimen shows normal appearance of the cylinder from the upper pole (Fig 2A) and less distinctive structures in the cylinder from the lower pole, indicating cortical necrosis (Fig 2B). Figure 2C, also tissue from the lower pole, shows necrotic tissue with loss of nuclear staining and accumulation of epithelial cells in the lumen, leaving bare basement membranes as signs of strong tubular damage. Polymorphonuclear cells can be seen in the interstitium. The interlobular artery also is involved and shows fresh thrombotic material in its lumen. The differential diagnosis of cortical necrosis includes ischemic or toxic causes, as well as smallvessel vasculitis and hemolytic uremic syndrome. Differentiation between cortical necrosis caused by primary arterial thrombosis or thromboembolism (eg, in the setting of atrial arrhythmias) or by endotoxin shock is not easy to distinguish morphologically. However, the latter commonly shows signs of intravascular coagulation that is not common in patients with
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American Journal of Kidney Diseases, Vol 50, No 6 (December), 2007: pp xli-xliii
A 66-year-old man was admitted with diarrhea, fever, chills, and anuric acute renal failure that developed during a course of 3 days. He had received en bloc infant kidneys in 1997 because of chronic glomerulonephritis and had excellent graft function, with a baseline creatinine level of 1.0 mg/dL (88.5 mol/L) thereafter. Stool cultures were negative for the following bacteria: Salmonella species, Shigella species, Yersinia species, Campylobacter species, Clostridium species, and Escherichia coli. An infection caused by cytomegalovirus, Leptospira species, and Bunyavirus could be ruled out. There were no other cases of diarrhea in the community of the patient. Antinuclear, anti-SCL 70, and antiphospholipid antibody test results were negative. No mutation was detected in any blood clotting factor. His medical history included atrial fibrillation, arterial obstructive disease, chronic bronchitis, hyperhomocysteinemia, and a varicella zoster infection in December 2006. Medications were cyclosporine A, prednisone,
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mycophenolate mofetil, losartan, amlodipine, nebivolol, furosemide, atorvastatin, digitoxin, phenprocoumon, and allopurinol. The following laboratory values were found on admission: leukocytes, 34 ⫻ 103/L (34 ⫻ 109/L); platelets, 135 ⫻ 103/L (135 ⫻ 109/L); international normalized ratio, 4.71; creatinine, 6.3 mg/dL (557 mol/L); estimated glomerular filtration rate (according to the Modification of Diet in Renal Disease Study equation), 7.0 mL/ min/1.73 m2 (0.12 mL/s/1.73 m2); blood urea nitrogen, 82 mg/dL (29.3 mmol/L); lactate dehydrogenase, 1,537 U/L (1,537 U/L); fibrinogen, 1,082 mg/dL (31.8 mol/L); fibrinmonomeres, negative; and cyclosporine A trough level, 107 ng/mL. Urine dipstick showed 3⫹ protein and 4⫹ blood, and sediment showed many leukocytes and erythrocytes, but no cellular casts. f What is your clinicopathologic diagnosis? Our patient had acute renal failure caused by cortical necroses in the infant kidney allografts. Damage confined to the kidneys most likely was induced by bacterial toxins. Bilateral renal cortical necrosis is a pathological diagnosis of a clinical entity characterized by abrupt onset of gross hematuria, oliguria, and anuria. It often occurs in individuals without pre-
existing renal disease and usually proceeds to end-stage renal failure. Pathologically, there is patchy to diffuse bilateral ischemic coagulative cortical necrosis, with characteristic sparing of the renal medulla. Its greatest incidence is in pregnant women with accidental hemorrhage (abruptio placentae, 50% to 60% of all causes) in the last trimester. It also may occur in infants and children, usually as a result of diarrhea and dehydration, whereas in nonpregnant adults, it usually occurs as a result of infections or poisoning. The main clinical feature is oliguria or anuria of sudden onset. Renal cortical necrosis can be induced in mice experimentally by intravenous injection of bacterial toxins and vasoconstrictor substances. Although it is believed to result from spasm of the renal interlobular arteries and afferent arterioles, the exact pathogenesis is obscure. All causes of acute cortical necrosis share 1 common denominator: a procoagulant factor capable of activating the coagulation system. Treatment is similar to that used in patients with other causes of acute renal failure, but the prognosis is poor. An extended period of supportive treatment usually is required because recovery from acute cortical necrosis is protracted. Characteristically, patients with severe acute cortical necrosis have a pro-
tracted oligoanuric period. Eventually, increasing quantities of urine may be excreted, and creatinine clearance may increase from 0 to about 10 mL/min during the first 1½ to 4 months. Renal function plateaus for 3 to 10 months, after which there is a secondary increase in glomerular filtration rate and tubular transport functions. After 9 to 24 months, renal function stabilizes and there is no further gain. Unfortunately, our patient remained dependent on dialysis and currently is listed for transplantation again.
