Hereditary thrombotic thrombocytopenic purpura (TTP) with co-occurring autosomal dominant polycystic kidney disease (ADPKD)

Background

Genetic disorders involving the kidneys and leading to renal failure are either chromosomal, monogenic or polygenic.1 Monogenic disorders are caused by a mutation of one gene, and they are inherited as either autosomal dominant, autosomal recessive or X-linked. Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent hereditary kidney disease, and it is the most common hereditary cause of end-stage renal disease in the adult population.1 It is caused by a monogenic mutation of either the PKD1 or the PKD2 gene, which encodes the polycystin-1 and polycystin-2 proteins, respectively.1 The PKD1 gene is located on chromosome 16p13.3, while the PKD2 gene is located on chromosome 4q21. When women with ADPKD get pregnant, the overall risk of fetal complications is similar to those without ADPKD while the risk of maternal complications such as the development of new onset hypertension, worsening or pre-existing hypertension, oedema and pre-eclampsia is increased.2

Hereditary thrombotic thrombocytopenic purpura (TTP) is another monogenic disorder, which may also affect the kidneys leading to renal failure. It is, however, inherited as autosomal recessive and caused by a mutation in the gene encoding for von Willebrand factor (vWf)-cleaving protease enzyme called ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13).3 Pregnancy in women with hereditary TTP may be the first presentation of the disease, and is usually associated with severe complications.3 Maternal complications may include hypertension, severe pre-eclampsia, neurological manifestations such as transient ischaemic attack and acute kidney injury.4 5 Fetal complications may include premature birth, intrauterine fetal death and stillbirth.4

Knowing the underlying genetic disorder, the pattern of inheritance and the clinical course is crucial to the management of all affected patients. This is especially relevant when counselling patients about the risk of passing on the disease to offspring and pregnancy outcomes, and the screening and counselling of other family members.

Case presentation

A woman in her late 20s, G1P0 at 16 weeks gestation, presented with a history of fatigue and spontaneous bluish discolouration over her arms and legs. This patient had no history of trauma or bleeding, fever, chills or headache. Her systemic review was unremarkable. She was using no medications apart from antenatal vitamins. All couples in the family are distant cousins and descend from the same tribe. Her paternal family history is unremarkable; however, her maternal family history reveals that her mother has chronic kidney disease secondary to ADPKD and started haemodialysis in her 70s. The patient’s eldest sister has one son, she had an ultrasound for her kidneys and it was unremarkable. Another sister had hereditary TTP diagnosed during the neonatal period and died in her 20s. The third sister also died in her 20s during her first pregnancy when she was presented with bleeding (died before testing was performed). The fourth sister is in her 20s, has never been pregnant and was diagnosed with hereditary TTP as an adolescent. The youngest sister is in her 20s with no previous pregnancies. She has no symptoms, and her kidney ultrasound tested negative for polycystic kidneys. The index patient’s family history is summarised in figure 1.

On clinical examination, she was conscious, alert and oriented. Her blood pressure was 164/83 mm Hg, pulse 85 beats/minute, respiratory rate 18 /minute and oxygen saturation 98% on room air. She was afebrile. Respiratory, cardiovascular and neurological examination was unremarkable. She had bilateral pitting lower limb oedema. She also had multiple ecchymotic patches over her arms, legs and thighs. Abdominal examination revealed a gravida uterus with a fundal height corresponding to 16 weeks of gestation. Urine examination showed no casts, white blood cells of 18–20, red blood cells of 20–25, blood as+2 and protein as+3.

Investigations

Initial and subsequent relevant laboratory investigations during the hospital course are summarised in (table 1). After admission, an ultrasound of her kidneys was performed, which showed bilateral cortical rounded echoic structures with posterior enhancement, representing a simple renal cyst (figure 2).

