Sanjeev Sethi

Publications (80)466.29 Total impact

• Article: AA Amyloidosis Associated With Systemic-Onset Juvenile Idiopathic Arthritis.

  Abhijeet Saha, Yogiraj Chopra, Jason D Theis, Julie A Vrana, Sanjeev Sethi
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  ABSTRACT: We report a 12-year-old boy with nephrotic syndrome due to renal AA amyloidosis. The AA amyloidosis was associated with a 3-year history of systemic-onset juvenile idiopathic arthritis. The presence of serum amyloid A protein was confirmed by laser microdissection of Congo Red-positive glomeruli and vessels followed by liquid chromatography and tandem mass spectrometry; this analysis excluded hereditary and familial amyloidosis. Aggressive management of the systemic-onset juvenile idiopathic arthritis resulted in improvement in clinical and laboratory parameters. The case represents an unusual cause of nephrotic syndrome in children. Early diagnosis of renal amyloidosis and management of systemic-onset juvenile idiopathic arthritis is paramount to preventing progression of kidney disease.
  American Journal of Kidney Diseases 05/2013; · 5.43 Impact Factor
• Article: C3 Glomerulonephritis Associated With Monoclonal Gammopathy: A Case Series.

  Ladan Zand, Andrea Kattah, Fernando C Fervenza, Richard J H Smith, Samih H Nasr, Yuzhou Zhang, Julie A Vrana, Nelson Leung, Lynn D Cornell, Sanjeev Sethi
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  ABSTRACT: BACKGROUND: C3 glomerulonephritis (GN) is a proliferative GN resulting from glomerular deposition of complement factors due to dysregulation of the alternative pathway of complement. Dysregulation of the alternative pathway of complement may occur as a result of mutations or functional inhibition of complement-regulating proteins. Functional inhibition of the complement-regulating proteins may result from a monoclonal gammopathy. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: 32 Mayo Clinic patients with C3 GN, 10 (31%) of whom had evidence of a monoclonal immunoglobulin in serum. OUTCOMES: Clinical features, hematologic and bone marrow biopsy findings, kidney biopsy findings, kidney measures, complement pathway abnormalities, treatment, and follow-up of patients with C3 GN that was associated with a monoclonal gammopathy. RESULTS: Mean age of patients with C3 GN associated with monoclonal gammopathy was 54.5 years. Bone marrow biopsy done in 9 patients revealed monoclonal gammopathy of undetermined significance in 5 patients, small lymphocytic lymphoma/chronic lymphocytic leukemia in one patient, and no abnormal clones in the other 3 patients. Kidney biopsy showed membranoproliferative GN with bright capillary wall C3 staining in all 10 patients. Evaluation of the alternative pathway of complement showed abnormalities in 7 of 9 patients tested. No mutation in complement-regulating proteins was detected in any patient. As an index case, one patient with C3 GN and chronic lymphocytic leukemia was treated with rituximab, cyclophosphamide, vincristine, and prednisone, and one patient with C3 GN and monoclonal gammopathy of undetermined significance was treated with dexamethasone and bortezomib. Both patients showed significant decreases in hematuria and proteinuria and stabilization of kidney function. LIMITATIONS: Studies to show evidence of direct activation of the alternative pathway by monoclonal immunoglobulin were not done. CONCLUSIONS: The study highlights the association of C3 GN and monoclonal gammopathy, in particular in the older population, and the importance of targeting the underlying hematologic malignancy as an approach to treating C3 GN.
  American Journal of Kidney Diseases 04/2013; · 5.43 Impact Factor
• Article: Mass spectrometry based proteomics in the diagnosis of kidney disease.