FINAL DIAGNOSIS Acute bilateral renal cortical necrosis of the kidney allografts, most likely caused by bacterial toxins. CASE PROVIDED AND AUTHORED BY Ulla T. Schulthei, MD,1 Heike Göbel, MD,2 Gero von Gersdorff, MD,1 Mike Stubanus, MD,1 Gerd Walz, MD,1 and Peter Gerke, MD,1 1Renal Division, Department of Medicine, and 2Department of Pathology, University Hospital Freiburg, Freiburg, Germany. © 2007 by the National Kidney Foundation, Inc. doi:10.1053/j.ajkd.2007.07.034 SUPPORT: None. FINANCIAL DISCLOSURE: None.
BRIEF CLINICAL PRESENTATION A 66-year-old man presented with sudden loss of kidney allograft function and anuria after a short episode of diarrhea. Function of the en bloc infant kidneys had been excellent since transplantation 10 years ago. Duplex sonography and a kidney biopsy were performed.
f What is your differential diagnosis? f What do you see by means of (A, C) duplex sonography in comparison to (B) a normal allograft?
f What is your interpretation of the light microscopy pictures? f What is your clinicopathologic diagnosis?
Figure 1. Duplex sonography shows kidney allograft from (A, C) this patient and (B) a healthy control patient.
Figure 2. Kidney biopsy specimen shows tissue from (A) the upper pole and (B, C) lower pole ([A, B] hematoxylin and eosin stain, [C] periodic acid– Schiff stain; original magnification ⫻100).
American Journal of Kidney Diseases, Vol 50, No 6 (December), 2007: pp xli-xliii
xli
QUIZ PAGE DECEMBER 2007 ANSWERS DISCUSSION f What is your differential diagnosis? The differential diagnosis includes prerenal, renal, and postrenal causes of acute anuric renal failure. Prerenal: hypovolemia caused by lack of intravascular volume because of watery diarrhea or third spacing. In the early posttransplantation period, arterial or venous thrombosis caused by small vessel size in en bloc infant kidneys may cause anuric renal failure. Renal: acute tubular necrosis, cytomegalovirus infection, acute rejection, hemolytic uremic syndrome, thrombophilia, antiphospholipid syndrome, and scleroderma. Postrenal: urinary tract obstruction.
either kidney. The differential diagnosis includes acute rejection, calcineurin-inhibitor toxicity, and microvascular thrombi, as in disseminated intravascular coagulation in hemolytic uremic syndrome. Figure 1B shows an unremarkable allograft with normal resistive index values and good perfusion in all areas, including the cortical region. f What is your interpretation of the light microscopy pictures?
other types of thrombosis or thromboembolism. Moreover, in this scenario, kidney involvement is often bilateral, whereas arterial occlusion usually affects only 1 kidney or part of 1 kidney. Renal vein thrombosis is difficult to see morphologically, offering only minor changes that are not pathognomonic for this entity. Sometimes a hemorrhagic component may point in this direction. f Full clinical presentation
f What do you see in (A, C) duplex sonography in comparison to (B) a normal control allograft? As shown in Fig 1A, perfusion of the allograft cortex is severely diminished in power-mode depiction. Intrarenal resistive index values are very high (Fig 1C) measured on a level of segmental and interlobular arteries in the upper, middle, and lower third of both kidneys. At 10.3 ⫻ 6.6 and 11.4 ⫻ 6.0 cm, both kidneys are normal size. There is no urinary obstruction. The diameter of the renal arteries and veins in these en bloc infant kidneys is within the normal range because of growth within the recipient’s body during several years. There are no signs of renal artery stenosis or renal vein thrombosis in
The kidney biopsy specimen shows normal appearance of the cylinder from the upper pole (Fig 2A) and less distinctive structures in the cylinder from the lower pole, indicating cortical necrosis (Fig 2B). Figure 2C, also tissue from the lower pole, shows necrotic tissue with loss of nuclear staining and accumulation of epithelial cells in the lumen, leaving bare basement membranes as signs of strong tubular damage. Polymorphonuclear cells can be seen in the interstitium. The interlobular artery also is involved and shows fresh thrombotic material in its lumen. The differential diagnosis of cortical necrosis includes ischemic or toxic causes, as well as smallvessel vasculitis and hemolytic uremic syndrome. Differentiation between cortical necrosis caused by primary arterial thrombosis or thromboembolism (eg, in the setting of atrial arrhythmias) or by endotoxin shock is not easy to distinguish morphologically. However, the latter commonly shows signs of intravascular coagulation that is not common in patients with
xlii
