Management of renal vascular disease in neurofibromatosis type 1 and the role of percutaneous transluminal angioplasty

Caroline Booth1,, Rebecca Preston2, Godfrey Clark1 and John Reidy2

1 Departments of Paediatrics and 2 Radiology, Guy's Hospital, London SE1 9RT, UK



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. The effectiveness of percutaneous transluminal angioplasty (PTA) in renal artery stenosis (RAS) associated with neurofibromatosis type 1 (NF1) has not been established. A review of the literature revealed 14 studies, mainly case reports, of which a total of 16 patients had been treated with PTA, all prior to any surgery being undertaken.

Methods. A retrospective case review of 10 children with renal vascular disease secondary to NF was conducted to evaluate the outcome of different treatment modalities, including PTA. Four patients had unilateral disease, while six had bilateral disease, which was associated with middle aortic syndrome in three. Treatment was a combination of antihypertensive drug therapy, PTA and surgery. PTA was performed 15 times on six patients, nine procedures prior to surgery.

Results. The success rate for PTA on primary stenoses was 33% with improvement in blood pressure (BP) control in another 33%. Angioplasties performed on stenoses post-surgery had a success rate of 67%. There were no major complications and PTA had no adverse effect on subsequent surgery. The pre-surgery results obtained at a tertiary referral centre are consistent with those reported in the literature.

Conclusion. PTA is a safe and moderately effective treatment modality for RAS secondary to NF1. Although there is only limited success in primary stenoses as there is no adverse effect on subsequent surgery we feel it should be considered as first line management when clinically indicated.

Keywords: neurofibromatosis; percutaneous transluminal angioplasty; renovascular hypertension; renal vascular disease



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Von Recklinghausen first described neurofibromatosis type 1 (NF1) in 1882 as a hamartous disorder arising from the neural crest involving ectodermal, neuroectodermal and mesodermal tissue. It is an autosomal dominant disorder with a frequency of one in 3000 [1]. The gene for NF1 is located on the pericentric region of chromosome 17 and has variable penetrance. Approximately 50% of cases result from spontaneous mutations.

The incidence of hypertension in NF1 is approximately 1% and may be a result of coarctation of the aorta, phaeochromocytoma or renal artery stenosis (RAS). In younger patients the most common cause is RAS, occurring seven times more frequently than phaeochromocytoma. Approximately 25% of patients with hypertension have abdominal aortic involvement [2]. In contrast to fibromuscular dysplasia where 95% of all stenoses are found in the distal two-thirds of the renal artery, in NF1 more than 50% of all stenoses are located at the ostia [2].

Treatment modalities in renal vascular disease secondary to NF1 involve a combination of drug therapy, percutaneous transluminal angioplasty (PTA) and surgery. It is generally felt that stenoses involving the renal ostium respond poorly to PTA. There have been mixed reports of the effectiveness of PTA in NF1 with success rates of approximately 30% [316]. Reasons cited for the poor outcome included position of the stenosis and the variable extent of fibrotic tissue involved [9]. Most reports in the literature are single case studies.

A retrospective review was conducted to evaluate the effectiveness of different treatment modalities, in particular PTA, in 10 patients with NF1 who presented to tertiary referral centre over the last 20 years with hypertension secondary to renal vascular disease. All children with NF1 and increased blood pressure (BP) routinely have angiography performed once phaeochromocytoma has been excluded due to the known association between NF1 and RAS.



   Subjects and methods
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
This was a retrospective study from a major paediatric regional centre. Ten children with NF1 were diagnosed with RAS from 1982 to 2000. There were equal numbers of male and female patients. The age at diagnosis of hypertension ranged from birth to 15 years (median 5 years). Nine of the patients presented with a systolic BP greater than the 95th percentile for age and gender based on the Report of the Second Task Force on Hypertension [17]. The presenting BP for the tenth patient was not recorded in the notes as she had been treated initially at another hospital. Six of the children had been diagnosed previously with neurofibromatosis due to a family history or evidence of neurocutaneous stigmata. Of these, four were discovered to be hypertensive at a routine clinic visit, one presented with general malaise and vomiting while the last patient was admitted with malignant hypertension and associated left lower facial nerve palsy. Of the other four patients, one was noted to be hypertensive on routine examination while the other three presented with symptoms ranging from general malaise and headaches to irritability and vomiting.

