Dr. J. Satish Kumar, MD, Department of Basic & Medical Sciences, AUST

General Medicine

Renal System

Name:_________________________________________

Learning Objectives: Describe the types, aetiology, pathogenesis, clinical manifestations, investigations & treatment of Glomerulonephritis, Acute Pyelonephritis, Nephrotic Syndrome, Chronic renal failure.

Function of Kidneys

• Remove toxic waste products• Remove excess water and salts• Play a part in controlling blood pressure• Produce erythropoetin (epo) which stimulates

red cell production• Helps to keep calcium and phosphate in

balance for healthy bones• Maintains proper pH for the blood

Glomerulonephritis- etiology -

“primary” (idiopathic)- pathology is confined to the kidney- any systemic features as direct consequence of glomerular dysfunction

“secondary”- kidney abnormality as a part of multi- system disorder

glomerulonephritis- location -

“focal”:<50% of all glomeruli“diffuse”: ≥50% of all glomeurli

“segmental”:part of individual glomerulus“global”: entire glomerulus

major determinants of glomerular injury

1. nature of primary insult and secondary mediator systems

2. site of injury within glomerulus

3. nature of injury- speed of onset- extent- intensity

1. primary insult

major insult to glomerulusa. immune attackb. metabolic stressc. mechanical stress

2. site of injury

a. injury to endothelium and subendothelial aspect of GBM(1) recruitment of leukocytes

inflammatory glomerulonephritis(2) perturbed hemostasis

thrombotic microangiopathy(1) or (2) + intrarenal vasoconstriction

mesangial cell contractionrenal failure

2. site of injury

b. injury localized to mesangial areaasymptomatic abnormalities of urinary sedimentmild renal insufficiency

c. injury to subendothelial aspect of GBM and visceral endothelial cells

proteinuria

2. site of injury

d. injury to mesangiummildly compromised GFR

e. injury to parietal epithelial cellscrescent formation(acute or subacute renal failure)

3. nature of injury

a. rapid, extensive, immune complex deposition (poststreptococcal glomerulonephritis)

diffuse acute inflammation

“acute diffuse proliferative glomerulonephritis”

acute renal failure

- complement activation- leukocyte recruitment- lysosomal enzyme release- free radical generation- purturbation of vascular tone & permeability

3. nature of injury

b. slow, but sustained IgA-immune complex formation (IgA nephropathy)

less active inflammation

relatively well maintained GFRor

slowly progressive renal insufficiency over decades

major mechanisms of injury

a. immune attack (immunologic glomerular injury)background abnormalities

i. dysregulation of humoral immunity autoantibodyii. cellular immune mechanism

modulating antibody productionantibody-dependent cell cytotoxicity“pauci-immune” glomerulonephritis

robust glomerular inflammation without immunoglobulin deposition

b. metabolic stress (metabolic injury)

hyperglycemia(1) advanced glycosylation end-products (AGEs)(2) reactive oxygen species

cell sorbitol accumulationmitogen-activated protein kinase

activation (3) high glucose-triggered glomerular hypertension

(i) mesangial cell hypertrophy(ii) increased mesangial cell matrix production(iii) reduced matrix catabolism(iv) glomerulosclerosis

c. mechanical stress(hemodynamic glomerular injury)

i. systemic hypertensionmalignant hypertension

massive fibrinoid necrosis of afferent arteriole and glomerulithrombotic microangiopathy

nephritic urinary sedimentacute renal failure

chronic sustained hypertensionarteriolar vasoconstriction and sclerosis

secondary glomerular and tubulointerstitial atrophy and sclerosis

c. mechanical stress(hemodynamic glomerular injury)

ii. glomerular hypertensionglomerular hypertension as an adaptive response to increased workload 2° to loss of other nephrons

sustained glomerular hypertension

increased mesangial matrix production

glomerulosclerosis

final common pathways of glomerular injury

1. secondary focal segmental glomerulosclerosis

2. tubulointerstitial inflammation and fibrosis (tubulointerstitial fibrosis)

final common pathways of glomerular injurysecondary focal segmental glomerulosclerosis

a. nephron losscompensatory changes in surviving nephrons

1. vasodilation of afferent arterioles2. glomerular hypertension3. glomerular hyperfiltration

sustained glomerular hypertension and hyperfiltrationTGF-β, angiotensin II, PDGF, CTGF, endothelins

accumulation of extracellular matrix

focal and segmental glomerulosclerosisglobal sclerosis proteinuria, hypertension,

progressive renal insufficiency

final common pathways of glomerular injurysecondary focal segmental glomerulosclerosis

b. glomerular hypertrophyintracapillary microthrombirecruited macrophageshyperlipidemia

glomerulosclerosis

Nephrotic syndrome-ifferential diagnosis of nephrotic and nephritic syndrome

Increased permeability of the basement membrane-podocyte system to albumine

Structural damage to the glomerulus due to inflammatory processes

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NEPHROSIS NEPHRITIS

*Nephrotic syndrome is a group of symptoms including protein in the urine (more than 3.5 grams per day), low blood protein levels, high cholesterol levels, high triglyceride levels, and swelling.

