HYPERTENSIVE NEPHROSCLEROSIS Dr. Nauman Tarif Fatima Memorial Hospital Lahore

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

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.

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

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

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’.

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

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.

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

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

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

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

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

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

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.

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

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

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

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

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

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

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