14th - 16th March, 2005 Sanjay Gandhi Postgraduate

14th - 16th March, 2005 Sanjay Gandhi Postgraduate
Coordinator: R.K. Gupta Professor & Head Department of Pathology SGPGIMS, Lucknow, India Sanjay Gandhi Postgraduate Institute of Medical Sciences Lucknow , INDIA US Coordinator: Surya V. Seshan Professor of Pathology Chief, Renal Pathology Weill Medical College of Cornell University New York, NY

Slide Seminar - I Pathology of Glomerular Diseases
Sharda Sabnis Chief, Division of Renal Pathology Armed Forces Institute of Pathology Washington DC Surya V Seshan Prof. of Pathology Chief, Renal Pathology Weill Medical College of Cornell University New York, NY

Slide Seminar - I Pathology of Glomerular Diseases Surya V Seshan & Sharda Sabnis
Case 1: 32 year obese white male with proteinuria Case 2: 35 year female with proteinuruia & hematuria Case 3: 48 year female with fever & proteinuria Case 4: 48 year female with fever, nephrotic syndrome & HTN Case 5: 55 yr male with H/O of HTN & atherosclerotic heart disease

Slide Seminar- I: Pathology of Glomerular Diseases - Case 1
32 year obese white male, a known case of nephrotic syndrome for last 5 months, presented with increased proteinuria (from 4.0 to 8.5 gm/day), increased creatinine (from 1.1 to 3.1 mg/dL) and decreased creatinine clearance (96 to 44 cc/min) No family history of renal disease P/E: BP 130/80 mm Hg lower extremity edema

Lab data: U/A 3+ protein (8.5 gm/day), 4-5 RBCs/hpf & fatty casts. BUN mg/dL S. Cr mg/dL Bld. sugar 115 mg/dL S. albumin gm/dL S. cholesterol mg/dL ANCA, ASO, VDRL, FANA negative, complements normal Open biopsy performed due to obesity

Slide Seminar - I: Pathology of Glomerular Diseases - Case 1

? Diagnosis

Slide Seminar – I : Pathology of Glomerular Diseases - Case 1
Differential diagnosis Focal segmental glomerulosclerosis, idiopathic or secondary (?obesity) Membranous Glomerulopathy Minimal Change Disease Less likely MPGN, Diabetic glomerulosclerosis, amyloid etc.

Immunofluorescence microscopy Five glomeruli IgM and C3: 2+ to 3+ in mesangium in all glomeruli. IgG, IgA, C1q, albumin, fibrinogen, and kappa and lambda light chains negative. These results suggest FSGS or IgM nephropathy or diabetic glomerulosclerosis. Additional information Had a previous clinical diagnosis of Fabry disease and was followed up. Angiokeratoma skin lesions were noted on the back. Neurological and cardiac exam not documented.

Fabry Disease End stage renal disease is common in hemizygous male around 3rd to 5th decade. Hetertozygous females have an attenuated disease. Renal accumulation of glycosphingolipids is seen mainly in podycytes, tubular epithelium, followed by endothelium and mesangial cells and myointimal cells of BVs. Evident as membrane bound Zebra bodies with “onion skin” pattern or concentric lamellation with a periodicity of 35 to 50 A˚ Glomeruli show mesangial widening thick BMs and focal or global sclerosis. Recurs in transplants but does not cause problems. Death around 5th decade due to severe cardiac or CNS complications. Recent studies of Rx with enzyme replacement infusion with purified alpha-Gal A produced by a genetically engineered human cell line or Chinese hamster ovocyte, seems to be effective and safe.

Final diagnosis Renal involvement in Fabry disease with changes of focal segmental glomerulosclerosis Extensive chronic tubulo-interstitial disease Arterial and arteriolar sclerosis.

