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Transcript
Dr.Mousavi Postinfectious glomerulonephritis (PIGN) is an immunemediated glomerulonephritis caused by nonrenal bacterial infections. In the past, most cases occurred in childhood and followed streptococcal upper respiratory tract or skin infections, and hence were called ‘post-streptococcal glomerulonephritis(PSGN). The past 3 decades have witnessed amajor shift in epidemiology and outcome. Because infection is usually ongoing at the time GN is diagnosed, the term infection-related glomerulonephritis(IRGN) has been proposed. In developed countries in the modern era, a significant proportion of cases afflict adults, particularly the elderly or immunocompromised. EPIDEMIOLOGY OF ADULT IRGN The incidence of IRGN in children and adults in both the industrialized and developing countries has decreased over the past 5 decades. This trend is likely due to improvement in living conditions, early and effective use of antibiotics, and the increasing practice of water fluorination, which attenuates the expression of Streptococcus pyogenes virulence Factors. Postinfectious GN can occur at any age but usually develops in children. Most cases occur in patients aged 5-15 years; only 10% occur in patients older than 40 years. There has been also a recent change in the age predominance in IRGN. In studies reported 4 decades ago,<6% of affected adults were elderly, compared with 34% in a recent report. This shift is likely due to improved life expectancy, higher frequency and severity of infections in the elderly population, and higher prevalence of diabetes. The global burden of IRGN in adults was 68,000 per year. The true incidence is likely much higher as epidemiologic studies included only symptomatic patients, and it is known that subclinical IRGN is at least four times more common than clinically evident disease. All reported series of adult IRGN after 1990, found a male predominance, with male:female ratio ranging from 1.4:1 to 3:1 Most reported patients were Caucasians and Asians, although Blacks, Hispanics, and Native Americans can be affected. Etiology The spectrum of causative pathogens and the sites and duration of infection differ in adults compared with children. In adults, staphylococcal infections are now as common as streptococcal infections and are 3-fold more common in the Elderly. In contrast to children in whom the latent period between infection and onset of renal disease is typically 1–6 weeks, in a significant percentage of adults and particularly elderly patients the infection is only discovered at the time of IRGN diagnosis. In one study of adult IRGN, 2/3of patients with staphylococcal infection were diabetics compared to only 8% with streptococcal infection. Themajority of cases of Staphylococcus-related GN are caused by Staphylococcus (S) aureus, with higher incidence of methicillin-resistant S. aureus (MRSA) than methicillin sensitive S. aureus, although rarely the disease can be caused by coagulase-negative Staphylococcus including S. epidermidis and S. hemolyticus. S. epidermidis is the leading pathogen in shunt nephritis. Cytomegalovirus (CMV), coxsackievirus, Epstein-Barr virus (EBV), hepatitis B virus (HBV), rubella, rickettsiae (as in scrub typhus), and mumps virus are accepted as viral causes only if it can be documented that a recent group A beta-hemolytic streptococcal infection did not occur. Acute GN has been documented as a rare complication of hepatitis A. Attributing glomerulonephritis to a parasitic or fungal etiology requires the exclusion of a streptococcal infection. Identified organisms include : Coccidioides immitis and the following parasites Plasmodium malariae, Plasmodium falciparum, Schistosoma mansoni, Toxoplasma gondii, filariasis, trichinosis, and trypanosomes Risk factor & Site of infection An immunocompromised background is present inover a half of adult cases in developed countries. Diabetes isa major risk factor in the United States, particularly in the elderly population, in whom it was present in 49% of patients in one study. Alcoholism is another common predisposing condition, particularly in Europe. Other less frequent risk factors are malignancy (most commonly carcinoma), severe malnutrition, synthetic heart valve, intravenous drug use, AIDS, and tuberculosis. The teeth and gums were a common site of infection in two series of adult IRGN from Europe, in which asignificant percentage of patients were alcoholics with or without cirrhosis. Poor oral hygiene and tooth decay in alcoholics make them particularly prone to dental bacterial infections and IRGN. In some adults with IRGN, there is more than one site of infection, and the cultures grow more than one bacterium. Of note, in a