Renal artery stenosis I70.1

Renovascular hypertension was first described by Goldblatt in 1934 in his article "Studies on experimental hypertension: The Production of Persistent Elevation of Systolic Blood Pressure by Means of Renal Ischemia", in which he demonstrated in animal experiments on a healthy kidney that a reduction in renal blood flow leads to renovascular hypertension (Rehder 2011).

The treatment of renal artery stenosis in the form of angioplasty was described by Dotter and Judkins in 1964 (Möller 2013). According to Teßarek (2017), Andreas Grüntzig first published the therapeutic possibility of balloon dilatation for renal artery stenosis with renovascular hypertension in 1978 .

Renal artery stenosis (NAST / NAS) is the narrowing of one or both renal arteries, which can lead to renovascular hypertension and / or ischemic nephropathy from a degree of stenosis of 65% - 70% (Herold 2021).

NAST is etiologically subdivided into:

• 1. arteriosclerotic alteration (ANAST)
• 2. renal fibromuscular dysplasia (FMD).

(Kuhlmann 2015)

The following differentiation is also frequently found:

• uncomplicated NAST, defined as NAST of any degree with
  • stable blood pressure
  • stable renal function
• complicated NAST, which usually always occurs bilaterally or unilaterally in functional single kidney disease with
  • poor blood pressure control despite triple therapy
  • deterioration of renal function
  • Occurrence of pulmonary edema (flash pulmonary edema) (Oberhuber 2019)

The incidence of NAST is on the one hand age-dependent and on the other hand dependent on concomitant risk factors:

• 200.000 - 300.000 per annum
• 30 % with pAVK
• 30 % under dialysis
• 25 % of patients with CHD
• 22 % with aortic aneurysm
• 8.3 with diabetes mellitus
• 2 % - 5 % in patients with pre-existing arterial hypertension

NAST is found in 27 % of all autopsies. (Teßarek 2017)

Atherosclerotic NAST (see "Etiology") is found preferentially in patients > 65 years of age (Herold 2021) and occurs in 6.8 % of people > 65 years of age, fibromuscular dysplasia (see "Etiology") without arterial hypertension is found in 3 % - 5 % of all otherwise healthy patients who have agreed to donate a kidney (Kasper 2015).

NAST can be caused by:

Arteriosclerotic changes

Arteriosclerotic renal artery stenosis (ANAST) is the most common cause, accounting for 75% of all NAST (according to Manski [2019], it is as high as 90%). It is found preferentially in older patients and more frequently in men than in women (Herold 2021). The stenosis is predominantly found at the outlet of the renal artery (Keller 2010).

Risk factors for atherosclerosis are:

• arterial hypertension
• Hyperlipidemia
• hyperuricemia
• diabetes mellitus
• male sex
• genetic factors (familial clustering)
• Smoking (Manski 2019)

Renal fibromuscular stenosis

Fibromuscular stenosis is differentiated between medial and perimedial fibroplasia (Manski 2019).

This fibromuscular form of renal stenosis is found in 25% of all NAST. It occurs preferentially at a younger age (in adolescents or young adults [Risler 2008]). The stenosis is predominantly found in the distal portion of the renal artery or in intrarenal arteries (Keller 2010).

The female sex is more frequently affected than the male. Bilateral stenosis is present in 60% (Herold 2021).

Rare causes such as:

• Aneurysm of the renal artery.
• arteritis such as in panarteritis nodosa or Takayasu arteritis (Herold 2021)
• middle aortic syndrome (Manski 2019)
• dissecting abdominal aortic aneurysm
• Compression of the artery by e.g. tumor, cyst etc.
• Neurofibromatosis Recklinghausen (Kuhlmann 2015)

In patients with Z. n . NTX may also be caused by:

• stenosis in the area of the anastomosis
• an artery left too long (Hegele 2015)

The kidney influences blood pressure through the secretion of renin and its subsequent conversion to angiotensin (Teßarek 2017).

• Arterial hypertension:

Lumen constriction of the renal artery of ≥ 60% and the resulting reduced perfusion pressure leads to activation of the renin- angiotensin- aldosteronesystem (also known as the "Goldblatt effect"), decreased sodium excretion and sympathetic activation (Kasper 2015), thus triggering systemic arterial hypertension (Herold 2021).

