4.2.1 Definition

Benign nephrosclerosis, also called hypertensive nephrosclerosis, is characterized by a very slowly progressive thickening and sclerosis of the renal resistance vessels due to long-standing poorly controlled hypertension.

4.2.2 Causes and Risk Factors

Older age, long-standing poorly controlled hypertension, and intrinsic kidney diseases are the main risk factors for hypertensive kidney disease. Some degree of benign nephrosclerosis is very common among individuals aged >60 years, and African Americans have been observed to be more prone to develop hypertensive nephrosclerosis and ESRD. The Multiple Risk Factor Intervention Trial showed that hypertensive nephrosclerosis occurs earlier and is more severe in African Americans. Additionally, men are more prone to develop hypertensive nephrosclerosis than women [6].

4.2.3 Prevalence

Although benign nephrosclerosis slowly progresses to ESRD in only a small percentage of individuals, it remains one of the most common causes of ESRD owing to the high prevalence of hypertension. In the United States, hypertensive nephropathy accounts for approximately 27.5% of incident dialysis patients according to the data from the 2016 US Renal Data System [7]. Moreover, new patients starting dialysis contributed to the continuously increasing prevalence of hypertension. The reported prevalence rate of hypertensive nephropathy greatly varies worldwide, accounting for 27% of new patients with ESRD in France, 21% in Italy, 7% in China, 6% in Japan, and approximately 12% in the European Dialysis and Transplant Association registry [8]. This variation may reflect differences in criteria for and accuracy of diagnosis of hypertensive nephropathy among various countries.

4.2.4 Clinical Manifestations

Physical examination may reveal changes in the retinal vessels, and <5% of patients with poorly controlled BP will develop renal failure during the subsequent 10–15 years.

Proteinuria develops in up to 40% of patients. Microalbuminuria has long been recognized as a major biomarker of hypertensive nephrosclerosis, and measurement of microalbuminuria level at screening and during treatment is widely recommended. However, research has consistently shown that it is clinically relevant only when increases in the macroalbuminuric range (>300 mg/day) occur in the presence of appropriate BP control. Investigators of the Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension trial reported that the histological progression of diabetic nephropathy persisted despite the maintenance of normal BP and microalbuminuria [9]. This trial illustrates the limitations of using microalbuminuria as a surrogate marker for CKD and a prognostic tool for the progression of CKD. In fact, microalbuminuria might represent vascular dysfunction and serve as a marker of cardiovascular risk instead of the progression of CKD. Conversely, macroalbuminuria may accurately represent renal parenchymal damage and should serve as a prognostic marker for the progression of CKD and a therapeutic target in the treatment of CKD.

Persistent increases in serum creatinine concentration reflect substantial renal parenchymal damage and some degree of irreversible kidney dysfunction. However, the serum creatinine concentration does not provide an accurate measure of the rate of progression of renal dysfunction. It is essential to utilize more accurate and sensitive measures for the estimation of glomerular filtration rate (GFR), which may guide targeted therapies to more effectively prevent disease progression and associated complications. The identification of an appropriate marker of early renal dysfunction remains challenging and depends on the underlying etiology of kidney disease. Hypertension-induced kidney injury can be associated with obvious markers of renal parenchymal disease, such as proteinuria. However, in the absence of overt glomerular disease such as in hypertensive nephrosclerosis or early diabetic nephropathy, evidence of early kidney injury remains elusive.

In the past decade, numerous researchers showed that serum cystatin C level could serve as an early marker of hypertension-induced kidney dysfunction and may accurately reflect the estimated GFR (eGFR) in various populations [10]. Investigators of the Heart and Soul Study evaluated the effect of baseline systolic BP by measuring the serum cystatin C level and estimating the GFR based on the serum creatinine concentration and reported that serum cystatin C level was better correlated with systolic BP than serum creatinine concentration in individuals with an eGFR >60 mL/min/1.73 m² [11].

4.2.5 Pathological Manifestations

Benign nephrosclerosis is histologically characterized by a series of vascular injuries, including afferent arteriolar hyalinization and interlobular thickening of the artery and arcuate artery endomysium. Renal pathology in benign nephrosclerosis is shown in Fig. 4.1. Cumulative evidence over the past years has suggested that high BP results in injury to the tubular cells, inducing epithelial–mesenchymal transition and tubulointerstitial fibrosis. Recent investigations have reported the association of podocyte effacement and loss with benign nephrosclerosis [12]. Benign nephrosclerosis-induced changes are summarized in Table 4.3.

Table 4.3

Benign nephrosclerosis-induced changes in the vascular, glomerular, and tubulointerstitial compartments

Compartment	Changes	Effects
Vessels	• Transition from smooth muscle cells to myofibroblasts, intimal thickening of the small arterioles	• Wall stiffness, with little or no effect on the lumen caliber
	• Thinning of the media, hyalinosis of the afferent arteriole	• Reduced filtration
	• Occlusion of the intraglomerular capillaries by hyaline material	• Hypoxia
	• Breakdown of elastic fibers in the large arteries	• Laminar-to-pulsatile flow shift in the arcuate, interlobular, and afferent arterioles
Glomeruli	Not applicable	• Increased intraglomerular pressure and microalbuminuria
	• ECM accumulation	• FSGS
	• Glomerular tuft entirely replaced by collagen	• Global glomerulosclerosis
	• Capsular adhesion and segmental scars	• Reduced filtration
Tubules	• Cell dilation and flattening, cell atrophy and loss	• Proteinuria
	• EMT	• Tubulointerstitial fibrosis and CKD

ECM extracellular matrix; FSGS focal segmental glomerulosclerosis; EMT epithelial–mesenchymal transition; CKD chronic kidney disease

4.2.6 Diagnosis

The diagnosis of hypertensive kidney disease is dependent on clinical manifestations and exclusion of other primary kidney diseases. A confirmed history of hypertension and signs of target organ damage, such as left ventricular hypertrophy, hypertensive retinal changes, and proteinuria, should establish the diagnosis. However, clarifying the diagnosis is occasionally very difficult in clinical practice when hypertension and CKD coexist. A flowchart for the diagnosis of benign nephrosclerosis is shown in Fig. 4.2.

Home and ambulatory BP monitoring (ABPM) is becoming increasingly recommended for the clinical evaluation of hypertension because of its ability to identify white-coat hypertension and masked hypertension [13]. Reference values for normal ambulatory BP in nonpregnant adults are summarized in Table 4.4, whereas diagnostic threshold values for ABPM (in mmHg) based on cardiovascular outcome are shown in Table 4.5.

Table 4.4

Reference values for normal ambulatory blood pressure in nonpregnant adults

Time	Normal	Hypertension threshold
24-h average	<115/75 mmHg	130/80 mmHg
Daytime (awake)	<120/80 mmHg	135/85 mmHg
Nighttime (asleep)	<105/65 mmHg	120/75 mmHg

Table 4.5

Diagnostic threshold values for ABPM (in mmHg) based on cardiovascular outcome [13]

ABPM characteristic	Men	Women	High-risk patients
Awake (mean)
SBP	135	125	120
DBP	85	80	75
Asleep (mean)
SBP	120	110	105
DBP	70	65	60

ABPM ambulatory blood pressure monitoring; SBP systolic blood pressure; DBP diastolic blood pressure

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