| disease | Rapidly Progressive Glomerulonephritis |
| alias | Rapidly Progressive Glomerulonephritis, Acuterapidly Progressive Glomerulonephritis, APG |
Rapidly progressive nephritis is the abbreviated term for acute rapidly progressive glomerulonephritis (APG). It has a sudden onset, with kidney function deteriorating sharply within days, weeks, or months, often presenting as oliguric (anuric) acute renal failure.
bubble_chart Etiology
The following diseases can cause rapidly progressive glomerulonephritis.
(1) Primary glomerular diseases
1. Primary diffuse crescentic glomerulonephritis
(1) Type I: IgG linear deposition (anti-glomerular basement membrane antibody-mediated).
(2) Type II: IgG granular deposition (immune complex-mediated).
(3) Type III: little or no IgG deposition (lack of immune response).
(4) Induced by anti-neutrophil cytoplasmic antibody (ANCA) (vasculitis).
2. Secondary to other primary glomerulonephritis: membranoproliferative glomerulonephritis (especially type II), membranous glomerulonephritis with superimposed anti-basement membrane nephritis, IgA nephropathy (rare).
(2) Associated with infectious diseases: Acute post-streptococcal glomerulonephritis, acute or subacute infective endocarditis, chronic sepsis and glomerulonephritis caused by visceral suppurative sexually transmitted disease foci.
Other infections: shunt nephritis, hepatitis B virus nephritis, human immunodeficiency virus infection (?).
(3) Associated with multisystem diseases: Systemic lupus erythematosus, Goodpasture syndrome, Henoch-Schönlein purpura, diffuse vasculitis such as necrotizing granulomatosis, hypersensitivity vasculitis and other types, mixed cryoglobulinemia, rheumatoid arthritis with vasculitis, malignant tumors, and relapsing polychondritis, etc.
(4) Drugs: Penicillamine, hydralazine, allopurinol, rifampin, etc.
bubble_chart Pathogenesis(1) Findings on Optical Microscopy The traditional view is that in the early stage, there is significant proliferation of parietal and visceral epithelial cells (predominantly parietal epithelial cells) within the renal capsule. The proliferating epithelial cells overlap in layers within the capsular space, forming epithelial crescents or encircling the entire parietal layer of the renal capsule, referred to as circumferential crescents. Some believe that crescent formation can occur within days of disease onset. Between the proliferating epithelial cells, fibrin, multinucleated macrophages, neutrophils, and red blood cells can be observed. These lesions can be quite extensive, affecting up to approximately 80% of the glomeruli. In longer-standing cases, newly formed collagen fibers may appear between the layers of proliferating epithelial cells, eventually leading to the formation of fibrous crescents. It is now widely accepted that the quantity and severity of crescent formation are closely related to prognosis. The mechanism of crescent formation remains unclear, with many attributing it to fibrin leakage through the diseased glomerular capillary walls into the capsular space, stimulating reactive proliferation of epithelial cells. However, whether fibrin alone can induce such significant epithelial cell proliferation is questionable, and other unknown influencing factors likely play a role. The role of macrophages has gained attention, as they promote fibrinogen deposition in the glomeruli, proliferate on the capsular wall, and transform into epithelioid cells, contributing to crescent formation. Crescents may resolve spontaneously.
Apart from the prominent glomerular lesions, this pathological change may also involve cellular infiltration, edema, and fibrosis in the interstitium. The extent of interstitial lesions also affects prognosis.
(2) Findings on Immunofluorescence Microscopy Two main patterns are observed: granular deposits of immune complexes and linear deposits of anti-basement membrane antibodies. Cases with linear immunofluorescence deposits are mostly IgG-positive, with approximately 1/2 to 2/3 of cases showing C3 deposits, while other immunoglobulins are rarely present. In the immune complex type, the prominent immunofluorescence changes include the presence of C3, IgG, and fibrin(ogen) at the sites of damaged glomerular capillary loops. Fibrin(ogen) is present in the crescents in over 70% of cases, easily seen in fresh proliferative crescents but often absent in older, so-called "old" crescents. Various immunoglobulins are never found in crescents.