• Ischemic nephropathy:

Ischemic nephropathy, triggered by reduced blood flow to the kidney, results from consecutive excretory dysfunction with an increase in creatinine and a decrease in glomerular filtration rate (Teßarek 2017).

Depending on the degree of stenosis, NAST often has only minor hemodynamic effects (Kasper 2015).

The following symptoms are suspicious for NAST:

• difficult-to-control hypertension despite the use of ≥ 3 different antihypertensives
• absence of nocturnal blood pressure lowering
• confirmed atherosclerosis (e.g., AVK, CHD, cerebrovascular disease) and concurrent hypertension
• recurrent phases of acute heart failure
• hypertensive crisis with pulmonary edema (flash pulmonary edema)
• epigastric flow murmur with existing hypertension
• Sudden deterioration of renal function with increase in creatinine of > 30 % - 50 % after initiation of therapy with an angiotensin II receptor blocker or an ACE inhibitor.
• onset of hypertension before the age of 25 or after the age of 50
• Kidney shrinkage with existing hypertension
• size difference of the kidney by > 1.5 cm (Herold 2021)
• arterial hypertension with
  • abdominal flow murmur
  • reduced kidney size of < 8 cm
• creatinine increase > 0.3 mg / d (Oberhuber 2019)

Further diagnosis is recommended in patients with:

• sudden onset of hypertension
• hypertension that is difficult to control with medication
• significant increase of serum creatinine and urea
• pain in the area of the renal bearings occurrence of pulmonary oedema
• acute left ventricular decompensation
• azotemia during treatment with ACE inhibitors (Teßarek 2017)
• Medical history:
  • Drug history
  • Evidence of previous pulmonary edema
  • History of cardiac events
• Thyroid examination
• Sonography:
  • with determination of the resistance index (RI)
• MRI:
  • indications of anomalies of the aorta
  • Alignment of the renal arteries
• CT angiography (usually only performed to clarify a re-stenosis or in the context of a planned interventional measure):
  • pacemaker carriers
  • Calcifications
• MAG 3 scintigraphy:
  • Determination of residual function in small kidneys
  • Function distribution
  • with a size difference of > 2 cm and a residual function < 10 %, a positive effect on renal performance after revascularization is no longer to be expected.
• ECG:
  • Indications of ischemia
• Echocardiography:
  • Wall thickness
  • left ventricular function
• ophthalmological examination:
  • Ocular fundus mirror examination (Teßarek 2017).

Imaging procedures in the presence of a NAST are:

Dopplersonography: Doppler sonography should be used as a screening procedure. Herewith can be determined:

• Peak systolic velocity (PSV)
• End diastolic velocity (EDV)
• reno- aortic quotient
• Resistive index (RI)

However, false negative results are found in 10 % - 20 %. (Manski 2019)

Duplex sonography: Duplex sonography is most commonly used for diagnosis. It is inexpensive, but the result depends on the examiner. It can be used to visualize the renal arteries, determine the flow velocity, estimate the degree of stenosis (Kasper 2015) and assess the intima of the vessels.

The sensitivity is 88%, the specificity 89% (Kuhlmann 2015).

Suspicious for stenosis are:

• Vmax A. renalis ≥ 2 m / sec
• RI (intrarenal resistance index) < 0.5
• RI- lateral difference > 5 (Herold 2021)
• reno- aortic quotient (RAQ) - assuming a normal flow in the aorta - of > 3.5 (Manski 2019).

However, duplex sonography is less suitable for the diagnosis of fibromuscular dysplasia and any changes in accessory renal vessels (Kasper 2015).

MR angiography: This allows good visualization of the renal arteries and the perirenal branches of the aorta, but not existing stents (Kasper 2015). The sensitivity is 97 %, the specificity 95 % (Kuhlmann 2015).

The examination is costly and should not be used above a GFR of < 30 ml / min / 1.73 m², as gadolinium can lead to nephrogenic systemic fibrosis [Herold 2021]). (Kasper 2015)

CT angiography: This also provides good imaging of the renal arteries and the perirenal branches of the aorta (kasper 2015). The sensitivity is 98% and the specificity is 94% (Kuhlmann 2015). The examination is expensive and a certain amount of contrast medium is required, which can be potentially nephrotoxic (Kasper 2015).

