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The Case | Renal dysfunction in a pregnant patient with IgA nephropathy
make your diagnosis
http://www.kidney-international.org & 2014 International Society of Nephrology Kidney International (2014) 85, 1477–1478; doi:10.1038/ki.2013.322
The Case | Renal dysfunction in a pregnant patient with IgA nephropathy Ladan Zand1, Amy Williams1, Dusica Babovic-Vuksanovic2, Rosemary Nwoko1, Lynn Cornell3 and Vesna Garovic1 1 Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA; 2Department of Medical Genetics, Mayo Clinic, Rochester, Minnesota, USA and 3Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
Correspondence: Vesna Garovic, 200 First Street SW, Rochester, Minnesota 55902, USA. E-mail: [email protected]
a
b
c
Figure 1 | Renal biopsy findings in a pregnant patient presenting with advanced renal dysfunction. (a) Arrow depicts the pathognomonic finding of underlying diagnosis in the intraluminal vessel by light microscopy (hematoxylin and eosin). (b) A partially sclerotic glomerulus shows mesangial hypercellularity and matrix expansion (Masson trichrome). (c) Immunofluorescence staining shows bright granular mesangial staining for immunoglobulin A.
An 18-year-old girl, 15 weeks pregnant, presented to our hospital for the evaluation of headache. Her history was significant for immunoglobulin A (IgA) nephropathy, with a baseline serum creatinine of 1.8 mg/dl. She had been diagnosed with IgA nephropathy at 11 years of age after presenting with an elevated creatinine and microscopic hematuria. Her renal biopsy at the time showed mild mesangial proliferation with mesangial IgA deposits. The patient was not undergoing any therapy for her IgA nephropathy before her pregnancy. The patient had no complaints other than headache. Her physical examination revealed a blood pressure of
162/109 mm Hg with normal mental status. The rest of her physical examination was unremarkable. Her laboratory workup was the following: creatinine, 8.5 mg/dl (0.6–1.1); blood urea nitrogen, 83 mg/dl (6–21); potassium, 6.1 mmol/l (3.6–5.2); hemoglobin, 10.4 g/dl (12.0–15.5); platelets, 223109/l (150–450109); aspartate aminotransferase, 23 U/l (8–43); alanine aminotransferase, 40 U/l (7–45); total bilirubin, 0.2 mg/dl (0.1–1.0); and international normalized ratio, 0.9 (0.8–1.2). Urine microscopy showed 21–30 RBC/ high-power field and occasional granular casts. A renal biopsy was performed for further evaluation of her renal failure (Figure 1a–c).
What is your diagnosis?
SEE NEXT PAGE FOR ANSWERS Kidney International (2014) 85, 1477–1478
1477
make your diagnosis
L Zand et al.: Atypical hemolytic uremic syndrome
The Diagnosis | Atypical hemolytic uremic syndrome Figure 1a shows evidence of thrombi in the blood vessels and is suggestive of a thrombotic microangiopathic process. The differential diagnosis of thrombotic microangiopathy (TMA) in pregnancy is listed in Table 1. The top differential diagnoses include atypical hemolytic uremic syndrome (aHUS), thrombotic thrombocytopenic purpura (TTP), and HELLP (hemolysis with elevated liver enzymes, and low platelets) syndrome. Early during pregnancy, in the absence of elevated liver enzymes and with a normal platelet count, HELLP syndrome is unlikely. The presence of severe renal failure requiring dialysis, along with the absence of profound thrombocytopenia, is more suggestive of aHUS rather than TTP. Atypical hemolytic uremic syndrome occurs in the absence of infection/diarrhea and accounts for 10% of the cases of hemolytic uremic syndrome. It is due to the activation of the alternative complement pathway (ACP) and carries a poor prognosis, with progression to end-stage renal disease in 50%1 and death in 25% of the cases.2 The most common form of aHUS is sporadic, without a known family history, and is typically associated with a trigger, such as malignancy, drugs, or organ transplantation.1 Even though pregnancy can be a