eMedicine Specialties > Nephrology > Hypertension and the Kidney
Nephrosclerosis: Differential Diagnoses & Workup
Updated: Oct 20, 2008
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
- Multimedia
Differential Diagnoses
Other Problems to Be Considered
Renal atherosclerotic disease
Cholesterol microembolization
Malignant hypertension
Mildly active primary renal disease
Hypertension and atherosclerotic renal artery 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%.5 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 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 renal 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.6 Although progressive disease can sometimes threaten renal 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, renal failure (ischemic nephropathy), recurrent episodes of congestive heart failure, and flash pulmonary edema. Sudden worsening of renal function in a patient who is hypertensive and who was started on an ACE inhibitor is also suggestive of renal vascular 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 greater than or equal to 50% stenosis in approximately 35% of nondiabetic patients and in up to approximately 50% of diabetic patients.7
Goals for identifying RAS include improving BP control and preserving renal 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 has recently been found to be associated with an increased risk for nephrogenic systemic fibrosis (NSF). Therefore, in May 2007, the US Food and Drug Administration (FDA) issued an updated recommendation that patients with estimated GFRs below 30 mL/min/1.73 m2 not be exposed to gadolinium.8
Most patients are treated medically, and drug therapy should include the use of an ACE inhibitor or ARB. Although the use of these agents can result in a fall in glomerular filtration 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 renal function favor using ACE inhibitors or ARBs despite elevated creatinine levels.
To minimize the potential hazard of these agents in patients with RAS, it is recommended that 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 renal function. It is also important to avoid volume depletion in these patients.
When progressive hypertension, renal 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 renal 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.9 The procedure was successful in 100% of cases. The mean age was 69 years, and 59% (n=629) had preprocedure serum creatinine levels greater than or equal to 1.5 mg/dL. These data indicate that follow-up systolic blood pressure was reduced by approximately 20 mm Hg and antihypertensive requirements fell from 2.4 to 2.0 medications per patient. The overall 4-yearsurvival was74%.
For patients with serum creatinine levels greater than or equal to 2.0 mg/dL, 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, and complications include hematomas, retroperitoneal hemorrhage, arterial dissections, pseudoaneurysm formation, arteriovenous fistula, rupture of the renal artery, vessel occlusion, or 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 renal failure and cholesterol embolism. As a result, approximately 20% of patients who undergo vascular intervention experience a worsening of renal function or develop ESRD; additionally, BP is not improved in 20-50% of patients. For some individuals, the actual risk of complications and restenosis may be higher than the true risk of clinical disease progression.
Management of renal arterial disease should be part of an integrated program of cardiovascular risk reduction, including blood pressure and lipid control, in addition to withdrawal of smoking. Patients with worsening hypertension, declining renal function, or history "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.
The question of whether angioplasty is superior to medical management is being assessed in the ongoing Cardiovascular Outcomes in Atherosclerotic Renal Artery Lesions (CORAL) trial, with the initial outcome results likely to be obtained by 2012.
In 2008, the initial results of the Angioplasty and Stenting for Renal Artery Lesions (ASTRAL) trial were presented at the annual Society for Cardiovascular Angiography and Interventions (SCAI)/American College of Cardiology meeting. In this trial, patients with an average creatinine value of 2 and renal artery atherosclerotic lesions were randomized either to angioplasty and stenting plus medical therapy or to medical therapy alone. After 27 months of follow-up, no differences in creatinine value, blood pressure, or mortality were evident.
It should be recognized that prospective interventions trials typically exclude those patients at higher risk and those with evident disease progression. Those patients with rapid loss of renal function 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.10,11
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. Renal 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 the patients' ages range from infants to the elderly. It may occur in patients with preexisting hypertension or in a previously normotensive patient. The incidence of malignant hypertension has been decreasing in Caucasians and may be related to improvement in BP control with antihypertensive medications and better understanding of the need for treatment. The incidence remains higher in African American 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. Renal 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).12
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.
Workup
Laboratory Studies
- Laboratory evaluation includes the following:
- Baseline complete blood cell count
- Creatinine level
- Electrolyte status
- Urinalysis
- Either a spot urine test for albumin or creatinine ratio or a 24-hour urine collection - To determine total protein excretion
- In a large series of patients, most had urine protein excretion of lower than 1 g/d; however, in some patients with biopsy-proven hypertensive nephrosclerosis, a 24-hour urinary protein excretion greater than 1 g/d has been described. When secondary changes of focal segmental glomerulosclerosis (FSGS) related to hyperfiltration develop, proteinuria can increase to the nephrotic range.
