HYPERTENSIVE NEPHROPATHY

Sepehr Raeisi: Nephrologist, MD

INTRODUCTION

1. The treatment of hypertension is the most common reason for office visits of non-pregnant adults to physicians in the United States.

2. The number of patients with hypertension is likely to grow as the population ages, since either isolated systolic hypertension or combined systolic and diastolic hypertension occurs in the majority of persons older than 65 years

3. The rising incidence of obesity will also increase the number of hypertensive individuals.

4. The national health and nutrition examination survey (NHANES) conducted from 2005 through 2008 estimated that approximately 29 to 31 percent of adults in the United States have hypertension

DEFINITIONS• Hypertension: The following definitions were suggested by

the seventh report of the Joint National Committee (JNC 7) based upon the average of two or more properly measured readings at each of two or more visits after an initial screen:

• Normal blood pressure: systolic <120 mmHg and diastolic <80 mmHg

• Prehypertension: systolic 120 to 139 mmHg or diastolic 80 to 89 mmHg

• Hypertension:• Stage 1: systolic 140 to 159 mmHg or diastolic 90 to 99 mmHg• Stage 2: systolic ≥160 or diastolic ≥100 mmHg

• Isolated systolic hypertension is considered to be present when the blood pressure is ≥140/<90 mmHg and

• isolated diastolic hypertension is considered to be present when

the blood pressure is <140/≥90 mmHg.

• Malignant hypertension is marked hypertension with retinal hemorrhages, exudates, or papilledema. Malignant hypertension is usually associated with a diastolic pressure above 120 mmHg

Types of Hypertension

• Primary HTN:

also known as essential HTN.

accounts for 95% cases of HTN.

no universally established cause known.

• Secondary HTN:

less common cause of HTN ( 5%).

secondary to other potentially rectifiable

causes.

A variety of risk factors have been associated with essential hypertension:

1. Hypertension tends to be both more common and more severe in blacks.

2. Hypertension in maternal, paternal or both parents.

3. Excess sodium intake

4. Excess alcohol intake

5. Obesity and weight gain are major risk factors for hypertension.

6. Physical inactivity

7. Dyslipidemia

8. Hypertension may be more common among those with certain personality

9. Vitamin D deficiency is associated with an increased risk of hypertension

Accurate Blood Pressure Measurement

1. The equipment should be regularly inspected and validated.

2. The operator should be trained and regularly retrained.

3. The patient must be properly prepared and positioned and seated quietly for at least 5 minutes in a chair.

4. The auscultatory method should be used.

5. Caffeine, exercise, and smoking should be avoided for at least 30 minutes before BP measurement.

6. An appropriately sized cuff should be used

Follow-up based on initial BPmeasurements for adults*

*Without acute end-organ damage

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Hypertensive Nephropathy

• Hypertensive nephrosclerosis is a disorder that is usually associated with

chronic hypertension.

• In addition to the level of blood pressure, it is clear that individual factors are involved. As an example,

• black patients have an approximate eight-fold elevation in the risk of hypertension-induced end-stage renal disease.

• Recent recognition of an association between two independent sequence variants in the APOL1 gene on chromosome 22 and renal disease in African-Americans, including focal segmental glomerular sclerosis and hypertension-related end-stage renal disease,

PATHOLOGY• Hypertensive nephrosclerosis is characterized

histologically by:1. vascular,

2. glomerular, and

3. tubulointerstitial involvement.

Vascular disease• The vascular disease consists of intimal thickening

and luminal narrowing of the large and small renal arteries and the glomerular arterioles. Two different processes appear to contribute to the development of the vascular lesions:1. A hypertrophic response to chronic hypertension that is

manifested by medial hypertrophy and fibroblastic intimal thickening, leading to narrowing of the vascular lumen. This response is initially adaptive by minimizing the degree to which the rise in systemic pressure is transmitted to the arterioles and capillaries.

2. The deposition of hyaline-like material (plasma protein constituents, such as inactive C3b, part of the third component of complement) into the damaged, more permeable arteriolar wall.

Glomerulosclerosis

• The glomeruli may show both focal global (involving the entire glomerulus)

and focal segmental sclerosis.

Interstitial nephritis• The vascular and glomerular diseases are associated with

an often severe interstitial nephritis.

• The etiology of the interstitial nephritis is incompletely understood. Studies in experimental animals have shown that severe stenosis of the main renal artery (as opposed to the intrarenal arteries in benign nephrosclerosis) can induce tubular atrophy and an intense chronic interstitial nephritis.

• The interstitial disease in the ischemic kidney is at least in part an active immunologic process that may be initiated by ischemia-induced alterations in antigen expression on the surface of the tubular epithelial cells.