American Journal of Kidney Diseases, Vol 50, No 6 (December), 2007: pp xli-xliii
A 66-year-old man was admitted with diarrhea, fever, chills, and anuric acute renal failure that developed during a course of 3 days. He had received en bloc infant kidneys in 1997 because of chronic glomerulonephritis and had excellent graft function, with a baseline creatinine level of 1.0 mg/dL (88.5 mol/L) thereafter. Stool cultures were negative for the following bacteria: Salmonella species, Shigella species, Yersinia species, Campylobacter species, Clostridium species, and Escherichia coli. An infection caused by cytomegalovirus, Leptospira species, and Bunyavirus could be ruled out. There were no other cases of diarrhea in the community of the patient. Antinuclear, anti-SCL 70, and antiphospholipid antibody test results were negative. No mutation was detected in any blood clotting factor. His medical history included atrial fibrillation, arterial obstructive disease, chronic bronchitis, hyperhomocysteinemia, and a varicella zoster infection in December 2006. Medications were cyclosporine A, prednisone,
xliii
mycophenolate mofetil, losartan, amlodipine, nebivolol, furosemide, atorvastatin, digitoxin, phenprocoumon, and allopurinol. The following laboratory values were found on admission: leukocytes, 34 ⫻ 103/L (34 ⫻ 109/L); platelets, 135 ⫻ 103/L (135 ⫻ 109/L); international normalized ratio, 4.71; creatinine, 6.3 mg/dL (557 mol/L); estimated glomerular filtration rate (according to the Modification of Diet in Renal Disease Study equation), 7.0 mL/ min/1.73 m2 (0.12 mL/s/1.73 m2); blood urea nitrogen, 82 mg/dL (29.3 mmol/L); lactate dehydrogenase, 1,537 U/L (1,537 U/L); fibrinogen, 1,082 mg/dL (31.8 mol/L); fibrinmonomeres, negative; and cyclosporine A trough level, 107 ng/mL. Urine dipstick showed 3⫹ protein and 4⫹ blood, and sediment showed many leukocytes and erythrocytes, but no cellular casts. f What is your clinicopathologic diagnosis? Our patient had acute renal failure caused by cortical necroses in the infant kidney allografts. Damage confined to the kidneys most likely was induced by bacterial toxins. Bilateral renal cortical necrosis is a pathological diagnosis of a clinical entity characterized by abrupt onset of gross hematuria, oliguria, and anuria. It often occurs in individuals without pre-
existing renal disease and usually proceeds to end-stage renal failure. Pathologically, there is patchy to diffuse bilateral ischemic coagulative cortical necrosis, with characteristic sparing of the renal medulla. Its greatest incidence is in pregnant women with accidental hemorrhage (abruptio placentae, 50% to 60% of all causes) in the last trimester. It also may occur in infants and children, usually as a result of diarrhea and dehydration, whereas in nonpregnant adults, it usually occurs as a result of infections or poisoning. The main clinical feature is oliguria or anuria of sudden onset. Renal cortical necrosis can be induced in mice experimentally by intravenous injection of bacterial toxins and vasoconstrictor substances. Although it is believed to result from spasm of the renal interlobular arteries and afferent arterioles, the exact pathogenesis is obscure. All causes of acute cortical necrosis share 1 common denominator: a procoagulant factor capable of activating the coagulation system. Treatment is similar to that used in patients with other causes of acute renal failure, but the prognosis is poor. An extended period of supportive treatment usually is required because recovery from acute cortical necrosis is protracted. Characteristically, patients with severe acute cortical necrosis have a pro-
tracted oligoanuric period. Eventually, increasing quantities of urine may be excreted, and creatinine clearance may increase from 0 to about 10 mL/min during the first 1½ to 4 months. Renal function plateaus for 3 to 10 months, after which there is a secondary increase in glomerular filtration rate and tubular transport functions. After 9 to 24 months, renal function stabilizes and there is no further gain. Unfortunately, our patient remained dependent on dialysis and currently is listed for transplantation again.
FINAL DIAGNOSIS Acute bilateral renal cortical necrosis of the kidney allografts, most likely caused by bacterial toxins. CASE PROVIDED AND AUTHORED BY Ulla T. Schulthei, MD,1 Heike Göbel, MD,2 Gero von Gersdorff, MD,1 Mike Stubanus, MD,1 Gerd Walz, MD,1 and Peter Gerke, MD,1 1Renal Division, Department of Medicine, and 2Department of Pathology, University Hospital Freiburg, Freiburg, Germany. © 2007 by the National Kidney Foundation, Inc. doi:10.1053/j.ajkd.2007.07.034 SUPPORT: None. FINANCIAL DISCLOSURE: None.