Kidney Disease


Systolic BP (mmHg)

Diastolic BP (mmHg)









Stage I HTN




Stage II HTN




BP classification was based on the eighth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (Reproduced with permission from James PA, et al. [3])

BP blood pressure; HTN hypertension

No acceptable unified definition of hypertensive kidney disease exists to date. Studies from the past decade showed that apolipoprotein L1 gene (APOL1)-associated glomerulosclerosis can occur with arteriolar nephrosclerosis, which can develop into mild to moderate systemic hypertension [4, 5], suggesting that genetic variants in glomerulosclerosis can lead to syndromes clinically indistinguishable from systemic hypertension-related renal arteriolar disease. Because genetic testing for APOL1 variants and other glomerulosclerosis-associated genetic variants is available and can precisely define disease pathogenesis, some experts suggest the abandonment of the term “hypertensive nephrosclerosis.” However, studies on the subject have only been restricted to African Americans. Furthermore, most experts agree that hypertensive kidney disease should be defined as damage to the kidney due to high BP. Hypertensive kidney disease can be classified as either benign or malignant according to the severity and rapidity of hypertension and arteriolar changes.

4.2 Benign Nephrosclerosis

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

The exact causes of high BP remain unclear, although some specific genetic variants have been identified to be associated with hypertension. Several risk factors are linked to hypertension, some of which are modifiable (e.g., being overweight or obese, low physical activity, tobacco use, unhealthy diet, and excessive alcohol consumption), whereas others are unmodifiable (e.g., age, race, and family history). Risk factors for the development of hypertension are listed in Table 4.2.

Table 4.2

Risk factors for the development of hypertension

Modifiable risk factors

Unmodifiable risk factors

• Being overweight or obese

• Sedentary lifestyle (lack of physical activity)

• Tobacco use

• Unhealthy diet (high in sodium)

• Excessive alcohol consumption

• Stress

• Sleep apnea

• Diabetes

• Age

• Race

• Family history

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

Most patients are observed to be hypertensive with nonspecific symptomatology on routine physical examination. Hypertension is usually present for many years, with persistent BP elevation and evidence of the following hypertension-related target organ damage:

  • Proteinuria less than 0.5 g/day

  • Hypertensive retinal changes

  • Left ventricular hypertrophy

  • Heart attack or heart failure

  • Stroke

  • Atherosclerosis

  • Aneurysm

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.


Fig. 4.1

Histopathological manifestations in benign nephrosclerosis. Hyaline degeneration (arrowhead) and intimal thickening (arrow) of renal arterioles are present (periodic acid-Schiff staining, ×400)

Table 4.3

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





• 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


Not applicable

• Increased intraglomerular pressure and microalbuminuria

• ECM accumulation


• Glomerular tuft entirely replaced by collagen

• Global glomerulosclerosis

• Capsular adhesion and segmental scars

• Reduced filtration


• Cell dilation and flattening, cell atrophy and loss

• Proteinuria


• 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.


Fig. 4.2

Flowchart for diagnosis of benign nephrosclerosis

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



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



High-risk patients

Awake (mean)









Asleep (mean)









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

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Oct 20, 2020 | Posted by in NEPHROLOGY | Comments Off on Kidney Disease

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