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Crescentic Glomerulonephritis • RPGN defined as any glomerular disease characterized by extensive crescents (usually >50%) as the principal histologic finding and by a rapid loss of renal function (usually a 50% decline in the glomerular filtration rate [GFR] within 3 mo) as the clinical correlate. • Transient azotemia with oliguria is common in patients with acute glomerulonephritis • Some patients have acute glomerulonephritis and present with rapidly progressive renal failure that develops within weeks to months and displays little tendency for spontaneous or complete recovery. • Glomerular crescents can complicate any glomerulopathy, even noninflammatory glomerulopathy. • In patients with noninflammatory glomerulopathies, the crescents tend to be fibrotic rather than cellular. • Cellular crescents are a manifestation of a severe inflammatory process. Classification Idiopathic or primary crescentic glomerulonephritis is classified into the following types: • Type I with linear deposits of immunoglobulin G (IgG) (anti–glomerular basement membrane [GBM] disease) • Type II with granular deposits of immunoglobulin (immune-complex mediated) • Type III with few or no immune deposits (pauciimmune) - Antineutrophil cytoplasmic antibody (ANCA)–associated (Renal-limited forms of ANCAassociated crescentic glomerulonephritis are thought to be related to small vessel vasculitis [SVV] with exclusive involvement of the glomerular capillaries.) • Type IV combinations of types I and III • Type V ANCA-negative renal vasculitis (5-10%) Pathophysiology RPGN can develop in any of the following clinical settings: • Complication of acute or subacute infectious process • Renal complication of multisystem disease: Secondary forms comprise more than 40% of cases. • In association with use of certain drugs: A review of published data on an association between hydrocarbon exposure and anti-GBM antibodymediated disease suggests the possibility of a casual relationship. • Primary glomerular disease in which the kidney is the sole organ involved and in which extrarenal manifestations are caused by renal function • Acute RPGN is mediated by antibody or cellular immunity or by interaction of the two arms of the immune system. • Deposition of antibody along the basement membrane and/or glomerular deposition of preformed soluble immune complexes can result in glomerulonephritis. • Lymphocytes and macrophages, along with deposited antibody, are important in the production of proliferation and proteinuria. • The involved lymphocytes are identified as T cells; most are helper T cells with some suppressor T cells. • Antibody- and cell-mediated immunity are together responsible for many lesions observed in patients with acute RPGN, and cell-mediated immunity • Crescents are defined as the presence of 2 or more layers of cells in the Bowman space. • The presence of crescents in glomeruli is a marker of severe injury. • The initiating event is the development of a physical disruption in the GBM. • The lesions are mediated by processes involving macrophages and cell-mediated immunity. • Following disruption of the glomerular capillary, circulating cells, inflammatory mediators, and plasma proteins pass through the capillary wall into the Bowman space. • Cells and mediators from the interstitium enter the Bowman space with disruption of the Bowman capsule, which leads to development of crescents • The major participants in crescent formation are coagulation proteins, macrophages, T cells, fibroblasts, and parietal epithelial cells. Activated macrophages contribute to the crescents by proliferating and releasing procoagulant tissue factor, interleukin-1 (IL-1) and tumor necrosis factor (TNF). T cells are not prominent components, but they play an important role in glomerular injury by antigen recognition and macrophage recruitment. • The reversibility of crescents correlates with relative predominance of cellular components. Whether crescents progress or resolve may depend upon the integrity of the Bowman capsule and resulting cellular composition of the crescent. Progression to fibrous crescents is more common when capsular rupture occurs and fibroblasts along with macrophages are prominent in the Bowman space. The presence of fibrous crescents usually correlates with glomerular sclerosis or irreversibility. Mortality/Morbidity • Renal failure at presentation carries an increased risk for endstage renal disease and death despite immunosuppressive therapy.1 Death or dialysis occurs in 73% of patients who are treated with conventional therapy and in 88% of patients if they are oligoanuric at time of presentation. Race • No racial predilection exists. Sex • For RPGN types I and III, a predilection for males exists. Age • RPGN has a broad age distribution, as follows: • RPGN type I generally occurs in young adults. • RPGN types II and III generally occur in older adults; the peak incidence occurs in the fourth to sixth decades of life. Clinical History Clinical and laboratory presentations of all types of acute RPGN are quite similar. • Some