Case presentation

1. Case presentation Dr. SahbanAlmalah Presenet by Dr. HasaninM.Ali

2. جمال عباس عليوي52 years oldmarriedInfertileD.O.A. 17-2-2011D.O.D. 03-3-2011 • Middle age patients with 1 year history of generalized fatigability , progressive weight loss , poor apettite , with productive cough yellowish to greenish sputum without hemoptysis , intermittant fever with some time drenching sweating sp. At night. • Last two months his condition deteriorated inform of exertionaldyspnea , orthopnea , increasing cough and fever , generalized body swelling and decrease U.O.P. • Nausea , vomiting with altered bowel motion. • No joint pain or swelling, No skin manifestations

3. He was admitted to Ibn Al Zuhr hospital at first of Feb.2011 • Investigations at that time shows: -B. urea 13Mmol/L -S. creatinin1 mg/dl -T. protein 48 g/L -S. Albumin 16 g/L -S. globulin 32 g/L • Sputum cytology : infiltration of inflammatory cells , no malignant cells. • Sputum AFB : 3 sample negative • CXR : ill defined consolidation seen in all zones of both sides, blunted both costophrenic angles ( pleural effusions), normal heart size, in conclusion highly suspecious of pulmonary. T.B. • Abdominal U/S: normal size liver and spleen moderate ascites and pelvic collection Rt kidney 13.7*3 cm cortical thickness 1.7 cm Lt kidney 12.5*5 cm cortical thickness 20 cm • Chest C-T scan……

4. Chest CT scan • Thick regular outline cavitary lesion at apical segment of right upper lobe measured 57*47 mm. • Wide spread reticulonodular and fibrotic changes seen at both lung field . • Multiple mediastinal LAP seen at subcarainal lesion causing widening of caraina. • Lt side pleural effusion associated with ascites. • The mediastinum is central. • Normal trachea and major bronchi. • The heart and major cardiothoracic vessels shows no abnormalities. • The thoracic skeleton and soft tissues show no obvious abnormalities. • Conclusion: T.B. can not be excluded. • So that they were started Anti T.B. medication.

5. He was referred to us as there was asuspecion of renal impair. • At admission pt. complaining from dyspnea even at rest , productive cough , low grade fever , generalized body odema, pallor . • Investigation at admission: -FBS 100 g/dl -B.urea77 mg/dl -S.creatinin2.2 mg/dl -S. Na 144meq/L -S.k3.7meq/L -S. Ca. 7 mg/dl -T.S. protein 34 g/L -S. Alb. 9 g/L -S. globulin 25 g/L - normal LFT. - G.U.E./ turbid , Albumin +++, Rbc few , pus cell 8-10. - Urine for protein/creatinin 5.5 - Blood film/ pcv35%, wbc8.500, plt 260.000 - ESR 85 mm/hr. - normocyticnormochromic with eosinophilia ( 6%). • Kidney biopsy was done for him.

6. Treatment started inform of : -Frusemide amp. 120 mg/day. -Spironalactone tablet 200 mg/day. -Simvastatin tablet 20 mg/day. -Paracetamol tablet 1500 mg/day. -Aspirin 100mg/day. -B6 tablet 40 mg/day. -Anti T.B. - Ceftriaxone vial 1g/day. • After 3 days his dyspnea and fever subside but still there was generalized body odema so we added: - Albumin infusion 20% 150 cc/day .

7. Serologicat test: -ANA negative - Anti ds DNA negative -ANCA normal. -C3 92.7 (N 84-193) - C4 21.9 (N 20-40). • S. Protein electrophoresis : -markdly reduced albumin , reduced B and Gama globulin with increased Alpha globulin. • Urine for Bence Jones protein : Negative. • At 28/2/2011 : -B.urea67 mg/dl - S.creatinin3 mg/dl - S.Na131 mg/dl -S. K 2.8meq/L - S.protein40 g/L -S.Albumin17 g/L -G.U.E. Albumin +++ , pus cell few , Rbc few , No cast. -WBC 12700 -PCV 32% • At that time He was clinically better afebrile , dyspnea and odema subside.

8. Kidney biopsy:

9. Amyloidosis • Amyloidosis is a group of diseases characterized by extracellular deposition of beta-sheet fibrils. • In the systemic forms, the amyloid causes progressive organ dysfunction leading to death of the patients. • Over 20 proteins capable of amyloid formation have been identified. They include : • Ig light chains (AL) in primary systemic amyloidosis, • Ig heavy chain (AH), • Amyloid A in secondary amyloidosis (AA), • Beta2-microglobulin in dialysis-associated arthropathy (Ab2M), • Amyloid beta protein (Ab) in Alzheimer disease and Down syndrome, • Hereditary forms that include transthyretin (ATTR), apolipoprotein A-I (AApoAI) and A-II (AApoAII), gelsolin (AGel), lysozyme (ALys), fibrinogen A-alpha chain (AFib), and others

