Nephrosclerosis Differential Diagnoses

Diagnostic Considerations

Other problems to consider in the differential diagnosis of nephrosclerosis include the following:

• Renal atherosclerotic disease
• Cholesterol microembolization
• Malignant hypertension
• Mildly active primary kidney disease
• Lead nephropathy

Renal atherosclerotic disease

Hypertension is frequently associated with atheromatous renal artery disease (RAS), especially in elderly patients. In 2002, a population-based study estimated the prevalence of atherosclerotic RAS among free-living, black and white Americans older than 65 years to be approximately 7%. ^[20] The prevalence can increase up to 20-45% of patients older than 50 years who have had an angiography performed because of peripheral or coronary artery disease.

Approximately 2.4% of cases of end-stage renal disease (ESRD) in the United States are attributed primarily to vascular disease. These data, however, need to be interpreted with caution since they are subjective and the result of assigning a diagnosis without evidence of causation.

On the other hand, follow-up studies of patients with known RAS treated conservatively indicate that progression to kidney failure is rare. Pillay et al (2002) reported on 85 subjects observed for at least 2 years and indicated that although mortality was high, both for those treated with or without renal revascularization, death was rarely directed to renovascular disease. ^[21] Although progressive disease can sometimes threaten kidney function and/or result in the development of accelerated hypertension, clinically progressive disease develops in 10-15% of subjects over a 5-year period. These figures are central to estimating the risks and benefits of revascularization in patients with RAS, particularly if they are asymptomatic.

The predominant clinical manifestations of atherosclerotic RAS include hypertension, kidney failure (ischemic nephropathy), recurrent episodes of congestive heart failure, and flash pulmonary edema. Sudden worsening of kidney function in a patient who is hypertensive and who was started on an angiotensin-converting enzyme (ACE) inhibitor is also suggestive of renovascular disease.

Not all patients with RAS are hypertensive. Olin et al (2002) studied 395 consecutive patients who had undergone arteriography as part of an evaluation for aortoiliac or peripheral vascular disease and who did not have the usual clues to suggest RAS and found stenosis of 50% or greater in approximately 35% of nondiabetic patients and in up to approximately 50% of diabetic patients. ^[22]

Goals for identifying RAS include improving blood pressure (BP) control and preserving kidney function. The diagnosis of RAS can be established with the use of Doppler ultrasound scanning, magnetic resonance (MR) angiography using gadolinium as the contrast agent, CT angiography, or intra-arterial renal angiography. Comparative studies on patients undergoing several tests indicate that both captopril renogram and Doppler studies can fail to detect significant lesions. Both tests are less reliable than either MR angiography or CT angiography. Doppler ultrasound can be highly accurate when stenosis is present. However, Doppler ultrasound studies are highly operator dependent, and failure to locate the critical vessel segment or an adverse body habitus can easily lead one to overlook high-grade lesions leading to false-negative tests. As a result, such studies are most useful when positive.

By contrast, MR angiogram can provide excellent detail regarding location and severity of atherosclerotic vascular lesion. CT angiography can provide excellent imaging comparable with intra-arterial renal angiography but has the drawbacks of requiring iodinated contrast. Iodinated contrast can cause acute renal failure designated contrast nephropathy. Contrast nephropathy occurs more frequently in patients with acute or chronic kidney disease. For this reason, MRI had previously been favored for renal artery imaging in this patient population. Unfortunately, the use of gadolinium-based contrast media for MRI was found to be associated with an increased risk for nephrogenic systemic fibrosis. Therefore, in May 2007, the US Food and Drug Administration (FDA)  recommended that patients with estimated GFRs below 30 mL/min/1.73 m² not be exposed to gadolinium. ^[23]

Most patients are treated medically, and drug therapy should include the use of an ACE inhibitor or angiotensin receptor blocker (ARB). Although these agents can reduce the glomerular filtration rate in patients with RAS, clinically important changes in kidney function are remarkably rare, even when these agents are applied to subjects at high risk for undetected RAS. A substudy of the Heart Outcomes Prevention Trial (HOPE) examining 980 patients with serum creatinine levels of 1.4-2.3 mg/dL demonstrated reduced combined cardiovascular endpoints in the group randomized to receive ramipril. These benefits were obtained with no excessive change in kidney function as compared with the placebo arm. Thus, the benefits of angiotensin II blockade regarding both cardiovascular outcomes and preservation of kidney function favor using ACE inhibitors or ARBs despite elevated creatinine levels.

To minimize the potential hazard of these agents in patients with RAS, diuretic agents should be temporarily withheld on initiation of an ACE inhibitor/ARB and serum creatinine and potassium values rechecked at frequent intervals until a stable dose is achieved without a significant change in kidney function. It is also important to avoid volume depletion in these patients.