References: Sessa A, Meroni M et al. Renal involvement in Anderson-Fabry disease. Nephrol 2003 March-April 16(2):310-3 Schiffmann R, Kopp J et al. Enzyme replacement therapy in Fabry disease: a randomized controlled trial. JAMA Jun 6; 285 (21): Cho ME, Kopp JB. Fabry disease in the era of enzyme replacement therapy: a renal perspective. Pediatr Nephrol 2004 Jun 19(6):583-93 SessaA, Meroni M et al. Evolution of renal pathology in Fabry disease. Acta Pediatr suppl Dec;92(443):6-8

End of Case 1

35 year Indian female Abdominal discomfort 4-5 months. Increased frequency , nocturia 4-5months. Low grade fever - 3 months No chills or rigors, no joint pain, rash, petechiae, hair loss. No cough, neurological symptoms. Found to have proteinuria & hematuria - July 03 Past h/o Jaundice 10 years back. Obstetric history- Normal Examination Pulse- 84/min, regular,BP-130/90 mmHg. No edema, petechiae, or lymphadenopathy. Systemic examination –NAD.

Investigation: Urine- Sp Gr-1025, 3+ Prot., WBC-30-35/HPF, RBC-50-60/HPF 24 hour urine protein 1.2gm/day Hb 9.2gm, TC-3580 cells/mm3 S.Creat-1.1mg/dl, T.Prot/Alb-6.4/3.0, T.Bilirubin-0.5/0.25 SGOT/SGPT-32/20 IU/L Anti-HCV Ab positive. HCV-RNA-Awaited HBsAg- Negative. C mg/dl (N mg) Serum electrophoresis- No M-band. Cryoglobulin- Negative. Coomb’s test Negative, dsDNA-1430 IU/ml. ANA- Awaited.

Slide Seminar- I : Pathology of Glomerular Diseases - Case 2

? Diagnosis

Differential diagnosis: Lupus nephritis with massive immune complex deposits in capillary lumina Hep-C associated GN with cryoglobulins Primary MPGN with cryoglobulins Primary or secondary cryoglobulinemias Waldenstrom’s macroglobulinemia

Discussion Lupus nephritis with severe lesions and without strong clinical evidence of SLE are occasionally encountered but rare - later develop full blown clinical SLE - probably less likely In lupus nephritis, intraluminal “thrombi” are massive ICs and can be associated with clinical evidence of cryoglobulinemia EM essential for defining deposits and TRIs Common viral infections are associated with low titer poly-specific auto-antibodies. High titer ANA, dsDNA, anti-cardiolipin antibodies and other subtypes antibodies may be found. Hep B & C, HIV and parvovirus-B19 more commonly associated with autoantibodies than others. Hepatitis C associated renal lesions: Most common renal lesion in Hep C is MPGN with or without cryoglobulins Less common MGN, FSGS IF shows strong C3, others uncertain and non-conclusive

Final Diagnosis Glomerular changes highly suggestive of MPGN with intracapillary “thrombi”, cryoglobulins cannot be excluded. Hep C associated GN > likely than Lupus Nephritis.

Follow-up In view of strong positive anti dsDNA she was started on steroids and pulse cyclophosphamide. Later her HCV-RNA has become positive. Liver function has remained normal. Puzzled as to continue immunosuppressive therapy or to start on interferon therapy?

References: Hansen KE, Arnasen J, Bridges AJ. Autoantibodies and common viral illnesses. Semin Arthritis Rheum. 1998,27(5):263-71 Meyers CM, Seeff LB, et at. Hepatitis C and renal disease: an update. Am J Kidney dis (4):631-57 Montagna G, Piazza V, Salvadeo A. Monoclonal cryoglobulinemia in hepatitis C virus-associated, membranoproliferative glomerulonephritis. Am J kidney dis 2003Aug;42(2):430 Tormo A, Rivera F, Munoz C, Trigueros M. Presence of hepatitis C virus in renal tissue in membranoproliferative glomerulonephritis and cryoglobulinemia. Nefrologia. 2003;23(2): Nefrologia. 2003;23(2):165-8.

End of Case 2

41 year African American male admitted for new onset nephrotic syndrome, and c/o pedal edema, joint pains and easy fatigability Past medical history of gouty arthritis and chronic renal failure. Meds: Lasix, Allopurinol, Family and social history not documented. P/E BP normal, no other findings except pedal edema and gouty deformity of hands.

