4th Science:40060

ARP lecture - Renal Disease

Dr. Tara McMorrow
tara.mcmorrow@ucd.ie
Tel: 01 716 6819

School of Biomolecular and Biomedical Science
Conway Institute
PHAR 40060 ARP Lecture 2: Objectives
At the end of this lecture, students should
have an understanding of the kidney in
relation to renal disease



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
Renal Disease Background:
Renal disease is a major problem world wide

Increasing incidence 80,000 new cases / year in
USA

Major causes include :
1. Diabetes
2. Hypertension
3. Glomerulonephritis

Mechanisms of development are unknown

Thus limited therapies are available
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
Kidney Sites Susceptible to Renal Disease
General: Renal medulla:
Low oxygen environment: Ischemia
Glomeruli:
Structure predisposes it to immune complex deposition
and complement fixation
Tubules
- generally involved in endstage or chronic kidney disease
Post-Renal Structures (ureters, bladder)
Malformations, Obstruction, Masses (i.e. cancer)
Acute Kidney Disease

Prerenal:
Decreased cardiac output and urine volume depletion
Drug-induced or related
Intrarenal:
Inflammatory disease
Acute tubular necrosis
Postrenal:
- Obstruction
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

Renal diseases are varied and can result from a toxic
insult 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 sclerotic
phenotype characterised by excess extracellular matrix
deposition
Regardless of the initial insult, development of renal
fibrosis leads to end-stage renal disease and ultimately
kidney failure
Renal Disease Classification
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
Glomerular Diseases

Glomerulonephritis (GN) is one of the most important causes of
renal disease world-wide.

Examples of GN include:
1. Membranous nephritis
2. Post-infectious glomerulonephritis
3. Lupus glomerulonephritis
4. IgA Nephropathy
5. Goodpastures Syndrome
6. Diabetic Nephropathy
7. Glomerulosclerosis
Glomerulonephritis
Glomerulonephritis is the third most common
cause of end-stage renal disease after
diabetes and hypertension
Accounts for 10-15% of ESRD patients
Immunological events lead to
- complement activation
- fibrin deposition
- platelet aggregation
- inflammation



Acute Glomerulonephritis Chronic Glomerulonephritis
Glomerulonephritis:
scarring of the cortex
Tubular Diseases
The main tubular disease is tubulointerstitial
nephritis
Acute tubulointerstitial nephritis- due to
hypersensitivity reactions to drugs
Chronic tubulointerstitial nephritis- due to
drugs, diabetes, chemicals


Acute Tubulointerstitial Nephritis
Chronic Tubulointerstitial Nephritis
Tubulointerstitial
Nephritis
Progressive Renal Disease
Common histological end point:

Scarring : 1. Glomerulosclerosis
2. Tubulointerstitial Fibrosis

Pathological process resulting from insult / injury
leading 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

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

Tubulointerstitial fibrosis
Tubulointerstitial fibrosis is a hallmark of
progressive renal disease

Progression of chronic renal insufficiency is
closely linked to the severity of tubulointerstitial
changes

Level of proximal tubular damage also correlates
closely with the degree of renal dysfunction
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 Kidney
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
ESRD
Patients with chronic renal impairment
tend to progress to ESRD
No treatment options except renal
replacement therapy i.e. dialysis
Transplantation-long waiting lists and
strict criteria
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
5 Stages of Kidney Disease
Many People With Kidney Disease Still in the Dark- March 2005 Report
Almost 45 percent of people with stage 4 kidney disease only one stage behind
kidney failure had 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.


Relevant References
Detection and Evaluation of Chronic
Kidney Disease. Snyder S and Pendergraph
B. 2005 AFP 72(9): 1723-1732

Management of Acute Renal Failure.
Needham E. 2005 AFP 72(9): 1739-1746
www.aafp.org/afp