trigger for the development of aHUS, recent studies suggest that up to 86% of these patients have an underlying mutation in the ACP.3 Evaluation of the ACP in our patient revealed a heterozygote missense mutation in the thrombomodulin gene (THBD), with a G to T conversion (c.1456 G4T), leading to substitution of aspartic acid (D) by tyrosine (Y) (D486Y). Her workup for mutations in the genes of the complement cascade, including complement factors H (CFH), I (CFI), B (CFB), membrane cofactor protein (MCP), complement component C (C3), and complement factor H–related protein (CFHR), was negative. Interestingly, the patient’s mother has the same THBD mutation, but has not developed aHUS to this date. This raises the possibility of incomplete penetrance of this mutation. Alternatively,
the underlying IgA nephropathy in our index patient may have contributed to the development of aHUS during pregnancy. Our patient had a normal platelet count at the time of presentation, and although thrombocytopenia is part of the triad of aHUS (in addition to anemia and renal failure), in the largest series of aHUS during pregnancy, the degree of thrombocytopenia was moderate, with 8 of the 20 patients having a platelet count 4100109/l. This is similar to our patient, whose platelet count reached a nadir of 105109/l following presentation. Intravascular hemolysis secondary to TMA was evidenced in our patient by the presence of anemia, an elevated lactate dehydrogenase of 414 U/l (122–222), and a low haptoglobin of 14 mg/dl (30–200), which was noted subsequently. Thrombomodulin gene mutations have been associated with aHUS. Delvaeye et al.4 sequenced the entire thrombomodulin gene in 152 patients with a clinical diagnosis of aHUS and 380 controls. Thrombomodulin gene mutations were identified in 7 of 152 patients (4.6%) and in none of the controls. Two of the seven cases had the same mutation as our patient (D486Y). Thrombomodulin increases the thrombin-mediated activity of plasma procarboxy peptidase B, which, in turn, inhibits C3a and C5a.4 It also facilitates CFI-mediated inactivation of C3b in the presence of CFH.4 Therefore, mutations in the THBD gene may result in the upregulation of the complement system and may lead to the development of aHUS. The patient was started and continued on daily hemodialysis during her pregnancy and at 32 weeks of gestation had a healthy baby boy by spontaneous vaginal delivery. Five months later, she underwent a living related kidney transplantation from her father. Her 1-year protocol biopsy showed features consistent with IgA nephropathy, but no evidence of recurrence of aHUS, with a baseline creatinine of 1.5 mg/dl. This may be due to the fact that the wild-type THBD (a membrane-bound glycoprotein) is present in the renal allograft and is protective against the development of aHUS.5
Table 1 | Differential diagnosis of TMA in pregnancy Severe pre-eclampsia associated with HELLP syndromea Acute fatty liver of pregnancya Thrombotic thrombocytopenic purpura Atypical hemolytic uremic syndrome Disseminated intravascular coagulation Antiphospholipid syndrome Malignant hypertension Scleroderma renal crises HELLP, hemolysis with elevated liver enzymes, and low platelets; TMA, thrombotic microangiopathy. a Specific for pregnancy.
1478
REFERENCES 1. 2. 3.
4. 5.
Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome. N Engl J Med 2009; 361: 1676–1687. Kaplan BS, Meyers KE, Schulman SL. The pathogenesis and treatment of hemolytic uremic syndrome. J Am Soc Nephrol 1998; 9: 1126–1133. Fakhouri F, Roumenina L, Provot F et al. Pregnancy-associated hemolytic uremic syndrome revisited in the era of complement gene mutations. J Am Soc Nephrol 2010; 21: 859–867. Delvaeye M, Noris M, De Vriese A et al. Thrombomodulin mutations in atypical hemolytic-uremic syndrome. N Engl J Med 2009; 361: 345–357. Edey MM. Thrombomodulin in atypical hemolytic-uremic syndrome. N Engl J Med 2009; 361: 1511.
