Etiology- genetic mutations, infection, toxin exposure, autoimmunity, atherosclerosis, hypertension, emboli, thrombosis, or diabetes mellitus. Even after careful study, however, the cause often remains unknown, and the lesion is called idiopathic. Inflammation of the glomerular capillaries is called glomerulonephritis. Persistent glomerulonephritis that worsens renal function is always accompanied by interstitial nephritis, renal fibrosis, and tubular atrophy.

1. NEPHRITIC SYNDROME
DR. K TEJESHWANI
JR2
DEPARTMENT OF GENERAL MEDICINE
MODERATOR-
DR. JYOTI VERMA

2. Glomerulus

3. PATHOGENESIS OF GLOMERULAR DISEASE
• Etiology- genetic mutations, infection, toxin exposure, autoimmunity, atherosclerosis, hypertension,
emboli, thrombosis, or diabetes mellitus.
• Even after careful study, however, the cause often remains unknown, and the lesion is called
idiopathic.
• Inflammation of the glomerular capillaries is called glomerulonephritis.
• Persistent glomerulonephritis that worsens renal function is always accompanied by interstitial
nephritis, renal fibrosis, and tubular atrophy.

4. The glomerulus is injured by a variety of mechanisms. A.
Preformed immune deposits can precipitate from the circulation and collect along
the glomerular basement membrane (GBM) in the subendothelial space or can
form in situ along the subepithelial space. B. Immunofluorescent staining of
glomeruli with labeled anti-IgG demonstrating linear staining from a patient with
anti-GBM disease or immune deposits from a patient with membranous
glomerulonephritis. C. The mechanisms of glomerular injury have a complicated
pathogenesis. Immune deposits and complement deposition classically draw
macrophages and neutrophils into the glomerulus. T lymphocytes may follow to
participate in the injury pattern as well. D. Amplification mediators as locally
derived oxidants and proteases expand this inflammation, and depending on the
location of the target antigen and the genetic polymorphisms of the host, basement
membranes are damaged.

5. APPROACH TO THE PATIENT

9. Clinical evaluation of
glomerular disease

10. • In nephrotic syndrome, the glomerular injury is manifested primarily as an increase in permeability
of the capillary wall to protein.
• By contrast, in nephritic syndrome, there is evidence of glomerular inflammation resulting in a
reduction in GFR, non-nephrotic proteinuria, edema and hypertension, and hematuria with RBC
casts.
• Fall in GFR - uremic symptoms with salt and water retention, leading to edema and hypertension.

12.  POSTSTREPTOCOCCAL GLOMERULONEPHRITIS
• Acute endocapillary proliferative glomerulonephritis
• Childhood PSGN- epidemic in underdeveloped countries.
• Affects immunocompetent children between the ages of 2 and 14 years, M>F.
• β-hemolytic streptococci infections of the skin (M types 49, 55, 57, 60) or upper respiratory tract (M types
1, 2, 4, 12)
• due to pharyngitis develops 1– 3 weeks after infection and 2–6 weeks after impetigo.
• Two antigens involved are-
• nephritis-associated plasmin receptor (NAPlr)
• streptococcal pyrogenic exotoxin B (SPEB)
• Antistreptolysin O (ASO) titers, increased in more than 65% of patients with PSGN following throat
infections, and
• anti-DNAse B titers, elevated in 73% of postimpetigo cases.
• associated with human leukocyte antigen (HLA)-DR4 and HLA-DR1
• Adult PIGN or IRGN- in immunocompromised patients (DM with diabetic foot/ cellulitis)
• MRSA MC organism, poor prognosis, no incubation period.

13. • Clinical Manifestations-
• Symptomatic children typically present with acute nephritic syndrome, microhematuria in 100%,
macroscopic hematuria in 30%, hypertension in 80%, edema in 80% to 90% (chief complaint in
60%), and oliguria in 25% to 40%. Nephrotic syndrome occurs in 2%.
• 20% of adults with PSGN have nephrotic syndrome, 80% to 86% have hypertension, 83% have
kidney impairment, and 43% have congestive heart failure.
• Rapidly progressive kidney failure with glomerular crescents occurs in less than 1% of children and
adults.
• reduced C3 levels in >90% of patients in the first week of disease; normalizes within 2 months.
• Kidney biopsy is not routinely indicated in PSGN but may be required for confirmation when clinical
features are atypical, such as nephrotic proteinuria, decreased C3 levels for more than a month
(suggesting transformation to C3 glomerulopathy), worsening kidney dysfunction, or adult age.