Benign nephrosclerosis

Light micrograph in benign nephrosclerosis showing a completely sclerotic glomerulus (upper left) adjacent to two shrunken glomeruli that are still intact. There is also prominent tubular atrophy and dilatation with intratubular hyaline casts (arrows). These changes are induced by ischemia resulting from arterial and arteriolar thickening (not shown). Courtesy of Helmut Rennke, MD.

CLINICAL MANIFESTATIONS• Nephrosclerosis is seen with normal aging, but is clearly

exacerbated by chronic hypertension.

• There are, however, three major groups at increased risk:1. Blacks

2. Patients with more marked elevations in blood pressure

3. Patients with underlying chronic renal disease, particularly those with diabetic nephropathy

• Hyperuricemia (independent of diuretic therapy) is a relatively early finding in benign nephrosclerosis, and appears to reflect the reduction in renal blood flow induced by the vascular disease

Proteinuria

• Protein excretion is usually mildly elevated (less than 1 g/day) in nephrosclerosis; this reflects the generally focal nature of the glomerular involvement.

• However, more prominent proteinuria can occur, occasionally reaching as high 10 g/day, with such affected patients being more likely to have superimposed renovascular disease or malignant hypertension.

Incidence of renal failure

• However, in the absence of one of the risk factors noted above, the rate of progression is generally slow and only a few patients with apparent essential hypertension develop progressive renal disease.

• An interesting clinical paradox is that benign hypertensive nephrosclerosis is one of the most common diagnoses in new patients starting maintenance dialysis.

DIAGNOSIS• The diagnosis of benign hypertensive nephrosclerosis is generally

inferred from the characteristic clinical features, since confirmation by renal biopsy is rarely indicated.

• Affected patients usually have a long history of hypertension that is typically accompanied by1. left ventricular hypertrophy,

2. a relatively normal urine sediment,

3. small kidneys, and,

4. if previous information is available, slowly progressive renal insufficiency with gradually increasing proteinuria that is usually nonnephrotic.

• In the future, recognition of the variants on the ApoL1 gene on chromosome 22 will likely provide a sensitive and specific diagnostic tool.

DIAGNOSIS

• Most important from a clinical viewpoint, the hypertension precedes the development of either proteinuria or renal insufficiency, and there is no other obvious cause of renal disease.

DIAGNOSIS• There is one disorder that commonly presents with similar

findings to hypertensive nephrosclerosis but is potentially reversible :• Ischemic renal disease due to bilateral renal artery stenosis.

• These patients are more likely to have a history of1. severe or refractory hypertension,

2. an acute elevation in blood pressure over a previously stable baseline, or

3. relatively rapid deterioration of renal function due to more complete occlusion of one or both renal arteries, or to removal of angiotensin driven renal perfusion by ACE inhibitor or ARB therapy.

DIAGNOSIS

• When the historical data are incomplete, a clinical diagnosis of benign nephrosclerosis may be incorrect unless confirmed by renal biopsy.

TREATMENT• The likelihood of progressing to renal failure is directly

related to the degree of blood pressure control.

Classification

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LIFESTYLE MODIFICATION

• Encourage lifestyle modification in patients with CKD to lower BP and improve long-term cardiovascular and other outcomes:1. We recommend achieving or maintaining a healthy weight (BMI

20 to 25).2. We recommend lowering salt intake to ˂90 mmol (˂2 g) per day

of sodium (corresponding to 5 g of sodium chloride), unless contraindicated.

3. We recommend undertaking an exercise program compatible with cardiovascular health and tolerance, aiming for at least 30 minutes 5 times per week.

4. We suggest limiting alcohol intake to no more than two standard drinks per day for men and no more than one standard drink per day for women.

Blood pressure management inCKD ND patients without diabetes mellitus

• We recommend that non-diabetic adults with CKD ND and urine albumin excretion ˂30 mg per 24 hours (or equivalent*) whose office BP is consistently ≥140mmHg systolic or ≥90mmHg diastolic be treated with BP-lowering drugs to maintain a BP that is consistently ˂140mmHg systolic and ˂90mmHg diastolic.

• We suggest that non-diabetic adults with CKD ND and urine albumin excretion of 30 to 300 mg per 24 hours (or equivalent*) whose office BP is consistently ˃130mmHg systolic or ˃80mmHg diastolic be treated with BP-lowering drugs to maintain a BP that is consistently ˂130mmHg systolic and ˂80mmHg diastolic.

• We suggest that non-diabetic adults with CKD ND and urine albumin excretion more than 300 mg per 24 hours (or equivalent*) whose office BP is consistently ˃130mmHg systolic or ˃80mmHg diastolic be treated with BP-lowering drugs to maintain a BP that is consistently ˂130mmHg systolic and ˂80mmHg diastolic.

• We suggest that an ARB or ACE-I be used in non-diabetic adults with CKD ND and urine albumin excretion of 30 to 300 mg per 24 hours (or equivalent*) in whom treatment with BP-lowering drugs is indicated.