(3) Findings on Electron Microscopy Fresh crescents show highly swollen epithelial cells, with cell volume increasing to 32 μm. In the early stages of proliferation, fibrin bundles (strands) and fibrinoid material are present between the proliferating capsular epithelial cells, the latter being more common in very fresh crescents, especially in cases caused by anti-basement membrane disease. Electron microscopy also reveals acute inflammatory changes such as proliferation and swelling of glomerular capillary endothelial cells and mesangial cells, as well as luminal narrowing. In some cases, fibrin or even small amounts of electron-dense deposits may be found on the endothelial side of the basement membrane. The glomerular basement membrane may exhibit irregular thickening, thinning, breaks, or spike-like projections. The basement membrane near the mesangial region may show significant thickening. Immune complex deposits may be located within the basement membrane on the endothelial side, and hump-like deposits may also appear on the epithelial side of the basement membrane.
The onset is often abrupt, primarily presenting with oliguria or anuria, hematuria (frequently gross hematuria with recurrent episodes), massive proteinuria, red blood cell casts with or without edema and hypertension. The disease progresses rapidly, with persistent episodes leading to progressive renal function impairment, which can develop into end-stage renal failure within weeks or months. There are three possible outcomes: ① rapid progression to uremia within weeks, presenting as acute renal failure; ② slower progression of renal impairment, developing into uremia over several months or a year; ③ in a few patients, the condition stabilizes after treatment, with some even achieving complete recovery or retaining varying degrees of renal function impairment.
In most cases, the diagnosis is generally not difficult to make based on the typical clinical manifestations, such as acute onset, rapid progression of the disease course, oliguria or anuria, gross hematuria accompanied by massive proteinuria, and progressive renal impairment, combined with renal biopsy showing pathological changes of crescent formation in more than 50% of the glomeruli. However, attention should be paid to atypical cases.
After confirming the diagnosis of this disease, it is still necessary to distinguish whether it is idiopathic or secondary. It is crucial to emphasize the diagnosis of the underlying disease cause, as the prognosis of rapidly progressive glomerulonephritis caused by various diseases differs, and the treatment methods and outcomes also vary. Most authors believe that the prognosis of acute poststreptococcal glomerulonephritis is better than that caused by systemic diseases. Furthermore, even among cases caused by systemic diseases, early diagnosis can lead to a better prognosis. For example, the prognosis of glomerulonephritis caused by purpura may be better than that of polyarteritis nodosa or pulmonary hemorrhage-renal syndrome. However, these diseases are often easily confused in diagnosis, and careful differentiation is necessary.
bubble_chart Treatment Measures
Treatment for this syndrome should be initiated as early as possible. If crescent formation exceeds 70% or serum creatinine concentration is above 5mg%, the chance of renal function recovery is minimal despite aggressive intervention, although case reports have documented severe cases improving with hemodialysis and intensive treatment. In such patients, high concentrations of anti-basement membrane antibodies or immune complexes are often present in the blood. If not cleared, these can continue to act on the glomeruli, causing irreversible damage. Additionally, coagulation triggered by immune reactions is a primary factor stimulating the proliferation of capsular epithelial cells and crescent formation. Animal experiments show that early heparin use can reduce or prevent crescent formation, thus the following measures may be adopted.
1. High-dose corticosteroids and immunosuppressants should be used to suppress inflammatory responses and reduce antibody production. Administer 480–1000mg methylprednisolone or 500–1000mg amber hydrocortisone intravenously for 4 consecutive days, or every other day for 4–6 doses. If intravenous injection is unavailable, oral high-dose prednisone or dexamethasone may be used. Our protocol involves 100–200mg amber hydrocortisone in 20ml of 5% glucose solution, administered intravenously every 1–2 hours, with a total daily dose of 500–1000mg for 3 days, followed by oral prednisone at 40mg/day. Early-stage cases with interstitial edema and inflammatory cell infiltration may respond better to short-term high-dose steroids. For cases with fibrotic crescents and interstitial fibrosis, or late-stage (third-stage) cases, dialysis is preferable.
