4th sc phar 40060-renal-2web

8/12/2019 4th Sc Phar 40060-Renal-2web

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4th Science:40060

ARP lecture - Renal Disease

Dr. Tara McMorrow

[email protected]

Tel: 01 716 6819

School of Biomolecular and Biomedical Science

Conway Institute
mailto:[email protected]:[email protected]


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PHAR 40060ARP Lecture 2: Objectives

At the end of this lecture, students should

have an understanding of the kidney in

relation to renal disease


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Functional unit of the kidney - Nephron

Nephron

Tubular Vascular

component component

Approx. 1 million nephrons in each mammalian kidney

Can lose up to 75% of nephron function and renal

function will be maintained by reserve nephrons

difficult to detect damage early


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Renal Disease Backg round :

Renal disease is a major problem worldwide

Increasing incidence80,000 new cases / year inUSA

Major causes inc lude :1. Diabetes

2. Hypertension

3. Glomerulonephritis

Mechanisms of development are unknown

Thus limited therapies are available


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General Characteristics

Early Renal Disease: Abnormal urine volume

and/or composition

Advanced: Edema, electrolyte abnormalities,

anemia, etc. Rate of Progression: Disease-dependent

Disease Course: Transient-fatal: Disease-

dependent Pain: Variable, depending on nature of

disease


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Kidney Sites Susceptible to Renal Disease

General: Renal medulla:

Low oxygen environment: Ischemia

Glomeruli:

Structure predisposes it to immune complex depositionand complement fixation

Tubules

- generally involved in endstage or chronic kidney disease

Post-Renal Structures (ureters, bladder)

Malformations, Obstruction, Masses (i.e. cancer)


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Acute Kidney Disease

Prerenal:

Decreased cardiac output and urine volume depletion

Drug-induced or related

Intrarenal: Inflammatory disease

Acute tubular necrosis

Postrenal:

- Obstruction


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Slow decline in kidney function- eventually progresses to End Stage Renal

Disease (ESRD)

Generally develops as a result of another condition

- Diabetes (28%)- Hypertension (25%)

- Glomerulonephritis (21%)- Polycystic Kidney Disease (4%)

- Other (23%): Obstruction, infection, drugs.

Chronic Kidney Disease


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Renal diseases are varied and can result from a toxicinsult or may be immune mediated

They may be classified by their location of onset -

Glomerular disease- glomerulonephritis

Tubulointerstitial disease- tubulointerstitial nephritis

Most of the conditions result in a fibrotic or scleroticphenotype characterised by excess extracellular matrixdeposition

Regardless of the initial insult, development of renalfibrosis leads to end-stage renal disease and ultimatelykidney failure

Renal Disease Classification


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Renal ultra-structure of normal and fibrotic tissue

(a) Normal kidney architecture displaying a normal glomerulus ( ), bowmans

space ( ), mesangial cells ( ), basement membrane ( ) supporting the tubular

epithelial cells ( ) separated by the interstitial space ( ).

(b) In the glomerular nephritis section there is an enlarged glomerulus, reduced

bowmans space, proliferating mesangial cells, an expansive interstitium and

disruption of tubular function.

(a) (b)

Kidney Histology


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Glomerular Diseases

Glomerulonephritis (GN) is one of the most important causes of

renal disease world-wide.

Examples of GN include:

1. Membranous nephritis2. Post-infectious glomerulonephritis

3. Lupus glomerulonephritis

4. IgA Nephropathy

5. Goodpastures Syndrome

6. Diabetic Nephropathy

7. Glomerulosclerosis


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Glomerulonephritis

Glomerulonephritis is the third most commoncause of end-stage renal disease afterdiabetes and hypertension

Accounts for 10-15% of ESRD patients

Immunological events lead to

- complement activation

- fibrin deposition- platelet aggregation

- inflammation


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Acute Glomerulonephritis Chronic Glomerulonephritis

Glomerulonephritis:

scarring of the cortex
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Tubular Diseases

The main tubular disease is tubulointerstitial

nephritis

Acute tubulointerstitial nephritis- due tohypersensitivity reactions to drugs

Chronic tubulointerstitial nephritis- due to

drugs, diabetes, chemicals


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Acute Tubulointerstitial Nephritis Chronic Tubulointerstitial Nephritis

Tubulointerstitial

Nephritis
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Progressive Renal Disease

Common histological end point: Scarr ing : 1. Glomerulosclerosis

2. Tubulointerstitial Fibrosis

Pathological process resulting from insult / injuryleading to tissue dysfunction and organ failure

Fibrosis - The Final Common Pathway for renal

diseases that progress to ESRF Level of fibrosis correlates closely with the degree of

renal dysfunction


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Glomerulosclerosis

Glomerulosclerosis is a key endpoint in

progressive renal disease

Leads to scarring of the glomeruli which

cannot be repaired

Eventually leads to end stage renal disease


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Tubulointerstitial fibrosis

Tubulointerstitial fibrosis is a hallmark ofprogressive renal disease

Progression of chronic renal insufficiency isclosely linked to the severity of tubulointerstitial

changes

Level of proximal tubular damage also correlatesclosely with the degree of renal dysfunction


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FIBROSIS :

1. Increased deposition of fibronectin,

collagens

2. Increased fibroblast proliferation

3. Increase in mononuclear cells

4. Accumulation of matrix proteins :- inadequate matrix degradation

The End-Stage K idney


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Kidney fibrosis (ESRD)

Tubulointerstitial Fibrosis is the final common pathway leading to

ESRF - correlates most closely with declining renal function

Caused by accumulation of excess extracellular matrix (ECM) in the

renal tubular interstitium


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ESRD

Patients with chronic renal impairment

tend to progress to ESRD

No treatment options except renalreplacement therapy i.e. dialysis

Transplantation-long waiting lists and

strict criteria


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Kidney Disease Summary

Prevalence of kidney disease

- 1 in 9 adults develop chronic kidney disease

Renal fibrosis is a common final pathway for

numerous kidney dysfunctions- e.g. Tubulointerstitial fibrosis, diabetic nephropathy

Renal fibrosis is characterised by:- loss of renal function

- decreased number of epithelial cells

- excess ECM accumulation

- infiltration of fibroblasts


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5 Stages of Kidney Disease

Many People With Kidney Disease Still in the Dark- March 2005 ReportAlmost 45 percent of people with stage 4 kidney diseaseonly one stage behind

kidney failurehad never been told there was anything wrong with their kidneys.

More than 20 million Americansone in nine adultshave chronic kidney

disease. More than 20 million more are at increased risk for developing

kidney disease, and most don't even know it.


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Relevant References

Detection and Evaluation of Chronic

Kidney Disease. Snyder S and Pendergraph

B. 2005AFP72(9): 1723-1732

Management of Acute Renal Failure.

Needham E.2005AFP72(9): 1739-1746

www.aafp.org/afp

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