Lab Data: Hb 4.0gm/dL, Hct 13%, Retic count Total protein 3.9 gm/dL, alb 1.8 gm/dl BUN 49mg/dL, Creat. 3.5mg/dL Cholesterol 300mg/dL. Electrolytes normal U/A: Protein 3+ (7- 8 Gm/day), 3+ blood, No bacteria, crystals or casts. Serum - Na 149, K 5.6, Cl 120, CO2 23

? Diagnosis

Differential Diagnosis Membranoproliferative GN (MPGN) Membranous GN (Allopurinol-related) Vasculitis-related lesions (Drug related) HSP, lupus nephritis, post-infectious GN etc. MCD and FSGS less likely.

Additional data Patient was known to have sickle cell disease, gouty arthritis and chronic renal disease. Light microscopy Congested, large glomeruli. Mesangial widening with lobular accentuation with moderate hypercellularity obliterating some capillaries, double contours Sickled RBCs in capillary lumina Chronic tubulo-interstitial disease.

Electron microscopy Subendothelial mesangial extension -focal and circumferential. Focal small subendothelial deposits Extensive foot process effacement Sickled RBCs in capillary lumen with Hb tactoids with deformed shapes Immunofluorescence microscopy Negative for IgG, IgA, IgM, C3, C1q, fibrinogen, albumin and kappa and lambda light chains.

Sickle Cell Disease Sickle cell anemia (homozygous Hb-SS) is prevalent in AA patients. Gene can occur rarely in Caucasians (Europe), and is found in North Africa, Middle East and India. Sickle cell anemia in 0.15% of AA children and Sickle cell trait in 8% in AA children. Disorder attributed to specific molecular lesion: substitution of valine for glutamic acid at the sixth residue of the β chain. Hematuria Renal infarction and papillary necrosis, which may predispose to UTI. Nephrotic syndrome which may progress to renal failure Abnormal tubular function Reduced concentration ability Reduced acid and Potassium secretion Increase uric acid and creatinine secretion Increased phosphate reabsorption

Final Diagnosis: Nephrotic syndrome: FSGS, MPGN-like changes with or without immune complexes Acute and chronic TID and papillary necrosis with bland scarring Congestion and hemorrhage

References Scheinman JI. Sickle cell disease and the kidney. Semin Nephrol Jan;23(1):66-76. Ataga KI, Orringer EP.Renal abnormalities in sickle cell disease. Am J Hematol Apr;63(4): Walker BR, Alexander F, Birdsall TR, Warren RL. Glomerular lesions in sickle cell nephropathy. JAMA Jan 18;215(3): Pham PT, Pham PC, Wilkinson AH, Lew SQ. Renal abnormalities in sickle cell disease. Kidney Int Jan;57(1):1-8.

End of Case 3

48 year African-American female with fever, headache and nausea Signs of nephrotic syndrome and HTN No family history of renal disease, IV drug abuser Lab data: U/A: proteinuria (4.5gm/d), 6-8 RBC, 5-6 WBC BUN 30mg/dL, Cr 3.2mg/dL, serum albumin 2.8gm/dL, glucose 108mg/dL Anemia (9.1gms/dL), platelets 210,000 Serology: normal complement level, ANA neg, HIV+, Hep C virus +, Hep B virus negative, cryoglobulins negative

? Diagnosis

Slide Seminar – I : Pathology of Glomerular Diseases – Case 4
Pathologically, the renal lesions in HIVAN represent a constellation of glomerular and tubulo-interstitial changes, which by themselves are non-specific. They are characterized by a range of cellular and collapsing features, some leading to FSGS. They include, glomerular capillary wall wrinkling, thickening, collapse (segmental or global), variable number of large, hyperplastic visceral epithelial cells containing abundant hyaline droplets, varying degrees of segmental and global mesangial hypercellularity and dilated Bowman spaces. Sometimes the global collapsing glomerulopathy may predominate and may rapidly progress to renal failure. Striking tubular findings include tubular cell degenerative change, dilatation of the lumina reaching microcystic proportions and containing proteinaceous casts. In addition, concomitant focal to extensive, active/chronic interstitial inflammation and fibrosis is present.