Following appropriate management of the patients’ hypertension aortography was performed. Four of the patients were found to have only unilateral disease. The other six had bilateral involvement, two of these patients had associated middle aortic syndrome both these patients presented with high creatinine levels. One of these as well as another patient presented with raised creatinine levels prior to subsequent angioplasty. No stents were used in any of the procedures.

The technical success of the procedure was characterized by an increase in the diameter of the artery and no significant stenosis on the immediate post-PTA angiogram. Outcome of PTA was primarily assessed in terms of its effect on BP. Success or cure was defined as the normalization of the child's BP off all medication. Partial success was an improvement in BP control with concurrent or decreased antihypertensive medication while failure was achieving neither of the two previous criteria [18]. The secondary outcome was a change in serum creatinine concentration.



   Results
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Four patients had unilateral renal vascular disease all with normal renal function. Two patients had non-stenotic small vessel disease, one associated with multiple small aneurysm formation. This was treated by superselective embolization of three small aneurysms (Figure 1Go). Seventeen months later she is well, off all medication with no change in her renal function. The other child has good BP control using antihypertensive medication. One patient who had a left proximal renal artery stenosis underwent angioplasty but as this failed she subsequently underwent a left autotransplant. A year after surgery she developed a distal anastomotic stenosis in the autotransplant that was successfully dilated and has been off all antihypertensive medication for the last 6 years. The last patient had been noted to have a right renal artery stenosis in 1981 at another hospital that was treated medically. In 1994 she presented to this hospital with increasingly difficult hypertensive control and she underwent a right nephrectomy for a renal artery aneurysm. She remains normotensive off all medication with a creatinine within the normal range (Table 1Go).



View larger version (70K):
[in this window]
[in a new window]
 
Fig. 1.  Superselective embolization of renal aneurysms: (a) pre-embolization and (b) post-embolization.

 

View this table:
[in this window]
[in a new window]
 
Table 1.  Clinical summary of patient data—unilateral renal vascular disease

 
Five out of six patients with bilateral disease had attempted angioplasty; the sixth patient was unsuitable for PTA due to concomitant medical problems. Her BP has been controlled by medication. Of the five remaining patients, one with MAS had surgical repair of both renal arteries and subsequent renal transplantation. This patient subsequently had angioplasty to the anastomosis of his aortic PTFE graft resulting in an improvement in both BP control and creatinine. Patient 2 underwent unsuccessful surgery to the right renal artery that resulted in nephrectomy. He then had successful angioplasty performed on the remaining renal artery since then his creatinine has always remained within normal range. Patient 3 had initial bilateral angioplasty with a good technical result. Restenosis occurred 5 months later and he had further angioplasty due to difficult to control BP and raised creatinine. This was unsuccessful and resulted in bilateral autotransplantation followed by a left nephrectomy. He has since had angioplasty performed twice on the remaining autotransplanted kidney, resulting in an improvement in creatinine and BP control on medication. Patient 4 had initial surgery on the right side and failed angioplasty on the left requiring surgery within 4 weeks. Ten years later he had subsequent angioplasty performed on the proximal end of the anastomosis, which improved the control of both BP and creatinine. The final patient was treated with bilateral angioplasty and remains normotensive and is off medication 12 months later (Table 2Go, Figure 2Go).


View this table:
[in this window]
[in a new window]
 
Table 2.  Clinical summary of patient data—bilateral renal vascular disease

 


View larger version (77K):
[in this window]
[in a new window]
 
Fig. 2.  Successful angioplasty of a proximal renal artery stenosis: (a) pre-angioplasty and (b) post-angioplasty.

