Undiagnosed fibromuscular dysplasia in a deceased donor kidney transplant successfully treated with angioplasty

Abstract

A 41-year-old man with end-stage renal disease received a deceased donor kidney transplant without complication. Maintenance immunosuppression consisted of tacrolimus, mycophenolate and prednisone. Two months after transplantation, his creatinine did not improve beyond 2–2.3 mg/dL, which prompted allograft biopsy. His biopsy showed tubular epithelial injury without rejection, and given concern for possible calcineurin-inhibitor toxicity, his tacrolimus was changed to sirolimus. Renal function improved, but 1 month later he presented to the hospital with seizure activity, severe hypertension, acute kidney injury and MRI findings suggestive of posterior reversible encephalopathy syndrome. Blood pressure was difficult to control, which had not been the case in the immediate posttransplant period, and addition of lisinopril worsened his renal function. Transplant renal artery stenosis was suspected, and allograft ultrasound with doppler confirmed our suspicion. The patient underwent an angiogram, showing 60% stenosis of the mid-distal transplanted renal artery. Interventional radiology successfully stented this lesion, with subsequent improvement in allograft function and blood pressure control. He did not require further intervention in follow-up.

Background

Transplant renal artery stenosis (TRAS) is a common cause of refractory hypertension (HTN) in renal transplant patients, with estimated prevalence between 1% and 23%.¹ TRAS originating near the surgical anastomosis most often represents trauma to the donor vessel related to surgery or endothelial damage from catheter placement.² Other potential aetiologies of TRAS include atherosclerosis, donor kidney malposition (with subsequent turbulent inflow), external compression of the renal artery and allograft rejection.³ Fibromuscular dysplasia (FMD) is a non-atherosclerotic disease of medium-sized vessels affecting the renal artery, resulting in focal stenosis and aneurysms potentially involving any portion of the vessel.⁴ Here, we report an unusual case of TRAS resulting in posterior reversible encephalopathy syndrome (PRES) secondary to FMD in the deceased donor kidney.

Case report

A 41-year-old Caucasian man with a history of end-stage renal disease secondary to reflux nephropathy, HTN, anxiety and prior failed deceased donor kidney transplant (DDKT) after 13 years requiring hemodialysis received a second DDKT. The donor was a 40-year-old woman who died from drug intoxication. Kidney Donor Profile Index was 52% with serum creatinine (SCr) peaking at 2.6 from a nadir of 0.3 mg/dL. Kidney donor biopsy frozen section showed 176 glomeruli with 1% glomerulosclerosis, 1% interstitial fibrosis and tubular atrophy without findings of arteriosclerosis or hyalinosis. Induction immunosuppression included basiliximab and solumedrol, followed by maintenance regimen of prednisone, tacrolimus and mycophenolic acid; target tacrolimus trough level was 7–10 ng/mL. Early after transplantation, blood pressure was well controlled on amlodipine 10 mg daily. Two months post transplant, he underwent diagnostic allograft biopsy as the posttransplant SCr nadired at 2–2.3 mg/dL. Allograft biopsy revealed tubular epithelial injury without any evidence of rejection. Due to suspected calcineurin inhibitor toxicity, he was transitioned from tacrolimus to sirolimus, with improvement in SCr to 1.0 mg/dL.

Three months later, he presented to the emergency department with generalised tonic–clonic convulsions. Vital signs were notable for a fever of 102°F, heart rate of 110 beats/min, blood pressure of 206/145 mm Hg, while saturating 99% on room air. Significant physical examination findings included tongue laceration and 4/5 strength in his upper extremities. Initial laboratory workup demonstrated leukocytosis of 25 000 predominantly neutrophils without bandemia, and SCr 1.7 mg/dL. An X-ray of the scapulae showed mildly displaced fractures of the bilateral scapular wings and CT scan of his chest and spine demonstrated thoracic vertebral body compression fractures of the T4, T6 and T9 vertebral bodies with buckling of the posterior cortex of T6; the head CT scan and lumbar puncture were unremarkable.

Investigations

Given the patient’s clinical presentation with seizure activity reported as well as severe HTN, brain MRI was performed, yielding multifocal T2/flair hyperintensity in the subcortical white matter, predominantly involving the bilateral parietal lobes, consistent with PRES. MRIs are shown in figure 1. PRES secondary to calcineurin inhibitors is well described in the literature; however, our patient had been off tacrolimus for over 1 month and currently taking sirolimus. Furthermore, the patient was started on carvedilol 25 mgtwo times per day and amlodipine 10 mg daily, but his blood pressure remained poorly controlled. Lisinopril 40 mg daily was then added with good response, but subsequently SCr was elevated to 2.3 mg/dL raising the suspicion for TRAS. Allograft ultrasound with doppler showed markedly increased velocities and spectral broadening of the distal aspect, highly suggestive of TRAS. Follow-up abdominal CT angiography demonstrated 60% long segment stenosis of the mid-to-distal transplant renal artery with further stenosis within the intraparenchymal subsegmental renal artery branches, suggestive of FMD. Transplant renal artery angiogram revealed beading of the intraparenchymal renal artery consistent with FMD (figure 2).

