1. HYPERTENSIVE NEPHROSCLEROSIS
Dr. Nauman Tarif
Fatima Memorial Hospital
Lahore

2. Overview
Hypertensive Nephrosclerosis [non-malignant]: Chronic hypertension of years, Absence of other causes of hypertension Minimal albuminuria. Lack of biopsy data led to the term: Hypertension attributable CKD

3. Burden of Hypertension
WHO estimates
40 % of adults>25 years of age
Responsible for 54% strokes & 47% MI
Studies did not show a direct evidence of ESRD secondary to HTN.
Equivocal in terms of placebo controlled studies upto 7 years
10-30% of ESRD patients in USA: HTN as cause.

4. Pathophysiology Afferent arteriolar tone: Myogenic effect
Na excretion: Tubular Glomerular feed back [TGF]
Increased arteriolar tone: Ischemic injury
Increased arterial stiffness [Aging, hyperlipidemia, smoking etc]
can amplify transmission of pressure wave to the renal microvasculature

6. Blood pressure
Genetic variability : eg APOL1
Preserved Myogenic response
Impaired Myogenic response
Glomerular pressure
Increased
Arterial Injury
Glomerular& Tubular ischemia
Hyalinosis
Decreased
contractility
Hypoxia & Increased ROS
Mesangial Expansion
Podocyte loss
Ischemic collapse
Glomerulosclerosis

8. Glomerulosclersis [GS] & HTN
Genetically mediated forms of GS:
Commonly present in patients with recent African ancestry
Lead to secondarily elevated blood pressure.
Majority of these patients are incorrectly categorized as having ‘hypertensive nephrosclerosis’.

9. Hypertensive Nephrosclerosis?
Most of the African Americans:
Reduced eGFR
High blood pressure
Low level proteinuria (Subnephrotic <2.5 g/d or <1 g per day)
Bland urinalysis
Hypertension­ related kidney disease:
No need of kidney biopsies

10. APOL1 gene: African origin Recessive Trait
Majority of patients diagnosed as hyertensive nephrosclerosis
APOL1 mRNA and protein is expressed:
Podocytes
Tubular cells
Glomerular endothelial cells
Gain of function mutation
Circulating APOL1 protein toxicity
ACE-I ineffective to halt the progression.

11. 13% of African Americans : (G1G1, G2G2 or G1G2 genotypes)
APOL1 G1 and G2 renal-risk variants are nearly universally found in individuals with recent African ancestry
13% of African Americans : (G1G1, G2G2 or G1G2 genotypes)
At heightened risk of non-diabetic kidney disease
Variation in APOL1 explains:
Excess risk of non-diabetic ESRD in African Americans
Reduced allograft survival of transplanted kidneys from deceased African American donors
APOL1 renal-risk variants were selected for approximately 10,000 years ago: protection they afford from certain forms of African sleeping sickness

12. APOL1-associated diseases: African Ancestry
HIV-associated nephropathy (HIVAN)
Idiopathic focal segmental glomerulosclerosis (FSGS)
Severe lupus nephritis
Sickle cell nephropathy
Attributed to the effects of essential hypertension
Approximately 70% of HIVAN and idiopathic FSGS in African Americans relates to variation in APOL1

13. APOL1 associated Glomerulosclerosis
Interstitial changes
Vascular changes as arteriolar nephrosclerosis
As a result of mild ­to ­moderate
Systemic hyper­tension

14. Histopathology APOL1 risk variant: Glomerulosclerosis Others:
Accelerated luminal narrowing in arcuate arteries & smaller renal arterioles potentially caused by hypertension
Risk factors:Ageing, a western diet, smoking, hyperlipidaemia & inflam­mation
Arteriolar nephrosclerosis reduces perfusion to the afferent arterioles, resulting in ischaemic collapse of the glomerular capillaries

16. Histopathology of arteiolonephrosclerosis
The walls of arterioles:
Thickened as a consequence of muscular hypertrophy
Accumulation of plasma protein insudates between endothelial cells and the muscularis. Complement (C3) smooth homogenous material through hyalinosis characteristically involves the afferent arterioles.
Lumina are narrowed
Arteries manifest
Medial (mus­cular) hypertrophy
Intimal fibroblastic thickening (fibrosis)
Both contribute to luminal nar­rowing.
Chronic tubular and interstitial lesions in the form of tubular atrophy and interstitial fibrosis are also present

17. Glomerular changes Complete sclerosis consequent to chronic ischaemia
Chronic ischaemic wrinkling and the collapse of capillary walls with the ultimate breakdown and consolidation of the capillary tufts
Accompanying accumulation of collagen in the urinary space leads to the formation of a solidified mass
Ischaemic obsolescence to distinguish them from other sclerosing lesions

22. APOL1 Related GS
Specific feature of the presence of two APOL1 renal ­risk variants
Complete solidification of the tufts but occur in the absence of collagen accumulation in the urinary spaces or appreciable shrinkage of the tufts.

23. Tubular changes with APOL1
The classic form:
Thick and wrinkled tubular basement membranes;
Thyroidization­ type:
Dilated lumina filled with hyaline casts and flattened epithelium

25. Pathophysiology Chronic hypertension
Narrowing of preglomerular arteries and arterioles
Reduction in glomerular blood flow
Intraglomerular hypertension and hyperfiltration
Hypertensive Glomerulosclerosis

26. Pathophysiology
Other factors contribute to Nephrosclerosis;
Preglomerular afferent arterioler vasoconstriction
Podocyte injury
Non-muscle mayosin heavy chain 9 (MYH9)
Apolipoprotein L1 (ApoL1) carriers

27. Clinical Presentation
HISTORY
Hypertension
Usually >10yeras of hypertension
Evidence of accelerated or poorly controlled BP
Complications of hypertension( heart failure, stroke etc )
Symptoms of uremia

28. Physical Findings
Hypertensive related end organ damage as; 1) Signs of left ventricular failure 2) Hypertensive changes in retinal vessels

29. Features Of Hypertensive Nephrosclerosis
Hypertensive retinal changes
Left ventricualr hypertrophy
Long standing hypertension
Proteinuria less than 0.5 gm/day
Hypertension diagnosed prior to the onset of proteinuria
Hypertension preceding renal dysfunction
No evidence of other renal disease
Biopsy findings compatible with diagnosis

30. Management
Effective treatment of hypertension usually slows progression of renal injury.