Pathology of the Kidney and Diabetic Nephropathy

Question 1

What is the difference between Nephrotic and Nephritic Kidney Disease?

Answer 1

• Nephrotic Kidney Disease: refers to proteinuria without blood in the urine
• Nephritic Kidney Disease: refers to the presence of red blood cells in the urine as well as proteinuria

Question 2

Describe the general features of a nephrotic kidney disease:

Answer 2

1. Proteinuria without blood in urine
2. Due to albumin and other proteins in the blood leaking into urine which results in proteinuia (more than 3.5g/day)- the more protein being lost, the more severe the symptoms
3. Causes low protein in blood that causes edema
4. Weight gain (due to fluid retention)
5. Hyperlipidemia
6. Few casts or cells in blood

Question 3

Describe the general features of a nephritic kidney disease

Answer 3

1. Presence of red blood cells in urine; with or without the formation of RBC/mixed cell castes
2. Results in variable levels of proteinuria
3. Acanthocytes (RBCs with altered shape- a ring structure attached to one end) make up >5% of urinary RBCs

Question 4

Name some major Nephrotic kidney diseases:

Answer 4

1. Minimal change disease
2. Focal segmental glomerulosclerosis
3. Membranous nephropathy
4. Diabetic nephropathy
5. SLE-associated nephritis

Question 5

Describe minimal change disease:

Answer 5

• Common cause of nephrotic kidney disease (especially among children)
• Characterised by proteinuria but normal pathology of the kidney under light microscopy
• Electron microscopy of minimal change disease biopsies show diffuse effacement (fusion) of the podocyte foot processes in the glomeruli
• Podocyte effacement causes an increase in glomerular permeability causing large quantities of albumin and other proteins to be filtered into the urine
• Cause is unknown but likely be due to an autoimmune disorder (kidneys with MCD when transplanted into healthy patients have normal function)

Question 6

Describe Focal Segmental Glomerulosclerosis:

Answer 6

• Some glomeruli (focal) are scarred (sclerosis) in a segmental manner
• Most common cause of nephrotic syndrome in adults
• FSGS is characterised by light microscopy by the presence of sclerosis in parts of some glomeruli (seen as an increase in eosinophilic tissue in the glomeruli)
• FSGS can be idiopathic or secondary (due to injury, toxins, infections etc.)

Question 7

Describe Membranous Nephropathy:

Answer 7

• In membranous nephropathy, the GBM thickens and develops woolly looking projections and there are area of GBM expansion (seen in light microscopy)
• When observed using electron microscopy it is seen that the GBM is extremely enlarged and thickened and podocyte foot processes become compressed

Question 8

Name some Nephritic Kidney Diseases:

Answer 8

1. Anti-GBM disease
2. Immune complex GN:
   - IgA nephropathy
   - Membranoproliferative GN
   - Lupus nephritis
   - Acute post-streptococcal GN
3. ANCA-positive GN

Question 9

What is Rapidly Progressive Glomerulonephritis?

Answer 9

• Acute onset of macroscopic haematuria (visible blood in urine), decreased urine output, fatigue and oedema
• Due to progressive loss of renal function occurring over a comparatively short period of time
• Characterised by inflammatory cells and red blood cells in urinary space
• Severe cases are characterised by fibrocellular crescents of proliferating cells (that form excessive fibrin) forming where organised glomerulus and Bowman’s capsule structures should exist
• Can cause a break in kidney space
• The major causes of rapidly progressive GN are anti-GBM disease, immune complex GN and ANCA-positive GN

Question 10

Describe Anti-GBM Disease:

Answer 10

• Autoimmune disease that results in the production of autoantibodies (IgG) against the GBM
• Results in characteristic linear antibody staining
• Antibodies cause damage to GBM resulting in leaking of inflammatory cells and proteins into the Bowman’s capsule causing inflammation and rapidly progressive GN
• These antibodies may also bind to lung capillaries and cause pulmonary haemorrhage (Goodpasture’s disease)

Question 11

Describe Immune Complex GN:

Answer 11

• Immune complexes (multiple antibodies bound to antigen) filtering into the kidney and becoming lodged in the kidney
• Results in characteristic granular antibody staining
• Types of immune complex GN include: IgA nephropathy, Membranoproliferative GN, Lupus nephritis and acute post-streptococcal GN

Question 12

Describe IgA Nephropathy:

Answer 12

• Most common form of glomerular nephritis (a type of immune complex GN)
• Initiating event is the deposition of IgA in the glomerular mesangial area
• Aetiology is unknown- possibly due to mucosal immunity dysfunction
• Results in excessive cellular content in glomerulus

Question 13

Describe Membranoproliferative GN:

Answer 13

• A form of glomerular nephritis (falls in immune complex category)
• Results in the proliferation of the GBM (GBM is thickened but also duplicated in some areas) and can result in deposits in the GBM
• Causes by immune complex deposition leading to activation of complement or dysregulation and persistent activation of the alternative complement pathway- both of which cause inflammation

Question 14

Describe Pauci-Immune (ANCA-positive) GN:

Answer 14

• Causes both slow and rapidly progressive glomerulonephritis
• Caused by anti-neutrophil cytoplasmic autoantibodies that are directed against parts of the neutrophils (e.g. PR3 and MPO) that trigger inflammation in the glomeruli
• Light microscopy often shows red blood cells in urinary space, crescentic formation and the deposition of ANCA antibodies on the GBM and fibrocellular crescents

Question 15

What is Tubulointersitial Nephritis?