  Sanjeev Sethi, Julie A Vrana, Jason D Theis, Ahmet Dogan
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  ABSTRACT: PURPOSE OF REVIEW: Laser microdissection (LMD) and mass spectrometry (MS) is a new technique that consists of dissection of glomeruli, tryptic digestion of dissected material, analysis by MS and generation of a protein profile using different algorithms. The review focuses on the use of this methodology as an ancillary technique in a clinical laboratory for the diagnosis of kidney diseases. RECENT FINDINGS: LMD/MS is used in the diagnosis and typing of kidney diseases with organized deposits such as amyloidosis. Uncommon and familial forms of renal amyloidosis are diagnosed and typed on the basis of the presence of specific amyloidogenic proteins. LMD/MS is used to confirm and identify immunoglobulins and complement factors in immune complex mediated and complement-mediated proliferative glomerulonephritis, respectively. In particular, LMD/MS can detect monoclonal immunoglobulins in cases of equivocal immunofluorescence studies in monoclonal immunoglobulins-associated glomerulonephritis. LMD/MS can detect specific complement factors of the alternative pathway and terminal pathway in complement-mediated glomerulonephritis. SUMMARY: LMD/MS is currently used for diagnosis and typing of amyloidosis. In addition, LMD/MS is useful in determining the type of immunoglobulins and complement factors in immune complex and complement-mediated glomerulonephritis, respectively.
  Current opinion in nephrology and hypertension 03/2013; · 3.96 Impact Factor
• Article: Laser Microdissection and Proteomic Analysis of Amyloidosis, Cryoglobulinemic GN, Fibrillary GN, and Immunotactoid Glomerulopathy.

  Sanjeev Sethi, Jason D Theis, Julie A Vrana, Fernando C Fervenza, Anjali Sethi, Qi Qian, Patrick Quint, Nelson Leung, Ahmet Dogan, Samih H Nasr
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  ABSTRACT: BACKGROUND AND OBJECTIVES: Organized deposits are present in amyloidosis, fibrillary GN, and immunotactoid glomerulopathy. However, the constituents of the deposits are not known. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Laser microdissection of glomeruli followed by mass spectrometry was performed to determine the composition of the deposits. The results were compared with cryoglobulinemic GN. RESULTS: The results are divided into four major groups: amyloidogenic proteins, structural/other proteins, complement proteins, and Igs. With regards to amyloidogenic proteins, large spectra numbers of apolipoprotein E are noted in amyloidosis (41.8±20.9) compared with fibrillary (15.6±12.5) and immunotactoid (12.3±12) glomerulopathy. Apolipoprotein E was absent in cryoglobulinemic GN. Serum amyloid P component is present in large spectra numbers in amyloidosis (14.1±6.7) and small spectra numbers in immunotactoid glomerulopathy, but it is absent in fibrillary and cryoglobulinemic GN. However, large spectra numbers of Ig γ-1 chain C region are present in immunotactoid glomerulopathy (47.3±34.6) compared with fibrillary (16.25±19.7) and cryoglobulinemic (13.3±4.9) GN. All cases of Ig light chain-associated amyloidosis showed spectra for the respective Ig light-chain C region (mean=10±1.7). CONCLUSIONS: Based on the spectra numbers, the study shows that the relative amount of apolipoprotein E to Ig light-chain C region/amyloidogenic proteins or Ig γ-1 chain C region is associated with the organization of the deposits in amyloidosis, fibrillary GN, and immunotactoid glomerulopathy. However, the absence of apolipoprotein E correlates with the lack of fibrillar deposits in cryoglobulinemic GN.
  Clinical Journal of the American Society of Nephrology 02/2013; · 5.23 Impact Factor
• Article: The diagnosis and characteristics of renal heavy-chain and heavy/light-chain amyloidosis and their comparison with renal light-chain amyloidosis.