• We recommend that an ARB or ACE-I be used in non-diabetic adults with CKD ND and urine albumin excretion ˃300 mg per 24 hours (or equivalent*) in whom treatment with BP-lowering drugs is indicated.

Goal blood pressure

• There is clear evidence that strict control of the blood pressure is beneficial in slowing the rate of progression of nondiabetic chronic kidney disease.

• ACE inhibitors/ARBs appear to be more protective than other antihypertensive drugs in patients with proteinuria.

Goals of Treatment

1. Treating SBP and DBP to targets that are <140/90 mmHg

2. Patients with diabetes or renal disease, the BP goal is <130/80 mmHg

3. The primary focus should be on attaining the SBP goal.

• ACE inhibitors/ARBs may not be of greater benefit than antihypertensive agents of different classes in other settings, such as patients without proteinuria and only mildly reduced kidney function as shown in a post-hoc analysis of ALLHAT and the previously mentioned meta-analysis.

• We and the K/DOQI work group on clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease recommend that

• Either an ACE inhibitor or ARB should be used in proteinuric nondiabetic kidney disease, although the strength of evidence favors the use of an ACE inhibitor. It is reasonable to switch to an ARB if cough limits use of an ACE inhibitor.

• The meta-analysis cited above found a significant 18 to 25 percent greater reduction in proteinuria with combined ACE inhibitors and ARBs compared to monotherapy.

• Despite this, we recommend NOT using combined therapy with ACE inhibitors and ARBs since no reliable study has demonstrated a long term beneficial effect on renal function with combined therapy, and ONTARGET found a significant increase in adverse outcomes, including mortality.

• Other antihypertensive drugs can be added as necessary to achieve the treatment goals described below. In both diabetic and nondiabetic patients, non-dihydropyridine calcium channel blockers may be preferred because of their antiproteinuric effects.

• Concurrent diuretic therapy will often be necessary in patients who already have renal insufficiency, since fluid overload is an important determinant of hypertension in this setting.

• The use of a diuretic may also restore the antiproteinuric effect of ACE inhibitor therapy among patients without an adequate antiproteinuric response because of an inability to restrict dietary sodium.

• However, to avoid inducing hypotension at the initiation of ACE inhibitor therapy, a previously administered diuretic should be transiently discontinued.

Progression despite blood pressure control

• In some patients, the plasma creatinine concentration and degree of proteinuria continue to rise despite seemingly good control of the systemic BP. Why such patients are susceptible to progressive renal injury is not known.

• It is possible, for example, that the variants on gene ApoL1 may play an important role in this setting or that some of these patients have a different renal disease that is exacerbated by hypertension.

Improvement of renal function• Although hypertensive nephrosclerosis is usually progressive, long-term

improvement in renal function is observed in a minority of patients. This was shown in a post-hoc analysis of the AASK trial mentioned above, in which glomerular filtration rate was estimated a median of 16 times during 12 years of follow-up.

• A positive slope (indicating an improvement of glomerular filtration rate) was present in three percent of patients; the glomerular filtration rate in these individuals improved at a rate of 1.1 mL/min per 1.73 m2 per year.

• Compared with patients whose renal function did not improve, those whose renal function improved were younger (51 versus 55 years), had lower median baseline urine protein-to-creatinine ratios (0.04 versus 0.07 g/g), and were more likely to have been randomly assigned to the lower target blood pressure (77 versus 49 percent).

SUMMARY AND RECOMMENDATIONS

• Hypertensive nephrosclerosis is a renal disorder associated with chronic hypertension.

• Risk factors include• black race associated with genetic variants, • severe hypertension, and• underlying chronic kidney disease, especially diabetic kidney

disease.

• Characteristic histologic findings include vascular, glomerular, and tubulointerstitial lesions.

• Patients present with a long history of hypertension that is typically accompanied by1. retinopathy and left ventricular hypertrophy,

2. and which precedes the development of either proteinuria or renal insufficiency.

1. Patients present with elevations in blood urea nitrogen and serum creatinine concentrations.

2. Protein excretion is usually less than 1 g/day, although greater amounts can occur.

3. Hyperuricemia may be observed.

4. The urinalysis is typically benign with the sediment revealing few cells or casts.

5. The rate of progression of renal disease is generally slow.

• The diagnosis of hypertensive nephrosclerosis is generally inferred from the characteristic clinical features; confirmation by renal biopsy is rarely indicated.

• Other obvious causes of renal disease should be excluded, especially bilateral renal artery stenosis.

• Effective treatment of the hypertension usually slows progression of renal injury.

• It is not clear whether ACE inhibitors and angiotensin II receptor blockers, which are the drugs of choice for renal protection in patients with proteinuric chronic renal failure, are also protective in patients with benign nephrosclerosis without proteinuria.

