Nephrology | Lupus Nephritis & Diabetic Nephropathy 1

Systemic Lupus Erythematosus Pathogenesis

 immune complex glomerulonephritis
Criteria for Classification of Patients with
 autoantibody production directed towards
SLE based on American Rheumatism
nucleoproteins and cytoplasmic and plasma
Association (ARA)
membrane constituents and specific plasma
**At least 4 of the 11 manifestations proteins
 malar rash  deposits may be found in all three
 discoid rash glomerular regions:
 photosensitivity o subendothelial
 oral ulcers o subepithelial
 arthritis o mesangial
 serositis (pleuritis / pericarditis)  deposition of circulating immune complexes
 renal disorder  in situ complex formation
o proteinuria >500 mg/day or  autoantibodies interact with self-antigens
cellular casts  nuclear  DNA, histone, Sm, RNP
 neurologic disorder  cytoplasmic  Ro, La
o seizures or psychosis  cellular  lymphocyte, platelet, endothelial
 hematologic disorders  basement membrane  heparan sulfate,
o hemolytic anemia laminin, collagen type IV
o leukopenia
o lymphocytopenia Classification of Lupus Nephritis (WHO)
o thrombocytopenia
 immunologic disorder Class I
o (+) LE test, anti-DNA antibody,  no abnormal findings
anti-SM antibody  normal findings on light microscopy but
o false (+) VDRL deposits present
o (+) ANA
Class II
 mesangial glomerulonephritis
Lupus Nephritis  confined to purely mesangial lesions
 IIA
Overview o Light microscopy
 renal involvement is clinically evident  minimal or no significant
in 40 – 85% changes
 all recognized clinical syndromes associated o Immunofluorescence and EM
with glomerular disease can occur  immune deposits IgG, IgM,
 nephrotic syndrome occurs commonly often and IgA complement
with associated renal insufficiency confined to mesangium
 90% of patients are female on 3 decades
rd  IIB
o Light microscopy
 multiple organ system involvement
 definite mesangial
 exacerbation of disease occur:
hypercellularity
o after sun exposure
o Immunofluorescence and EM
o drug use (estrogens, penicillin,
 immune deposits are
hydralazine)
present only on mesangium
o dietary modification
o cigarette smoking associated with
adverse renal outcome
 Nephrology | Lupus Nephritis & Diabetic Nephropathy 2