Captopril renal scintigraphy: One week before performing captopril renal scintigraphy, ACE inhibitors must first be paused. Scintigraphy is performed before and 1 h after captopril administration (recommended dosage: 25 mg p. o.). Pathological findings are:

• Decreased unilateral or bilateral function compared to baseline.
• differences in kidney size (signs of organ atrophy)
• delay in maximum secretion (> 11 min)
• the retention of the radionuclide is cortical

The sensitivity and specificity of the test are 90% (Manski 2019).

Intra-arterial angiography: Confirmation of the diagnosis is possible with intra-arterial digital subtraction angiography (i. a.- DSA). However, this examination should only be performed if the patient agrees to possible PTA and the possibility of balloon catheter dilatation exists (Herold 2021).

With i. a. DSA, the severity and exact localization of vascular lesions can be visualized. In diseases of the great vessels, the examination is considered the gold standard and is usually performed during a planned intervention (Kasper 2015).

Dangers of DSA are: athero-embolism, dissection and contrast agent toxicity (Kasper 2015).

The sensitivity of the method is 100%, the specificity is also 100% (Kuhlmann 2015).

• Decrease in GFR (both poststenotic and contralateral kidneys are affected by systemic hypertension and atherosclerotic NAST [Kasper 2015]).
• Hypokalemia (in the absence of diuretic use).
• Creatinine elevation
• Increase in renin (showing a sensitivity and also specificity of 80%).
• In urine: mild proteinuria (Manski 2019).
• Thyroid diagnostics (Teßarek 2017)

• chronic pyelonephritis
• Page's kidney (compression of the kidney by e.g. retroperitoneal haemorrhage, tumorous changes, renal cysts etc. can lead to activation of the renin-angiotensin-aldosterone system)
• congenital hypoplasia of the kidney
• Congenital dysplasia of the kidney
• Irradiation damage of the kidney
• renin-producing tumors such as:
  • Wilms tumor
  • renal cell carcinoma (Manski 2019)

• left ventricular hypertrophy
• renal fibrosis
• ischemic nephropathy (deterioration of renal function due to NAST)
• Tissue hypoxia (due to decrease in cortical perfusion during the course of the disease) (Kasper 2015).

The treatment of NAST depends on the type of stenosis, the age of the patient, any comorbidities (Herold 2021) and the type of NAST (complicated or uncomplicated [see "Classification"]). In patients with uncomplicated NAST, angioplasty shows no benefit over conservative treatment according to the ASTRAL and CORAL- study (Oberhuber 2019).

The treatment itself can be conservative or in the form of percutaneous transluminal angioplasty or surgery (see below "Internal therapy" and "Surgical therapy") (Herold 2021).

Elderly patients, patients with significant comorbidity, a RI- value > 0.8 should be treated conservatively with several antihypertensives including ACE inhibitors or ARBs (angiotensin II receptor blockers) (Herold 2021). For detailed information on the choice of medication, dosage, etc., see "Arterial Hypertension."

The target blood pressure should be < 140 - 130 / 70 - 79 mmHg (Oberhuber 2019).

In addition to blood pressure control, it is recommended:

• Statins for lipid lowering (target LDL < 70 mg / d).
• physical activity
• Inhibitors of the RAS system such as ACE inhibitors or ARBs (angiotensin II receptor blockers) are recommended.
  • always recommended for unilateral stenosis
  • recommended in bilateral stenosis or NAST in single kidney under close creatinine and potassium control
• Antiplatelet agents
• HbA1c should be ≤ 7.5 % in diabetics (Oberhuber 2019)

The invasive therapeutic options of NAST are

• percutaneous transluminal angioplasty (PTA)
• open surgical vascular operation

Both methods are indicated for bilateral involvement (because of the great risk of renal failure) and for single kidney (Manski 2019).

Surgically, several options are available (especially in younger patients without comorbidity [Herold 2021]):

• Bypass surgery with bypass of the stenotic area.
• excision of the stenosis
• Re-implantation of the renal artery into the aorta
• Nephrectomy (only rarely indicated in e.g. ischemic renal atrophy, malignant hypertension) (Keller 2010)
• Percutaneous transluminal angioplasty (PTA)

Indications for percutaneous transluminal angioplasty with or without stenting are:

• Fibromuscular stenosis: In this case, PTA without stent leads to a success rate of up to 50% (Herold 2021).
• ANAS: In ANAST, PTA- stent therapy is not effective in up to > 70 % of patients and is recommended only in exceptional cases such as:
• refractory hypertension
• rapid progressive renal insufficiency
• in cases of pulmonary oedema secondary to hypertension (Herold 2021).