10. SECONDARY (AA) AMYLOIDOSIS: • Also called reactive amyloidosis occurs in patients with chronic inflammatory diseases. Rheumatoid arthritis (adult or juvenile) currently accounts for up to 40 % of cases . • The other major conditions associated with AA amyloidosis are ankylosingspondylitis, psoriatic arthritis. • chronic pyogenic infections (bronchiectasis, osteomyelitis, chronic skin or decubitus ulcer infections in intravenous drug users or paraplegics, or tuberculosis). • Inflammatory bowel disease (primarily Crohn's disease with suppurative infections). • Cystic fibrosis, some neoplasms (particularly renal cell carcinoma and Hodgkin lymphoma). • A number of genetic disorders associated with chronic inflammation have also been reported to cause AA amyloidosis. These include familial Mediterranean fever, hyperimmunoglobulinemia D syndrome (HIDS), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), and Muckle-Wells syndrome. • On the other hand, not all autoimmune diseases (including those associated with chronic inflammation) lead to amyloid formation, as AA amyloidosis is rare in patients with systemic lupus erythematosus and diabetes mellitus.

11. Clinical manifestations and site of deposition • The clinical manifestations of the renal disease vary with the site of involvement: • Glomerular deposits —common presentation. • Nearly 75 % of patients present with proteinuria. • The degree of proteinuria can range from mild to massive (>20 g/day). • The urine sediment is typically benign (reflecting the lack of inflammation), • The plasma creatinine concentration may be normal or only moderately elevated. • End-stage renal disease develops in approximately 20 % of those with the nephrotic syndrome, with poor patient survival overall.

12. Vascular and tubular amyloid deposits —Occasionally the amyloid deposits are primarily limited to the vessels, leading to narrowing of the vascular lumens. • These patients usually present with slowly progressive chronic kidney disease with little or no proteinuria. • Prognosis in such patients appears to be more favorable. • Even less common is heavy tubular deposition, potentially leading to signs of tubular dysfunction such as type 1 (distal) renal tubular acidosis or polyuria due to nephrogenic diabetes insipidus. • Acquired Fanconi syndrome has been reported in rare cases

13. Crescenticglomerulonephritis: It is an extremely rare complication superimposed upon renal amyloidosis. • Almost all reported patients have had AA amyloidosis due to rheumatoid arthritis or its variants. • A possible mechanism is amyloid fibril-induced ruptures in the capillary loops, leading to fibrin entry into Bowman's space. • Another possibility is that the glomerulonephritis is related to rheumatoid arthritis or its therapy. • Two factors argue against this hypothesis: not all affected patients have had rheumatoid arthritis; and crescenticglomerulonephritis is not a characteristic feature of renal involvement in rheumatoid arthritis. • The possible presence of crescenticglomerulonephritis should be suspected in a patient with renal amyloidosis who develops acute renal failure in association with an active urine sediment. Optimal therapy of this problem is not known.

14. Pathogenesis: AA amyloidosis is associated with increased hepatocyte production of the acute phase reactant serum amyloid A (SAA); this process may be stimulated by the release of cytokines (perhaps interleukin-1) from activated macrophages. Cleavage in circulating monocytes/macrophages results in the generation of smaller fragments, called AA protein, that can then deposit in the tissues. • Light microscopy :Light microscopy in renal amyloidosis typically reveals diffuse glomerular deposition of amorphous hyaline material, initially in the mesangium and then in the capillary loops. These nodules only weakly stain with periodic acid Schiff's (PAS) and methenaminesilver stain because they are composed mostly of amyloid fibrils and not extracellular matrix as in diabetes mellitus. • Scanty deposits of amyloid may go undetected by light microscopy, especially when thin sections are used. • . There is also a poor correlation between the extent of glomerularamyloid deposits and the degree of proteinuria.

15. Immunofluorescence : • Amyloid deposits also may be seen in the small arteries, arterioles, and tubular basement membranes. • Immunofluorescence microscopy is negative for immunoglobulins and complement in AA amyloidosis but is typically positive for lambda or kappa light chains in the AL amyloid. • False negatives with immunofluorescence (using single commercially prepared antisera against the kappa and lambda light chains of immunoglobulin) can occur in 25 to 35 percent of cases. To increase sensitivity in this setting, the antisera from multiple venders may be used, and immunoperoxidase can also be helpful.