patients present with signs and symptoms of renal disease, for example, anemia, hematuria, fluid retention, oliguria, or even uremia. • Symptoms of weakness, nausea, and vomiting (indicative of azotemia) usually dominate the clinical picture. • Other patients present with signs and symptoms of their primary etiology (eg, Goodpasture syndrome, Wegener granulomatosis, systemic lupus erythematosus [SLE]). • Still others give a history of a flulike or viral prodrome. Vague aches and pains or frank arthritis, sinusitis, otitis, episcleritis, skin rash, neuritis, or encephalopathy are uncommon and are more common with a multisystem disease (suggesting secondary form). • Oliguria, abdominal or flank pain, and hemoptysis may occur (eg, Goodpasture syndrome). • Peripheral swelling may be present. • Physical • Blood pressure may be normal or slightly elevated. • Peripheral edema may be present in 10% of patients. • Pallor is common. • Skin rash: A lesion suggesting leukocytoclastic vasculitis may be present. Causes • o o o o • o o o o o o o o o Infectious diseases Poststreptococcal glomerulonephritis (PSGN) Infective endocarditis Occult visceral sepsis Hepatitis B infection (with vasculitis and/or cryoglobulinemia) Multisystem diseases SLE Henoch-Schönlein purpura Systemic necrotizing vasculitis (including Wegener granulomatosis) Microscopic polyarteritis Goodpasture syndrome Essential mixed (IgG and immunoglobulin M [IgM]) cryoglobulinemia Malignancy Relapsing polychondritis Rheumatoid vasculitis • o o o o o o • o o o o o o • o o Drugs Penicillamine Hydralazine (rare case reports) Allopurinol (with vasculitis) Rifampin (rare case reports) Propylthiouracil, thiamazole, carbimazole, benzylthiouracil Aminoguanidine Primary glomerular disease Idiopathic or primary crescentic glomerulonephritis Type I with linear deposits of IgG (anti-GBM disease) Type II with granular deposits of immunoglobulin (immune-complex mediated) Type III with few or no immune deposits (pauciimmune) - ANCA-associated (renal-limited microscopic polyarteritis) Type IV combinations of types I and IIIa Type V ANCA-negative renal vasculitis (5-10%) Superimposed on another primary glomerular disease Membranoproliferative glomerulonephritis (MPGN) type II Membranous glomerulonephritis Differential Diagnoses • Acute Renal Failure • Nephritis, Interstitial • Glomerulonephritis, Acute • Thrombotic Thrombocytopenic Purpura • Hemolytic-Uremic Syndrome • Hypertension • Hypertension, Malignant Paradigm for the diagnosis of crescentic GN Treatment & Medication • Early and aggressive treatment is warranted to preserve renal function • A nephrologist should be involved early in the disease course • Renal diet: Provide a low-salt, low-protein (0.8 g/kg/d) diet, if renal dysfunction is present. Restrict potassium if the patient has hyperkalemia. Avoid malnutrition • No specific limitations are necessary other than limiting activity after renal biopsy Medication - Principles of therapy • Supportive therapy involves control of infection, control of volume status (providing dialysis if required), and smoking cessation • Specific therapy is directed toward providing immunosuppressive therapy (eg, glucocorticoids, cyclophosphamide, azathioprine, mycophenolate [MMF]), plasma exchange (in patients presenting with lifethreatening pulmonary hemorrhage or advanced renal failure, ie, creatinine level of >500 µmol/L1 ), and anticoagulant agents • Recently, monoclonal antibodies (eg, infliximab, rituximab), alemtuzumab, pentoxifylline (reduces TNF), mizoribine (a purine synthesis inhibitor), and antithymocyte globulin have been used with encouraging results in a small number of patients, but controlled trials are needed • At present, the mainstay of therapy remains cyclophosphamide and steroids for induction of remission Glucocorticoids • Pulses of intravenous methylprednisolone (5-20 mg/kg) followed by high-dose oral prednisone (2 mg/kg) daily or on alternate days for 2-3 months have shown improved 1-year renal survival rates of 40-70% Methylprednisolone Prednisone • Potent anti-inflammatory steroid with greater antiinflammatory potency and fewer tendencies to induce retention of salt and water than prednisolone • Adult: 0.5-1 g (5-20 mg/kg) IV bolus qd for 3 d, followed by prednisone 2 mg/kg PO daily or on alternate days for 2-3 mo • Pediatric: 30 mg/kg IV qd for 3 d, followed by prednisone 2 mg/kg PO qd • Decreases inflammation through multiple mechanisms. Reduced to its pharmacologically active form prednisolone. • When used on a long-term basis, alternate-day therapy may elicit fewer adverse effects than daily therapy • Adult: 2 mg/kg PO qd for 2-3 mo; then, taper dose • Pediatric: Administer as in adults Methylprednisolone Interaction: • Coadministration with digoxin may increase digitalis toxicity secondary to hypokalemia; estrogens may increase levels of methylprednisolone; phenobarbital, phenytoin, and rifampin may decrease levels of methylprednisolone (adjust dose); monitor patients for hypokalemia when taking medication concurrently with diuretics Contraindication: • Documented hypersensitivity; viral, fungal, or