  Samih H Nasr, Samar M Said, Anthony M Valeri, Sanjeev Sethi, Mary E Fidler, Lynn D Cornell, Morie A Gertz, Angela Dispenzieri, Francis K Buadi, Julie A Vrana, Jason D Theis, Ahmet Dogan, Nelson Leung
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  ABSTRACT: Little is known about the rare entities of heavy- and light-chain amyloidosis (AHL) and heavy-chain amyloidosis (AH). Here, we report the renal and hematological characteristics, pathology, and outcome of 16 patients with renal AH/AHL (5 with AH and 11 with AHL) and compare them with 202 patients with renal light-chain amyloidosis (AL) diagnosed during the same time period. All cases were diagnosed by kidney biopsy that showed Congo red-positive deposits. Amyloid typing was done by laser microdissection and mass spectrometry (LMD/MS) on 12 patients or by immunofluorescence on four patients. All patients with renal AH/AHL were Caucasians, with a male/female ratio of 2.2 and a median age at biopsy of 63 years. Compared with patients with renal AL, those with renal AH/AHL had less frequent concurrent cardiac involvement, higher likelihood of having circulating complete monoclonal immunoglobulin, lower sensitivity of fat pad biopsy and bone marrow biopsy for detecting amyloid, higher incidence of hematuria, and better patient survival. The hematological response to chemotherapy was comparable with renal AL. In 42% of patients, AH/AHL could not have been diagnosed without LMD/MS. Thus, renal AH/AHL is an uncommon and underrecognized form of amyloidosis, and its diagnosis is greatly enhanced by the use of LMD/MS for amyloid typing. The accurate histological diagnosis of renal AH/AHL and distinction from AL may have important clinical and prognostic implications.Kidney International advance online publication, 9 January 2013; doi:10.1038/ki.2012.414.
  Kidney International 01/2013; · 6.61 Impact Factor
• Article: Membranous glomerulonephritis is a manifestation of IgG4-related disease.

  Mariam P Alexander, Christopher P Larsen, Ian W Gibson, Samih H Nasr, Sanjeev Sethi, Mary E Fidler, Yassaman Raissian, Naoki Takahashi, Suresh Chari, Thomas C Smyrk, Lynn D Cornell
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  ABSTRACT: IgG4-related disease (IgG4-RD) is a systemic immune-mediated disease that typically manifests as fibro-inflammatory masses that can affect nearly any organ system. Renal involvement by IgG4-RD usually takes the form of IgG4-related tubulointerstitial nephritis, but cases of membranous glomerulonephritis (MGN) have also been described. Here we present a series of 9 patients (mean age at diagnosis 58 years) with MGN associated with IgG4-RD. All patients showed MGN on biopsy, presented with proteinuria (mean 8.3 g/day), and most had elevated serum creatinine (mean 2.2 mg/dl). Seven patients had known extrarenal involvement by IgG4-RD, with 5 patients having concurrent IgG4-related tubulointerstitial nephritis. Immunohistochemical analysis for the phospholipase A2 receptor, a marker of primary MGN, was negative in all 8 biopsies so examined. Six of 7 patients with available follow-up (mean 39 months) were treated with immunosuppressive agents; one untreated patient developed end-stage renal disease and underwent transplantation, without recurrence at 12 years after transplant. All 6 treated patients showed decreased proteinuria (mean 1.2 g/day), and most showed decreased serum creatinine (mean 1.4 mg/dl). Thus, MGN should be included in the spectrum of IgG4-RD and should be suspected in proteinuric IgG4-RD patients. Conversely, patients with MGN and an appropriate clinical history should be evaluated for IgG4-RD.Kidney International advance online publication, 19 December 2012; doi:10.1038/ki.2012.382.
  Kidney International 12/2012; · 6.61 Impact Factor
• Article: Atypical postinfectious glomerulonephritis is associated with abnormalities in the alternative pathway of complement.

  Sanjeev Sethi, Fernando C Fervenza, Yuzhou Zhang, Ladan Zand, Nicole C Meyer, Nicolò Borsa, Samih H Nasr, Richard J H Smith
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  ABSTRACT: Postinfectious glomerulonephritis is a common disorder that develops following an infection. In the majority of cases, there is complete recovery of renal function within a few days to weeks following resolution of the infection. In a small percentage of patients, however, the glomerulonephritis takes longer to resolve, resulting in persistent hematuria and proteinuria, or even progression to end-stage kidney disease. In some cases of persistent hematuria and proteinuria, kidney biopsies show findings of a postinfectious glomerulonephritis even in the absence of any evidence of a preceding infection. The cause of such 'atypical' postinfectious glomerulonephritis, with or without evidence of preceding infection, is unknown. Here we show that most patients diagnosed with this 'atypical' postinfectious glomerulonephritis have an underlying defect in the regulation of the alternative pathway of complement. These defects include mutations in complement-regulating proteins and antibodies to the C3 convertase known as C3 nephritic factors. As a result, the activated alternative pathway is not brought under control even after resolution of the infection. Hence, the sequela is continual glomerular deposition of complement factors with resultant inflammation and development of an 'atypical' postinfectious glomerulonephritis.Kidney International advance online publication, 12 December 2012; doi:10.1038/ki.2012.384.
  Kidney International 12/2012; · 6.61 Impact Factor
• Article: Urinary Albumin Excretion Patterns of Patients with Cast Nephropathy and Other Monoclonal Gammopathy-Related Kidney Diseases.

