February 15, 2001 (Thurs)

Pathology 10am

Dr. Tran

Meredith/Gill

P021510.doc

Scribed by: James Morgan

Diabetic Nephropathy Page 1 of 4

Some abbreviations to help: Diabetic Nephropathy (DN); Mesangium/mesangial (MSG); Patient (pt), Normal (NL), Abnormal (ABN), Diagnosis (Dx); Diabetes Mellitus (DM); Proteinuria (ProtU); Hematuria (HemU). Note: This scribe includes both lecture and the notes.

DIABETIC NEPHROPATHY (DN)

  1. Epidemiology
  2. Progression of DN to End Stage Kidney Disease (ESKD)
  3. 25-30% of all DN  ESKD
  4. 25-50% of Type I (IDDM)  ESKD
  5. 15-25% of Type II (NIDDM)  ESKD

-actually ~50% of End Stage DN is from NIDDM b/c more people have NIDDM

  1. Pathology

Lesion / Staining /
Appearance
/ Pathogenesis / Differential Dx
Location
Glomerulosclerosis /

Nodular (aka Intercapillary Glomerulosclerosis or Kimmelstiel-Wilson Disease)

/ Eosinophilic (H&E)
PAS+
Argyophilic
Blue (Trichrome) /

Laminated, acellular nodule (varied in size)

Fig 21-32

/ As nodules  in size capillaries are closed off in addition to thickening of capillary loop BMs, progressive occlusion capillary lumens  ischemia
Nodule consists of central mass of MSG matrix containing:
  1. electron dense granules and droplets
  2. collagen fibers
/
  1. Amyloidosis
*confirm w/Congo Red (apple green in polarized light)
*also using Thyoflavin T (irridescent under UV light).
*PAS (-)
  1. Light Chain Disease
*accumulation of light chain fragments in nodule
*confirm by IF study of kappa & lambda (will irredesce)
3. DN nodules will be laminated
-Nodule is in the MSG or intercapillary region of glomerular tuft
-1+ nodules per tuft
-Wrinkling of GBM
Diffuse / PAS +
Argyophilic
Blue (Trichrome) / 1. Early stage = MSG proliferation.
2.  GBM thickness
3. Wrinkling of GBM
*May have MSG nodules (unusual to see nodular lesion w/o diffuse glomerulosclerosis)
Fig 21-32 (vs. NL 21-16A) / Expansion of MSG matrix /


*Bolded areas were emphasized by Dr. Tran
global (entire glomerulus)
diffuse (>50% glomeruli)
Capsular Drop Lesion / Eosinophilic (H&E) / Homogenous, waxy, eosinophilic mass / Formed by accumulation of electron-dense granular particles ~5nm in diameter
w/in Bowman’s capsule
*looks like it is b/t Bowman’s parietal epithelium and the GBM
Fibrin Cap Lesion (aka. exudative lesion) / Eosinophilic (H&E)
Red
(Trichrome) /

Waxy

/ Formed by accumulation of electron-dense granular particles ~5nm in diameter / NOT pathognomic of DM, but are commonly seen.
*Also seen in: Arterionephrosclerosis, Reflux Nephropathy, FSG, Chronic GN
In the lumens of 1+ capillary loops
  1. Micro Lesions (4 types):

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  1. Gross
  2. Early Stage (Slide: Enlarged kidney 15cm long {NL=11.5-12cm})
  3. Large due to:

-glycosylated proteins that can’t be metabolized (see later)

-Insulin-like Growth Factor

  1. Others disease that lead to enlarged kidneys

-Lymphoma of the kidney

-Amyloidosis

-Early stage DM

  1. Late Stage (long-standing DN)
  2. Becomes small

-granular outer surface

-irregular subcapsular scarring

  1. reason for scarring

DN causes microvascular changes  narrowing of vessels coming in  obstruction/infarction of tissue  fibrous scarring which leads to slight retraction of tissue

  1. Slide: Kidney is only 6cm; scarring in subcapsular area

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  1. Other Lesions
  1. Tubules
  2. Appearance

1)Tubular atrophy w/BM thickening

2)’d lipid deposition

3)’d #’s of protein filled lysosomes (esp. in the proximal tubules)

  1. Vasculature
  2. Hyalin Change (thickening of wall)

1)involving only afferent arteriole

-in Benign HTN, NL aging, Amyloidosis

2)when bothafferentandefferentarterioles are involved = Diagnostic of DN

  1. Interstitium
  2. varying amount of fibrosis and chronic inflammatory infiltrate
  3. Microscopic Examination
  4. LM

a. ’d MSG matrix,  collagen,

  1. Scanning EM (fig 21-31)
  2. Thickened BM looks laminated
  3. Pores (~8nm in diameter) important in pathogenesis
  4. Immuno-EM
  5. loss of Heparan Sulfate-proteoglycan
  6.  Type IV collagen (in GBM)
  7. IF
  8. IgG = diffuse, linear deposition on GBM (most frequent finding)

-May also have linear deposit of IgA, IgM, C3, fibrinogen, albumin, ceruloplasmin

-also, linear deposits along tubular BM and Bowman’s capsule

  1. Fibrin Cap , and Arteriolar Hyalin Lesions

-localization of IgM (w/Clq, C3, C4)

  1. Ig and C’ (complement) localization in DM pt

1)due to:

-non-specific trapping

-secondary to BM or MSG dysfunction

  1. Course of DN
  2. Pre-clinical Phase (This applies to IDDM b/c the onset of NIDDM is more difficult to Dx so early changes are not clear)
  3. Early  in GFR (20-50%) – IDDM
  4. kidneys  in size also (initial)
  5. w/insulin Tx, returns to NL levels (wks-mos)
  6. Microalbuminuria (defined as : 20mcg/min < Microalbuminuria < 200mcg/min)
  7. Cannot detect with dipstick (only measures >150 mg/24h)

-so use RIA (Radio-Immuno Assay)

  1. Clinical Phase (usually at least 10 years, but average 15-20 years after onset of IDDM)
  2. ProtU (proteinuria) = when detectable by dipstick, clinically defines the onset of DN
  3. >150mg prot/24h
  4. this is important b/c once ProtU is detectable, decline to ESKD is imminent

1)avg. time = 5 years (range: months  decades)

2)the time before ProtU can be ’d by strict glycemic control, genetics, etc. (vs. post-detectable ProtU when glycemic control does not matter – see below)

  1. degree of ProtU ~ Prognosis

1)ProtU >3g/24h = poor prognosis

2)Only 5-10% develop Nephrotic Syndrome (DN = major cause of Nephrotic S/d)

  1. Diabetic Retinopathy

-Majority of IDDM pt w/renal disease (vs. 56% of NIDDM with renal disease)

  1. Retinopathy (seen on retinal exam) + ProtU (clinical) = assume DN

-can skip the biopsy (save the pt. time, hassle and $$)

  1. Hypertension (HTN)
  2. ½ - ¾ of those with ProtU develop HTN
  3. ’s w/progression to renal insufficiency
  4. must control HTN for better prognosis
  5. HemU (hematuria)
  6. rare
  7. if present, look for an additional nephropathy
  1. Role of Glycemic Control in Prevention of DN
  2. Basically this was a study to see how glycemic control affected the outcome of DN
  3. Group 1 = Sub-Q insulin (bid) x 4 years.

-linear deterioration of renal function (expected)

  1. Group 2 = standard Tx x’s 2 years then insulin pump (continuous infusion) x’s 2 years

-linear deterioration for 1st 2 years (expected)

-same rate for the 3rd and 4th year (unexpected)

  1. Results where that once ProtU was at clinical levels, cannot stop progression of RN (even with strict glycemic control)
  2. Other studies have indicated, however, that pre-clinical glycemic control is beneficial
  1. Pathogenesis of Renal Disease in DM
  2. Glycosylation of Proteins
  3. hyperglycemia  irreversible glycosylation of proteins and their products

 products accumulate and form cross links

 the cross-linked proteins then trap more proteins (albumin, IgG, LDL)

  1. occurs in GBM (thickened) and MSG matrix (expansion).
  1. ’d anionic charge and change of conformation of glycosylated proteins
  2. this would seem to help the NL glomerular repulsive selectivity – BUT –

-glycosylated albumin can get through GBM easier

-due to change in shape and how the charge is physically presented

  1. Macrophage receptors for glycosylated proteins
  2. when activated ’d PDGF, TNF, IL (’d vascular permeability)
  1. Diminished Charge Selectivity (due to DM)
  2.  in Sialic Acid
  3. NL is responsible for the negative charge glomerular capillary wall
  4. ’d in DM pts for unknown reason

-leads to ’d permeability to circulating anionic proteins (i.e. albumin)

  1.  in Heparan Sulfate
  2. Provides glomerular GAG’s w/ their anionic charge

-gives charge selectivity

  1. in DM there is a  in sulfation of GAG’s

-therefore, have ’d selectivity

  1. Renal Hypertrophy
  2. Due to accumulation of glycosylated proteins/products in GBM/MSG matrix
  3. Can also be due to:

-’d rate of synthesis

-’d rate of degradation

  1. Tubular/Interstitial ’s due to Insulin-like Growth Factor
  1. Renal Hyperfiltration and hemodynamic changes
  2. initially, hypertrophy of kidney = ’d size of glomerulus with its microvasculature

leads to ’d vascular resistance (’d RPF) and ’d filtration (surface area)

  1. ’d Growth Hormone and /or glucogon (vasodilation)
  2. ’d prostaglandin in diabetes (is vasodilatory)

-primary or secondary to Growth Hormone

  1. Excess Atrial Peptides
  2. released in response to volume expansion

-induced by glucose enhanced renal Na+ reabsorption

-expansion is common in DM

  1. cause renal vasodilation and hyperfiltration
  1. ’d Kinin = vasodilation
  2. ’d dietary protein intake (to replenish lost protein) can lead to hyperfiltration
  1. Complications of DM (he went over these very quickly)
  2. Pyelonephritis
  3.  glucose in urine = good for bacterial growth
  4. slide: lots of inflammatory cells
  5. Necrotizing Papillitis
  6. ’d blood supply eventually causes necrosis of papillae
  7. Sx: Fever

HemU

Renal colic

’d BUN/Creatinine levels

  1. Acute Tubular Necrosis (ATN)
  2. Sx: Hypotension, shock
  3. discussed in other lecture
  1. Staging of DN (most of this info came from last years scribe b/c he went over it in about 2 minutes)

Stage of Diabetic Nephropathy
I / II (silent) / III
(@risk for nephropathy) / IV
(overt DN) / V
Renal Function / Early hyperfunction (GFR) / NL / Persistent Microalbuminuria* / Clinical ProtU >500mg/24h* / ESKD
Size /  (early hypertrophy) / GBM = thickened (depending on progression of disease)
Time after Dx / At Dx / 4-7 years / 7-10 years / 15-18 years / 25 years

“When there are many words, transgression is unavoidable, but he who restrains his lips is wise.”

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