When progressive hypertension, kidney insufficiency, or circulatory congestion develops, renal revascularization should be considered. Renal revascularization (ie, percutaneous transluminal angioplasty/stent, surgery) may result in improvement in BP control in 50-80% of patients, but cure is unusual in patients with long-standing hypertension. Vascular intervention (percutaneous transluminal angioplasty or surgery) may also improve or stabilize kidney function in selected patients.

Dorros et al reported a retrospective registry examination regarding 1058 patients subjected to angiography and stenting observed for at least 6 months. ^[24] The procedure was successful in 100% of cases. The mean age was 69 years, and 59% (n=629) had preprocedure serum creatinine levels of 1.5 mg/dL or higher. On follow-up, systolic BP was reduced by approximately 20 mm Hg and antihypertensive requirements fell from 2.4 to 2.0 medications per patient. The overall 4-year survival was 74%. For patients with serum creatinine levels of 2 mg/dL or higher, survival at 4 years was less in those with bilateral disease, despite successful revascularization (55% unilateral vs 36% bilateral, P< 0.05). Serum creatinine levels improved or remained unchanged in 74% and were considered worse in 27% of those with bilateral disease.

The complication rate for renal artery stenting varies considerably between centers. Complications include the following:

• Hematomas
• Retroperitoneal hemorrhage
• Arterial dissections
• Pseudoaneurysm formation
• Arteriovenous fistula
• Rupture of the renal artery
• Vessel occlusion
• Infection

Restenosis occurs in 14-20% of cases. Treatment failures or restenosis can be treated with repeat endovascular procedures or in some cases by surgical endarterectomy.

Some patients may develop contrast-induced acute kidney injury and cholesterol embolism. As a result, approximately 20% of patients who undergo vascular intervention experience a worsening of kidney function or develop ESRD; additionally, BP does not improve in 20-50% of patients. For some individuals, the risk of complications and restenosis may be higher than the risk of clinical disease progression.

Management of renal arterial disease should be part of an integrated program of cardiovascular risk reduction, including BP and lipid control, in addition to smoking cessation. Patients with worsening hypertension, declining kidney function, or a history of "flash" pulmonary edema unexplained by cardiac function alone warrant further diagnostic studies and intervention. Whether renal revascularization changes the natural history and mortality of patients with RAS is not clear. To date, no randomized trial has shown a survival benefit for either endovascular or surgical revascularization compared with medical management in patients with RAS.

In 2009, the result of the Angioplasty and Stenting for Renal Artery Lesions (ASTRAL) trial was published. ^[25] The goal of the study was to determine whether revascularization with best medical therapy would improve kidney function compared with medical therapy alone in patients with renal artery atherosclerotic lesions. Eight hundred and six patients from 57 hospitals (mainly from the United Kingdom) with an average creatinine of 2 mg/dL were randomized and followed for a median of 33.6 months. At the end of the trial, the authors concluded that there was no added benefit from revascularization (with respect to improvement in kidney function or BP control) and that there were substantial risks associated with the revascularization (renal embolization, renal artery occlusion and perforation, and cholesterol embolism).

The trial has been criticized for design weaknesses, which include exclusion of patients who were thought to definitely benefit from revascularization, enrollment of patients with normal kidney function (25%) and near-normal kidney function (15%), and enrollment of patients without hypertension and those with renal artery stenosis of 60-70%. Lastly, the rate of adverse events from revascularization was estimated as 9%, which is higher than the rate reported from other studies.

The Cardiovascular Outcomes in Atherosclerotic Renal Artery Lesions (CORAL) trial, published in 2014, also concluded that in patients with atherosclerotic RAS and hypertension or chronic kidney disease who are receiving comprehensive, multifactorial medical therapy, the addition of renal-artery stenting did not confer a significant benefit with respect to preventing major adverse renal and cardiovascular events. CORAL included 947 patients for a median follow-up period of 43 months. The only significant difference between the stent and the medical therapy–only groups in was a consistent modest difference in systolic blood pressure favoring the stent group. ^[26]

It should be recognized that prospective interventions trials (as seen with the ASTRAL trial) typically exclude those patients at higher risk and those with evident disease progression or rapid loss of kidney function who are most likely to benefit from renal revascularization. Recognizing RAS and identifying patients who will benefit from revascularization remains a significant challenge for clinicians. For reviews on this subject, the reader is referred to the 2005 article by Garovic and Textor and the 2008 article by Textor. ^{[27, 28]}

Cholesterol microembolization

Besides renal artery stenosis, cholesterol microembolization can also mimic hypertensive nephrosclerosis. Cholesterol embolization is frequently found at autopsy in white patients older than 50 years, at a rate varying from 4.7-17.7%. This condition is also observed in black patients; it was present in 2 of 39 patients who underwent biopsies for the African American Study of Kidney Disease (AASK).

