Nephropathy, ischemic

As early as 1842, Christian Johann Doppler described the Doppler effect named after him (Katsi 2013). In 1934, Harry Goldblatt was the first to prove the connection between a narrowing of the renal arteries and the consecutive increase in blood pressure in a study on dogs. However, it took decades before stenoses of the renal arteries were treated surgically and later interventionally (Prischl 2017).

In 2001, Rademacher et al. were the first to establish criteria for which patients with renal artery stenosis did not benefit from interventional therapy. With regard to blood pressure improvement, an intervention showed a positive predictive value of 94% and a negative predictive value of 97% with a resistance index of ≥0.8. With regard to renal function improvement, the predictive value ranged from 71-82% depending on the baseline creatinine clearance. Conversely, this means that a high resistance index of ≥ 80 is prognostically unfavourable with regard to the success of an intervention (Sturm 2008 / Prischl 2017).

Ischemic nephropathy refers to the sequelae of renal artery stenosis (NAST [Lenz 2015]).

NAST can lead to different clinical symptoms: In the case of a hemodynamically effective uni- or bilateral NAST, renovascular hypertension occurs. If renal function is also impaired as a result, this is referred to as ischemic nephropathy (Herold 2021).

Etiologically, renal artery stenosis is differentiated between fibromuscular dysplasia and arteriosclerotic stenosis (ANAST = ARSS = artherosclerotic renal artery stenosis [Prischl 2017]).

Arteriosclerotic renal artery stenosis (ANAST) occurs more frequently in men than in women and prefers older age. The incidence is generally 1% in hypertensive patients, and already approx. 7% in patients > 65 years of age (Herold 2021). A decisive risk factor is smoking and an existing diabetes mellitus type 2 disease (Mehnert 2003).

Nephropathy caused by renal fibromuscular stenosis - defined as an idiopathic, non-atherosclerotic, segmental disease in the muscle cells of the arterial wall (Prischl 2017) - is found more frequently in women than in men. It prefers a younger age, i.e. the 3rd or 4th decade of life (Hoyer 2015) and occurs bilaterally in 60% (Herold 2021). A familial cluster of the disease is found in approximately 10% of patients (Hoyer 2015).

In patients > 50 years, chronic renal failure is caused by ischemic nephropathy in 5%-20% (Blum 2018).

It is also the most common vascular cause of bilateral renal dysfunction (Seitz 2008).

Etiologically, 75% (Herold 2021) of ischemic nephropathies are caused by arteriosclerotic changes in the renal arteries (Geiger 2003) or the aorta near the ostium (Lenz 2015). However, before renal artery stenosis can become hemodynamically relevant, there must be a degree of stenosis of at least 65%-70% (Herold 2021).

Second in etiology is fibromuscular dysplasia, which occurs in approximately 25% (Herold 2021). In this case, the stenoses are not located close to the outlet, but often in the middle or distal to the renal artery. It is not uncommon for other arteries to be affected such as:

• carotid artery
• intracerebral arteries (Hoyer 2015).

Only rarely are other causes found, such as aneurysm of the renal artery, panarteritis nodosa, Takayasu arteritis (Herold 2021).

Most often, ANAST develops secondarily to primary hypertension. Sometimes, however, it also develops as a result of other atherosclerotic risk factors.

The lumen narrowing of the renal artery stenosis of 60% or more leads to an activation of the renin-angiotensin-aldosterone system, also known as the "Goldblatt effect". This causes renovascular hypertension (see also "Definition"), which in turn can lead to damage to the kidney (Herold 2021).

Arteriosclerotic remodelling processes in the area of the vessel walls of the renal arteries and later also of the distal arteries and arterioles lead to ischaemic renal damage. The latter causes cortical scarring with consecutive shrinkage of the affected kidney (Hoyer 2015).

Intrarenally, chronic ischemic tissue damage occurs in ischemic nephropathy due to persistent arterial underperfusion, which can cause glomerulosclerosis, tubulointerstitial fibrosis, and tubular atrophy to develop. These changes are caused by:

• Cytokine production
• oxidative stress
• profibrotic or prosclerosing effects of aldosterone and angiotensin II (Hoyer 2015).

