NEPHRITIC SYNDROME. Clinical Manifestations

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

6. Clinical evaluation of glomerular disease

7. 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. F all in GFR - uremic symptoms with salt and water retention, leading to edema and hypertension.

8. 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.

9. 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.

10. A cute and subacute disease- “starry sky” pattern - C3 with IgG, and IgM, children. A ctive disease- “garland” pattern , subepithelial hump deposits and heavy proteinuria, IgA + C3, adults, high risk for sclerosis S ubacute to chronic injury- mesangial pattern ,C3

11. 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- fl uid 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.

12. ANTIGLOMERULAR BASEMENT MEMBRANE DISEASE A utoab 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)

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

14. 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.

15. 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.

16. 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

17. 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.

18. TREATMENT U se 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.

19. ANCA SMALL-VESSEL VASCULITIS

20. 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.

21. Pathology- The acute vascular lesion of pauci-immune SVV is segmental fibrinoid necrosis, often accompanied by leukocyte infiltration and leukocytoclasia . F ocal 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.

22. 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. O ral 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- A vacopan (CCX168; selective C5a receptor inhibitor), IFX-1, an anti-C5a antibody Maintenance Therapy- A zathioprine 2 mg/kg/day >> mycophenolate mofetil (MMF) 2 g/day. Relapse Therapy- R ituximab is the best treatment for relapses.

23. 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) I mmune 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.

24. OLD TYPE 1 OLD TYPE 2

25. EXAMPLES OF TYPE 1

26. 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.

27. 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/1.73m 2 ), 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.

28. OLD TYPE 2

29. C3 Glomerulopathy-

30. 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.

31. 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. E culizumab, a monoclonal antibody directed at C5, which is activated by C3 - not first line.

32. 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.

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

34. L upus 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.

35. 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

36. 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.

37. 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.

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

39. Thankyou