- Innes et al (1993) reviewed 185 cases of patients with renal biopsy specimens that were classified solely as hypertensive nephrosclerosis.13 In 40% of these patients, urinary protein excretion was greater than 1.5 g/d, with 22% excreting more than 3 g/d and 18% having serum albumin values less than 3 g/dL. Similar findings were reported by Harvey et al (1992).14 Freedman et al (1994) questioned these findings because many biopsy specimens showed segmental and diffuse glomerulosclerosis.15 Harvey et al attributed these lesions to the effect of hypertension, but Freedman et al believed that these patients had idiopathic FSGS, not hypertensive nephrosclerosis.14,15
- The contrasting conclusions of Harvey et al and Freedman et al highlight the problems of distinguishing hypertensive nephrosclerosis from primary glomerular disease purely on clinical grounds. Nevertheless, in black people who are hypertensive, do not have diabetes, and have mild-to-moderate renal failure and proteinuria less than 2 g/d, renal biopsy specimens are likely to show morphological lesions consistent with the clinical diagnosis of hypertensive nephrosclerosis. On the other hand, the diagnosis of hypertensive nephrosclerosis in a young white patient is unusual, and these findings suggest an alternative diagnosis.
Imaging Studies
- An echocardiogram may be required to assess left ventricular size.
- Renal imaging with either an ultrasound or an intravenous pyelogram reveals that kidney size is usually symmetric and may be normal or modestly reduced.
- The renal calices and pelves are normal.
- Renal asymmetry or irregularities in the contour raise the possibility that hypertension could be secondary to renal artery stenosis or reflux nephropathy.
Other Tests
- ECG typically shows left ventricular hypertrophy; however, this may not be evident on the ECG tracings. The sensitivity of ECG in helping to detect left ventricular hypertrophy may be as low as 22%.
Procedures
- A definitive diagnosis of hypertensive nephrosclerosis cannot be made without a renal biopsy, especially in the white patient population. In the absence of a renal biopsy, the diagnosis of hypertensive nephrosclerosis is one of exclusion.
Histologic Findings
Upon gross pathologic examination, the kidneys are shrunken and scarred. According to Tracy and Ishii (2000), the descriptive pathologic abnormalities of benign nephrosclerosis seen on renal biopsy specimens include glomeruli obsolescence, interstitial fibrosis, arterial intimal fibroplasia, arteriolar hyalinization in arterioles (most notably afferent), and small arteries (arcuate and interlobular artery, see Media file 1).2
Myointimal hypertrophy of the interlobular arteries, hyaline degeneration, and sclerosis of afferent arterioles are the most characteristic findings of hypertensive nephrosclerosis. Interlobular arteries often show reduplication of the internal elastic lamina and medial hypertrophy. The arterial wall shows hyaline changes, appearing as eosinophilia, and distinctively periodic acid-Schiff–positive deposits (see Media file 2). The arteriolar lumen is narrowed.
Early in the disease process, the glomeruli are normal. With time, ischemic changes become visible, including wrinkling of the glomerular tuft and thickening of the Bowman capsule (see Media file 3). Occasionally, mild focal mesangial cell proliferation and matrix expansion occur. Eventually, complete glomerular hyalinosis and obsolescence ensue with the development of secondary tubular atrophy and interstitial fibrosis (see Media file 4). In contrast, the presence of enlarged glomeruli and the absence of collapse of the basement membrane suggest that the patient is most likely developing secondary FSGS superimposed on primary hypertensive disease.
With immunofluorescence, no specific pattern is noted, with the exception of an increased prevalence of immunoglobulin M deposits in the arterioles and mesangium. Fibrinoid necrosis and microinfarcts are features of malignant or accelerated hypertension, not nephrosclerosis. Of note, electromicroscopy examination of renal biopsy specimens may help to distinguish primary FSGS from secondary FSGS. In primary FSGS, foot process effacement is widespread; in secondary FSGS, it is more localized.
As noted by Fogo et al (1997), none of the above lesions is pathognomonic.16 Consider the diagnosis of hypertensive nephrosclerosis only when the constellation of these changes is present in the absence of other lesions of primary glomerular disease.
More on Nephrosclerosis |
| Overview: Nephrosclerosis |
 Differential Diagnoses & Workup: Nephrosclerosis |
| Treatment & Medication: Nephrosclerosis |
| Follow-up: Nephrosclerosis |
| Multimedia: Nephrosclerosis |
| References |
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Further Reading
Keywords
nephrosclerosis, hypertension, hypertensive nephrosclerosis, hypertensive nephropathy, nephroangiosclerosis, end-stage renal disease, ESRD, end stage renal disease, end-stage kidney disease, end stage kidney disease, hypertensive retinopathy, left ventricular hypertrophy, minimal proteinuria, progressive renal insufficiency, benign nephrosclerosis, nephroangiosclerosis, blood pressure control, BP control, HN