tubercular skin infections Prednisone Interaction: • Coadministration with estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics Contraindication: • Documented hypersensitivity; viral infection, peptic ulcer disease, hepatic dysfunction, connective-tissue infections, Methylprednisolone Pregnancy • C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus Precautions • Hyperglycemia, edema, osteonecrosis, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, growth suppression, myopathy, and infections are possible complications of glucocorticoid use; may result in partial loss of hypertension control Prednisone Pregnancy • B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals Precautions • Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use Immunosuppressive agents (cytotoxics) • Addition of cytotoxic agents to corticosteroids has yielded varying success in treating patients with crescentic glomerulonephritis. • Although pulse cyclophosphamide is often preferred in lupus nephritis, oral cyclophosphamide appears to have an advantage in Wegener granulomatosis. • Oral versus intravenous: Recently completed, prospectively randomized Cyclophosphamide daily oral versus PulSed (CYCLOPS) trial has shown very little difference in time to remission and time to relapse between daily oral or intermittent intravenous cyclophosphamide for induction therapy • Cyclophosphamide 3 mg/kg/d for 12 weeks is a common recommendation, but the duration of therapy may be longer (4-6 mo) in patients with pauci-immune glomerulonephritis. • This therapy should be followed by the administration of azathioprine (1.5-2 mg/kg/d) or methotrexate (5-20 mg qwk as a single dose) until the patient is in remission for at least 6-12 months. • The duration of azathioprine therapy to prevent further relapses is unknown, but it should be at least for 2 years • Continuing cyclophosphamide for longer than 6 months is not necessary, as recently shown by Cyclophosphamide versus Azathioprine during Remission (CYCAZAREM) trial, where the time to relapse was identical whether the patient was given cyclophosphamide for less than 6 months or more than 6 months. • Recent evidence suggests that mycophenolate mofetil (CellCept) 0.75-1 g bid may also be effective in patients with pauci-immune vasculitis. Cyclophosphamide • Activated in the liver to its active metabolite, 4hydroxycyclophosphami de, which alkylates the target sites in susceptible cells in an all-or-none–type reaction. • Adult: 3 mg/kg PO qd for 12 wk • Pediatric: 2 mg/kg/d PO qd Azathioprine • Mechanism by which azathioprine affects autoimmune diseases is unknown. Slow acting, and its effects may persist after discontinuation. • Adult: 3 mg/kg PO qd for 12 wk • Pediatric: 2 mg/kg/d PO qd • Allopurinol may increase risk of bleeding or infection and may • Toxicity increases with enhance myelosuppressive effects allopurinol; concurrent use of cyclophosphamide; may with ACE inhibitors may potentiate doxorubicin-induced induce severe leukopenia; cardiotoxicity; may reduce digoxin may increase levels of serum levels and antimicrobial effects of quinolones; methotrexate metabolites chloramphenicol may increase halfand decrease effects of life of cyclophosphamide, while anticoagulants, decreasing metabolite neuromuscular blockers, and concentrations; may increase effect cyclosporine of anticoagulants; coadministration with high doses of phenobarbital may increase rate of metabolism and leukopenic activity of cyclophosphamide; thiazide diuretics may prolong cyclophosphamide-induced Contraindication: • Documented hypersensitivity, severely depressed bone marrow function Pregnancy • D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus Precautions • Regularly examine hematologic profile (particularly neutrophils and platelets) to monitor for hematopoietic suppression; regularly examine urine for RBCs, which may precede hemorrhagic cystitis; young adults in reproductive age group should be advised about the risk of infertility, and appropriate steps should be taken to avoid this problem (either considering use of a sperm bank or use of leuprolide to suppress gonadotrophic function during the treatment course); malignancy of urinary bladder or lymphatic system may Contraindication: • Documented hypersensitivity Pregnancy • D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus Precautions • Increases risk of neoplasia; caution with liver disease and renal impairment; hematologic toxicities may occur Antibiotics • Therapy must be comprehensive and should cover all likely pathogens in the context of this clinical setting. Trimethoprim-sulfamethoxazole • Long-term treatment with TMP (160 mg) and SMX (800 mg) bid has been reported in a prospective, controlled, double-blind trial to sustain remission of Wegener granulomatosis. • The mechanism of this effect is not clear. Eradication of Staphylococcus aureus in the anterior nares of patients with Wegener granulomatosis has recently been reported to sustain remission of Wegener granulomatosis. • TMP-SMX is also helpful as Pneumocystis carinii pneumonia (PCP) prophylaxis in