Differential diagnosis of nephrotic and nephritic syndrome

• Urine: proteinuria (>3.5g, v. 40mg/m2/h)

• Serum: hypoproteinemia, hypalbuminemia, hypercholesterinemia

• Urine: hematuria, proteinuria, erythrocyte casts

• Serum: normal total protein level

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NEPHROSIS NEPHRITIS

*

Differential diagnosis of nephrotic and nephritic syndrome

• GFR normal• BP: no hypertension• Decreased

intravascular volume

• GFR decreased• BP: hypertension• Increased

intravascular volume

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NEPHROSIS NEPHRITIS

*

Conditions leading to nephrotic syndrome

• Conditions causing heavy proteinuria– Primary nephrosis: • Idiopathic nephrotic syndrome (INS) (=MCNS, lipoid

nephrosis)• FSGS• Membranosus nephropathy• Membranoproliferatíve GN

– Secondary nephrosis• SLE, Schönlein-Henoch nephropathy, amiloid nephropathy,

diabetic nehropathy

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*

Mechanisms of proteinuria

– Structure of the filtration barrier– Role of the basement membrane– Humoral factors– Role of the podocyte

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Structure of the filtration barrier

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Podocyte

Foot processes

Fenestrated endothelium

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Mechanisms of proteinuriaMechanisms of proteinuria

– Structure of the filtration barrier– Role of the basement membrane– Humoral factors– Role of the podocyte

Treatment-Hypovolemia/hypervolemia?• Because of dynamic change of intravascular volume in

nephrosis, treatment should be tailored in according to the volume state

• Evaluation:– Blood pressure, CVP– U[K+]/(U[K+]+U[Na+]) correlates with plasma aldosterone level

and is useful in monitoring hyovolemic states

• Clinical estimate

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*•(Donckerwolcke 2001 [110 MCNCS])

Treatment of nephrotic syndrome

• Supportive treatment• Treatment of steroid sensitive cases• Treatment of steroid resistant NS (FSGS)

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Supportive tretment

• Restore plasma volume/decrease edema

• Decrease proteinuria

• Prevent renal damage

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Supplementary measures

• Sodium restriction• Protein restriction 1g/kg + losses– Decreases proteinuria– Decreases sodium retention– Decreases the danger of development of secondary FSGS– Decreases the compensatory protein synthesis of the liver

(hypoercholesterinemia& thrombophylia)

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Supplementary measures• ACE inhibitors– Decreases proteinuria

• Hemodynamic effect• Direct effect on podocytes

– Decreases fibrosis

• Indomethacin– Decreases GFR and proteinuria

• Steroid: prednisone– Remission within 4 weeks

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Definitions- Renal failure• Azotemia: Elevated blood urea nitrogen– (BUN>28mg/dL) & Creatinine (Cr>1.5mg/dL)

• Uremia: azotemia with symptoms or signs of renal failure

• End Stage Renal Disease (ESRD): uremia requiring transplantation or dialysis

• Chronic Renal Failure (CRF): irreversible kidney dysfunction with azotemia >3 mos.

• Creatinine Clearance (CCr): rate of filtration of creatinine by the kidney (marker for GFR)

• Glomerular Filtration Rate (GFR): the total rate of filtration of blood by the kidney.

Renal Failure• Acute Renal Failure

– Prerenal azotemia• An abnormally high level of

nitrogen-type wastes in the bloodstream. It is caused by conditions that reduce blood flow to the kidneys.

– Postrenal azotemia• An obstruction of some kind (i.e.,

bladder cancer, uric acid crystals, urethral stricture etc)

– Intrinsic Renal Disease• Usually glomerular disease• Usually leads to End Stage Renal

Disease

Chronic Renal Failure-Definition

• CRF is defined as a permanent reduction in glomerular filtration rate (GFR) sufficient to produce detectable alterations in well-being and organ function. This usually occurs at GFR below 25 ml/min.

• About 100 to 150 per million persons in the U.S. develop CRF annually

• Average annual cost is $25,000 – 35,000 per patient per year

• Progressive and irreversible deterioration in glomerular +/- tubular function measured over months and years

Chronic Renal Failure-Causes• Diabetic Nephropathy– Diabetes most common contributor to ESRD

• Hypertension– CFR with Hypertension causes 23% of ESRD annually

• Glomerulonephretis: 10%• Polycystic Kidney Disease: 5%• Rapidly progressive glomerulonephrities (vasculitis): 2%• Renal Vascular Disease (i.e., renal artery stenosis)• Medications• Analgesic Nephropathy (progression after many years)• Pregnancy: high incidence of increased creatitine and HTN

during pregnancy associated with CRF

Stages of Chronic Renal Failure

1. Silent – GFR up to 50 ml/min.2. Renal insufficiency – GFR 25 to 50 ml/min.3. Renal failure – GFR 5 to 25 ml/min4. End-stage renal failure – GFR less than 5

ml/min.