Ischemic nephropathy with progressive lumen narrowing can lead to a restriction of renal function in the sense of chronic renal insufficiency - also referred to as "chronic kidney disease" (CKD).

The occurrence of a renal infarction is rare in the case of a gradually developing complete occlusion, since the vessels of the renal capsule are nutritively sufficient (Geiger 2003).

Patients show no or only non-specific symptoms in the first stages of CKD, such as:

• Poor performance
• fatigue (Kuhlmann 2015)

In advanced CKD, there are then:

• Edema
• Shortness of breath (due to pleural or pericardial effusions)
• Loss of appetite
• Itching
• Lack of concentration
• Bone pain (Kuhlmann 2015)
• Polyneuropathy (predominantly affects the sensory nerves, motor nerves are only affected in severe uremia) (Woolliscroft 2013).

In contrast, unilateral stenosis of the renal artery usually causes no symptoms (Geiger 2003).

Evidence of ischemic nephropathy may include (Geiger 2003):

- arterial hypertension before the age of 25 years or after the age of 60 years.

- proteinuria with bland urine sediment

- diabetes mellitus type 2 disease

- recurrent pulmonary oedema

- hypertensive end organ damage such as:

• peripheral occlusive disease
• cerebrovascular diseases
• coronary heart disease
• hypertensive retinopathy III - IV

- hypertension with:

• confirmed atherosclerosis
• flow murmur epigastric, paraumbilical or in the area of the flanks
• pulmonary edema in the context of a hypertensive crisis, so-called "flash pulmonary edema

• recurrent pulmonary edema in bilateral renal artery stenosis, so-called "Pickering syndrome" (Oberhuber 2019)
• multiple episodes of acute heart failure
• Renal shrinkage (< 8 cm [Oberhuber 2019])
• Size difference of the kidneys of > 1.5 cm in hypertensive patients
• Creatinine increase of > 30 % - 50 % during treatment with angiotensin II receptor blockers or ACE inhibitors
• arterial hypertension difficult to control despite use of 3 or more antihypertensives
• Lack of circadian rhythm in 24-hour blood pressure measurement
• deterioration of renal function after implantation of an aortic stent graft (Prischl 2017)

- In the event of sudden occlusion of the renal artery, the following may occur:

• severe flank pain
• Hematuria
• Increase of LDL in the serum

The diagnosis is aimed at detecting significant renal artery stenosis. However, the invasiveness and intensity of the diagnosis should be made depending on any indication for angioplasty (Hoyer 2015).

Physical examination: On physical examination, a stenotic murmur is found epigastrically, paraumbilically, or in the flank region. Otherwise, the physical examination is unremarkable in ischemic nephropathy (Hoyer 2015). Only the later stages of chronic renal insufficiency are associated with abnormalities such as e.g. lower leg oedema, dyspnoea etc. (for more details see d.).

Long-term blood pressure measurement: Here, a disturbed circadian rhythm with a lack of night setback is shown as an indication of secondary hypertension, regardless of the cause (Oberhuber 2019).

Abdominal sonography

• kidneys are reduced in size or show a lateral difference of > 1.5 cm (Hoyer 2015)
• surface smooth with small retractions
• rarely larger scarring retractions occur
• Parenchyma:
  • Parenchymal rim narrow
  • Echogenicity normal to increasing
  • Parenchymal defects as an indication of past renal embolism or renal infarction
• Due to arteriosclerotic altered renal vessels:
  • in the parenchyma and in the hilar region small echoes with attenuation or extinction of sound
  • vessels sometimes pulsating and double contoured (Seitz 2008)

Color-coded duplex sonography (FKDS): Color-coded duplex sonography is the best screening method for suspected renal artery stenosis (Herold 2021). Sensitivity is 85% and specificity is 92% (Prischl 2017). Pathological values are:

• intrarenal resistance index (RI) < 0.5
• Lateral difference of the RI > 5
• Vmax A. renalis ≥ 2 m/s.

