• Information
  1. Glomerular Structure
  2. Proximal Convoluted Tubule
  3. Loop of Henle
  4. Distal Convoluted Tubule
  5. Collecting Ducts
  6. Blood Supply

• RENAL GLOMERULAR DISEASES
  1. Classification of Renal Disease
  2. Classification of Glomerular Diseases
  3. IgA Glomerulonephritis
  4. Diffuse Proliferative Glomerulonephritis
  5. Membranoproliferative Glomerulonephritis
  6. Crescentic Glomerulonephritis
  7. Lupus Nephritis
  8. ANCA+ Glomerulonephritis
  9. Polyarteritis Nodosa (PAN)
  10. Heinoch-Schonlein Purpura
  11. Post-Infectious Glomerulonephritis
  12. Focal Segmental Glomerular Sclerosis with Hyalinosis (FSGSH)
  13. Membranous Nephropathy
  14. Minimal Change Disease
  15. Diabetic Nephropathy
  16. Hereditary Nephritis (Alport's Syndrome)
  17. Acute Tubular Necrosis
  18. Acute Interstitial Nephritis
  19. Chronic Interstitial Nephritis
  20. Systemic Sclerosis

A. Glomerular Structure [1,2]

1. Renal artery branches to afferent arterioles which feed glomular capillary
2. Glomerular capillary juxtaposes to filtration membrane and exits to efferent arteriole
3. Exiting efferent arteriole then feeds second capilary bed providing blood to medulla
4. Medullary blood vessels are called vasa recta
5. Glomular Ultrafiltration Barrier
   1. Three layers
   2. Fenestrated endothelial cells: 70-100nm opening called fenestrae
   3. Glomular basement membrane
   4. Subendothelial space (inferior to GBM) lined with podocytes (epithelial cells)
6. Glomerular Basement Membrane (GBM)
   1. GBM is kidney's major filtration barrier, normally 300-350nm thick
   2. GBM has three layers: Lamina rare internal, lamina densa, lamina rare external
   3. High negative charge due mainly to heparan sulfate, also to sialic acid
   4. Filtration barrier effective pore size ~55Å but is negatively charged
   5. Transport of negatively charged molecules is inhibited by negative charges
   6. Negative charges on heparan sulfate and chondroitin sulfate side chains
   7. Type IV collagen is a major constituent of GBM, and laminin-11 isoform critically important
7. Podocytes
   1. Specialized epithelial cells with slit diaphragm playing key role in filtration
   2. Line subepithelial space juxtaposed to Lamina rare external of GBM
   3. Highly differentiated cells with volunious cell body
   4. Have long foot-processes that extend toward GBM
   5. Foot processes separated by 30-40nm thin membrane called slit diaphragm
   6. Key protein components of slit diaphragm: Nephrin, Neph1 and Neph2, FAT1 and FAT2, podocin and CD2 associated protein (CD2AP), ZO-1
   7. Mutations in these proteins can lead to congenital (rare) nephrotic syndromes
8. Mesangial cells found in glomerular interstitium
   1. Phagocytic (cleaning up) action
   2. Contractile function: respond to angiotensin II
9. Ultrafiltration into Bowman's space within Bowman's capsule
   1. Normal blood flow in 2 kidneys is 650mL/min (~12% blood volume)
   2. About 150 -180 L of plasma filtered per day
   3. Of every 125mL/min ultrafiltrate formed, 124mL will ultimately be resorbed
   4. Normally, <40mg albumin is excreted per day
10. Bowman's capsule lined with parietal epithelium

B. Proximal Convoluted Tubule

1. Major site of resorption of glucose, Na, K, HCO3-
2. Brush border absorptive cells
3. Cell borders tightly interdigitated so cannot appreciate on normal stained sections

C. Loop of Henle

1. Thin loops proximally and in medulla: Descending (DLH) and Ascending (ALH)
2. Thick ascending limb (TAL) in cortex distally
3. Prominent basement membrane
4. Major portion of salt and water resorption, with distinct permeabilities in DLH and ALH

D. Distal Convoluted Tubule

1. Cell borders interdigitated
2. Major site of aldosterone sensitive Na/K ATPase regulation
3. Na+ and Cl- cotransporter
4. Major site of acid excretion
5. Calcium regulation (vitamin D sensitive area)

E. Collecting Ducts

1. Cell borders are recognized
2. Major site of vasopressin (antidiuretic hormone, ADH) action
   1. Control of H2O permeability
   2. Aquaporin 2 is the major water channel protein