Kidney International (2014) 85, 1477–1478
http://www.kidney-international.org & 2014 International Society of Nephrology Kidney International (2014) 85, 1477–1478; doi:10.1038/ki.2013.322
The Case | Renal dysfunction in a pregnant patient with IgA nephropathy Ladan Zand1, Amy Williams1, Dusica Babovic-Vuksanovic2, Rosemary Nwoko1, Lynn Cornell3 and Vesna Garovic1 1 Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA; 2Department of Medical Genetics, Mayo Clinic, Rochester, Minnesota, USA and 3Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
Correspondence: Vesna Garovic, 200 First Street SW, Rochester, Minnesota 55902, USA. E-mail: [email protected]
a
b
c
Figure 1 | Renal biopsy findings in a pregnant patient presenting with advanced renal dysfunction. (a) Arrow depicts the pathognomonic finding of underlying diagnosis in the intraluminal vessel by light microscopy (hematoxylin and eosin). (b) A partially sclerotic glomerulus shows mesangial hypercellularity and matrix expansion (Masson trichrome). (c) Immunofluorescence staining shows bright granular mesangial staining for immunoglobulin A.
An 18-year-old girl, 15 weeks pregnant, presented to our hospital for the evaluation of headache. Her history was significant for immunoglobulin A (IgA) nephropathy, with a baseline serum creatinine of 1.8 mg/dl. She had been diagnosed with IgA nephropathy at 11 years of age after presenting with an elevated creatinine and microscopic hematuria. Her renal biopsy at the time showed mild mesangial proliferation with mesangial IgA deposits. The patient was not undergoing any therapy for her IgA nephropathy before her pregnancy. The patient had no complaints other than headache. Her physical examination revealed a blood pressure of
162/109 mm Hg with normal mental status. The rest of her physical examination was unremarkable. Her laboratory workup was the following: creatinine, 8.5 mg/dl (0.6–1.1); blood urea nitrogen, 83 mg/dl (6–21); potassium, 6.1 mmol/l (3.6–5.2); hemoglobin, 10.4 g/dl (12.0–15.5); platelets, 223109/l (150–450109); aspartate aminotransferase, 23 U/l (8–43); alanine aminotransferase, 40 U/l (7–45); total bilirubin, 0.2 mg/dl (0.1–1.0); and international normalized ratio, 0.9 (0.8–1.2). Urine microscopy showed 21–30 RBC/ high-power field and occasional granular casts. A renal biopsy was performed for further evaluation of her renal failure (Figure 1a–c).
What is your diagnosis?
SEE NEXT PAGE FOR ANSWERS Kidney International (2014) 85, 1477–1478
1477
make your diagnosis
L Zand et al.: Atypical hemolytic uremic syndrome
The Diagnosis | Atypical hemolytic uremic syndrome Figure 1a shows evidence of thrombi in the blood vessels and is suggestive of a thrombotic microangiopathic process. The differential diagnosis of thrombotic microangiopathy (TMA) in pregnancy is listed in Table 1. The top differential diagnoses include atypical hemolytic uremic syndrome (aHUS), thrombotic thrombocytopenic purpura (TTP), and HELLP (hemolysis with elevated liver enzymes, and low platelets) syndrome. Early during pregnancy, in the absence of elevated liver enzymes and with a normal platelet count, HELLP syndrome is unlikely. The presence of severe renal failure requiring dialysis, along with the absence of profound thrombocytopenia, is more suggestive of aHUS rather than TTP. Atypical hemolytic uremic syndrome occurs in the absence of infection/diarrhea and accounts for 10% of the cases of hemolytic uremic syndrome. It is due to the activation of the alternative complement pathway (ACP) and carries a poor prognosis, with progression to end-stage renal disease in 50%1 and death in 25% of the cases.2 The most common form of aHUS is sporadic, without a known family history, and is typically associated with a trigger, such as malignancy, drugs, or organ transplantation.1 Even though pregnancy can be a trigger for the development of aHUS, recent studies suggest that up to 