14. Acute and subacute disease-
“starry sky” pattern - C3 with IgG,
and IgM, children.
Active disease-
“garland” pattern, subepithelial
hump deposits and heavy
proteinuria, IgA + C3, adults, high
risk for sclerosis
Subacute to chronic injury-
mesangial pattern ,C3

16. Treatment-
• culture and treatment of any persistent streptococcal infection- oral penicillin, intramuscular
penicillin (a single intramuscular injection of 1.2 million units of benzathine penicillin in adults, or half
this dose in small children), erythromycin (in patients allergic to penicillin), or cephalosporins.
• Oral treatments are given in doses every 6 hours for 7 to 10 days.
• Treatment of acute nephritic syndrome- fluid and sodium intake restriction and loop diuretic
administration.
• An oral long-acting calcium antagonist is usually sufficient to control hypertension.
• Dialysis (hemodialysis or peritoneal dialysis) is required in 25% to 30% of adults but seldom in
children.

18.  ANTIGLOMERULAR BASEMENT MEMBRANE DISEASE
• Autoab directed against glomerular basement antigens ( + DAH + RPGN) frequently develop a
glomerulonephritis termed antiglomerular basement membrane (anti-GBM) disease.
• When present with lung hemorrhage and glomerulonephritis ( + DAH+ RPGN+ α3 NC1 domain of
collagen IV.) - pulmonary-renal syndrome called Goodpasture’s syndrome.
• MECHANISM-
• First hit- HLA class II alleles, including DRB1∗1501 and DR4 alleles (DR1 and DR7 confer
strong and dominant protection)
• Second hit- smoking, hydrocarbon exposure, lung infection.
• appears in two age groups: in young men in their late twenties and in men and women in their
sixties and seventies.
• Younger patients - hemoptysis, a sudden fall in hemoglobin, fever, dyspnea, and hematuria (pallor,
dry inspiratory crackles, signs of consolidation, or respiratory distress)
• Older patients are more likely to present with isolated glomerulonephritis (dark or red urine, oliguria)

19.  In the presence of severe glomerular
inflammation, linear deposition of Ig G +/- C3
along the GBM is pathognomonic.
 Hemosiderin laden macrophages in BAL or
sputum diagnostic of alveolar hemorrhage.
 DLCO increased.

20. TREATMENT
• Treatment recommendations for acute severe
disease were devised to reduce levels of
circulating pathogenic antibodies as rapidly as
possible and to lessen their contribution to rapid
glomerular destruction.
• Once the disease is controlled,
immunosuppression usually can be tapered off
over 3 months, and subsequent relapse is
uncommon.
• Prognosis at presentation is worse if there are >50%
crescents on renal biopsy with advanced fibrosis, if
serum creatinine is >5–6 mg/dL, if oliguria is present,
or if there is a need for acute dialysis.

22.  IgA NEPHROPATHY
• classically characterized by episodic hematuria
associated with the deposition of IgA in the mesangium.
• male preponderance, a peak incidence in the second and
third decades of life.
• Innocent bystander mechanism-
• Mucosal antigen challenge provokes polymeric IgA (pIgA)
production by plasma cells of MALT;
• altered glycosylation of the hinge region of IgA1 ->
improper clearance by liver.
• IgA accumulates in liver -> anti- glycan Ab produced ->
immune complexes formed -> reach hepatic vein -> IVC -
> kidney glomerulus -> mesangium.

23.  Secondary causes-
Diseases of mucosa-
• Celiac disease
• Whipple’s disease
• Tropical sprue
• IBD
• Crohn’s disease
• UC
• HIV
Liver pathologies impairing clearance-
• Cirrhosis/ Alcholic liver disease/ NASH
Sero-negative spondyloarthropathies-
• Ankylosing spondylitis
• Reactive arthritis
• IBD arthritis
• Psoriatic arthritis
• Juvenile idiopathic arthritis

24. Clinical Manifestations
• The two most common presentations of IgA nephropathy are-
• i) in > 50% recurrent episodes of macroscopic hematuria during
or immediately following an upper respiratory infection
(synpharyngitic haematuria) often accompanied by proteinuria
and
• ii )30-40% persistent asymptomatic microscopic haematuria.
• Nephrotic syndrome (5%) is uncommon.
• Rarely, patients present with acute renal failure and a rapidly
progressive clinical picture- 1%.
• IgA nephropathy is a benign disease for the majority of patients,
and 5– 30% of patients may go into a complete remission, with
others having hematuria but well-preserved renal function.
• In the minority of patients 5- 10% (CKD/CGN) who have
progressive disease, progression is slow, with renal failure seen
in only 25–30% of patients with IgA nephropathy over 20–25
years.