Answer 15

• Cause of nephritis (RBCs in urine) that does not target the glomeruli (which are mostly normal), rather involving pathologies of the tubules and interstitium
• Causes of tubulointerstitial nephritis include:
  1. Oxalate poisoning: tubules to undergo an inflammatory reaction: tubules become spread apart, with immune cells interspersed between them

2. Tubular inflammatory disease: results in widely spaces tubules with inflammatory cells interspersed
3. Acute Tubular Necrosis: loss of circulation to kidney tissue causes the death of the tubular cells causing dilated tubules, epithelial flattening, loss of brush border and shedding of cells

Question 16

What is Polycystic Kidney Disease?

Answer 16

• The kidney forms multiple cysts which take over normal kidney structure and function
• Main cause is autosomal dominant polycystic kidney disease (ADPKD)

Question 17

What is autosomal dominant polycystic kidney disease (ADPKD)?

Answer 17

• Cysts progressively replace normal kidney tissue
• Disease caused by mutations in PKD1 or PKD2 gene (mutations of PKD often result in less severe phenotype)- that encode PC1 and PC2 proteins needed to regulate intracellular calcium and cilia function
• Disease can often be silent but can result in a loss of kidney function causing high BP, kidney infection, kidney stones, liver cysts, abdominal pain etc.

Question 18

What is the difference type type 1 diabetes and type 2 diabetes?

Answer 18

Type 1 Diabeties:

• Hyperglycaemia due to diminished production of insulin
• Autoimmune disease

Type 2 Diabetes:
- Hyperglycaemia due to insulin resistance

Question 19

What are the main complications of diabetes?

Answer 19

• Usually occur 15-20 years after disease onset
• High blood glucose levels lead to a range of events including inflammation, oxidative stress and the release of growth factors and cytokines
• The complications include:
  1. Diabetic retinopathy (eyes)
  2. Cerebrovascular disease (brain)
  3. Coronary heart disease (CVS)
  4. Diabetic nephropathy (kidney)
  5. Neuropathy (PNS)
  6. Peripheral vascular disease (lower limbs)
  7. Diabetic foot ulcers (feet)

Question 20

What is the definition of diabetic nephropathy?

Answer 20

• Diabetic nephropathy is classified by the presence of a degree of persistent albuminuria and also a reduction in kidney filtration (reduced eGFR) due to complications from diabetes
• The severity of DN is determined using an algorithm based on albuminuria levels and also degree of kidney function
• DN is the leading cause of end stage renal disease

Question 21

Describe the epidemiology of diabetic nephropathy:

Answer 21

• Common complication of diabetes (50% of patients with diabetes for more than 20 years will develop DN)
• Peak incidence is found in people who have had diabetes for 10-20 years
• The severity and incidence of DN are higher in some ethnic groups

Question 22

Describe the natural progression of diabetic nephropathy:

Answer 22

• For the first few years of diabetes there is no change to kidney function (albuminuria slowly increases)
• After 5-10 years there is an increase in kidney function as hyperfiltration occurs
• After the period of hyperfiltration, kidney function will decline
• As kidney function declines, blood pressure increases

Question 23

What are the patho-mechanisms in diabetic nephropathy?

Answer 23

• Chronic high blood glucose causes metabolic and haemodynamic changes in the body

1. Metabolic changes:
   - Advanced glycation end productions are formed which act on receptors called RAGEs
   - Activation of RAGEs on cells in the kidney causes inflammation, ECM production, cell growth, angiogenesis
2. Haemodynamic changes:
   - High blood glucose upregulates the RAAS which causes the retention of salt and an increase in BP
   - The RAAS system also triggers cell hypertrophy and growth, inflammation, fibrosis, oxidative stress and changes to GF expression
3. Metabolic and haemodynamic changes cause a state of increased oxidative stress and also result in high levels of TFG-B (involved in fibrosis), VEGF (related to proteinuria), PKC, TNF-a (pro-inflammatory) and IL-1B (pro-inflammatory)
4. These GFs and cytokines result in renal inflammation and fibrosis which causes micro- and macro- vascular complications

Question 24

What are the 3 major histological changes seen in diabetic nephropathy?

Answer 24

1. Mesangial expansion (PAS+ material)
   - Proteins involved are collagen IV and fibronectin
2. Thickening of the GBM
3. Glomerular sclerosis- due to intraglomerular hypertension
   - Accumulation of ECM

Question 25

What Pathological Findings are seen in Diabetic Nephropathy?

Answer 25

1. Light microscopy:
   - Increased solid spaces in tuft
   - Positive periodic‐acid Schiff material (mesangial matrix)
   - Large acellular accumulation of matrix (Kimmelstiel‐Wilson nodules/lesions)
   - Matrix expansion in both glomeruli and in the tubular interstitium
2. Immunofluorescence:
   - Deposition of albumin, immunoglobulins, fibrin, other plasma proteins along the GBM (the deposition is non-specific in diabetic nephropathy)
3. Renal vasculature:
   - Signs of atherosclerosis/ hypertension, hyperlipidaemia, arteriolar hyalinoses
4. Electron microscopy:
   - Mesangial area enlarged
   - Prominent matrix, large component of tuft
   - Thickened basement membrane and capillary walls
   - Podocyte loss, foot process effacement (stretching and thinning of the foot processes)

Question 26

How is Diabetic Nephropathy treated?

Answer 26

1. Strict glycaemic control:
   T1D: insulin
   T2D: drugs to restore insulin action, increase secretion or promote urinary glucose secretion
2. Treatment of co-morbidities such as high BP using ACE inhibitors
3. New treatments:
   - Anti-fibrotic agents
   - Anti-inflammatory agents
   - Reducing intracellular signalling mechanisms e.g. PKC

• Likely a combination therapy most effective