Figure 1.

Brain MRIs showing multifocal bilateral signal abnormalities in juxtacortical white matter.

Figure 2.

Angiogram of transplanted kidney showing 60% stenosis of mid-distal transplant renal artery and multiple short segment stenoses of intraparenchymal subsegmental branches.

Treatment

Percutaneous balloon angioplasty with a 5 mm×20 mm Sterling balloon improved the stenosis to less than 40% on postangioplasty imaging (figure 3). Post angioplasty, the blood pressure markedly improved with systolic pressures averaging <140 mm Hg and SCr trending down to 1.1 mg/dL.

Figure 3.

Angiogram of the same transplanted kidney after balloon angioplasty demonstrating less than 40% stenosis of the transplanted renal artery.

Outcome and follow-up

One year after intervention, the patient is maintained on metoprolol 50 mg two times per day and doxazosin 2 mg daily with well-controlled blood pressure and stable allograft function (SCr 1 mg/dL). He has not required further vascular intervention.

Discussion

FMD has a reported prevalence between 2% and 4% based on previous studies of potential kidney donors. It represents the second most common anatomical abnormality in patients being evaluated for potential living kidney donation and may occur without clinical manifestations, even in those with bilateral FMD.^{5 6} Pretransplant detection is best achieved with CT angiography, and is widely used as a screening tool for those undergoing donor evaluations. Several case reports describe postoperative complications in kidney recipients with donor FMD allografts, and the failure to detect FMD in potential donors may lead to renal hypoperfusion and subsequent allograft failure.⁷ Despite potential complications, one single-centre retrospective study of living donors with FMD showed similar allograft outcomes compared with all other living donor recipients.⁸ HTN, progressive deterioration of allograft function and ACE inhibitor‐induced renal failure are the most common manifestations.⁹ In general, potential kidney donors with FMD are discouraged from donating due to potential renal artery stenosis progression after transplantation and associated allograft loss.¹⁰ FMD in a renal allograft remains a challenging diagnosis and should be considered in patients with refractory HTN and/or allograft dysfunction without signs of rejection. Typically, duplex ultrasound reveals a step-up in peak systolic velocity in the mid-to-distal portion of the main renal artery or a delayed systolic upstroke (tardus et parvus waveform) in arterial branches distal to the stenosis. Although the risk of renal artery dissection following percutaneous transluminal angioplasty has been reported, catheter-based angiography with percutaneous transluminal angioplasty remains the gold standard approach.^{11 12}

PRES was initially described by Hinchey et al in 1996 as a clinical neuroradiological entity.¹³ PRES is usually associated with hypertensive emergency, eclampsia/pre-eclampsia, sepsis, connective tissue disease/vasculitis, cancer chemotherapy, bone marrow/solid organ transplant and is well described secondary to calcineurin inhibitors such as tacrolimus. MRI is essential for the diagnosis with findings consistent of vasogenic oedema in the deep white matter in the occipital and parietal lobes. PRES classically presents with headache, visual abnormalities, focal neurological deficits, altered mentation or seizures, and the exact pathophysiology of remains unclear. Although few individuals can develop PRES with normotension, there may be episodes of HTN and transiently dysfunctional autoregulation causing vasogenic oedema. In addition to endothelial dysfunction, vasoconstriction-mediated hypoperfusion may play a role in the pathogenesis. Adverse effects of calcineurin inhibitors include neurotoxicity other than PRES, with frequency of calcineurin inhibitor-induced neurotoxicity among solid organ transplant recipients from 7% to 32%. Reported prevalence of PRES after solid organ transplant is only 0.49%, and most associated with tacrolimus. The hypothesised mechanism of calcineurin inhibitors causing PRES includes direct cytotoxic effects on brain endothelium resulting in dysfunction or demyelination in patients with PRES.¹⁴ PRES secondary to mTOR inhibitors such as sirolimus has been described in scarce case reports.¹⁵

This case illustrates the importance of recognising transplant renal artery stenosis in the setting of refractory HTN after deceased donor renal transplantation. We report an unusual case of FMD diagnosed 5 months after deceased donor kidney transplantation resulting in seizures from PRES due to hypertensive emergency. PRES has previously been well described in relation to calcineurin inhibitors; however, our patient’s tacrolimus was discontinued 3 months prior to his presentation. Given significant improvement in his blood pressure and lack of persistent neurologic symptoms after balloon angioplasty, the FMD-associated TRAS was likely cause of his PRES. Our case and several others have demonstrated improvement in allograft function and Blood pressure control after revascularisation; however, little is known regarding long-term outcomes and rates of reintervention in this patient population.

Learning points.

• Identify causes of hypertension after renal transplantation.

• Review differential diagnosis for transplant renal artery stenosis.

• Review diagnosis and treatment of fibromuscular dysplasia (FMD) post renal transplant.

• Recognise potential FMD post renal transplant and identify screening techniques for donors.