  Nelson Leung, Morie Gertz, Robert A Kyle, Fernando C Fervenza, Maria V Irazabal, Alfonso Eirin, Shaji Kumar, Stephen S Cha, S Vincent Rajkumar, Martha Q Lacy, Steve R Zeldenrust, Francis K Buadi, Suzanne R Hayman, Samih H Nasr, Sanjeev Sethi, Marina Ramirez-Alvarado, Thomas E Witzig, Sandra M Herrmann, Angela Dispenzieri
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  ABSTRACT: BACKGROUND AND OBJECTIVES: Multiple myeloma is responsible for a wide variety of renal pathologies. Urinary protein and monoclonal spike cannot be used to diagnose cast nephropathy (CN). Because albuminuria is a hallmark of glomerular disease, this study evaluated the percentage of urinary albumin excretion (%UAE) as a tool to differentiate CN from Ig light chain amyloidosis (AL), light chain deposition disease (LCDD), and acute tubular necrosis (ATN). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Patients were selected from the Renal Biopsy Database and the Dysproteinemia Database. Participants were excluded if laboratory data were missing within 1 week of the renal biopsy. The %UAE was obtained from urine protein electrophoresis. RESULTS: From 1992 to 2011, 260 patients were biopsied (177 with AL, 28 with LCDD, 43 with CN, and 12 with ATN). The %UAE for CN patients was significantly lower (7%) than for ATN (25%), LCDD (55%), and AL (70%) patients (P<0.001). Significant differences were also found in serum creatinine, serum albumin, free light chain ratio, total urine protein, and urine monoclonal spike; only the %UAE remained independently associated with CN in a logistic regression model (P<0.001). The area under the curve for the receiver operator characteristic curve for %UAE was 0.99. At <25%, the %UAE had a sensitivity of 0.98, specificity of 0.94, positive predictive value of 0.75, and negative predictive value of 0.99. CONCLUSIONS: This study showed that %UAE was significantly less in CN than the other three renal lesions and %UAE may thus be helpful in diagnosis of CN.
  Clinical Journal of the American Society of Nephrology 09/2012; · 5.23 Impact Factor
• Article: Low- and high-molecular-weight urinary proteins as predictors of response to rituximab in patients with membranous nephropathy: a prospective study.

  Maria V Irazabal, Alfonso Eirin, John Lieske, Laurence H Beck, Sanjeev Sethi, Timothy M Borland, John J Dillon, Patrick H Nachman, Samih H Nasr, Lynn D Cornell, Nelson Leung, Daniel C Cattran, Fernando C Fervenza
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  ABSTRACT: BACKGROUND: Selective urinary biomarkers have been considered superior to total proteinuria in predicting response to treatment and outcome in patients with membranous nephropathy (MN). METHODS: We prospectively tested whether urinary (U) excretion of retinol-binding protein (RBP), α1-microglobulin (α1M), albumin, immunoglobulinIgG and IgM and/or anti-phospholipase 2 receptor (PLA(2)R) levels could predict response to rituximab (RTX) therapy better than standard measures in MN. We also correlated changes in antibodies to PLA(2)R with these urinary biomarkers. RESULTS: Twenty patients with MN and proteinuria (P) >5 g/24 h received RTX (375 mg/m(2) × 4) and at 12 months, 1 patient was in complete remission (CR), 9 were in partial remission (PR), 5 had a limited response (LR) and 4 were non-responders (NR). At 24 months, CR occurred in 4, PR in 12, LR in 1, NR in 2 and 1 patient relapsed. By simple linear regression analysis, UIgG at baseline (mg/24 h) was a significant predictor of change in proteinuria at 12 months (Δ urinary protein) (P = 0.04). In addition, fractional excretion (FE) of IgG, urinary alpha 1 microglobulin (Uα1M) (mg/24 h) and URBP (μg/24 h) were also predictors of response (P = 0.05, 0.04, and 0.03, respectively). On the other hand, UIgM, FEIgM, albumin and FE albumin did not predict response (P = 0.10, 0.27, 0.22 and 0.20, respectively). However, when results were analyzed in relation to proteinuria at 24 months, none of the U markers that predicted response at 12 m could predict response at 24 m (P = 0.55, 0.42, 0.29 and 0.20). Decline in anti-PLA(2)R levels was associated with and often preceded urinary biomarker response but positivity at baseline was not a predictor of proteinuria response. CONCLUSIONS: The results suggest that in patients with MN, quantification of low-, medium- and high-molecular-weight urinary proteins may be associated with rate of response to RTX, but do not correlate with longer term outcomes.
  Nephrology Dialysis Transplantation 09/2012; · 3.40 Impact Factor
• Article: How I treat amyloidosis: the importance of accurate diagnosis and amyloid typing.