2. Anticoagulants such as low-molecular-weight heparin, urokinase, and warfarin, combined with dipyridamole, should be used. Heparin therapy should begin early, be administered for an extended period at a moderate dose, and be closely monitored for bleeding tendencies. A safer regimen is 50–75mg heparin in 250ml of 5% glucose solution administered via intravenous drip daily. Urokinase is given twice daily at 20,000–40,000 units per dose intravenously, maintaining euglobulin lysis time at 90–100 minutes. As long as no contraindications such as bleeding arise, long-term continuous heparin use combined with dipyridamole (intravenous or oral) may have synergistic effects.
3. Dialysis therapy: Given the progressive and poor prognosis of this condition, and the lack of definitive efficacy with non-dialysis treatments, end-stage renal failure cases should undergo peritoneal dialysis or hemodialysis. These methods are safer than long-term steroid or immunosuppressant use. Peritoneal dialysis is preferable for elderly patients, those with poor cardiovascular function, or bleeding tendencies. For patients planned for plasma exchange, hemodialysis may be performed first.
4. Plasma exchange: This reduces circulating antibody or immune complex levels. Exchange 2–4L of plasma daily or three times weekly, combined with steroids and cytotoxic drugs, particularly for RPGN with linear IgG deposits in glomeruli, which shows significant short-term efficacy. For non-anti-basement membrane antibody-mediated RPGN, plasma exchange combined with immunosuppressants may also be effective. Such patients may have an "abortive" form of systemic necrotizing vasculitis. Due to the lack of comparative prospective studies on glucocorticoid pulse therapy plus immunosuppression versus plasma exchange plus glucocorticoids and immunosuppressants, the efficacy of plasma exchange remains uncertain. Recent improvements in plasma exchange technology, including specialized plasma filters and containers to adsorb antibodies, allow most plasma to be reinfused, reducing the need for large volumes of fresh plasma and lowering hepatitis C incidence.
5. Post-transplant RPGN recurrence is possible, but the likelihood for each case is unpredictable. For patients with circulating anti-basement membrane antibodies, observe for 3–6 months after initiating hemodialysis before kidney transplantation. Whether bilateral nephrectomy before transplantation reduces recurrence remains inconclusive.
6. Anti-ICAM-1 and VCAM-1, as well as their counter-receptors LFA-1, Mac-1, and VLA-4, can inhibit proteinuria and leukocyte infiltration in the glomeruli induced by anti-GBM antibodies in a mouse model.
The prognosis is poor with a high fatality rate, and the 5-year survival rate is approximately 25%. However, there are reports that crescents may disappear, lesions may improve, and renal function may recover, so active diagnosis and treatment are essential. The prognosis is related to the following factors: ① underlying disease; ② extent of crescent formation; ③ proliferative lesions; ④ interstitial lesions; ⑤ early diagnosis; ⑥ complications.
(1) Differentiation from prerenal or postrenal acute renal failure Additionally, attention should be paid to prerenal factors exacerbating renal damage in rapidly progressive glomerulonephritis.
(2) Differentiation from acute interstitial nephritis or acute tubular necrosis When differential diagnosis is difficult, a renal biopsy is necessary to clarify the diagnosis.
(3) Severe poststreptococcal glomerulonephritis Most cases of this disease are reversible, with oliguria and renal dysfunction lasting for a short duration. Renal function is generally expected to recover within 4–8 weeks of the disease course. Renal biopsy or dynamic disease course observation can aid in differentiation.
(4) Differentiation from hemolytic uremic syndrome, malignant hypertension, etc. Additionally, acute renal failure caused by Legionnaire's disease is treatable. Since it is often accompanied by pulmonary lesions, there have been reports of cases misdiagnosed as pulmonary hemorrhage-nephritis syndrome.
