Sindrom Nefritik

01Pathophysiology

Nephritic syndrome is fundamentally a disease of glomerular inflammation. Unlike nephrotic syndrome, where the primary problem is a permeability defect in the filtration barrier, nephritic syndrome results from an inflammatory insult that damages the glomerular capillary wall, allowing red blood cells and moderate amounts of protein to leak into the urine.

The inflammation can be triggered by three broad mechanisms. The first is immune complex deposition, where circulating antigen-antibody complexes become trapped in the glomerulus (as in post-streptococcal GN or lupus nephritis) or form in situ when antibodies bind to antigens already planted in the glomerular structures. This activates the complement cascade, which recruits neutrophils and macrophages that release proteases and reactive oxygen species, directly injuring the GBM and endothelial cells. This is why many forms of nephritic syndrome present with low serum complement levels, and this finding is heavily tested.

The second mechanism is anti-GBM antibody disease (Goodpasture syndrome), in which autoantibodies target the type IV collagen (alpha-3 chain) in the basement membrane. Because this same collagen is found in the pulmonary alveolar basement membrane, patients classically present with the combination of glomerulonephritis and pulmonary hemorrhage. On immunofluorescence, these antibodies deposit in a smooth, continuous pattern described as linear IgG staining, which is a hallmark finding.

The third mechanism is pauci-immune vasculitis, driven by anti-neutrophil cytoplasmic antibodies (ANCA). Here, immunofluorescence shows little to no immune deposits ("pauci-immune"), and the damage is caused by direct neutrophil-mediated injury to the vessel wall. This category includes granulomatosis with polyangiitis (GPA, c-ANCA/PR3) and microscopic polyangiitis (MPA, p-ANCA/MPO).

The downstream consequences of this inflammation explain the clinical presentation. Damaged glomeruli allow RBCs to pass through gaps in the GBM, producing hematuria. Because RBCs are squeezed through these irregular openings, they become dysmorphic and can aggregate into RBC casts within the tubular lumen. The inflammatory damage also reduces the glomerular filtration rate (GFR), leading to oliguria and azotemia (rising BUN and creatinine). Reduced GFR triggers sodium and water retention through activation of the renin-angiotensin-aldosterone system (RAAS), producing hypertension and edema. Proteinuria occurs but is typically in the sub-nephrotic range (), because the damage is inflammatory rather than a pure permeability defect.

02Classification and Clinical Manifestation

03Diagnostic Workup

The best initial test for any patient suspected of nephritic syndrome is a urinalysis with microscopy. The hallmark finding is the presence of RBC casts, which are considered pathognomonic for glomerulonephritis and localize the bleeding to the glomerulus rather than the lower urinary tract. Dysmorphic RBCs further support a glomerular origin. Proteinuria will be present but typically in the sub-nephrotic range. If proteinuria exceeds $3.5g\mathrm{/}day3.5\backslash \; g/day$, consider overlap with nephrotic syndrome (as seen in MPGN, diffuse proliferative lupus nephritis, or advanced IgA nephropathy).

After confirming the nephritic picture, the next step is to determine the underlying cause using serologic testing. The single most important branching point in the workup is the complement level. This divides nephritic syndrome into two camps:

Low complement narrows the differential to PSGN, lupus nephritis (Class III or IV), and MPGN. If a child presents 1 to 3 weeks after a sore throat with low C3 and an elevated ASO titer, PSGN is the diagnosis and no biopsy is needed if the clinical picture is classic. In adults with low C3 and C4 plus positive ANA and anti-dsDNA, lupus nephritis is the leading diagnosis. In MPGN, the C3 is persistently low (unlike PSGN, where C3 normalizes within 6 to 8 weeks).

Normal complement points toward IgA nephropathy, anti-GBM disease, and ANCA-associated vasculitis. IgA nephropathy classically presents with gross hematuria occurring within 1 to 2 days of an upper respiratory infection (this short latency is a key discriminator from PSGN). Anti-GBM disease is suspected when there is concurrent pulmonary hemorrhage. ANCA testing distinguishes GPA (c-ANCA/anti-PR3) from MPA (p-ANCA/anti-MPO).

Renal biopsy is the most accurate (gold standard) test and is indicated when the diagnosis is uncertain, when RPGN is suspected (rapidly rising creatinine over days to weeks), or when histologic classification will change management (as in lupus nephritis, where the ISN/RPS class determines therapy). Biopsy results are interpreted using three modalities: light microscopy (cellular proliferation, crescent formation), immunofluorescence (pattern and type of immune deposits), and electron microscopy (location of deposits: subepithelial, subendothelial, mesangial).

A critical teaching point: in RPGN, do not delay biopsy. Crescents on biopsy (proliferation of parietal epithelial cells in Bowman's space) indicate severe, potentially irreversible damage. The percentage of glomeruli with crescents correlates with prognosis and urgency of treatment.