  Nelson Leung, Samih H Nasr, Sanjeev Sethi
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  ABSTRACT: Amyloidosis is a rare group of diseases characterized by deposition of amyloid fibrils in soft tissues. More than 28 types of amyloid have been identified. They all share common ultrastructural and chemical characteristics. Treatments are available for many types but are type specific. Therefore, confirmation and typing of amyloid are essential before initiating treatment. Monoclonal protein studies should be performed on suspected cases, but the diagnosis requires a tissue biopsy. Congo red stain and electron microscopy are helpful to discriminate between amyloid and other pathologic fibrils. Once amyloid is confirmed, typing should be performed. Immunofluorescence and immunohistochemistry are frequently used and are helpful, but this approach has limitations, such as availability, specificity and sensitivity of commercial antibodies. Genetic mutational analysis is vital for ruling in and out hereditary amyloidoses but is unhelpful in nonmutated forms. The most advanced technique of amyloid typing is laser microdissection followed by mass spectrometry. Using proteomics, laser microdissection followed by mass spectrometry can directly identify proteins with or without mutations. Finally, imaging studies, such as cardiac MRI with gadolinium and (123)I-labeled SAP scintigraphy not only assist in evaluation of patients with known amyloidosis but cardiac MRI has detected amyloid in patients previously unsuspected of the disease.
  Blood 09/2012; 120(16):3206-13. · 9.90 Impact Factor
• Article: Renal Amyloidosis Associated With a Novel Sequence Variant of Gelsolin.

  Sanjeev Sethi, Jason D Theis, Patrick Quint, William Maierhofer, Paul J Kurtin, Ahmet Dogan, Edward W Highsmith
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  ABSTRACT: We present a case of a 75-year-old woman who presented with progressive kidney failure. Kidney biopsy performed to determine the cause of kidney failure showed amyloidosis of undetermined type. Laser microdissection of the Congo Red-positive glomeruli followed by mass spectrometry studies showed a large number of spectra matching apolipoprotein E, serum amyloid P component, and gelsolin, consistent with a diagnosis of gelsolin-associated renal amyloidosis. Sequencing of the gelsolin gene revealed a previously undescribed sequence variant, a guanine to adenine substitution at nucleotide 580 of the coding sequence, corresponding to a predicted glycine to arginine mutation at amino acid 194. Gelsolin amyloidosis typically involves the nerves and skin, with only rare reported involvement of the kidney. An atypical finding on electron microscopy was that of a swirling pattern of the amyloid fibrils. The novel gelsolin variant may be responsible for the unusual clinical and pathologic presentation. The report also highlights the usefulness of laser microdissection and mass spectrometry in the typing of difficult cases of amyloidosis.
  American Journal of Kidney Diseases 08/2012; · 5.43 Impact Factor
• Article: Immunotactoid glomerulopathy: clinicopathologic and proteomic study.