patients who are on corticosteroids and other immunosuppressive agents • Adult • TMP 160 mg/SMX 800 mg PO q12h; adjust dose per renal function: CrCl >25 mL/min: No change CrCl 15-25 mL/min: Reduce dose by 50% CrCl <15 mL/min: Not recommended • Pediatric • <2 months: Do not administer >2 months: 5-10 mg/kg/d PO tid/qid, based on TMP Interactions: • May increase PT when used with warfarin (perform coagulation tests, and adjust dose accordingly); coadministration with dapsone may increase blood levels of both drugs; coadministration of diuretics increases incidence of thrombocytopenia purpura in elderly; phenytoin levels may increase with coadministration; may potentiate effects of methotrexate in bone marrow depression; hypoglycemic response to sulfonylureas may increase with coadministration; may increase levels of • Contraindications: • Documented hypersensitivity; megaloblastic anemia due to folate deficiency • Pregnancy • C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus • Precautions • Discontinue at first appearance of skin rash or sign of adverse reaction; obtain CBC counts frequently; discontinue therapy if significant hematologic changes occur; goiter, diuresis, and hypoglycemia may occur with sulfonamides; prolonged IV infusions or high doses may cause bone marrow depression (if signs occur, administer 5-15 mg/d leucovorin); caution in folate deficiency (eg, patients with chronic alcoholism, the elderly, patients receiving anticonvulsant therapy, or patients with malabsorption syndrome); hemolysis may occur in individuals with G-6-PD deficiency; patients with AIDS may not tolerate or respond to TMP-SMX; caution in renal or hepatic impairment (perform urinalyses and renal function tests during therapy); give fluids to prevent crystalluria and stone formation Follow-up Further Inpatient Care • Intensive plasma exchange: Plasmapheresis (24 L of plasma qd or 3 times/wk), combined with glucocorticoids and cytotoxic agents, is beneficial in anti–GBM-mediated disease, provided therapy is initiated before renal failure has progressed to require dialysis support. • Plasma exchange is also valuable as an adjunctive measure in patients with positive ANCA results who present with life-threatening pulmonary hemorrhage (ie, MEthylprednisolone versus Plasma EXchange [MEPEX]) or advanced renal failure Further Inpatient Care • Plasma exchange increased the rate of renal recovery in ANCA-associated systemic vasculitis that presented with renal failure when compared with intravenous methylprednisolone; however, patient survival and adverse event rates were similar in both groups • In the absence of any response within 3-5 weeks, acceptance of a diagnosis of end-stage renal disease is preferable to death secondary to iatrogenic causes Further Inpatient Care • High-dose intravenous immunoglobulin has been reported to be successful in suppressing the activity of pauci-immune ANCA-positive vasculitis. The mechanism is not clear, but pooled normal immunoglobulin contains antibodies that neutralize ANCA and suppress complement activation through a nonspecific effect of the immunoglobulin heavy chains • Intravenous immunoglobulin may have a role in the temporary management of severe pauci-immune vasculitis when severe infection is present in patients in whom it is desirable to withhold cytotoxic agents and high-dose corticosteroids until the infection is controlled Further Inpatient Care • In difficult to treat cases of ANCA-associated vasculitis, humanized monoclonal anti-CD52 antibodies (alemtuzumab, CAMPATH-1H) that selectively deplete lymphocytes may be considered. In a recent study by Walsh et al, CAMPATH-1H induced remission in such a group of patients, but relapse and adverse events were common.3 Further study of CAMPATH-1H as an induction agent is warranted. Further Outpatient Care • After induction of remission with oral cyclophosphamide and steroids, conversion to oral azathioprine (2 mg/kg/d) at 3 months appears to be safe and effective compared to continuation of cyclophosphamide for 1 year (if clinical signs of activity are minimal and preferably ANCA is negative). • The duration of maintenance therapy with azathioprine to prevent further relapses is unknown but should be at least for 2 years. Studies of longer periods of azathioprine maintenance (2 y vs 4 y) are in progress (eg, Randomized trial of prolonged REmission-MAINtenance therapy in systemic vasculitis [REMAIN]). • Monitor BUN, electrolyte, and serum creatinine levels in all patients. • Drug-responsive relapses may occur as late as 2-4 years after remission. • RPGN may recur after renal transplantation. At present, after initiating dialysis, a waiting period of 36 months is recommended before considering renal transplantation. • No convincing evidence suggests that a bilateral nephrectomy performed before a renal transplantation reduces the risk of recurrent disease in patients with renal allografts • For patients who have achieved remission, evaluation at 2-month intervals is usually sufficient. The following testing is recommended: o Urinalysis with special emphasis on the presence of