minority of adult cases, the infection is not clinically evident,and some patients with clinically evident infection may have negative cultures, especially following antibiotics. pathogenesis This could occur by a number of different mechanisms: (1) by introduction of an antigen into the glomerulus (planted antigen) (2) by the deposition ofcirculating immune complexes (3) by alteration of a normalrenal antigen that causes it to become a self-antigen (4)by induction of an autoimmune response to a self-antigen byway of antigenic mimicry. It is conceivable that more than one streptococcal antigen may be involved in the pathogenesis of acute PSGN, and more than one pathogenic mechanism may be at play simultaneously. The fact that IRGN can be caused by so many different bacteria but develops in only a minority of infected patients argues for critical host factors in disease susceptibility. There is some evidence for a genetic predisposition to IRGN. recent study found asignificantly higher frequency of HLADRB1*03011 allele in Egyptian children with PSGN compared with controls.Other studies found an association with HLADPA1*01,DPA1*0201 and HLA-DRW4. A defect in the regulating mechanisms of the alternative pathway of complement has been suggested for patients with persistent IRGN. CLINICAL FEATURES OF ADULT IRGN The clinical renal manifestations of acute adult IRGN bear some similarities to and notable differences from childhood IRGN. In both age groups, symptomatic patients most commonly manifest acute nephritic syndrome, with new onset hematuria and proteinuria, edema, hypertension, and reduced renal function. Hypertension is present in 60–84% of adult patients at presentation, and is more frequent in the elderly. In one study in the elderly, new-onset or longstanding hypertension was present in 12% and 72% of cases, seizures may herald the development of severe hypertension and fluid overload in childhood IRGN, they are not a typical feature of adult IRGN. Encephalopathy presenting as confusion, headache, somnolence,or even convulsion is not common and may affect children more frequently than adults. The encephalopathy is not always attributable to severe hypertension, but may be the result of central nervous system vasculitis instead. Peripheral edema occurs in 2/3 of adult patients, because of water and sodium retention. The edema typically appears in the face and upper extremities. Ascites and anasarca may occur in children. Anuria is infrequent, however, and if persistent may indicate the development of crescentic glomerulonephritis. New-onset or exacerbated heart failure is not uncommon in elderly patients with IRGN and is attributable to the higher prevalence of underlying cardiovascular disease and decreased ability to handle the salt and water retention associated with glomerulonephritis. Aside from congestive heart failure, extrarenal manifestations rarely occur in adults with IRGN. Interestingly, purpura was present in 18% of adult patients with IRGN. IgA-dominant Staphylococcus-related GN also rarely has a Henoch–Scho¨nlein purpura (HSP)–like presentation, including lower extremity purpuric rash. Patients with shunt nephritis, who are usually children and only rarely adults, frequently have recurrent fever, anemia, hepatosplenomegaly, and cerebral symptoms. The degree of proteinuria varies from o1 to>3 g/day, with a quarter to a third of patients having full nephrotic syndrome. Almost all patients have microhematuria, with or without red blood cell casts, and gross hematuria occurs in 17–56% of patients. Subclinical microscopic hematuria may be four times more common than overt acute PSGN The hematuria is microscopic in more than two thirds of cases. Patients presenting with macroscopic anemia commonly report gross hematuria and transient oliguria. Leukocyturia is frequent, reported in 58–65% of patients Serum creatinine at presentation is elevated in the vast majority of patients, and it is higher in elderly patients than younger adults, and higher in those with underlying diabetic Glomerulosclerosis. In one study, 67% of elderly patients (>64 years) had a peak serum creatinine >4 mg/dl as compared with 32% in younger adults (16–64 years),(P=0.03). In contrast to children in whom the need for dialysis for severe acute renal failure is uncommon, close to a half of elderly patients require acute dialysis for uremic symptoms and/or fluid overload. Hypocomplementemia is present in 35–80% of adults with IRGN, compared with about 90% of children. In most patients, C3 is depressed with or without depression of C4. Usually, serum complement levels normalize within 2 months of Presentation, except in those with persistent infection. Patients with shunt nephritis frequently have positive