  Samih H Nasr, Mary E Fidler, Lynn D Cornell, Nelson Leung, Fernando G Cosio, Salwa S Sheikh, Abdulrazack A Amir, Julie A Vrana, Jason D Theis, Ahmet Dogan, Sanjeev Sethi
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  ABSTRACT: Background Immunotactoid glomerulopathy (ITG) is a rare glomerular disease. Here, we report the largest clinicopathologic series of ITG and define its proteomic profile.Methods The characteristics of 16 ITG patients who were identified from our pathology archives are provided between 1993 and 2011. We also performed laser microdissection and mass spectrometry (LMD/MS) in three cases.ResultsPresentation included proteinuria (100%), nephrotic syndrome (69%), renal insufficiency (50%) and microhematuria (80%). Hypocomplementemia was present in 46% and a serum M-spike in 63%. Hematologic malignancy was present in 38%, including chronic lymphocytic leukemia in 19%, lymphoplasmacytic lymphoma in 13% and myeloma in 13%. The pattern of glomerular injury was membranoproliferative (56%), membranous (31%) or proliferative (13%) glomerulonephritis. The microtubular deposits were immunoglobulin light chain restricted in 69% and had a mean diameter of 31 nm (range 17-52). During an average of 48 months of follow-up for 12 patients, 50% had remission, 33% had persistent renal dysfunction and 17% progressed to end-stage renal disease. Proteomic analysis by LMD/MS revealed the presence of immunoglobulins, monotypic light chains, complement factors of the classical and terminal pathway and small amount of serum amyloid P-component.Conclusions Hematologic malignancy, particularly lymphoma, is not uncommon in ITG. ITG appears to have a better prognosis than other paraprotein-related renal lesions, with a half of patients expected to recover kidney function with immunosuppressive therapy or chemotherapy. The proteomic profile of ITG is consistent with deposition of monotypic immunoglobulins and activation of the classical and terminal pathway of complement.
  Nephrology Dialysis Transplantation 08/2012; · 3.40 Impact Factor
• Article: Idiopathic membranoproliferative glomerulonephritis: does it exist?

  Fernando C Fervenza, Sanjeev Sethi, Richard J Glassock
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  ABSTRACT: When membranoproliferative glomerulonephritis (MPGN) was first delineated as a discrete clinico-pathological entity more than a half-century ago, most cases were regarded as idiopathic (or primary) in nature. Advances in analysis of pathogenetic mechanisms and etiologies underlying the lesion of MPGN have radically altered the prevalence of the truly idiopathic form of MPGN. In addition, MPGN as a category among renal biopsies showing glomerulonephritis has diminished over time. In the modern era, MPGN is mainly classified morphologically on the basis of immunoglobulin (Ig; monoclonal or polyclonal) and complement (C3 only or combined with Ig) deposition and secondarily on the basis of its appearance on ultra-structural examination. Idiopathic MPGN is a diagnosis of exclusion, at least in many adults and a portion of children, and a systematic approach to evaluation will often uncover a secondary cause, such as an infection, autoimmune disease, monoclonal gammopathy, neoplasia, complement dysregulation or a chronic thrombotic microangiopathy. Idiopathic MPGN remains an 'endangered species' after its separation from these known causes.
  Nephrology Dialysis Transplantation 07/2012; · 3.40 Impact Factor
• Article: C3 glomerulonephritis: clinicopathological findings, complement abnormalities, glomerular proteomic profile, treatment, and follow-up.

  Sanjeev Sethi, Fernando C Fervenza, Yuzhou Zhang, Ladan Zand, Julie A Vrana, Samih H Nasr, Jason D Theis, Ahmet Dogan, Richard J H Smith
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  ABSTRACT: C3 glomerulonephritis (C3GN) is a recently described disorder that typically results from abnormalities in the alternative pathway (AP) of complement. Here, we describe the clinical features, kidney biopsy findings, AP abnormalities, glomerular proteomic profile, and follow-up in 12 cases of C3GN. This disorder equally affected all ages, both genders, and typically presented with hematuria and proteinuria. In both the short and long term, renal function remained stable in the majority of patients with native kidney disease. In two patients, C3GN recurred within 1 year of transplantation and resulted in a decline in allograft function. Kidney biopsy mainly showed a membranoproliferative pattern, although both mesangial proliferative and diffuse endocapillary proliferative glomerulonephritis were noted. AP abnormalities were heterogeneous, both acquired and genetic. The most common acquired abnormality was the presence of C3 nephritic factors, while the most common genetic finding was the presence of H402 and V62 alleles of Factor H. In addition to these risk factors, other abnormalities included Factor H autoantibodies and mutations in CFH, CFI, and CFHR genes. Laser dissection and mass spectrometry of glomeruli from patients with C3GN showed accumulation of AP and terminal complement complex proteins. Thus, C3GN results from diverse abnormalities of the alternative complement pathway leading to subsequent glomerular injury.
  Kidney International 06/2012; 82(4):465-73. · 6.61 Impact Factor
• Article: Secondary focal and segmental glomerulosclerosis associated with single-nucleotide polymorphisms in the genes encoding complement factor H and C3.