The result in color-coded duplex sonography depends on the experience of the examiner (Herold 2021). Especially in case of V. a. unilateral processes of the kidney this examination is indispensable (Geiger 2003).

MR angiography: MRI angiography is the second choice in terms of diagnostics. The advantage is that the examination is non-invasive. The disadvantage is an overestimation of the degree of stenosis (Hoyer 2015). The sensitivity is 100% and the specificity is 96% (Prischl 2017). MR angiography is contraindicated from a GFR< 30 ml / min with gadolinium, otherwise there is a risk of nephrogenic systemic fibrosis (Herold 2021).

Spiral CT: Here, a relative contraindication exists with the use of a potentially nephrotoxic contrast agent from a GFR < 30 ml / min. In addition, the radiation exposure is quite high (Herold 2021). The sensitivity of spiral CT is 93% and the specificity is 81% (Prischl 2017).

Intra-arterial digital subtraction angiography (i.a.- DSA): i.a.- DSA is the gold standard for confirming the diagnosis. However, it should only be performed if the patient agrees to possible PTA and the possibility of balloon catheter dilatation exists. On examination, a hemodynamically relevant stenosis can be estimated from a systolic transtenotic pressure gradient of > 10 - 15 % (Herold 2021).

Captopril-assisted renal scintigraphy: It is an established investigation of the functional relevance of a stenosis and is conclusive for renovascular hypertension. A positive test result is positively predictive of improvement in blood pressure after intervention. However, sensitivity decreases with impaired renal function (Oberhuber 2019).

The following tests are no longer recommended as screening tests for ischemic nephropathy:

• selective renal vein renin determination
• Captopril- radionucleide- scintigraphy (sensitivity is > 90 % and specificity > 90 % (Prischl 2017).
• Captopril- test
• Plasma renin activity (sensitivity is 75 - 100 % and specificity is 60 95 % (Prischl 2017) (Oberhuber 2019).

In ischemic nephropathy may be present:

• proteinuria with bland urine sediment (Geiger 2003)
• Creatinine increase (Herold 2021)
• Hematuria
• Increase of LDL in serum (Geiger 2003)
• decreased eGFR (Hoyer 2015)
• Increase in cystatin (reliable in early stages of renal failure)
• Determination of the degree of albuminuria by the quotient albumin / creatinine (Oberhuber 2019)

Histologically, arteriosclerotic ischemic nephropathy shows focal glomerulosclerosis. However, biopsy is rarely required for diagnostic reasons (Geiger 2003).

In fibromuscular dysplasia, there is increased deposition of collagen fibers plus disintegration of elastic fibers in the media of the renal artery. The intima is rarely affected by these changes. Sometimes there is also a medial hyperplasia of the vascular smooth muscle (Hoyer 2015).

In fibromuscular dysplasia differential diagnosis should be considered:

• Marfan syndrome
• Alport syndrome
• Ehlers-Danloss syndrome

(Hoyer 2015)

• sudden occlusion of the renal artery by dissection (rarely occurring) (Geiger 2003)
• Cholesterol embolism
• Dissection of the intima
• Worsening of renal function due to contrast medium
• Re-stenosis (occurs in > 30% of patients with arteriosclerotic stenosis) (Herold 2021)

There is no specific treatment for ischemic nephropathy (Hoyer 2015). In earlier years, interventional measures were increasingly used in this context: in 1996, there were still 7,660 interventions, in 2000 already 18,520 and in 2005 estimated around 35,000. Three large studies STAR (2009), ASTRAL (2009) and CORAL (2014) with a long recruitment period of 5 - 7 years showed that stent implantation brought considerable risks but no significant benefit. Subsequently, revascularization procedures decreased by up to 75% (Pischl 2017).

Patients with advanced age, an RI- value > 0.8 and high comorbidity should be treated conservatively. Various antihypertensives using ARBs or ACE inhibitors are available (Herold 2021), see also "Internal therapy".

The target values for blood pressure control are < 140 / 90 mmHg, but not < 125 / 75 mmHg. An exception exists in the case of additional albuminuria of > 30 mg / g. In this case, blood pressure values should be adjusted to ≤ 130 / 80 mmHg.