04Management and Treatment

For PSGN, the critical concept is that this condition is self-limited, especially in children. Treatment is purely supportive. Loop diuretics (furosemide) manage fluid overload and hypertension. Antihypertensives (calcium channel blockers or hydralazine acutely) are used if blood pressure remains elevated. Antibiotics are given only if active streptococcal infection is still present, but they do not alter the course of the glomerulonephritis. Prognosis is excellent in children; adults have a higher risk of progression to chronic kidney disease. The complement level (C3) should normalize within 6 to 8 weeks; failure to do so should prompt reconsideration of the diagnosis (think MPGN or C3 glomerulopathy).

For IgA nephropathy, first-line therapy is RAAS blockade with an ACE inhibitor or ARB. This reduces intraglomerular pressure and proteinuria, which is the strongest modifiable risk factor for progression. If proteinuria remains above 1 g/day despite optimized RAAS blockade for 3 to 6 months, a course of corticosteroids (e.g., the TESTING protocol: methylprednisolone 0.4 g/day IV x 3 days at months 1, 3, 5 with oral methylprednisolone in between) may be considered. SGLT2 inhibitors (dapagliflozin 10 mg/day) have emerged as an important adjunctive therapy for proteinuric kidney disease, including IgA nephropathy (supported by the DAPA-CKD trial and EMPA-KIDNEY data).

For RPGN of any type, the guiding principle is that crescentic GN is a renal emergency. Delay in treatment leads to irreversible scarring and end-stage renal disease. The approach depends on the underlying mechanism (Type I, II, or III). All severe cases receive pulse IV corticosteroids followed by a cytotoxic agent. Plasmapheresis is critical in anti-GBM disease because it physically removes the pathogenic antibodies from the circulation. In ANCA-associated vasculitis, rituximab has become the preferred induction agent in many centers based on the RAVE and RITUXVAS trials, with equivalent efficacy and a more favorable safety profile compared to cyclophosphamide.

For lupus nephritis, biopsy classification (ISN/RPS) drives treatment. Class I and II (minimal or mesangial) need no immunosuppression beyond general lupus management. Class III and IV (focal and diffuse proliferative) require aggressive induction followed by maintenance. Class V (membranous) may overlap with nephrotic syndrome and is treated with immunosuppression if proteinuria is significant. Hydroxychloroquine should be continued in all patients with lupus nephritis, as it reduces flares and improves renal survival. Importantly, cyclophosphamide is contraindicated in pregnancy; mycophenolate is also teratogenic (Category D). If a woman of childbearing age requires treatment, azathioprine is the safest option among conventional immunosuppressants.

05Differential Diagnosis and Distractors

06Traps and High-Yield Pearls

The most common mistake students make with nephritic syndrome questions is confusing the timeline of hematuria onset after an upper respiratory infection. When a vignette describes hematuria occurring 1 to 2 days after a pharyngeal illness, many students reflexively choose PSGN because they associate "sore throat then hematuria" with streptococcal disease. However, the correct answer is IgA nephropathy. PSGN requires a latency period of at least 1 to 3 weeks (pharyngitis) or 3 to 6 weeks (skin infection) for immune complexes to form and deposit. IgA nephropathy, by contrast, causes hematuria concurrently or within days of the mucosal infection because the IgA immune response is immediate. This distinction is tested repeatedly.

A second common trap involves complement levels. Students must memorize that low complement narrows the differential to only three conditions: PSGN, lupus nephritis, and MPGN. Everything else (IgA nephropathy, Goodpasture, ANCA vasculitis, Alport) has normal complement. Furthermore, within the low-complement group, the pattern matters: PSGN has low C3 with normal C4 (alternative pathway), while lupus nephritis has low C3 and low C4 (classical pathway activation by immune complexes containing C1q).

A third high-yield trap is the immunofluorescence pattern. Linear IgG staining is Goodpasture and only Goodpasture. Granular ("lumpy-bumpy") staining indicates immune complex deposition (PSGN, lupus, MPGN). Pauci-immune (negative IF) means ANCA-associated vasculitis. "Full house" staining (all immunoglobulin classes plus complement) is essentially diagnostic of lupus nephritis. Test-writers frequently include IF results in the vignette stem and expect you to immediately narrow the diagnosis.

Finally, students often miss that RPGN is a clinical emergency, not a histologic curiosity. If a vignette describes rapidly declining renal function over days to weeks with RBC casts, the next best step is renal biopsy (to classify the crescentic GN and guide immunosuppressive therapy), not conservative management or observation. Delaying biopsy in this setting is the wrong answer. The percentage of crescents on biopsy directly correlates with the urgency and intensity of treatment, and once crescents become fibrotic (sclerosed), the damage is irreversible.

The core competency being tested in nephritic syndrome questions is the ability to use clinical context clues (timeline, complement levels, serologies, and IF patterns) to identify the correct subtype and then match it to the appropriate management, whether supportive (PSGN) or emergent immunosuppression (RPGN).