28. TREATMENT
• Use of angiotensin-converting enzyme (ACE) inhibitors in patients with proteinuria or declining renal function.
• In patients with persistent proteinuria after ACE inhibitor therapy, steroid treatment or other
immunosuppressives have demonstrated conflicting results.
• Tonsillectomy and fish oil.
• Accordingly, the 2021 KDIGO guidelines suggest that corticosteroids should be initiated in high-risk patients
only if proteinuria remains greater than 1 g/day after supportive care has been optimized for 3 to 6 months
and only after a thorough discussion of potential adverse events with patients.
• At present, no evidence supports combined intravenous (IV) and oral corticosteroid therapy over a purely oral
prednisolone regimen, starting with 1 mg/kg/day for 2 months, then reduced by 0.2 mg/kg/day per month or
low dose at 0.4 mg/kg/ day methylprednisolone with tapering over 6 months.
• KDIGO also points out that corticosteroids should be used very restrictively or be avoided in obese patients
(body mass index > 30 kg/m2) or in patients with a GFR of less than 30 to 50 mL/min/1.73 m2, diabetes
mellitus, latent infection, secondary IgAN, active peptic ulcers, or psychiatric illness.

29.  ANCA SMALL-VESSEL
VASCULITIS

31. • The most common antigen targets of ANCAs are proteinase 3
(PR3) and myeloperoxidase (MPO) present in the azurophilic
granules of neutrophils.
• ANCA patterns- screening with IF and confirmation with
ELISA.
• c-ANCA- cytoplasmic pattern, ELISA against Ab PR3.
• P-ANCA- perinuclear pattern, ELISA against Ab MPO.

32. Pathology-
• The acute vascular lesion of pauci-immune SVV is
segmental fibrinoid necrosis, often accompanied by
leukocyte infiltration and leukocytoclasia.
• Focal necrotizing lesions can affect different vessels-
• involvement of glomerular capillaries causes nephritis;
• of alveolar capillaries, pulmonary hemorrhage;
• of dermal venules, purpura;
• of upper respiratory tract mucosal venules, rhinitis and
sinusitis;
• of abdominal visceral arteries, abdominal pain; and
• of epineural arteries, mononeuritis multiplex.

35. • Induction Therapy-
• One approach begins with methylprednisolone 7 mg/kg/day IV for 3 days, followed by
oral prednisone 1 mg/kg/day, tapering to an alternate-day regimen and discontinuing
within 3 to 6 months.
• Alternatively, corticosteroids can be administered as prednisolone 1 mg/kg/day tapered
to 0.25 mg/kg/day by 3 months.
• Oral cyclophosphamide 2 mg/kg/day or cyclophosphamide at 0.35 to 0.5 g/m2 IV per
month.
• Rituximab- four infusions of 375 mg/m2.
• Newer drugs under trial- Avacopan (CCX168; selective C5a receptor inhibitor), IFX-1,
an anti-C5a antibody
• Maintenance Therapy-
• Azathioprine 2 mg/kg/day >> mycophenolate mofetil (MMF) 2 g/day.
• Relapse Therapy-
• Rituximab is the best treatment for relapses.

36.  MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS
• MPGN is characterized by thickening of the GBM with
mesangio-proliferative changes often leading to a lobular
appearance of the glomerular tuft.
• EM- silver methamine staining- double contour/ tram track
appearance. Subendothelial deposits.
• (Type I MPGN) Immune complex–mediated. IF- granular
IgG/IgM +/- C3 in capillary wall > mesangium. Activation of
classical complement activation – Low C3/C4.
• (Types II) Complement mediated/ C3 glomerulopathy-
non-immunoglobulin-mediated and driven by the alternate
complement pathway. IF- C3 predominant staining in
mesangium./ capillary wall +/- IgG.

37. OLD TYPE 1
OLD TYPE 2

38. EXAMPLES OF TYPE 1

40. • Presentation-
• Patients with MPGN present with proteinuria, hematuria, and pyuria (30%);
• systemic symptoms of fatigue and malaise that are most common in children with
type I disease;
• or an acute nephritic picture with RPGN and a speedy deterioration in renal
function in up to 25% of patients.
• Low serum C3 levels are common.
• Fifty percent of patients with MPGN develop ESRD 10 years after diagnosis, and
90% have renal insufficiency after 20 years.
• Nephrotic syndrome, hypertension, and renal insufficiency all predict poor
outcome.

