Transcript sleeping sickness

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
Glomerular& Tubular ischemia
Impaired Myogenic response
Arterial Injury
Hyalinosis
Hypoxia & Increased ROS
Glomerular pressure
Increased
Decreased
contractility
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?
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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.
• 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
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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;
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Preglomerular afferent arterioler vasoconstriction
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Podocyte injury
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Non-muscle mayosin heavy chain 9 (MYH9)
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Apolipoprotein L1 (ApoL1) carriers
Clinical Presentation
HISTORY
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Hypertension
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Usually >10yeras of hypertension
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Evidence of accelerated or poorly controlled BP
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Complications of hypertension( heart failure, stroke etc )
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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
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Hypertensive retinal changes
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Left ventricualr hypertrophy
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Long standing hypertension
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Proteinuria less than 0.5 gm/day
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Hypertension diagnosed prior to the onset of proteinuria
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Hypertension preceding renal dysfunction
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No evidence of other renal disease
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Biopsy findings compatible with diagnosis
Management
Effective treatment of hypertension usually slows
progression of renal injury.