cellular casts: BUN, electrolyte, and serum creatinine levels should be evaluated in all patients. o C-reactive protein or ESR (whichever correlates better with disease activity in a given patient) o ANCA (in ANCA-positive patients at 6- to 9-mo intervals): An increasing ANCA titer is often evidence of an impending relapse. A 4-fold or higher rise in ANCA titer may herald a relapse and require preemptive intervention. o Anti-GBM titers in patients with anti-GBM Inpatient & Outpatient Medications • Administer oral cyclophosphamide for 4-6 months, followed by azathioprine or methotrexate until the patient is in remission for 6 months to 1 year. • Administer prednisone as a low-dose alternative for 6-9 months. • Administer trimethoprim-sulfamethoxazole 160/800 mg bid (for Wegener granulomatosis) if renal function normal. Decrease the dose as guided by renal function. A lower dosage as PCP prophylaxis may be considered. Transfer Patients may need to be transferred to another center for the following: • Plasmapheresis • Dialysis • Ventilatory support Deterrence/Prevention • Because patients with pauci-immune vasculitis typically have a prodrome lasting for weeks to months—during which time they experience 1 or more vague symptoms (eg, intermittent fever, weight loss, anorexia, arthralgias, shortness of breath, hemoptysis, middle ear effusions, conjunctivitis, episcleritis, nasal septal perforation, saddle nose deformity)—a high index of clinical awareness, early diagnosis, and treatment may prevent significant morbidity and mortality associated with this condition. Prognosis • In general, the prognosis is poor and aggressive therapy is warranted. The chance of renal recovery exceeds the chance of dying in most cases. Intravenous methylprednisolone as an adjunctive therapy plus less than 18% normal glomeruli and severe tubular atrophy increased the chance of therapy-related death over the chance of dialysis independence. Plasma exchange treatment plus severe tubular atrophy and less than 2% normal glomeruli increased the chance of therapy-related death over that of dialysis independence.5 • Fifty percent of patients require maintenance dialysis within 6 months of disease onset. • Spontaneous remission is uncommon, except among patients with infection as the basis for formation of antigen-antibody complexes, in whom removal of the Poor prognostic factors are as follows: o Large crescents in more than 80% of glomeruli (especially if fibrocellular or acellular) o Initial serum creatinine level of more than 500 µmol/L or GFR of less than 5 mL/min at presentation o Oliguria o Presence of anti-GBM antibody o Age older than 60 years o Coexistence of HLA-DR2 and HLA-B7 Patient Education • Patients receiving immunosuppressive therapy should be educated about early signs of infection and advised to see their physician or health care worker at the early signs of infection in order to monitor WBC count. • Patients on a high dose of prednisone should be monitored for the development of diabetes and peptic ulcer disease and receive therapy to prevent steroid-induced osteoporosis. Medicolegal Pitfalls • A high index of clinical awareness is important in order to make an early diagnosis in patients presenting with ill-defined fever, weight loss, anorexia, arthralgias, hemoptysis, middle ear effusions, deafness, nasal septal perforation, and saddle nose deformity. • Consider eradication of S aureus in anterior nares of patients with Wegener granulomatosis for sustained remission. • Be careful with immunosuppressive therapy (both cytotoxic agents and high-dose corticosteroids) in patients who may have active infection. • Ensuring that the patient has no active infection is important before starting immunosuppressive therapy in order to prevent significant morbidity and mortality associated with treatment of this disease. • Intravenous immunoglobulin may be useful to control disease activity when the patient has associated active infection and the need to hold immunosuppressive agents. • The adverse effects and toxicities of long-term corticosteroid and immunosuppressive therapy must be discussed with the patient. • With long-term steroid use, monitoring the patient for the development of diabetes, peptic ulcer disease, and osteoporosis is important, as is prescribing cytoprotective agents (to prevent peptic ulceration) and preventive therapy for steroid-induced osteoporosis. • In patients who are in the reproductive age group, discuss and document the effect on fertility of cytotoxic therapy. Patients should be counseled for sperm or egg preservation, or consideration should be given to leuprolide therapy to inhibit gametogenesis during treatment with cyclophosphamide therapy. • To prevent risk of hemorrhagic cystitis, patients on oral cyclophosphamide should be encouraged to drink plenty of fluids so that the metabolites of cyclophosphamide do not concentrate in the bladder. • The possibility of late malignancy associated with cytotoxic therapy should be discussed and documented in the patient's chart. • Failure to diagnose or empirically treat pending diagnosis, with a