Class III Laboratory Findings

 focal and segmental proliferative GN
 Light microscopy
o mesangial deposits and segmental
capillary cell proliferation with
obliteration of capillary lumen <50%
of glomeruli involved
o those that are involved show only
focal damage occupying <50% of
glomerular surface
 Electron microscopy
o immune deposits in mesangium
subendothelial and subepithelial
 Immunofluorescence
o granular deposits of IgG, IgM, and
IgA (less), C3 and C4 on
mesangium and capillary walls
Class IV
 diffuse proliferative GN
 Light microscopy
o basically the same as class II,
excecpt that changes are more
pronounced and more widespread
>50% of glomerular population
o in addition, focal areas of necrosis
and crescent formation and nuclear
debris (hematoxylin bodies)
o capillary walls are greatly thickened,
“wire loop” appearance due to large
subendothelial deposits
o small and large segmental or
circumferential crescents may be
noted
 Electron microscopy
o deposits are large and more
abundant in all sites of glomeruli,
especially on the subendothelial and
mesangial
 Immunofluorescence
o diffuse granular staining throughout
glomeruli for IgG, C3, C4, IgM and
occasional IgA
Class VI
 glomerular sclerosis
 presence of complete or segmental sclerotic
glomeruli
 ANA (antinuclear antibody)
o sensitivity = 90%
o specificity = 70%
o usually of IgG class
o it is not the presence of ANA that
makes diagnosis of SLE but rather
its presence as one constellation of
laboratory and clinical signs and
symptoms
o also found in:
 rheumatoid arthritis
 Sjogren syndrome
 chronic active hepatitis
 infectious mononucleosis
 infective endocarditis
 lepromatous leprosy
 scleroderma
 polymyositis
 normal aging
 malaria
 Anti-dsDNA
o 40 – 92%
o highly specific for SLE
o IgG class correlate best with renal
disease
 Anti-ssDNA
o prevalence is high but low specificity
 Anti-Sm
o antibody to ribonuclear antigen
o highly specific for SLE but not
sensitive
o 25% (+) in all patients with SLE
 Anti-nRNP (ribonucleoprotein)
o antibody to ribonuclear antigen
o 30 – 60% (+) in patients with SLE
o its presence defines a subset of
patient (mixed connective tissue
disorder)
Treatment
 Inductioin therapy
o 3 i.v.MP pulses (0.5 – 1 g each)
o Prednisone 0.5 – 1 mg/kg/day
o Cyclophosphamide 1 – 2 mg/kg/day
for severe cases
 Maintenance therapy
o Prednisone 0.2 – 0.3 mg/kg/day
o Azathioprine 1.2 mg/kg/day
 Flare up
o increase in plasma creatine >30%
or in protu >2 g/day
o see induction therapy
 Nephrology | Lupus Nephritis & Diabetic Nephropathy
Diabetic Nephropathy
Overview
 disorders of kidney structure and function
that arise secondary to DM, either IDDM or
NIDDM
 includes disorders that affect the glomeruli,
tubules, and interstitium and intrarenal
vasculature
 diabetic glomerulopathy
o refers to disorders of glomerular
structure and function that arise as a
consequence of longstanding DM
Incidence
 NIDDM
o 15 – 60%
o ESRD  57%
 IDDM
o 35%
o ESRD  3%
Stages of Diabetic Glomerulopathy
Stage I – Initial Stage
 begins with onset of abnormal glucose
homeostasis
 hyperfunctioning / hypertrophy stage
 increased GFR (as much as 40 – 50%)
 increased renal plasma flow
 increased renal sizes
 may have transient microalbuminuria
o disappears with good glycemic
index
o present during periods of poor
metabolic control and with exercise
o may be associated with increased
β2 microglobulin excretion
Stage II – Incipient Glomerulopathy
 usual time period 7 to 10 years after onset of
abnormal glucose homeostasis
 persistent microalbuminuria
o urinary albumin excretion greater
than 30 mg/24hrs (20 g/min) and
less than or equal to 300 mg/24 hrs
(200 g/min)
 microalbuminuria is not associated with
increased β2 microglobulin
 GFR remains elevated
 kidney continues to be enlarged
 slight increase in blood pressure
 associated with proliferative nephropathy
3
 without improvement of glycemic control:
o increase in urinary albumin
excretion
o further increase blood pressure
o GFR declines to normal
 at this stage, the rate of increase of albumin
excretion can be influenced by glycemic
control and reduction of blood pressure (for
type 1 DM)
Stage III – Overt Glomerulopathy
 time that elapses between stage II and
stage III averages 7 to 10 years
 development of qualitatively detectable
abnormal proteinuria (usually >500 mg/day
or >200 g/min of albumin excretion)
 most patients have established hypertension
 GFR will have decreased to normal or
slightly subnormal rate of decline in GFR is
0.8 – 1.1 ml/min/month
 kidneys remain enlarged
 excellent glycemic control seems to have
little effect on the future rate of progression
