APOL1 AND HYPERTENSION-ATTRIBUTED KIDNEY DISEASE

Genetic variants in APOL1 have been found to be strongly associated with kidney disease, including ESKD [36,37], FSGS [38], HIV-associated nephropathy [38], and hypertension-attributed CKD [16▪▪,36], as summarized in Table 2. Two APOL1 variants are pathogenic, termed G1 and G2; the renal disease risk is almost entirely recessive: specifically, either homozygosity for either variant or dual heterozygosity confers risk. Recent work has extended these observations. In the AASK study, study participants were more likely (23%) to have two APOL1 risk variants compared with controls (12%), whereas the percentages with one risk variant allele were similar between cases (42%) and control (45%). The presence of two APOL1 risk alleles was also associated with more proteinuria at baseline urine protein/creatinine ratio more than 0.6 g/g, odds ratio 6.3, with 48% having two APOL1 risk alleles, suggesting more severe kidney disease, and was associated with a greater chance of progressing to serum creatinine more than 3 mg/dl or ESKD during follow-up (odds ratio 4.6), with 40% having two APOL1 risk alleles (Table 2).

Several points can be made about this genetic risk. First, about one-quarter of African Americans with hypertension-associated CKD, as defined within AASK, have two APOL1 risk alleles. On the other hand, three-quarters of such patients do not have the risk genotype – and as in other kidney diseases (FSGS, HIV-associated nephropathy), one APOL1 risk allele does appear not to confer increased risk. Thus, APOL1 variants may not account for all the increased African-American predispositions to clinically diagnosed hypertension-attributed disease. Second, the presence of the APOL1 risk alleles marks hypertensive individuals who have more proteinuria at presentation and who progress faster, despite the use of effective therapies and optimal levels of blood pressure control, at least as these are presently conceived. Further, even when more severe phenotypes are considered, that is, heavier proteinuria or progression to more advanced levels of renal insufficiency, the majority of subjects lack two APOL1 risk alleles. With regard to progression of kidney disease in the AASK study, there was no interaction between APOL1 genotype and response to any particular antihypertensive therapy or blood pressure goal during the controlled trial phase, which suggests that there is no favored therapeutic approach for these high-risk patients compared with other patients. Third, although studies are in progress, we still do not know whether the histology differs between those with two APOL1 risk alleles and others – specifically whether they have more segmental glomerulosclerosis and/or more solidified glomerulosclerosis (rather than obsolescent glomeruli) compared with other subjects. Fourth, it was noted above that among African Americans, ESKD attributed to hypertension has a peak incidence at ages 30–59 years and this disease process likely began some 10–25 years before. This aligns fairly well with the incidence peak for FSGS (ages 15–39) associated with genetic variation in APOL1 [38]. Thus, it may be that age-dependent onset of APOL1 nephropathy, with injury initiating in the second, third, and fourth decades of life, leads to what are presently thought of as two diseases (FSGS and hypertension-attributed nephrosclerosis), but that may arise due to similar biologic mechanisms.

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How does the new information about APOL1 change our views of hypertension-attributed CKD? It suggests a model in which genetically influenced ‘primary’ kidney disease in individuals with two APOL1 risk alleles and manifesting as arterionephrosclerosis may lead to hypertension, rather than the reverse. Not all APOL1 two-risk allele subjects develop CKD, and therefore other genetic or environmental factors must contribute. Although there could be a dominant effect of a single APOL1 risk allele, it has not been shown in the AASK study or in other studies of glomerular disease to date.

What causes arterionephrosclerosis in African Americans who lack two APOL1 risk alleles and in those of European and Asian descent? Certainly hypertension may play a role, but we may need to broaden our thinking to include other possible causes of microvascular pathology, as listed in Table 3. These include age [39], diabetes [40], obesity [41], oxidative stress [42], and smoking [43]. The syndrome of nodular glomerulosclerosis with marked arteriosclerosis has been associated with cigarette smoking [44,45]. A number of genetic mutations, including FBN1 (Marfan syndrome), ABCC6 (pseudoxanthoma elasticum, PXE), MGP (Keutel syndrome), and GGC6 (PXE-like), have been associated with arterial remodeling and vascular disease, although not associated with arterionephrosclerosis [46]; it now appears that APOL1 variants are a primary cause of arterionephrosclerosis. Notably, diabetic nephropathy and nodular glomerulosclerosis are associated with thickened glomerular basement membranes, which is not a feature of either APOL1 nephropathy or most cases of arterionephrosclerosis. We have little understanding about what is distinctive about diabetic nephropathy and nodular glomerulosclerosis that would lead to basement membrane thickening, but presumably this arises by mechanisms that are different from mechanisms driving the arterial pathology.

— Update: 11-02-2023 — cohaitungchi.com found an additional article Arteriolar Nephrosclerosis – A Complication of Hypertension from the website www.icliniq.com for the keyword hypertensive arteriolar nephrosclerosis.

Introduction

Arteriolar nephrosclerosis, also known as hypertensive nephrosclerosis, is a condition affecting the renal tissues as a consequence of uncontrolled hypertension. The increased arterial pressure, when transmitted to the glomerular microcirculation, will result in injury to the glomeruli and result in glomerulosclerosis. It serves as one of the common causes of renal failure. The symptoms may be attributed to renal failure, and the treatment is aimed at controlling elevated blood pressure.

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What Is Arteriolar Nephroscelerosis?

Arteriolar nephrosclerosis is a progressive impairment of the kidneys due to poorly controlled blood pressure. The poorly controlled hypertension results in damage to the renal tubules, blood vessels, glomeruli, and the interstitium. This, in turn, progresses to end-stage renal disease.

What Is the Difference Between Benign and Malignant Hypertension?