F. Blood Supply

1. Renal Artery: branch of the distal descending aorta at level of umbilicus
2. Note that kidney has a dual capillary system
   1. Glomerular capillaries have high pressure required for filtration
   2. Vasa recta feed medullary region and other cortical portions
   3. These vessels are critically involved in the countercurrent exchange in medulla
3. Compromise of glomerular blood flow can affect distal vessel
   1. Thus, decreased filtration, increased volume loss can lead to medullary ischemia
   2. Ischemia can lead to acute tubular necrosis, one of earliest injuries

1. Glomerular Disease [3]
   1. Inflammatory disesases are typically associated with proliferation
   2. Non-inflammatory diseases are typically without proliferation
   3. Vasculitis (inflammatory) is usually divided into ANCA+ and ANCA- syndromes
   4. Hereditary Proteinuria Syndromes - due to abnormalities in GBM, podocytes, others [1]
2. Tubular Disease
3. Interstitial Disease
4. Vascular Disease
   1. Renal Artery Stenosis: atherosclerotic and congenital (FMD) forms
   2. Renal Vein Thrombosis
   3. Cholesterol emboli syndrome
5. Renal disease is also classified clinically
   1. Divided into nephritis or nephrotic syndrome
   2. Nephritis is progressive azotemia with reduced glomerular filtration rate
   3. In nephritis, the number and/or function of the renal filtering units is reduced
   4. Nephrotic syndrome is loss of protein through damage of GBM (usually podocytes)
   5. In nephrotic syndrome, the podocytes and slit diaphragm are damage (pores too large)
   6. Glomerular diseases can cause either nephritis or nephrotic syndrome (sometimes both)
   7. Tubular and interstitial diseases cause azotemia, that is, nephritic type syndromes

B. Classification of Glomerular Diseases [3]

1. Primary Renal Disease: Proliferative
   1. IgA Nephropathy [4]
   2. IgM Nephropathy
   3. Other Mesangioproliferative Glomerulonephritis
   4. Membranoproliferative Glomerulonephritis: Types I and II
   5. Cresencentic (Rapidly Progressive) Glomerulonephritis: immune or pauci-immune forms
2. Secondary Renal Disease: Non-Proliferative
   1. Lupus Nephritis
   2. Postinfectious Glomerulonephritis
   3. Hepatitis B or C Virus Associated Glomerulonephritis
   4. Idiopathic Cryoglobulinemias
   5. Systemic Vasculitis: ANCA+, ANCA- (such as Henoch-Schonlein Purpura)
3. Primary Renal Disease: Nonproliferative
   1. Focal Segmental Glomerulosclerosis (Idiopathic FSGSH)
   2. Membranous glomerulopathy
   3. Minimal change disease
   4. Thin basement membrane disease
4. Secondary Renal Disease: Nonproliferative
   1. Diabetic Nephropathy
   2. Amyloidosis
   3. Light chain nephropathy
   4. HIV Associated Nephropathy (Secondary FSGSH)
   5. Alport's Syndrome
   6. Drug Induced Glomerulonephritis
5. Hereditary Proteinuria Syndromes [1]
   1. Congenital Nephrotic Finnish Syndrome - mutation of nephrin (Chr 19q13.1), 1:8200 live births, massive proteinuria in urtero, nephrotic syndrome, autosomal recessive (AR)
   2. Corticosteroid Resistant Nephrotic Syndrome - mutation of podocin (Chr 1q25-31) mild proteinuria in early adulthood, early minimal changes, AR
   3. Pierson's Syndrome - mutation in laminin ß2 chain (Chr 3p21), nephrosis in infants, diffuse mesangial sclerosis, microcoria (fixed narrowing of pupil), AR
   4. Nail-Patella Syndrome - mutation in LMX1B transcription factor (Chr 9q34.1), regulates podocyte genes; variable penetrance (autosomal dominant, AD), nephrotic syndrome, skeletal and nail dysplasias in children
   5. Denys-Drash Syndrome - mutation in WT1 transcription factor (Chr 11p13), regulates podocytegenes, male pseudohermaphroditism with progressive glomerulopathy, AD
   6. Focal Segmental Glomerulosclerosis 1 - mutations in alpha-actinin-4 (Chr 19q13), leads to abnormalities in podocytes, mild proteinuria in adolescence, slow progression, AD
   7. Focal Segmental Glomerulosclerosis 2 - mutations in TRPC6 (Chr 11q21), abnormal calcium-permeable cation channel, leads to abnormal podocyte function, adolescent proteinuria progresses to end-stage renal disease in adulthood, AD