16. PROGNOSIS : • If untreated, AA amyloidosis is a serious disease with a significant mortality due to end-stage renal disease, infection, heart failure, bowel perforation, or gastrointestinal bleeding . • Patients with persistently high circulating levels of SAA are at particular risk to develop these complications of disease. • As an example, in a Japanese study of 42 patients with AA amyloidosis associated with rheumatoid arthritis the ten-year survival was 19 % ; survival was adversely impacted by the presence of azotemia and/or cardiac involvement at the time of diagnosis

17. Treatment: • Importance of control of the underlying disease — Successful treatment of the underlying inflammatory process (as with cytotoxic agents in rheumatoid arthritis or antibiotics with chronic infection) can lead to stabilization of or improvement in renal function, reduction in protein excretion, and partial resolution of amyloid deposits. • Serial serum amyloid P component (SAP) scintigraphy was carried out in 221 patients, with evidence of regression from baseline in 87 (39 %). SAA levels in those regressing were significantly lower than those in whom the amyloid was unchanged (48 %) or increased (12 %).

18. Colchicine: • IT has become accepted therapy for secondary amyloidosis. • In familial Mediterranean fever (FMF), for example, colchicine (in a dose of 1 to 1.2 mg/day) markedly reduces the frequency of attacks of abdominal pain, diminishes the incidence of clinical renal disease (including prevention of recurrence in the renal transplant), and can stabilize the glomerular filtration rate in patients with mild proteinuria. • IT is not likely to be effective in FMF patients who already have chronic renal failure, since irreversible glomerular injury is probably present. • Anecdotal successes with chronic colchicine therapy (0.6 mg BID) have also been reported in patients with AA amyloid due to inflammatory bowel disease, Behcet's disease, and in intravenous drug users with suppurative skin lesions; proteinuria due to renal amyloidosis may be markedly reduced and renal function may remain stable over long periods of time. However, repeat renal biopsy in one such patient did not demonstrate a reduction in total amyloid deposition despite almost complete resolution of proteinuria. • It is not clear whether the efficacy of colchicine in some of these settings is related to a direct reduction in amyloid fibril production or to decreased activity of the primary disease (as may be the case in FMF, in which attacks may be associated with massive neutrophilic infiltration into affected tissues). • Regardless of the mechanism, colchicine must be continued indefinitely unless the underlying inflammatory disease can be corrected.

19. Anti-cytokine therapy (under investigation): • Increasing use of biologics with activities against proinflammatory cytokines (tumour necrosis factor alpha and Interleukin-1) for diseases such as RA and AS may impact risk factors for the development of AA amyloid, and also be associated with reversal of established disease . • Tumor necrosis factor receptor-associated periodic syndrome (TRAPS), which is responsive to etanercept or infliximab , or Muckle-Wells disease/familial cold autoinflammatory disease, which appears to be responsive to interleukin-1 receptor antagonism, is under investigation . • An anti-interleukin-6 receptor antibody has been shown to attenuate experimental AA amyloid, and to reverse AA amyloidosis complicating juvenile idiopathic arthritis

20. Cyclophosphamide: • A small retrospective study reported that cyclophosphamide may provide a significant survival benefit in French patients with rheumatoid arthritis and renal AA amyloid • In this study of 15 such patients, of whom six received monthly cyclophosphamide following confirmation of renal involvement, the survival of patients treated with pulse cyclophosphamide was longer than that of those administered non-alkylating drug regimens (mean survival of 165 and 46 months, respectively). • Trends toward decreased proteinuria and maintenance of renal function were also noted with cyclophosphamide. • Similar results were confirmed in cohort study reported from Japan. • Prospective studies are required to properly assess the role and toxicity of this agent in this setting.

21. Eprodisate: • IT is the first of the low molecular weight anionic sulfonates whose efficacy in slowing renal disease progression in patients with AA amyloidosis has been reported. • A two-year double-blind multicenter international study randomly assigned 183 patients with AA amyloidosis with renal involvement to receive oral eprodisate (800 mg to 2400 mg/day in divided doses depending upon renal function) or placebo. • Significantly more patients on active treatment had renal function that remained stable or improved compared to those receiving placebo (40 versus 27 percent, respectively). • There was no significant difference in mortality, proteinuria, or the tissue content of AA amyloid. • The drug was well-tolerated. A nonsignificant trend toward a higher proportion of patients with chronic diarrhea was noted (four percent versus one percent for eprodisate and placebo, respectively). • Further studies of this novel approach to treatment of amyloidosis are anticipated. • At present, eprodisate is not available for clinical use.

22. DIALYSIS AND RENAL TRANSPLANTATION: • Patients with renal amyloidosis who progress to end-stage renal disease can be treated with either dialysis or renal transplantation. • Hemodialysis and continuous ambulatory peritoneal dialysis (CAPD) appear to be equally effective, with the limiting factors being the degree of extrarenalamyloid deposition, hypotension with hemodialysis, and peritonitis with CAPD. • The experience with renal transplantation in renal amyloidosis is mostly limited to AA amyloidosis, since patient survival is often relatively short in AL amyloidosis. However, increased survival and renal transplantation in AL amyloidosis has been reported. • Recurrent amyloid deposition in the transplant occurs in 20 to 33 % of cases due to continued activity of the underlying disease. However, graft loss due to recurrence is uncommon.

23. Thank you