Benign hypertension is a chronic condition with an unknown cause slowly affecting the tissues as sequelae. Whereas malignant hypertension is a very high blood pressure that occurs rapidly, affecting the organs and causing damage. Arteriolar nephrosclerosis occurs as a complication of benign or chronic hypertension.

What Is the Pathophysiology of Arteriolar Nephrosclerosis?

In patients with uncontrolled high blood pressure, it affects the components of the kidneys, causing nephropathy. In arteriolar nephrosclerosis, there is a narrowing of the renal arteries caused by the deposition of homogenous pink hyaline material along the walls of the blood vessels. This, in turn, reduces the blood flow and oxygenation to the tissues causing ischemia;

slowly affecting the renal tissues causing interstitial fibrosis, tubular atrophy, and morphological changes in the glomeruli.

What Are the Morphological Changes Encountered in Glomeruli Due to Arteriolar Nephroscelerosis?

The glomeruli show three types of morphological changes, it includes;

• Obsolescent Glomeruli – Partially or fully collapsed glomerular tuft with the extracellular material in the Bowman’s capsule.
• Solidified Global Glomerulosclerosis – The glomeruli are completely replaced by collagen, and the glomerular tuft is expanded.
• Segmental Glomerulosclerosis – In which the part of the glomeruli undergoes sclerosis.

How Does Arteriolar Nephrosclerosis Progress to Kidney Failure?

The above-said alterations in the glomeruli and periglomerular sclerosis (scarring around the glomeruli) will affect the functional nephrons reducing the functioning capacity of the kidneys, which subsequently progresses to kidney failure. Two proposed pathogenesis for kidney failure through hypertensive nephrosclerosis are;

• Glomerular Sclerosis – The blood flow to the kidneys is decreased due to the narrowing of the renal arteries; thus, the kidneys shrink and lose function, causing kidney failure.
• Glomerular Hypertension and Hyperfiltration – The glomeruli undergo sclerosis and renal tissue ischemia due to chronic hypertension. On the other hand, the unaffected nephrons try to compensate for the functional loss and do more work to filter the waste products leading to renal failure.

What Is the Epidemiology of Arteriolar Nephrosclerosis?

Arteriolar nephrosclerosis is one of the common causes of kidney failure. 17 to 25% of the patients under dialysis are affected by this condition due to uncontrolled hypertension. Studies report that the black population is highly susceptible to arteriolar nephrosclerosis.

Who Is at High Risk for Arteriolar Nephrosclerosis?

• High blood pressure.
• Old age.
• Pre-existing kidney disease.
• Diabetes.
• Obesity.
• Chronic inflammation.
• Smoking.

What Are the Symptoms of Arteriolar Nephrosclerosis?

Symptoms may be attributed to progressing renal failure. It includes:

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• Tiredness.
• Lethargy.
• Vomiting.
• Nausea.
• Pruritus (itching all over the body).
• Loss of appetite.
• Confusion.
• Proteinuria (presence of protein in the urine).

How Is Arteriolar Nephrosclerosis Diagnosed?

Diagnosis of this condition is based on the following:

1. Clinical History:

A thorough clinical history of the symptoms associated with the condition and the elevated blood pressure gives a major clue in diagnosing arteriolar nephrosclerosis.

2. Monitoring Blood Pressure:

The patient’s blood pressure levels are elevated.

3. Ultrasound of Kidney:

Ultrasonographic examination of the kidney would reveal the deterioration of the kidney tissues owing to sclerosis and reduced kidney size due to reduced blood supply and tissue ischemia.

4. Kidney Biopsy:

Microscopic examination of the kidney tissues would reveal sclerosis of the glomeruli. The presence of homogenous pink hyaline material along the walls of the blood vessels causes the thickening of the blood vessels. Biopsy also shows the capillary basement membrane’s thickening, the capillary lumen’s collapse, and periglomerular scarring.

5. Blood Examination:

Blood examination would reveal the signs of decreased kidney function, such as elevated serum creatinine and urea levels.

6. Urine Examination:

Examination of urine would reveal the presence of protein in the urine, and the tiny tube-shaped particles called urinary casts in the urine sediments.

How Is Arteriolar Nephrosclerosis Managed?

The prime goal of treatment in arteriolar nephrosclerosis is to control elevated blood pressure levels. Followed by correcting the complications;

1. ACE Inhibitors – Angiotensin-converting enzyme inhibitors can be prescribed to reduce the high blood pressure levels.

2. ARB Drugs – Angiotensin II receptor blockers would also help in controlling hypertension.

3. Combination Drugs – A combination of ACE Inhibitors and ARB can be given in cases with severely high blood pressure levels.

4. Calcium Channel Blockers And Thiazide Diuretics – Can also be given to reduce hypertension.

5. Chronic Kidney Disease – Kidney disease caused by ischemia can be managed by restricting salt and fluid intake.

6. End-Stage Renal Disease – In such cases, dialysis is indicated, or kidney transplantation is the treatment of choice.

7. Non-pharmacological Measures– Other general measures such as:

• Regular exercise.
• Weight loss.
• Salt restrictions.
• Limited water intake.

This would help control blood pressure and reduce the load on the kidneys.

What Is the Prognosis of Arteriolar Nephrosclerosis?

The prognosis of this condition largely depends on blood pressure control and the amount of kidney damage. As renal failure develops slowly, the prior treatment would help prevent permanent kidney damage. Studies state that only 1 to 2 % of people develop renal failure after 5 to 10 years of arteriolar nephrosclerosis.

Conclusion

Arteriolar nephrosclerosis is a blood vessel disorder of the kidney caused as a result of chronic uncontrolled hypertension. It is reported to be one of the common causes of renal failure. The prognosis is reported to be good, with prompt management of hypertension.