 
A total of 32 stenoses were detected in the 10 patients reviewed. Seventeen were primary stenoses while 15 occurred following surgery. Only one patient has progressed to end-stage renal failure. Fifteen angioplasties were performed on six of the patients, nine prior to any surgery and six postoperatively. Technical success was reported in 10 of the 15 angioplasties (Tables 1Go and 2Go). Of the total 15 angioplasties performed, clinical success/cure was seen in seven (47%), five (33%) resulted in improved BP control although the patients still required some antihypertensive medication with only three (20%) failing to show any improvement (Table 3Go). In the four cases where renal function was noted to have deteriorated prior to treatment, post-PTA there was an improvement of greater than 15% in the serum creatinine. Evaluation of the timing of PTA revealed a success rate in the pre-surgical group of 33% compared with 67% post-operatively (Table 3Go). There were no complications reported with any of the procedures and PTA did not adversely interfere with subsequent surgery.


View this table:
[in this window]
[in a new window]
 
Table 3.  Clinical outcomes of PTA at Guy's Hospital

 



   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Renal artery stenosis is the most frequently reported vascular lesion in neurofibromatosis [2] and as seen in our group of patients, may be unilateral or bilateral. Greene et al. [19] described two basic categories of stenosis in NF1. The first involves larger vessels such as the aorta, carotid and proximal renal arteries, which are surrounded by neurofibromatosis or ganglioneuromatous tissue. Intimal proliferation, thinning of the media and fragmentation of elastic tissue may lead to stenosis or aneurysm formation. The second type is unrelated to neural malformation, but probably reflects a dysplasia of small vessels. Lesions occur in many arteries and involve the minute intrarenal branches. With use of electron microscopy, Greene et al. [19] identified smooth muscle elements within the abnormal cells and concluded that the vascular lesion is a form of mesodermal dysplasia. It is unknown whether the histological lesion seen in renal artery stenosis associated with NF1 influences the outcome of therapy.

Treatment of hypertension due to RAS in NF1 is usually a combination of drug therapy, PTA and surgery. Studies of PTA have reported this technique as an effective and safe treatment for hypertension caused by renal artery stenosis in children [3]. Courtel et al. [4] demonstrated that the success of PTA was closely related to the type of stenosis, with angioplasty of an isolated lesion having a success rate of 70% while it appeared ineffective in cases were multiple stenoses were present.

On a review of the literature there were 16 reported cases of children with NF1 with RAS who had undergone angioplasty. All of these were undertaken prior to any surgery being attempted and only a few reports looked at long-term outcome. There were 10 males and six females with the age range between 3 and 29 years (median 10 years). Thirty three per cent had a successful result, 13% had an improvement in BP control on medication while 54% required surgery. In a few of the patients medication was only completely weaned several months after the angioplasty was performed (Table 4Go).


View this table:
[in this window]
[in a new window]
 
Table 4.  Published outcomes from PTA in neurofibromatosis

 
Success rates at this tertiary referral centre prior to any surgical intervention are 33%, which is similar to that seen in the literature. A further 20% of patients benefited from an improvement in BP control. Potential complications of PTA include haemorrhage or haematoma at the puncture site, transient renal failure induced by contrast media, spasm of the renal artery, embolization of the kidney, renal infarction, dissection, perforation or rupture of the renal vasculature, anuria and balloon rupture. There were no major complications experienced by any of our patients. The advantages of PTA over surgery are multiple. The use of local anaesthetic is precluded in younger infants but the reduced morbidity from lack of a surgical incision and reduced stay in hospital is advantageous to all age groups. PTA did not interfere with subsequent surgery if this was necessary [20].

Renal vascular disease in NF1 presents a difficult management problem; treatment should be patient-specific within a multidisciplinary setting. Although there is only limited success with primary stenoses, PTA is not detrimental to subsequent vascular reconstruction and has few complications when undertaken by an experienced radiologist. Following surgery there is a high rate of recurrent stenoses but these respond well to PTA. As a result, we feel angioplasty should be first line management when clinically indicated in both primary stenoses and those following surgery. PTA is an effective adjunct to drug therapy and surgery and should be considered when dealing with RAS in NF1.