86% of these patients have an underlying mutation in the ACP.3 Evaluation of the ACP in our patient revealed a heterozygote missense mutation in the thrombomodulin gene (THBD), with a G to T conversion (c.1456 G4T), leading to substitution of aspartic acid (D) by tyrosine (Y) (D486Y). Her workup for mutations in the genes of the complement cascade, including complement factors H (CFH), I (CFI), B (CFB), membrane cofactor protein (MCP), complement component C (C3), and complement factor H–related protein (CFHR), was negative. Interestingly, the patient’s mother has the same THBD mutation, but has not developed aHUS to this date. This raises the possibility of incomplete penetrance of this mutation. Alternatively,
the underlying IgA nephropathy in our index patient may have contributed to the development of aHUS during pregnancy. Our patient had a normal platelet count at the time of presentation, and although thrombocytopenia is part of the triad of aHUS (in addition to anemia and renal failure), in the largest series of aHUS during pregnancy, the degree of thrombocytopenia was moderate, with 8 of the 20 patients having a platelet count 4100109/l. This is similar to our patient, whose platelet count reached a nadir of 105109/l following presentation. Intravascular hemolysis secondary to TMA was evidenced in our patient by the presence of anemia, an elevated lactate dehydrogenase of 414 U/l (122–222), and a low haptoglobin of 14 mg/dl (30–200), which was noted subsequently. Thrombomodulin gene mutations have been associated with aHUS. Delvaeye et al.4 sequenced the entire thrombomodulin gene in 152 patients with a clinical diagnosis of aHUS and 380 controls. Thrombomodulin gene mutations were identified in 7 of 152 patients (4.6%) and in none of the controls. Two of the seven cases had the same mutation as our patient (D486Y). Thrombomodulin increases the thrombin-mediated activity of plasma procarboxy peptidase B, which, in turn, inhibits C3a and C5a.4 It also facilitates CFI-mediated inactivation of C3b in the presence of CFH.4 Therefore, mutations in the THBD gene may result in the upregulation of the complement system and may lead to the development of aHUS. The patient was started and continued on daily hemodialysis during her pregnancy and at 32 weeks of gestation had a healthy baby boy by spontaneous vaginal delivery. Five months later, she underwent a living related kidney transplantation from her father. Her 1-year protocol biopsy showed features consistent with IgA nephropathy, but no evidence of recurrence of aHUS, with a baseline creatinine of 1.5 mg/dl. This may be due to the fact that the wild-type THBD (a membrane-bound glycoprotein) is present in the renal allograft and is protective against the development of aHUS.5
Table 1 | Differential diagnosis of TMA in pregnancy Severe pre-eclampsia associated with HELLP syndromea Acute fatty liver of pregnancya Thrombotic thrombocytopenic purpura Atypical hemolytic uremic syndrome Disseminated intravascular coagulation Antiphospholipid syndrome Malignant hypertension Scleroderma renal crises HELLP, hemolysis with elevated liver enzymes, and low platelets; TMA, thrombotic microangiopathy. a Specific for pregnancy.
1478
REFERENCES 1. 2. 3.
4. 5.
Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome. N Engl J Med 2009; 361: 1676–1687. Kaplan BS, Meyers KE, Schulman SL. The pathogenesis and treatment of hemolytic uremic syndrome. J Am Soc Nephrol 1998; 9: 1126–1133. Fakhouri F, Roumenina L, Provot F et al. Pregnancy-associated hemolytic uremic syndrome revisited in the era of complement gene mutations. J Am Soc Nephrol 2010; 21: 859–867. Delvaeye M, Noris M, De Vriese A et al. Thrombomodulin mutations in atypical hemolytic-uremic syndrome. N Engl J Med 2009; 361: 345–357. Edey MM. Thrombomodulin in atypical hemolytic-uremic syndrome. N Engl J Med 2009; 361: 1511.
Kidney International (2014) 85, 1477–1478