Immunofluorescence microscopy Focal IgM, C3 staining in the mesangial and sclerotic areas, suggesting nonspecific trapping. EM Apart from noting tubulo-reticular inclusions (TRIs) in the glomerular endothelial and infiltrating mononuclear cells, varied thickening of GBM and foot process effacement, no specific ultrastructural abnormalities are identified. The presence of frequent TRIs may help establish the diagnosis.

A spectrum of renal lesions with varied clinical presentation can occur with HIV infection. They include from tubular functional abnormalities (fluid, electrolyte and acid-base imbalance) to structural changes involving the renal parenchyma secondary to HIV associated nephropathy (HIVAN), predominantly tubulo-interstitial disease due to prerenal (ischemia, blood loss, sepsis) causes, parenchymal lesions secondary to acute tubular necrosis, interstitial nephritis, nephrotoxicity secondary to antiviral, antifungal and aminoglycoside drugs, opportunistic infections, malignancies, other forms of immune complex glomerulopathies, IgA nephropathy, amyloidosis and thrombotic microangiopathies (HUS,TTP). Other intercurrent or metabolic renal disease can also develop in these patients or may be superimposed on HIVAN.

Although the pathogenesis of HIVAN is not completely elucidated, a direct cytopathic effect by the various HIV proteins on the glomerular epithelial and tubular lining cells has been considered. Indirectly, effects of viral gene products, cytokines and growth factors elaborated by monocytes and lymphocytes in response to the active infection may contribute to altered glomerular permeability and glomerular and tubular cell injury, leading to a change in the cell phenotype (dedifferentiation) and proliferation characteristics, apoptosis, thereby initiating mechanisms of glomerulosclerosis. Other factors or triggering mechanisms that may be needed to promote this process are a predisposition for glomerulosclerosis in African American individuals, viral load, host immunological factors and virus host interactions.

The prognosis is generally poor in patients having HIVAN with the more severe pathological lesions, in the African American population, in advanced stage of HIV infection, with nephrotic range proteinuria and higher creatinine levels at the time of initial presentation. These patients reach renal failure within months to 3 yrs. Several trials with steroids, with or without anti viral medications, ACE – inhibitors and more recently protease inhibitors have shown variable benefit in reducing proteinuria, and stabilizing the creatinine levels and thus postponing the onset of end stage renal disease.

Diagnosis HIV-associated nephropathy

References Rao TKS, Fillipone EJ, Nicastri AD et al: Associated focal segmental glomerulosclerosis in the acquired immunodeficiency syndrome. N Engl J Med 310:669, 1984 D’Agati VD, Appel GB: Renal pathology of human immunodeficiency virus infection. Semin Nephrol 18: 406, 1998 Madiwale C, Venkataseshan VS. Renal lesions in AIDS: a biopsy and autopsy study. Indian J Pathol Microbiol 42: 45-54, 1999. Schwartz EJ, Klotman P: Pathogenesis of human immunodeficiency virus (HIV) – associated nephropathy. Semin Nephrol 18: 436, 1998 Ross MJ, Klotman PE. Recent progress in HIV-associated nephropathy. J Am Soc Nephrol 13: , 2002 Kimmel PL, Phillips TM, Ferrura-Centino A. HIV-associated immune-mediated renal disease. Kidney Int 44: , 1993

End of Case 4

55-year-old white man with a history of hypertension (on medications) and atherosclerotic heart disease for the past few years, presented with progressive edema of his legs during the last 3 months. No history of shortness of breath, chest pain, nausea/vomiting at this time. Other past medical history included gastro-esophageal reflux disease, arthroscopic knee surgery and chronic low back pain. P/E Physical examination was essentially unremarkable, except for 3+ leg edema.

Lab findings Nephrotic range proteinuria (6.4gm/24hrs) microhematuria, BUN 52mg/dl,creat 2.3mg/dl Negative serologic tests (ANA, ANCA, HCV, HBV, RhF), Normal complement levels and serum protein electrophoresis. Renal biopsy was performed.