Diabetic Nephropathy

• What can be done to reduce the risk of problems?– Blood glucose control– Blood pressure control– Using ACE inhibitors and AT II antagonists– Diet– Controlling blood lipids and cholesterol– Smoking

Treatment for Diabetic NephropathyStageStage AssessmentAssessment TreatmentTreatment

No ProteinuriaNo Proteinuria Monitor BP & GlucoseMonitor BP & Glucose

Screen for Screen for micoalbumininuriamicoalbumininuria

Hypertension drugs if Hypertension drugs if needed (BP should be needed (BP should be 130/85 or lower). Dietary 130/85 or lower). Dietary advice for sugar and fat, advice for sugar and fat, stop smokingstop smoking

MicroalbuminuriaMicroalbuminuria Close monitoring of BP, Close monitoring of BP, Glucose and blood lipids, Glucose and blood lipids, monitor urinary proteins monitor urinary proteins & CCr& CCr

Add more Hypertension Add more Hypertension drugs if needed needed. drugs if needed needed. Monitor cholesterol and Monitor cholesterol and add ACE inhibitor if add ACE inhibitor if neededneeded

ProteinuriaProteinuria Close monitoring of BP, Close monitoring of BP, glucose and blood lipids, glucose and blood lipids, monitor urinary protein monitor urinary protein and 24 CCrand 24 CCr

BP should be lower than BP should be lower than 125/75, low protein diet125/75, low protein diet

Declining kidney functionDeclining kidney function Prepare for dialysis &/or Prepare for dialysis &/or transplanttransplant

Metabolic changes

• Na+ excretion initially increased• Edema occurs when GFR continues to diminish.• NH4+ excretion declines adding to metabolic

acidosis.• Bone CaCO3 begins to act as a buffer for the acidosis

and leading to chronic bone loss and bone lesions develop (renal osteodystrophy).

• Accumulations of normally secreted uremic toxins

Uremic Syndrome

• Uremia occurs in stage 3 & 4 of CRF. It means literally “urine in the blood”– Symptomatic azotemia– Fever, Malaise– Anorexia, Nausea– Mild neural dysfunction– Uremic pruritus (itching)

Associated problems with CFR• Immunosuppression

– Increased risk of infection– People with CFR should be vaccinated regularly

• Anemia– Due to reduced erythropoietin production by kidney. Usually doesn’t

occur until 6-12 mos prior to dialysis• Hyperuricemia (Gout)

– Increased uric acid in system– Pain in joints, may contribute to renal dysfunction

• Hyperphosphatemia– Increased parathyroid hormone levels– Increased phosphate load from bone metabolism

• Hypertension• Poor coagulation• Proteinuria

Chronic Renal Failure• Chronic Renal Failure and Its

Progression

• Functional Adaptation to Nephron Loss– Increased amount of sodium

that escapes reabsorption– Excessive amount of potassium

in blood– Increased ammonia

concentration– Calcium and phosphorus

metabolism are markedly altered

Complications

Management of complications

• Erythropoietin• Sodium bicarbonate• Calcium-based phosphate binders• Vitamin D supplementation• Statins• Anti-hypertensives

Treatment of Chronic Renal Failure• Metabolic Acidosis• Anemia• Renal Osteodystrophy• Uremic Neuropathy• Sexual Dysfunction• Hypertension

Conservative Treatment

Dialysis Transplant

Hemodialysis Peritoneal Related Donor Cadaver Donor

Home Center

Treatment of End Stage Renal Failure

• Hemodialysis– Uses a mechanized

filter to remove impurities from the blood system

– Essentially replaces kidney with a machine

– Dialysis usually occurs a couple times per week.

Treatment of End Stage Renal Failure

• Peritoneal Dialysis– Uses the

abdominal cavity as a filter

Treatment of End Stage Renal Disease

• Survival of People with ESRD– Data show a mean expected remaining life span of

just under 8 years for people 40-44 beginning dialysis and just over 4 years for people 60-64

• Adequacy of Dialysis

• Nutrition

Chronic Renal Failure• Physical Rehabilitation – benefits of exercise• Vocational Rehabilitation– The goal should be to help the person with chronic renal

failure to resume all the duties, responsibilities and benefits he or she enjoyed prior to the illness

– Gainful employment is extremely important for an adult in the earning period of his or her life, to regain self-esteem and to interact with society confidently• Fear of losing financial benefits may deter some people • Some research has shown that multidisciplinary

predialysis intervention leads to maintenance of job