1. Overview of Glomerulonephritidies
Madeleine V. Pahl, M.D.
University of California, Irvine

2. Objectives To define common primary and secondary glomerular disorders
To discuss involved pathophysiology
To review their clinical presentation
To review clinical course and therapy

3. Definition (R. J. Glassock)
A primary GN is a disease where the sole organ involved is the kidney (the glomeruli)
Clinical manifestations due to the consequences or pathophysiologic derangements that resulted in glomerular damage
In contrast secondary GNs have manifestations due to systemic disease and glomerular injury

4. Presentation: Clinical Syndromes
Asymptomatic: hematuria (gross or microscopic) and/or proteinuria (< 3g/day)
Acute glomerulonephritis (AGN)
Rapidly progressive glomerulonephritis (RPGN)
Chronic glomerulonephritis (CGN)
Nephrotic Syndrome (NS)

5. Clinical Syndromes: AGN
Abrupt onset of variable degrees of hematuria, proteinuria, reduced GFR, sodium and fluid retention, HTN and oliguria
Tendency to spontaneous recovery
Association with proliferative GN, ie. bacterial infection

6. Clinical Syndromes: RPGN
More insidious onset, not abrupt
Dominated by progressive loss of GFR and oliguria
Little tendency for spontaneous recovery
Classification and terminology of this group of disorders (Type I, II, II)

7. Clinical Syndromes: CGN
Clinical expression of a wide variety of glomerular diseases
Vague, all inclusive term refers to progressive reduction in GFR
Varying degrees of hematuria, proteinuria, HTN
Course may be protracted but usually relentless
Composite plot of reciprocal serum creatinine versus time in six patients with chronic kidney disease.

8. Clinical Syndromes: NS
Heavy proteinuria (> 3-3.5g/day )
Reduced serum albumin
Edema
HTN
Hyperlipidemia
Lipiduria

9. Pathology Minimal change Focal and segmental glomerulosclerosis
Proliferative GN
Pure mesangial proliferative
Endocapillary proliferative
Extra-capillary proliferative (crescenteric)
Membrano-proliferative
Membranous GN
Fibrillary/ Immunotactoid GN, Collageno-fibrotic GN, Lipoprotein GN (deposits of Apo E Nephron 83: 193, 1999)

10. Normal Glomerular Histology
From tutorial: J. Charles Jennette, M.D.

11. Common Primary Glomerulonephritidies
Minimal Change Disease
Focal Segmental Glomerulosclerosis (FSGS)
IgA Nephropathy (Bergèr’s Disease)
Membranoproliferative GN (Types I, II, III)
Membranous GN

12. Case #1
20 yo Caucasian male develops frothy urine and notes ankle edema. He takes no medication or drugs.
On exam he has a BP 180/98 and pitting lower extremity edema.
He has a Cr = 2mg/dl and 12g/day urinary protein excretion.
HIV, HBSAg, and Hepatitis C negative.

13. FSGS
Incidence among all biopsied patients rising, up to 25% of all adults
Most common pattern among African Americans, some secondary forms more common in whites (obesity and hereditary)
Children usually present with NS, adults with asymptomatic proteinuria

14. UpToDate®

15. FSGS
UpToDate®

16. FSGS: Histopathologic Variants
Glomerular “tip” lesion:
epithelial cell proliferation and sclerosis in segment adjacent to origin of proximal tubule,
common in whites with heavier proteinuria, preserved GFR, good response to treatment and outcome
“Collapsing/malignant” variant:
global collapse of capillary loops with visceral epithelial cell proliferation (similar to HIV),
common in AA with massive proteinuria, worse prognosis
Obesity:
fewer glomeruli with FSGS but remaining with glomerulomegaly.
Increasing in prevalence, likely white, less likely NS, progression slower

17. FSGS-Pathophysiology
Podocyte injury (JASN 2012; 23:381-99)
Unknown: increased glomerular permeability factor Suggested by studies demonstrating in-vitro glomerular permeabiliy (NEJM 334:878, 1996)
Certain forms of the soluble urokinase plasminogen activating receptor (suPAR) (Nat Med. 2011;17(8):952)
Expression of a specific microRNA called miR-193a produced FSGS in mice (Nat Med Apr;19(4):481-7)
Controversial role of Parvovirus B-19 (KI 59:2126, 2001)
Evidence for hyperfiltration: Glomerulomegaly and obesity, sleep apnea, or remnant kidney
Genetic Defect: role of MYH9 or APOL1 in African Americans (Nat Genetics Oct;40(10): ; Science Aug 13;329(5993):841-5)

18. FSGS: Clinical Course
Tendency for progressive renal failure, ESRD in 5-20 yrs
Factors associated with progression:
magnitude of proteinuria, higher serum Cr,
AA ethnicity, response to corticosteroids,
degree of sclerosis, TI damage, “collapsing” variety
Recurrence in allograft in up to 30%. Treatment with plasmapheresis (Clin Nephrol 56:271, 2001) and Rituximab (Transplantation Aug 15;88(3):417-20)

19. FSGS: Treatment Rituximab (Intern Med. 2012;51(7):759-62)
Prednisone mg/kg/day. Total duration of 6 month before declaring pt steroid resistant, then alternate day. Complete and partial response rate 50-60% ( JASN 9:1333, 1998)
Cytotoxic therapy (cyclophosphamide, chlorambucil, MMF) may be useful but not proven (KI 55(S70): S26, 1999).
CsA at 5 mg/kg/day may be effective, relapses common, long term use may be required (KI 55(S70): S26, 1999).
Synthetic ACTH (Am J Kidney Dis. 2006;47(2):233)
Rituximab (Intern Med. 2012;51(7):759-62)
Plamapheresis, in recurrent disease in transplant patients (Semin Nephrol. 2000;20(3):309)