Patients should

• eat a Mediterranean diet
• as well as a salt-reduced diet of < 5 g / d.
• Avoidance of iatrogenic kidney damage caused by e.g. drugs, contrast media, etc.
• Physical activity
• Body- Mass- Index < 25 kg /^m2
• Abstinence from nicotine
• moderate alcohol consumption (Hoyer 2015)

In the CORAL study published in 2014, which included 947 patients and lasted over 5 years, the following combination proved to be very effective for renal artery stenosis caused by arteriosclerosis:

• RAAS- blocker e.g. candesartan 4 - 16 mg / d (Paumgartner 2013) with or without hydrochlorothiazide.
• Calcium antagonist e.g. amlodipine 5 - 10 mg / d (Paumgartner 2013)
• Statin e.g. atorvastatin 10 - 80 mg / d (Aktories 2017)

(Hoyer 2015)

Treatment with statins should aim for a target LDL- value of < 70 mg / dl (Oberhuber 2019).

Diabetes control should optimally achieve a target HbA1c < 7.5% (Hoyer 2015).

In unilateral renal artery stenosis, it is recommended to always give inhibitors of the RAS- system (Oberhuber 2019) such as ACE- inhibitors (e.g., ramipril 1.25 - 10 mg / d [Paumgartner 2013]), renin inhibitors (e.g., aliskiren 150 mg / d [Aktories 2017]), angiotensin- receptor antagonists ( e.g., candesartan 4 - 16 mg / d [Paumgartner 2013]).

(Schwabe 2018)

Surgical treatment of ischemic nephropathy in the form of percutaneous transluminal angioplasty (PTA) with or without stenting is indicated for fibromuscular dysplasia (Herold 2021).

Contraindications to PTA are:

• Worsening of renal function after contrast administration.
• Re-stenosis
• Cholesterol emboli
• Intimal dissection

(Herold 2021)

If very rigid vessel wall changes are present, surgical revascularization at a center specializing in this area may be indicated (Hoyer 2015).

In the case of atherosclerosis-related NAST of > 70 %, PTA stent treatment is generally not effective (Herold 2021).

However, it may be indicated for certain indications of NAST, such as:

• refractory hypertension
• secondary to pulmonary oedema due to hypertension
• rapidly progressive renal failure

However, patients with an intrarenal resistance of ≥ 0.8 usually no longer benefit from stenosis removal (Herold 2021).

In a 2014 study, patients with "Pickering syndrome" (recurrent pulmonary edema associated with bilateral renal artery stenosis [Oberhuber 2019]) were also shown to benefit from intervention (Ritchie 2014).

Predictors that reduce the likelihood of improvement in BP and/or renal function after removal of renal artery stenosis are:

• Male gender
• age > 65 years
• diabetes mellitus
• no sudden onset of arterial hypertension or worsening of blood pressure
• pronounced arteriosclerosis
• duration of hypertension > 10 years
• degree of stenosis < 70
• Non-smoker
• proteinuria of > 1 g / d
• GFR < 40 ml / min
• diastolic blood pressure < 80 mmHg
• systolic blood pressure < 160 mmHg (Oberhuber 2019)

After angioplasty or surgery, blood pressure normalization is found in about 75% of patients with fibromuscular stenosis, compared with only about 20% of patients with arteriosclerotic stenosis, who often have fixed nephrogenic hypertension.

Overall, the prognosis of ischemic nephropathy is unfavorable. The 5-year mortality is about 50 % (Herold 2021).

The average survival time in dialysis patients with renal artery stenosis is 25-34 months, and the 5-year mortality is > 80 % (Oberhuber 2019).

Follow-up

After percutaneous transluminal angioplasty, follow-up examinations should be performed with regard to:

• Blood pressure control
• renal function
• Electrolytes
• Serum potassium
• blood count because of a possible eosinophilia (as an indication for an adjustment of the
• adjustment of the antihypertensive medication
• Duplex sonography

at discharge, after 3 and 6 months and then 1 x annually (Oberhuber 2019).

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