  Sanjeev Sethi, Fernando C Fervenza, Yuzhou Zhang, Richard J H Smith
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  ABSTRACT: Genetic causes of focal and segmental glomerulosclerosis (FSGS) typically involve mutations and allele variants of genes expressed in podocytes or, more rarely, glomerular basement membranes. In this report, we describe a 60-year-old woman with chronic kidney disease whose kidney biopsy showed FSGS. Immunoglobulins and C3 were undetectable in immunofluorescence studies. Electron microscopy showed subendothelial fluffy granular material with occasional double-contour formation suggestive of capillary wall injury and prompting work-up for a prothrombotic state. Evaluation of the alternative pathway of complement showed a novel polymorphism in short consensus repeat (SCR) 12 of complement factor H (CFH; c.2195C>T, p.Thr732Met) and a previously reported but largely uncharacterized polymorphism in complement factor C3 (c.463A>C, p.Lys155Gln). Dysregulation of the alternative pathway is associated with atypical hemolytic syndrome and dense deposit disease, but heretofore has not been associated with FSGS. This case highlights the expanding spectrum of complement-mediated glomerular disease and shows that FSGS with features of capillary wall injury should prompt evaluation for abnormalities in the alternative pathway. This case also expands the list of genetic polymorphisms that can be associated with an FSGS phenotype.
  American Journal of Kidney Diseases 05/2012; 60(2):316-21. · 5.43 Impact Factor
• Article: Association of a novel complement factor H mutation with severe crescentic and necrotizing glomerulonephritis.

  Fernando C Fervenza, Richard J H Smith, Sanjeev Sethi
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  ABSTRACT: Severe crescentic and necrotizing glomerulonephritis typically is associated with anti-glomerular basement membrane or antineutrophil cytoplasmic antibodies. In this report, we describe a 23-year-old man with severe crescentic and necrotizing glomerulonephritis. Both anti-glomerular basement membrane and antineutrophil cytoplasmic antibody titers were negative. Kidney biopsy showed bright C3 staining in the mesangium and along capillary walls and no staining for immunoglobulins. Electron microscopy showed waxy deposits (many mesangial; few intramembranous or subendothelial), prompting evaluation of the alternative pathway of complement. Alternative pathway evaluation showed a novel mutation in short consensus repeat (SCR) 19 of complement factor H. In addition, the patient carried complement factor H and C3 risk alleles. Prompt treatment with intravenous steroids followed by oral steroids resulted in symptom alleviation and improved kidney function. This case shows what is to our knowledge a unique and previously unpublished cause of severe crescentic and necrotizing glomerulonephritis. Furthermore, the case demonstrates an expanding spectrum of complement-mediated glomerulonephritis and shows that crescentic and necrotizing glomerulonephritis with solely complement deposits should be evaluated for abnormalities in the alternative pathway of complement.
  American Journal of Kidney Diseases 04/2012; 60(1):126-32. · 5.43 Impact Factor
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  Article: Laser microdissection and mass spectrometry-based proteomics aids the diagnosis and typing of renal amyloidosis.