 vigorous anti-hypertensive therapy
o reduce degree of proteinuria
o slow rate of decline of GFR
 most patients  nephrotic syndrome
 proliferative retinopathy progresses
 blood pressure continues to rise
 GFR continues to decline below normal
 serum creatinine may still be normal
Stage IV – Azotemic Glomerulopathy
 time elapsed from stage III to stage IV
averages 3 to 5 years
 distinct and abnormal elevatioin in serum
creatinine and/or BUN
 GFR decreased to 30 – 50% of normal
nondiabetic values
 heavy proteinuria
 hypertension, edema, hypoalbuminemia
 patients may also suffer from extrarenal
manifestations such as:
o ISHD
o CHF
o neuropathy
o CVA
o occlusive renal vascular disease
o peripheral vascular insufficiency
o severe proliferative retinopathy
 kidneys remain large, although at later stage
there is reduction in size
 excellent glycemic control at this stage has
little effect on rate of progession
 Nephrology | Lupus Nephritis & Diabetic Nephropathy
 rigorous blood pressure control slow decline
of GFR but still patient slowly and
predictably progress to ESRD
 proliferative retinopathy progress leading to
blindness
Stage V – End-Stage Glomerulopathy
 time elapsed from stage IV to V averages 2
to 5 years but in patients with poorly
controlled blood pressure, may even be
shorter
 GFR <10 ml/min
 uremic symptoms
Pathology
Diffuse glomerulosclerosis
 diffuse intercapillary glomerulosclerosis
 most common lesion
 diffuse increase in the volume of mesangial
matrix and mesangial cells
 increased width of GBM
 capsular drops and ficrin caps may be
present
 hyaline arteriosclerosis, particularly efferent
arteriole, may also be findings
Nodular glomerulosclerosis
 Kimmelstiel-Wilson lesion
 relatively specific for DM
 PAS (+), laminated intercapillary nodules on
a background of an increase in mesangial
matrix
 nodules are acellular
 nondiabetic renal diseases that may roughly
give similar patterns:
o amyloidosis
o MPGN type II
o light chain nephropathy
Changes in Diabetic Glomerulopathy
 hyperfiltration
 renal and glomerular hypertrophy
 mesangial cell hypertrophy and matrix
accumulation
 glomerular basement membrane thickening
 functional alterations in glomerular filtration
barrier
4
Mechanisms for Glomerular Hyperfiltration
Due to atrial natriuretic peptide
Glycosuria
+
Increased reabsorption of glucose coupled to Na at
proximal tubules
+
Increased total body Na and ECF
Release of ANP – natriuresis
Increase in intraglomerular pressure / increase in
GFR
Glomerular hypertension
Exapnsion of mesangium and ECM
Triggers for Glomerulosclerosis
 glomerular hypertension
 direct effects of hyperglycemia on mesangial
cells
 advanced glycosylation end-products
 growth factors
o growth hormone
o insulin-like growth factor
o angiotensin II
o arginine vasopressin
o endothelin
 cytokines (eg., TGF-β)
 hyperlipidemia
 cell sorbitol accumulation and myoinositol
deficiency secondary to activation of the
aldose reductase polyol pathway
Hyperglycemia
 changes in endothelial and mesangial cells
shape
 generalized basement membrane thickening
 vasoconstriction
 decrease in cell life span
 mesangial cells synthesize more ECM
Amadori reaction
 haemoglobin A1c (reversible)
 advanced glycosylated products (AGEs)
 irreversible
o form covalent bonds with amino acid
groups on other proteins 
extensive cross-linking of protein
o have specific receptors in
endothelial, mesangial cells and
monocytes
 Nephrology | Lupus Nephritis & Diabetic Nephropathy 5

Polyol pathway hyperglycemia Normal Kidney vs. Kidney Disease

Glucose

Aldolase reductase

Sorbitol

Decreased myoinositol

Loss of cellular function

Decreased structural integrity

Other Renal Diseases in Patients

with Diabetes Mellitus

Renal Arterial Occlusive Disease

 atherosclerosis of 1 or both renal arteries
which may aggravate tendency to
hypertension
o sudden worsening of hypertension
o difficult to control hypertension
o grade III and IV hypertensive
retinopathy
o lateralizing abdominal bruits
o disparity in renal size
o hyperreninemia (elevated renin)

Renal Medullary and/or Papillary Necrosis

 sloughed off papillae may cause urinary
tract obstruction
 associated with acute ascending bacterial
pyelonephritis

Urinary Tract Infection

 increased incidence especially in diabetic
female patients
 relapses of infection following treatment
 fungal UTIs are common

Renal Tubular Acidosis

 usually type IV RTA
 aldosterone secretion rates are abnormally
low in relation to concomitant hyperkalemia
 a primary defect in renin secretion may be at
fault

o
Acute Renal Failure 2 to Contrast Media or
NSAIDs