1. Category: nephritic in majority, others with nephrotic
2. Light Microscopy: mesangial proliferation, focal or diffuse glomerulonephritis
3. Immunofluorescence: IgA1 >> IgM/G, some IgG and C3 (IgA2 not observed)
4. EM: Mesangial deposits, increased cell matrix
5. Etiology: Unclear (some association with respiratory or gut infection)
6. Mainly affects men in the second decade of life

B. Diffuse Proliferative Glomerulonephritis [5]

1. Category: nephritic
2. Light Microscopy
   1. Diffuse mesangial cell proliferation
   2. Note that focal proliferative glomerulonephritis is probably precorsor lesion
3. Immunofluorescence: IgA, IgG, IgM, C3b
4. EM: marked subendothelial deposits
5. Etiology: systemic lupus erythematosus, idiopathic, Goodpasture's Syndrome

C. Membranoproliferative Glomerulonephritis [3]

1. Category: nephrotic 50%, nephritis ~40%, urinary abnormalities ~10%
2. Light Microscopy
   1. Type I: increased mesangial cells and matrix, lobular glomeruli
   2. Type II: dense transmembranous, refractile immune deposits
3. Immunofluorescence
   1. Type I: granular deposits of C3 in all patients, immunoglobulins common
   2. Type II: C3 is present, ig generally not seen
4. EM
   1. Type I: marked subendothelial deposits of immune complexes (IC)
   2. Type II: electron dense material distributed homogenously within GBM; no IC or Igs
5. Etiology unknown

D. Crescentic Glomerulonephritis [2]

1. Category: nephritis
2. Light Microscopy: crescent formation, lobular formations
3. Immunofluorescence: Disease dependent.
4. EM: Disease dependent
5. Etiology
   1. End stage kidney disease of many types
   2. Anti-glomerular basement membrane Abs
   3. ANCA diseases: Wegener's, PAN, others
   4. Systemic Lupus Erythematosus (SLE)

E. Lupus Nephritis [2,3]

1. Category: nephritic (types II-IV) or nephrotic (type V)
2. Light Microscopy
   1. Variable degrees of inflammatory cells
   2. Variable mesangial cell proliferation (maximal in type IV)
   3. Crescents form in IIIb and IV disease
3. Immunofluorescence: IgG, IgM, IgA, C3b, histones
4. EM: subendothelial (types II-IV) or subepithelial (type V) deposits

F. ANCA+ Glomerulonephritis [2]

1. Category: nephritic multisystem
2. Light Microscopy: granulomatous or non-granulomatous leukocytoclastic vasculitis
3. Immunofluorescence: Immune complexes
4. EM: proliferation
5. Eiotlogy
   1. Idiopathic vasculitis, often multisystem
   2. Associated with various types of anti-neutrophil cytoplasmic autoantibodies
   3. These autoantibodies stain either cytoplasmic (cANCA) or perinuclear (pANCA) patterns
   4. Wegener's Granulomatosis associated with cANCA pattern
   5. ANCA+ Glomerulonephritis (RPGN) is usually a pANCA pattern
   6. Polyarteritis Nodosa (PAN) is usually a pANCA pattern
   7. Arteriolar ± capillary vascular destruction

G. Polyarteritis Nodosa (PAN)

1. Category: Necrotizing vasculitis
2. Light Microscopy: aneurysmal dilation proximal to vascular inflammation, medium arteries
3. Immunofluorescence: Immune complex deposition and complement activation in vasculature
4. EM: nothing significant
5. Etiology
   1. >80% of true PAN cases are p-ANCA+
   2. Lesions are different ages

H. Heinoch-Schonlein Purpura

1. Category: nephritic multisystem
2. Light Microscopy: Mesangial and endothelial cell proliferation
3. Immunofluorescence: IgA key to diagnosis, usually also with IgG and complement
4. EM: proliferation
5. Etiology: Related to hypersensitivity vasculitis, with joint, skin, GI, renal and other organs

I. Post-Infectious Glomerulonephritis [2]

1. Category: nephritic
2. Light Microscopy
   1. Diffuse mesangial proliferation
   2. Neutrophils and macrophages usually present
   3. Hemorrhage possible, tissue engorgement
3. Immunofluorescence: Sparse IgG and C3 deposition on granular Loops
4. EM: Subepithelial "humps" with proliferation of mesangium
5. Etiology: Streptococcal (Group A, ß-hemolytic) infection most common