   Notes
 
Correspondence and offprint requests to: Caroline Booth, Department of Paediatrics, Level 12, Guy's Tower, London SE1 9RT, UK. Email: caroline.booth{at}kcl.ac.uk Back



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

  1. Riccardi VM. Von Recklinghausen neurofibromatosis. N Engl J Med1981; 305: 1617–1626[ISI][Medline]
  2. Schurch W, Messerli FH, Genest J et al. Arterial hypertension and neurofibromatosis: renal artery stenosis and coarctation of abdominal aorta. Can Med Assoc J1975; 113: 879–885[Abstract]
  3. Mali WP, Puijlaert CB, Kouwenber HJ et al. Percutaneous transluminal renal angioplasty in children and adolescents. Radiology1987; 165: 391–394[Abstract]
  4. Courtel JV, Soto B, Niaudet P et al. Percutaneous transluminal angioplasty of renal artery stenosis in children. Pediatr Radiol1998; 28: 59–63[ISI][Medline]
  5. Martin EC, Diamond NG, Casarella WJ. Percutaneous transluminal angioplasty in non-atherosclerotic disease. Radiology1980; 135: 27–33[ISI][Medline]
  6. Baxi R, Epstein HY, Abitbol C. Percutaneous transluminal renal artery angioplasty in hypertension associated with neurofibromatosis. Radiology1981; 139: 583–584[Abstract]
  7. Guzzetta PC, Potter BM, Kapur S, Ruley EJ, Randolph J. Reconstruction of the renal artery after unsuccessful percutaneous transluminal angioplasty in children. Am J Surg1983; 145: 647–651[ISI][Medline]
  8. Lund G, Sinailo A, Castaneda-Zuniga W, Cragg A, Salomonowitz E, Amplatz K. Percutaneous transluminal angioplasty for the treatment of renal artery stenosis in children. Eur J Radiol1984; 4: 254–257[ISI][Medline]
  9. Millan VG, McCauley J, Kopelman RI, Madias NE. Percutaneous transluminal renal angioplasty in nonatherosclerotic renovascular hypertension, long-term results. Hypertension1985; 7: 668–674[Abstract]
  10. Mallmann R, Roth FJ. Treatment of neurofibromatosis associated renal artery stenosis with hypertension by percutaneous transluminal angioplasty. Clin Exp Hypertens A1986; 8: 893–899[ISI][Medline]
  11. Gardiner GA Jr, Freedman AM, Shlansky-Goldberg R. Percutaneous transluminal angioplasty: delayed response in neurofibromatosis. Radiology1988; 169: 79–80[Abstract]
  12. Robinson L, Gedroyc W, Reidy J, Saxton HM. Renal artery stenosis in children. Clin Radiol1991; 44: 376–382[ISI][Medline]
  13. Tegtmeyer CJ, Matsumoto AH, Angle JF. Percutaneous transluminal angioplasty in fibrous dysplasia and children. In: Novick AC, Scoble J, Hamilton C, eds. Renal Vascular Disease. WB Saunders Company Ltd, London, UK, 1996; 363–383
  14. Fossali E, Minoja M, Intermite R, Spreafico C, Casalini E, Sereni F. Percutaneous transluminal renal angioplasty in neurofibromatosis. Pediatr Nephrol1995; 9: 623–625[ISI][Medline]
  15. Kurien A, John PR, Milford DV. Hypertension secondary to progressive vascular neurofibromatosis. Arch Dis Child1997; 76: 454–455[Abstract/Free Full Text]
  16. McTaggart SJ, Gelati S, Walker RG, Powell HR, Jones CL. Evaluation and long-term outcome of pediatric renovascular hypertension. Pediatr Nephrol2000; 14: 1022–1029[ISI][Medline]
  17. Horan MJ, Falkner B, Kimm Sue YS et al. Report of the Second Task Force on blood pressure in children. Pediatrics1987; 79: 1–25[Abstract]
  18. Maxwell MH, Bleifer KH, Franklin SS, Varady PD. Cooperative study on renovascular hypertension: demography analysis of the study. J Am Med Assoc1972; 220: 1195–1204[Medline]
  19. Greene JF, Fitzwater JE, Burgess J. Arterial lesions associated with neurofibromatosis. Am J Clin Pathol1974; 62: 481–487[ISI][Medline]
  20. Chevalier RL, Tegtmeyer CJ, Gomez RA. Percutaneous transluminal angioplasty for renovascular hypertension in children. Pediatr Nephrol1987; 1: 89–98[ISI][Medline]
Received for publication: 26. 7.01
Accepted in revised form: 2. 2.02