Making the diagnosis is not difficult when patients present acutely following an angiographic procedure, transluminal angioplasty, or anticoagulant treatment or as a complication of vascular surgery. However, in many cases, the disease is chronic, patients are relatively asymptomatic, and, presumably, the disease is the result of a spontaneous renal cholesterol embolism. These patients may present with nephrotic-range proteinuria. Kidney biopsy specimens show classic needle-shaped crystals in the glomeruli or renal arteries.

Malignant hypertension

Malignant hypertension is relatively uncommon, occurring in approximately 1% of patients with hypertension. Men are more frequently affected than women, and patients' ages range from infants to the elderly. Patients may have preexisting hypertension or be previously normotensive. The incidence of malignant hypertension has been decreasing in whites, possibly because of improvement in BP control with antihypertensive medications and better understanding of the need for treatment. The incidence remains higher in black and Asian patients.

The clinical presentation reflects the deleterious effects of high BP on target organs. Systolic BP can range from 150-290 mm Hg while diastolic BP can vary from 100-180 mm Hg. Keith-Wagener grade III (hemorrhages and exudates) and grade IV retinal changes (papilledema) are the hallmarks of malignant hypertension. Acute heart failure and pulmonary edema can be the presenting signs in approximately 10% of patients. Left ventricular hypertrophy is present in as many as 75% of patients at presentation.

At presentation, greater than 60% of patients complain of headaches with a cerebrovascular event (eg, focal cerebral ischemia, cerebral/subarachnoid hemorrhage) occurring in close to 5-10% of patients. True hypertensive encephalopathy is characterized by headache, nausea, vomiting, and visual blurring, together with impaired cognitive function, generalized seizures, or cortical blindness. Kidney involvement is common, but the degree of severity varies. Proteinuria is common, but overt nephrotic syndrome is unusual. More than 30% of patients will have an elevated serum creatinine level at presentation. A microangiopathic hemolytic anemia (schistocytes, thrombocytopenia, increased fibrin degradation products, and increased fibrinogen) is frequently present. Other symptoms include weakness, malaise, fatigue, and weight loss.

Untreated, the outcome is extremely poor, with 1-year survival of less than 25% in patients with grade IV retinopathy. In studies from 1950s-1960s, uremia was the major cause of death (50-60%), with heart failure and cerebrovascular diseases accounting for the remaining 30-40% of deaths. This dismal outcome has improved thanks to better antihypertensive therapy and the availability of dialysis. African American patients have higher mortality and greater degree of renal impairment.

Malignant hypertension complicated by organ failure (eg, hypertensive encephalopathy, intracranial hemorrhage, congestive heart failure and pulmonary edema, acute myocardial infarction, unstable angina, dissecting aortic aneurysm, eclampsia) is a medical emergency and requires rapid reduction in BP. Rapid normalization of BP is not necessary and should be avoided because it can precipitate end-organ ischemia (eg, stroke, acute renal failure). In uncomplicated malignant hypertension, rapid BP reduction is not as critical as in the previous group with BP reduction by up to 20% of the presenting values, or a systolic BP of greater than 170 mm Hg in the first 24 hours has been an acceptable target. For a review of this subject, see Kitiyakara and Guzman (1998). ^[29]

Lead nephropathy

Chronic lead exposure can result in renal failure, which typically presents as tubulointerstitial nephritis on histology. The main route of lead clearance is through the kidneys. Lead can be absorbed in the proximal tubule, which, in turn, results in mitochondrial injury and impairment of tubular transport. Clinically it can present as renal failure and new-onset hypertension with nonglomerular-range proteinuria. Typically, prolonged exposure to high levels of lead is required for the development of lead nephropathy.

Knowledge of exposure to potential sources is a key factor for the diagnosis. Blood lead levels can be measured, but the levels can be normal if the exposure is no longer present. Another test would be EDTA-lead mobilization test, which evaluates the body’s lead burden. Alternatively, x-ray fluoroscopy can be used to determine skeletal lead stores. In a patient presenting with renal failure and new-onset hypertension and potential exposure in the past, lead nephropathy should be considered as part of the differential diagnosis when evaluating the patient.

Renal biopsy findings

Renal biopsy findings that mimic hypertensive nephrosclerosis can be observed in various clinical conditions, even in the absence of hypertension. These conditions include hemolytic uremic syndrome, postpartum renal failure, scleroderma, chronic radiation nephritis, and obesity. Reaching an accurate diagnosis can be difficult in patients presenting late in the course of renal failure.