J. Focal Segmental Glomerular Sclerosis with Hyalinosis (FSGSH) [1,6]

1. Category: non-inflammatory glomerular disease, nephrotic
2. Light Microscopy
   1. Focal segmental glomerular sclerosis
   2. Increased mesangial cellularity
3. Immunofluorescence: IgM and C3 in scarred areas (non-specific)
4. EM: +/-
5. Etiology [3]
   1. HIV Disease
   2. Intravenous Drug Abuse
   3. Heroin Nephropathy
   4. IgA nephropathy
   5. Transplant rejection
   6. Recurrent disease is frequent in renal transplant patients [6]
6. Can lead to major secondary tubular atrophy with inflammation

K. Membranous Nephropathy

1. Category: nephrotic
2. Light Microscopy
   1. Thickened basement membrane loops
   2. Increased mesangial matrix but not cell number
3. Immunofluorescence: Immune complex (IC) deposition, IgG, C3 in granular pattern
4. EM: subepithelial deposition with pathomnemonic electron dense deposits
5. Etiology
   1. Thickened basement membranes without proliferation due to IC deposition
   2. Type V Lupus Nephritis causes similar disease
   3. There is a systemic inflammatory component to many of these cases

L. Minimal Change Disease

1. Category: nephrotic syndrome, non-inflammatory
2. Light Microscopy: mild mesangial cell proliferation
3. Immunofluorescence: nothing
4. Electron Microscopy (EM): epithelial foot process effacement
5. Etiology
   1. Unknown cause (common) - associated with poor prognosis
   2. Drugs (rare): NSAIDs, gold therapy
   3. Associated with malignancy (rare)
   4. There is a systemic inflammatory component to many of these cases

M. Diabetic Nephropathy

1. Category: nephrotic with progression to azotemia
2. Light Microscopy
   1. Hyaline arteriolar change
   2. Kimmelstiel-Wilson lesions
   3. Glomerular sclerosis, nodular or diffuse
   4. Vascular disease: arteriolar narrowing with intimal thickening
3. Immunofluorescence
   1. Nonspecific linear deposition of all kinds of proteins
   2. Albumin is frequently found
4. EM: thickened mesangial matrix, thickened basement membrane
5. Etiology
   1. Glycosylation of proteins with secondary changes
   2. Hyperfiltration followed by glomerular hypertrophy and then sclerosis

N. Hereditary Nephritis (Alport's Syndrome)

1. Category: proteinuria
2. Light Microscopy: possible lipid laden (foamy) macrophages
3. Immunofluorescence: negative
4. EM: split or laminated basement membrane
5. Etiology: hereditary disease of type IV collagen (basement memebrane)
6. Alport's Syndrome: Association with sensory deafness and lenticonus

O. Acute Tubular Necrosis

1. Category: Ischemic Tubular Injury
2. Light Microscopy: thin brush border, lost individual tubular cells; leukocytes in vasa recta
3. Immunofluorescence: --
4. EM: --
5. Etiology: Ischemic disease; renal toxins including drugs, myoglobinuria, others

P. Acute Interstitial Nephritis [5]

1. Category: Drug or Infection
2. Light Microscopy: Interstitial edema, neutrophilic tubule infiltration
3. Immunofluorescence: In hypersensitivity, antibodies may be present, C3 on tubular BM
4. EM: Dissolution of tubular basement membranes (BM)
5. Etiology
   1. Drug induced reactions: penicillins, methicillins, sulfa, NSAIDs
   2. Acute pyelonephritis from hematogenous spread or ascending infection

Q. Chronic Interstitial Nephritis

1. Category: Obstructive and Nonobstructive
2. Light Microscopy: Tubular atrophy, interstitial fibrosis, tubular necrosis
3. Immunofluorescence: nothing significant
4. EM: nothing significant
5. Etiology
   1. Ischemia
   2. Infectious - chronic pyelonephritis
   3. Obstruction
   4. Papillary necrosis
   5. Radiation nephropathy

R. Systemic Sclerosis

1. Category: Autoimmune fibrosing disease
2. Light Microscopy: Immune infiltration various organs with secondary fibrosis
3. Immunofluorescence: Anti-RNP Abs (possibly anti-collagen also)
4. EM: --
5. Etiology
   1. Usually 20-50 year old women
   2. Dysfunctional vascular regulation
   3. Imbalance of vasoconstrictive and vasodilatory hormones

References

1. Tryggvason K, Patrakka J, Wartiovaara J. 2006. NEJM. 354(13):1387
2. Chadban SJ and Atkins RC. 2005. Lancet. 365:1797
3. Hricik DE, Chung-Park M, Sedor JR. 1998. NEJM. 339(13):888
4. Donadio JV and Grande JP. 2002. NEJM. 347(10):738
5. Ambrus JL and Sridhar NR. 1997. JAMA. 278(22):1938
6. Savin VJ, Sharma R, Sharma M, et al. 1996. NEJM. 334(14):878