Systolic BP (mmHg)
Diastolic BP (mmHg)
Stage I HTN
Stage II HTN
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
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
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
• Sleep apnea
• 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 .
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 . 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 . This variation may reflect differences in criteria for and accuracy of diagnosis of hypertensive nephropathy among various countries.
4.2.4 Clinical Manifestations
Proteinuria less than 0.5 g/day
Hypertensive retinal changes
Left ventricular hypertrophy
Heart attack or heart failure
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 . 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 . 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 .
4.2.5 Pathological Manifestations
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
• Breakdown of elastic fibers in the large arteries
• Laminar-to-pulsatile flow shift in the arcuate, interlobular, and afferent arterioles
• 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
• Tubulointerstitial fibrosis and CKD
Reference values for normal ambulatory blood pressure in nonpregnant adults
Diagnostic threshold values for ABPM (in mmHg) based on cardiovascular outcome