20. Common Secondary Glomerulonephritidies
Infection
Malignancy
Drugs and toxins
Metabolic
Rheumatologic Disorders
Vasculitidies
Hereditary/Familial

21. GLOMERULAR DISEASES ASSOCIATED WITH INFECTIOUS AGENTS, TUMORS OR DRUGS
Infection
Glomerular disease
Bacteria of all types
MCGN, diffuse proliferative GN
E coli and Shigella species
HUS
Malaria
Membranous GN, MCGN
Syphilis
Membranous GN
Leprosy, schistosomiasis, TB
Amyloidosis
Hepatitis B virus
FSGS, MCGN, Membranous
Hepatitis C virus
HIV
FSGS (collapsing variant), IgA nephropathy, immune complex GN, HUS
Parvovirus
FSGS

22. Tumor
Glomerular Disease
Lymphoma and leukemia
Minimal change disease, Membranous, MCGN
Myeloma
Amyloidosis, light chain nephropathy
Carcinoma (lung, gastrointestinal, uterine, prostate, etc)
Membranous, MCGN, HUS
Drug
Glomerular Disease
Heroin
FSGS, MCGN
NSAIDs
Minimal change disease, Membranous
Penicillamine, captopril
Membranous
Tacrolimus, cyclosporine
HUS
Bisphosphonates
FSGS

23. Case #2
28 yo woman with known SLE for 1 year and history of arthralgias develops proteinuria and hematuria
BP 138/86, faint malar rash, mild pitting edema
Cr 0.7
24 hr: 2.5 g of protein
DS-DNA positive high titer and low C3

24. Classification of Lupus Nephritis
ISN Classification KI 2004;65(2):521
Comparison to WHO
Minimal mesangial lupus nephritis (class I) 
Mesangial proliferative lupus nephritis (class II) 
Focal lupus nephritis (class III)
Diffuse lupus nephritis (class IV)  
Membranous lupus nephritis (class V) 
Sclerosing lupus nephritis (class VI)  a healing /scarring of prior injury; advanced stage of chronic class III, IV, or V
Overlap of SLE and ANCA GNs — ANCA found in 20% of SLE and some have superimposed ANCA GN, with prominent necrosis and crescent with minimal endocapillary proliferation or subendothelial deposits

25. Class IV
Most common and severe (historically 50% developed ESRD in 5 yrs)
Class IV showed higher rate of ESRD compared to I, II, III or V—14.5% vs 4.6%
Present with hematuria and proteinuria /nephrotic syndrome, frequent HTN and reduced GFR.
Serology: reduced C3, positive anti-DNA
Histology: > 50 % glomeruli with endocapillary GN.
Subclasses:
Diffuse segmental or global proliferative nephritis, active vs chronic and/or sclerosing
Active disease: necrotizing changes, crescents and marked IgG and C3 deposition with thickening of GN capillary wall like MPGN.

26. Histology: Class IV

27. Severe Lupus Nephritis: “Optimal” Therapy
There is no universally agreed upon “optimal therapy” for severe proliferative lupus nephritis
Therapeutic approaches are divided into “Induction” therapy (first 6-12 months of treatment) and “Maintenance” therapy (beyond 6-12 months
Generally, the earlier intensive “Induction” therapy is begun the better the response
Combined therapy (cytotoxic agents and steroids) are indicated in most cases
Complete and/or partial remissions are the goal of induction therapy, accompanied the minimum amount of untoward side-effects (particularly infection)

28. Lupus Nephritis: “Induction” therapy choices
Probability of developing ESRD
Oral cyclophosphamide 2.0mg/kg/d for 3-6 months, with daily or alternate-day oral prednisone (±or 3 IV MP pulses)
IV Cyclophosphamide mg/m2 monthly for 3-6 months (mini-dose or maxi-dose)
with daily or alternate-day oral prednisone (± monthly IV MP pulses)
Oral Mycophenolate mofetil 2-3gms/d, with oral daily oral alternate-day prednisone (± IV MP pulses)
Oral Tacrolimus (±MMF)
(prepared by R. Glassock, 2007)

29. ALMS Trial: MMF v IV CP Induction Therapy
Largest prospective randomized trial in SLE, 88 centers, 370 patients with Class III, IV, V
At the end of a 6 months induction: no difference in remission rate for oral MMF compared to “maxi-dose” IV CP in patients with “severe” lupus nephritis (neither superior or inferior)- about a 60% remission rate overall
During a 6 months course of induction the adverse event rates were similar for oral MMF and IV CP (leukopenia, alopecia, amenorhea, infection in CP; anemia, diarrhea, infections in MMF)
(Appel G, et al JASN, 2009 May;20(5): )

30. Lupus Nephritis: Maintenance Therapy
The primary goals of maintenance therapy in LN are:
1) to prevent or minimize relapses
(“renal flares” )
2) to reduce the side-effects of the
therapy;
3) to improve quality of life
4) to reduce the risk of ESRD and death
Evaluation of efficacy and safety of maintenance therapy requires long-term follow up (perhaps 5 years minimum)

31. Clinical Trial in Maintenance Therapy
ALMS trial: after 3 yrs regardless of induction therapy, MMF (16.4% flare) was superior to AZA (32.4% flare), irrespective of race, gender,region and more AE with AZA (NEJM 2011; 365: )
MAINTAIN nephritis trial (EURO-lupus nephritis trial high vs low dose cyclophosphamide) at 48 mo. no statistical difference between AZA (25% flare) and MMF (19% flare). (Ann Rheum Dis 2010; 69: )
Recent review concludes that maintenance therapy with either MMF or AZA is overall well tolerated and leads to excellent results (Nephrol. Dial. Transplant. (2013) 28 (6): ).