Moderate to severe renal insufficiency

• Many physicians are reluctant to administer ACE inhibitors to patients with moderate to severe renal failure because of the fear of inducing adverse side effects, particularly hyperkalemia, and/or precipitating acute renal failure.

• As previously mentioned, however, data from the Chinese and REIN trials showed that the benefits with ACE inhibitor therapy were independent of the initial severity of renal failure.

• Even with optimal management, some patients are unable to tolerate the administration of ACE inhibitors.

• Termination of the ACE inhibitor should be considered if:1. Hyperkalemia cannot be controlled or

2. The serum creatinine concentration increases more than 30 percent above the baseline value.

3. Such a decline in renal function is uncommon if the patient is not volume depleted, diuretics have been transiently withheld prior to initiation of therapy, and the patient does not have bilateral renovascular disease.

• Screening — The optimal interval for screening for hypertension is not known. The 2007 United States Preventive Services Task Force (USPSTF) guidelines on screening for high blood pressure recommend screening every two years for persons with systolic and diastolic pressures below 120 mmHg and 80 mmHg, respectively (normal BP in JNC 7), and yearly for persons with a systolic pressure of 120 to 139 mmHg or a diastolic pressure of 80 to 89 mmHg (prehypertension in JNC 7) [40] . (See "Overview of preventive medicine in adults")

Glomerulosclerosis• Global sclerosis is thought to reflect ischemic injury, leading to

nephron loss. This can be further categorized histologically as either solidified (in which the entire tuft is involved) or obsolescent (in which the tuft is retracted and Bowman's space is filled with collagenous-type material). The solidified form is more commonly associated with African-Americans than with Caucasians, and might contribute to the increased prevalence of nephrosclerosis in African-Americans.

• Focal segmental sclerosis is typically associated with glomerular enlargement, which is probably a compensatory response to nephron loss. However, the combination of hypertrophy and a rise in intracapillary pressure in these glomeruli may gradually lead to hemodynamically-mediated segmental sclerosis.

• Screening — The optimal interval for screening for hypertension is not known. The 2007 United States Preventive Services Task Force (USPSTF) guidelines on screening for high blood pressure recommend screening every two years for persons with systolic and diastolic pressures below 120 mmHg and 80 mmHg, respectively (normal BP in JNC 7), and yearly for persons with a systolic pressure of 120 to 139 mmHg or a diastolic pressure of 80 to 89 mmHg (prehypertension in JNC 7) [40] . (See "Overview of preventive medicine in adults")

Glomerulosclerosis

• The altered hemodynamics may be due in part to abnormal metabolism of nitric oxide.

• In the spontaneously hypertensive rat which exhibits severe glomerulosclerosis with age, the chronic administration of intravenous arginine (the precursor of nitric oxide) significantly reduced severe glomerular injury.

• Screening — The optimal interval for screening for hypertension is not known. The 2007 United States Preventive Services Task Force (USPSTF) guidelines on screening for high blood pressure recommend screening every two years for persons with systolic and diastolic pressures below 120 mmHg and 80 mmHg, respectively (normal BP in JNC 7), and yearly for persons with a systolic pressure of 120 to 139 mmHg or a diastolic pressure of 80 to 89 mmHg (prehypertension in JNC 7) [40] . (See "Overview of preventive medicine in adults")

Examination

• Appropriate measurement of BP in both arms• Optic fundi• Calculation of BMI ( waist circumference also may be useful)

• Auscultation for carotid, abdominal, and femoral bruits

• Palpation of the thyroid gland.

Examination-contd.• Thorough examination of the heart and lungs • Abdomen for enlarged kidneys, masses, and abnormal

aortic pulsation• Lower extremities for edema and pulses • Neurological assessment

Retina Normal and Hypertensive Retinopathy

Normal Retina Hypertensive RetinopathyA: HemorrhagesB: Exudates (Fatty Deposits)C: Cotton Wool Spots (Micro Strokes)

A B

C

• Since a decline in GFR induced by an ACE inhibitor typically occurs within the first few days after the onset of therapy, the serum creatinine and potassium concentrations should be remeasured three to five days after the institution of therapy.

• The ACE inhibitor dose should be slowly increased, if tolerated, to attain treatment goals. Diuretics are usually given for volume and blood pressure control and for the prevention and treatment of hyperkalemia.

• Additional measures to help avoid hyperkalemia include1. limiting the dietary intake of potassium-containing foods,

2. avoiding NSAIDs, and, if necessary,

3. the use of low doses (such as 5 mL with meals) of the potassium-binding resin, sodium polystyrene sulfonate (Kayexalate™ ). Low dose Kayexalate therapy is much better tolerated than the higher doses used to treat hyperkalemia.