serum cryoglobulin, positive antinuclear antibody, circulating immune complexes (ICs), elevated serum IgM or IgG levels, and elevated erythrocyte sedimentation rate. Aside from patients with shunt nephritis or infectious endocarditis-associated GN, the vast majority of adults with IRGN have negative testing for cryoglobulin. with the exception of a reported case of IgA-dominant IRGN due to staphylococcal line infection Anti-neutrophil cytoplasmic antibody (ANCA) seropositivity (directed against MPO or PR3) occurs in 8% of elderly patients with IRGN overall and in 25% of patients with infectious endocarditis–associated GN, where it may contribute to the development of the characteristic diffuse crescentic and necrotizing GN. Therefore, ANCA testing is recommended in all patients with infectious endocarditis–associated GN and in any patient with IRGN whose biopsy shows diffuse crescents and/or any lesion of fibrinoid necrosis to rule out concurrent ANCA-mediated disease. Conversely, infectious endocarditis should be excluded in patients presumed to have ANCA-associated glomerulonephritis because of the attendant risks of immunosuppression. prognostic factors The independent poor prognostic factors in adult IRGN include: older age higher serumCreatinine at biopsy more tubulointestinal scarring the presence of underlying conditions Diffuse crescent formation Proteinuria may persist for 6 months and microscopic hematuria for up to 1 year after onset of nephritis. Approximately 15% of patients at 3 years and 2% of patients at 710 years may have persistent mild proteinuria. Long-term prognosis is not necessarily benign. Some patients may develop hypertension, proteinuria, and renal insufficiency as long as 10-40 years after the initial illness. In contrast to childhood PSGN and epidemic PSGN, which usually resolve, sporadic adult IRGN has a guarded prognosis, with a significant proportion developing chronic kidney disease or endstage renal disease (ESRD). TREATMENT AND OUTCOME The treatment of adult IRGN should include eradication of infection and management of complications of nephritis. Hospital admission may be necessary, particularly in elderly patients who are vulnerable to complications such as congestive heart failure. Active infection should be eradicated with antibiotics and, if needed, with surgery. Treatment of acute nephritic syndrome includes antihypertensivedrugs, diuretics, and dietary salt restriction. In patients with persistent moderate or heavy proteinuria, renin– angiotensin system blockade is recommended to slow disease progression. The role of immunosuppressive therapy in the treatment of sporadic bacterial IRGN in adults has not been tested in a randomized prospective clinical trial; the available data are based on observations from retrospective studies. Despite the frequent use of steroids for the treatment of adult IRGN (used in 22–48% of patients in various studies for renal insufficiency with or without crescentic disease), none of the studies in which statistical analysis was performed found a beneficial effect of steroids on outcome. In adult patients with diffuse crescentic and necrotizing IRGN (particularly those with positive ANCA titers), a course of pulse steroids with or without cyclophosphamide can be offered (based on extrapolation from other etiologies of rapidly progressive glomerulonephritis), provided that there is no active infection or contraindication related to the immunocompromised state. The addition of steroids is unlikely to be harmful in PSGN, but for other IRGN the risks of using steroids should be carefully balanced against potential benefits. creatinine Pulse Methyl P 4.5 4 3.5 3 Plasma exchange +IVIG 2.5 2 1.5 1 0.5 0 Kidney Biopsy creatinine blood flow: 10o-150cc/min 30-50cc/min Plasma removal 30-50cc/min Plasma exchange*6 • IVIG(2gr/kg) • 94/11/27 4/1 94/11/28 3/5 94/11/29 3/3 94/11/30 3 94/12/1 2.8 94/12/2 2/4 94/12/3 2/2 Plasma exchange Thrombocytopenia Fever Seizure DATE PLT 94/12/2 109000 94/12/3 73000 94/12/4 33000 94/12/5 28000 94/12/7 33000 94/12/8 30000 Sepsis workup U/C: Negative B/C: Negative ESR:3 CRP: - AB: Vancomycin Neurological consult(Tonic clonic seizure) Phenytoin Brain CT/brain MRI(R/O CNS vasculitis) EEG Dopler sonography carotid artery Brain CT/MRI:No significant leision EEG:No epileptic discharge Dopler sonography carotid artery :Normal Hematologycal consult BMA&BMB:Normal PBS:Hypochrome:1+ Anisocytosis:1+ Schistocyte:RARE Retic:0.5% LDH:557 Echocardiography(Ruled out endocarditis) cardiac systolic & diastolic function was normal without any valvular disease. No vegetation creatinine Pulse Methyl P 4.5 4 3.5 3 Plasma exchange +IVIG 2.5 2 1.5 1 0.5 0 Kidney Biopsy creatinine Thank you very much for your attention The End