Angioplasty is not recommended in:

• asymptomatic unilateral NAST (Oberhuber 2019).

Contraindications of PTA are:

• Cholesterol embolism
• Dissection of the intima
• Renal function deterioration after contrast administration
• Re- stenosis (this occurs in > than 30% of patients with arteriosclerotic stenosis) (Herold 2021).

Patients with an RI ≥ 8 usually do not benefit from the procedure (Herold 2021).

Blood pressure usually cannot be normalized by re-vascularization. The majority of patients continue to require medication to control their hypertension (Kasper 2015).

In Z. n. NTX:

• Endoluminal intervention with vascular angioplasty:

This intervention is indicated when a dissection occurs in the area of the anastomosis. If necessary, the additional insertion of a stent is required (Hegele 2015).

• Interventional endoluminal intervention: This can lead to flow improvement if the anastomosis is markedly stenosed (Hegele 2015).
• Revision to change the position: If there is kinking and / or the artery is left too long, the position of the kidney should be changed, e.g. intraperitoneally (Hegele 2015).

Atherosclerotic NAST: This, if left untreated, leads to progression in about 50% in 5 years, which can go as far as total occlusion in up to 16% (Manski 2019). This progression seems to be arrested by intensive drug treatment with statins and antihypertensive drugs (Kasper 2015).

Atherosclerotic NAST is also a strong predictor of both cardiovascular morbidity and mortality (Kasper 2015).

Surgical intervention (see above) can lead to cure or at least significant blood pressure reduction in patients suffering from hypertension < 5 years in approximately 80%-90% (Keller 2010).

In patients with hypertension that has been present for a longer period of time, angioplasty, for example, can lead to a normalization of blood pressure in only about 20 % of patients, since this is often a case of fixed nephrogenic hypertension. According to the CORAL study, stent therapy does not improve the prognosis (Herold 2021). Serious complications such as cholesterol embolism, stent occlusion, etc. are possible (Kuhlmann 2015).

Fibromuscular dysplasia: In fibromuscular dysplasia, complete occlusion of the artery or aneurysm formation rarely occurs. Renal function itself is usually preserved (Kasper 2015).

Angioplasty leads to normalization of blood pressure in approximately 75% of patients (Herold 2021). The 5 - 10 years- long-term results are good (Kuhlmann 2015).

Bilateral stenosis: If bilateral arteriosclerotic NAST is involved, surgical revascularization can lead to an improvement in blood pressure in 70% to 90% of cases, but normotensive values are rarely achieved (Keller 2010).

Unilateral stenosis: Patients with unilateral occlusion of the renal artery and arteriosclerotic stenosis of the opposite side have the highest risk of bilateral occlusion with consecutive renal failure and severe hypertensive derangement. More than 50% of these patients become terminally renal insufficient within 2 years (Keller 2010).

Mortality: In terms of therapeutic measures, the highest mortality is found in surgical procedures in the perioperative period. In less experienced hospitals this is around 10 %, in experienced hospitals between 0 % - 5 %. If there is also a disease of the aorto-iliac segment, the rate of perioperative renal failure with the need for dialysis increases in addition to mortality and is between 8 % and 18 %.

Conservative or interventional measures continue to show better outcomes in studies (Oberhuber 2019

Ischemic nephropathy: Patients who progress toischemic nephropathy have a very poor prognosis: 5-year mortality is approximately 50% (Herold 2021).

Renal failure requiring dialysis: The prognosis of renal failure requiring dialysis triggered by NAST is even less favorable. The median survival is 27 months, and the 5-year survival rate is 12% (Manski 2019).

Control examinations should take place before discharge, after 3 and after 6 months, then once a year. The following examinations are recommended:

• Control of the blood pressure setting
• Control of antihypertensive therapy
• Control of:
  • Kidney function
  • Electrolytes
  • Eosinophilia (to detect cholesterol embolism)
• Color-coded Doppler sonography (alternatively also CT possible, but more cost-intensive) (Oberhuber 2019)

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