41. Treatment
• Patients with normal kidney function, no active urinary sediment, and non-nephrotic range
proteinuria can be treated conservatively.
• Patients with nephrotic syndrome and preserved kidney function- prednisone 1 mg/kg/day
(maximum dose 60–80 mg/ day) for 12 to 16 weeks -> response + -> prednisone tapered to
A/D therapy over 6 to 8 months. If there is less than a 30% reduction in proteinuria after 12 to
16 weeks-> taper and discontinue -> Calcineurin inhibitors may be considered.
• Patients who present with impaired kidney function (eGFR < 60 mL/min/1.73m2), with or
without nephrotic syndrome, but without crescents or severe tubulointerstitial fibrosis on
kidney biopsy, and an active urinary sediment (arbitrarily defined as >10 red blood cells per
high-power field)- corticosteroids.
• Patients presenting with rapidly progressive disease and crescents on biopsy can be treated
as in other forms of crescentic glomerulonephritis with pulse methylprednisolone followed by
oral corticosteroids and cyclophosphamide.
• In secondary MPGN, treating the associated infection, autoimmune disease, or neoplasms is of
demonstrated benefit.

42. OLD TYPE 2

43. C3 Glomerulopathy-

44. • Presentation-
• DDD is primarily a disease of children and young
adults, whereas the other C3 glomerulopathies are
reported to present in an older age group (mean
age 30).
• Patients with DDD present with proteinuria, which
may be nephrotic range, and/or hematuria, which
may be macroscopic or microscopic. Partial
lipodystrophy and Drusen bodies in the retina may
also be present. Prognosis is poor, with 50% of
patients progressing to ESRD.
• C3GN patients are clinically less well defined, but
approximately two-thirds have hematuria and one-
third have proteinuria. C3 levels are low with
normal C4.

45. Treatment
• Treatments that have been tried include renin angiotensin system blockade, corticosteroids and
other immunosuppressants, anticoagulants, and plasma exchange.
• (KDIGO) controversies conference recommended that all patients should receive optimal blood
pressure control and
• patients with moderate disease—defined as urine protein greater than 500 mg/24 h despite
supportive therapy, moderate inflammation on kidney biopsy, or recent rise in creatinine—should
receive prednisone or MMF.
• In severe disease with proteinuria more than 2 g/24 h, severe disease on biopsy, or progressive
creatinine increase, the KDIGO conference suggested the use of methylprednisolone pulse dosing
and other immunosuppressants.
• Eculizumab, a monoclonal antibody directed at C5, which is activated by C3 - not first line.

46.  LUPUS NEPHRITIS
• Lupus nephritis is a common and serious complication of systemic lupus
erythematosus (SLE).
• The most common clinical sign of renal disease is proteinuria, but hematuria,
hypertension, varying degrees of renal failure, and active urine sediment with red blood
cell casts can all be present.
• Anti-dsDNA antibodies that fix complement correlate best with the presence of renal
disease.
• Hypocomplementemia is common in patients with acute lupus nephritis (70–90%), and
declining complement levels may herald a flare.
• A kidney biopsy should be performed in most patients with renal involvement to
establish the histologic subtype, which guides therapy.

48. • Class 1 and 2 nephritis- lupus
podocytopathy can be present ->
effacement of foot process ->
nephrotic syndrome.
• No T/t required.

49. • Lupus nephritis is presented under acute nephritic syndromes because
of the aggressive and important proliferative lesions seen in class III–V
renal diseases.
• Class III lesions have the most varied course. Hematuria and
proteinuria are present, and some patients also have an active urinary
sediment, nephrotic syndrome, hypertension, and a decreased GFR.

50. • Patients with class IV lesions commonly have high anti-DNA antibody titers, low
serum complement, hematuria, red blood cell casts, proteinuria, hypertension, and
decreased renal function; 50% of patients have nephrotic-range proteinuria.
• Patients with crescents on biopsy often have a rapidly progressive decline in renal
function

51. • The class V lesion describes subepithelial
immune deposit producing a membranous
pattern; a subcategory of class V lesion is
associated with proliferative lesions and is
sometimes called mixed membranous and
proliferative disease.
• Patients with lupus nephritis class V, like
patients with idiopathic membranous
nephropathy (IMN), are predisposed to renal
vein thrombosis and other thrombotic
complications.
• A minority of patients with class V will
present with hypertension and renal
dysfunction.

52. • Most studies define complete kidney response as a reduction in proteinuria to
less than 0.5 g/day or a urine protein to creatinine ratio less than 0.5 g/g,
absence of glomerular hematuria and red blood cell casts, and normal or stable
GFR.
• However, long-term kidney survival is best predicted by reducing proteinuria to
less than 0.7 to 0.8 g/day after 1 year of treatment
• The term partial response requires a 50% reduction in proteinuria to sub-
nephrotic levels, and stability or improvement in GFR and is usually achieved
before complete response criteria are met.
• In LN patients in remission, quarterly monitoring (including blood pressure,
kidney function, proteinuria, urinary sediment, and serum C3 and C4) is
recommended, with anti-dsDNA measured at least biannually.

56. References
• Harrison's Principles of Internal Medicine, Twenty-First Edition
• COMPREHENSIVE CLINICAL NEPHROLOGY 7th edition

57. • Thankyou