Treatment

She was admitted as a case of pre-eclampsia with the suspicion of TTP for further workup. Autoimmune tests, ADAMTS13 activity and inhibitors profile, genetic testing for ADAMTS13 were sent. Initial fetal ultrasound showed a single viable intrauterine pregnancy with an estimated gestational age of 16 weeks and 6 days. After admission, she received methyldopa and labetalol for blood pressure control, as well as pulse steroids and plasma exchange through a central line. Her clinical and laboratory parameters did not improve. Ten days after admission, she developed shortness of breath, haemoptysis, severe hypertension and hypoxaemia. Her chest X-ray revealed diffuse bilateral extensive infiltrates. She was transferred to the intensive care unit where she was intubated, mechanically ventilated and started on broad-spectrum antibiotics, intravenous diuretics and an intravenous nitroglycerin infusion for volume overload.

Transthoracic echocardiogram showed reduced a left ventricular ejection fraction of 40%–45%. Bronchoscopy revealed old clots in the trachea and left main bronchus but there was no acute bleeding. She also developed acute kidney injury with a peak creatinine of 1.49 from an initial level of 0.8 mg/dL. This was managed conservatively. An ultrasound scan of the kidney showed two bilateral simple cortical cysts. In addition, she had therapeutic thoracentesis for right pleural effusion. Despite continuing on high-volume plasma exchange and steroids, her clinical and laboratory parameters did not improve. Repeat fetal ultrasound showed oligohydramnios and a non-viable pregnancy. She underwent surgical termination of pregnancy after conducting a multidisciplinary meeting between all involved teams and the family. She continued to receive plasma exchange and steroids, and rituximab was added after the operation. A kidney biopsy was performed and showed changes suggestive of acute and chronic thrombotic microangiopathy. She improved dramatically over the next few days and was successfully extubated. Her laboratory investigation results including creatinine, platelets and haemoglobin, improved. After discharge, the results of ADAMTS13 activity profile and genetic testing were available and are shown in table 1. She was switched to a plasma infusion every 3 weeks, and steroids were tapered off.

Outcome and follow-up

Four years later, she was admitted with nausea, vomiting and epigastric pain. During the admission, an ultrasound scan of the abdomen was performed which revealed multiple cysts of different sizes affecting both kidneys consistent with polycystic kidney disease (figure 2). This was redemonstrated on a CT scan of the abdomen which was done to rule out pancreatitis. She likely had viral gastritis, which improved with conservative management. Her creatinine at that time was normal, and she had no proteinuria. She was informed that she has ADPKD based on her radiological findings and family history. She remains under outpatient follow-up and is asymptomatic. From the TTP point of view, she is in complete remission and has not required plasma infusion in the last 2 years (with a platelet count between 250 and 330 × 10⁹ /L, and a haemoglobin level between 105.0 and 118.0 g/L). In terms of ADPKD, her last creatinine is 0.9 mg/dL, and her urine protein to creatinine ratio (PCR) is 0.05 mg/mg on perindopril (peak urine PCR was 1.13 mg/mg). We informed the patient of the previously mentioned maternal and fetal complications, which may occur in pregnant patients with hereditary TTP or ADPKD. She was strongly advised against any unplanned pregnancy. However, she was informed that even planned pregnancy with close monitoring and prophylactic plasma infusion may not prevent the occurrence of some complications such as pre-eclampsia.5 This may be especially true in her case because she has two genetic conditions that may predispose to severe pre-eclampsia, given that the pregnancy outcomes of similar patients are unknown. She has discussed the pregnancy plan with her spouse and some of her family members, and has opted to avoid pregnancy. However, when she was referred to the gynaecology team for counselling about contraceptive methods, she refused tubal ligation. She and her spouse decided to pursue reversible male contraceptive methods.

We advised her that all her siblings need to be screened with measurements of ADAMTS13 activity. This is particularly important for her two sisters who are not known to have hereditary TTP and have never been pregnant before. All living sisters have had an ultrasound scan of the kidneys (found to be normal). We have advised that other adult siblings will also need to have an ultrasound of their kidneys, and we have strongly recommended that other family members see their family physicians for screening and counselling including premarital counselling.