? Diagnosis End Slide Show

Based on the above clinical presentation of nephrotic range proteinuria and mild renal insufficiency in the absence of significant serologic findings and a systemic illness (infection, auto-immune, metabolic or neoplastic) in an adult points to a limited number of possibilities, such as membranous glomerulonephritis, a progressive form of focal segmental glomerulosclerosis or other forms of chronic glomerular lesions. A mild nephritic picture characterized by microhematuria, hypertension and renal insufficiency may also indicate advancing IgA nephropathy or rarely other forms of focal or early diffuse proliferative glomerulonephritis.

Light Microscopy: The glomeruli are variably enlarged showing diffuse, mild to moderate mesangial expansion with mainly increase in matrix and a few cells with focal lobular accentuation and early mesangial interposition. Most of the peripheral capillary walls are thickened and PAS positive. Focal tubular atrophy is accompanied by minimal interstitial fibrosis and sparse lymphocytic infiltrate. The small arteries and arterioles exhibit moderate medial hypertrophy and intimal thickening. Special stain for amyloid (Congo red) is negative. Immunofluorescence Microscopy: Reveals 1+ IgG, trace-1+ IgM, 1-2+ C3 and 1+ kappa and lambda light chains along the glomerular capillary walls and mesangial in a granular and diffuse global distribution.

Electron Microscopy: The glomerular capillary basement membranes show irregular thickening and expansion of the basement membranes due to uneven dark dense deposits with fibrillar structures, occupying the lamina densa, as well as lamina rara, externa and interna. The mesangial areas are markedly expanded, with increase in cells, a modest amount of matrix and abundant deposits which have a fibrillary configuration. This fibrillar material on high magnification appears fairly long, haphazardly arranged with a solid core, occasionally having a round to stellate cross section replacing the glomerular extracellular matrix. The fibrils range in thickness from 18-22nm.

Diagnosis: Fibrillary Glomerulonephritis

Differential diagnosis: Based on preliminary examination of the renal biopsy by light microscopy shows fairly nonspecific mesangial findings containing predominantly PAS positive matrix and some increase in cells. The lack of pale staining, homogeneous glassy material in the mesangium and glomerular capillary walls and subsequent negative staining for Congo Red excludes amyloid deposits. The inclusion of immunofluorescence data to above findings suggests immune-complex type of disease not attributable to any known etiology. However, despite a negative workup for serum and urine monoclonal proteins, a monoclonal gammopathy related glomerular disease could still be considered. Since the deposits are mainly polyclonal (IgG, kappa, lambda and C3) by IF also aids in excluding the above possibility. No significant tubulo-interstitial and vascular disease is noted. However, the application of ultrastructural examination in such a case is useful in determining the pattern, location and the nature of the deposits.

References: D'Agati V, Appel GB, Markowitz GS, Truong L, Seshan S, Kim DU, Sacchi. Fibrillary glomerulonephritis: defining the disease spectrum. In Monoclonal Gammopathies and the Kidney, P. Aucouturier et al (eds), Kluwer Academic Publishers, Great Britain, 2003, p Fogo A, Qureshi N, Horn RG: Morphologic and clinical features of fibrillary glomerulonephritis versus immunotactoid glomerulopathy. Am J Kidney Dis 22:367, 1993 Iskandar SS, Herrera GA. Glomerulopathies with organized deposits. Sem diagn pathol. 19: , 2002. Schwartz MM, Korbet SM, Lewis EJ. Immunotactoid glomerulopathy. J Am Soc Nephrol 13: , 2002 Churg J, Venkataseshan VS. Fibrillary glomerulonephritis without immunoglobulin deposits in the kidney. Kidney Int 44: , 1993. Bridoux F, Hugue V, Coldefy O et al. Fibrillary glomerulonephritis and immunotactoid (microtubular) glomerulopathy are associated with distinct immunologic features. Kidney Int 62: , 2002.

End of Case 5

14th - 16th March, 2005 Sanjay Gandhi Postgraduate

Similar presentations

Presentation on theme: "14th - 16th March, 2005 Sanjay Gandhi Postgraduate"— Presentation transcript:

Similar presentations

About project

Feedback

Log in

Auth with social network:

14th - 16th March, 2005 Sanjay Gandhi Postgraduate

Similar presentations

Presentation on theme: "14th - 16th March, 2005 Sanjay Gandhi Postgraduate"— Presentation transcript:

Similar presentations

About project

Feedback