  Sanjeev Sethi, Julie A Vrana, Jason D Theis, Nelson Leung, Anjali Sethi, Samih H Nasr, Fernando C Fervenza, Lynn D Cornell, Mary E Fidler, Ahmet Dogan
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  ABSTRACT: Accurate diagnosis and typing of renal amyloidosis is critical for prognosis, genetic counseling, and treatment. Laser microdissection and mass spectrometry are emerging techniques for the analysis and diagnosis of many renal diseases. Here we present the results of laser microdissection and mass spectrometry performed on 127 cases of renal amyloidosis during 2008-2010. We found the following proteins in the amyloid deposits: immunoglobulin light and heavy chains, secondary reactive serum amyloid A protein, leukocyte cell-derived chemotaxin-2, fibrinogen-α chain, transthyretin, apolipoprotein A-I and A-IV, gelsolin, and β-2 microglobulin. Thus, laser microdissection of affected areas within the kidney followed by mass spectrometry provides a direct test of the composition of the deposit and forms a useful ancillary technique for the accurate diagnosis and typing of renal amyloidosis in a single procedure.
  Kidney International 04/2012; 82(2):226-34. · 6.61 Impact Factor
• Article: Membranoproliferative glomerulonephritis--a new look at an old entity.

  Sanjeev Sethi, Fernando C Fervenza
  New England Journal of Medicine 03/2012; 366(12):1119-31. · 53.30 Impact Factor
• Article: Clinicopathologic correlations in multiple myeloma: a case series of 190 patients with kidney biopsies.

  Samih H Nasr, Anthony M Valeri, Sanjeev Sethi, Mary E Fidler, Lynn D Cornell, Morie A Gertz, Martha Lacy, Angela Dispenzieri, S Vincent Rajkumar, Robert A Kyle, Nelson Leung
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  ABSTRACT: Renal involvement is common in multiple myeloma. In this study, we examined kidney biopsy findings in patients with multiple myeloma and correlated them with their clinical renal and hematologic characteristics. Case series. 190 Mayo Clinic patients with multiple myeloma who underwent kidney biopsy between 1997-2011 were identified from our kidney biopsy database. Patients had an established diagnosis of multiple myeloma or multiple myeloma was diagnosed shortly after the results of kidney biopsy, which prompted bone marrow biopsy. Myeloma cast nephropathy (MCN), AL amyloidosis, and monoclonal immunoglobulin deposition disease (MIDD). Renal morphologic changes, clinical renal and hematologic characteristics at kidney biopsy, renal and patient outcomes. Paraprotein-associated lesions were seen in 73% of patients; non-paraprotein-associated lesions, in 25%; and no pathology, in 2%. The most common paraprotein-associated lesions were MCN (33%), MIDD (22%), and amyloidosis (21%). The most common non-paraprotein-associated lesions were acute tubular necrosis (9%), hypertensive arteriosclerosis (6%), and diabetic nephropathy (5%). Patients with MIDD were younger than those with MCN or amyloidosis. Urine paraprotein size and bone marrow plasma cell percentage were higher in MCN than amyloidosis or MIDD. Nephrotic syndrome was more common in amyloidosis than MIDD. Percentage of albuminuria was highest in amyloidosis and lowest in MCN. Median kidney survival from kidney biopsy was 20, 30, and 51 months for MCN, amyloidosis, and MIDD, respectively (P = 0.2). Median patient survival from multiple myeloma diagnosis was 44, 58, and 62 months for MCN, amyloidosis, and MIDD, respectively (P = 0.4). Retrospective nature. The spectrum of renal lesions in multiple myeloma is more heterogeneous than previously reported. Clinical features favoring amyloidosis over MIDD include older age, absence of kidney failure, presence of nephrotic syndrome, absence of hematuria, and >50% albuminuria.
  American Journal of Kidney Diseases 03/2012; 59(6):786-94. · 5.43 Impact Factor
• Article: Adenovirus-induced interstitial nephritis following umbilical cord blood transplant for chronic lymphocytic leukemia.

  Mira Keddis, Nelson Leung, Sandra Herrmann, Ziad El-Zoghby, Sanjeev Sethi
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  ABSTRACT: We present a case of a 27-year-old man who received an unrelated donor umbilical cord blood transplant for chronic lymphocytic leukemia. His postsurgery course was complicated by acute kidney injury, hemorrhagic cystitis, and pancytopenia. Transjugular kidney biopsy showed interstitial nephritis. Viral inclusions were present in tubular epithelial cells, and in situ hybridization studies confirmed the presence of adenovirus. Kidney function improved after a short course of cidofovir. Adenovirus-induced interstitial nephritis should be considered in the differential diagnosis in all cases of interstitial nephritis occurring in immunocompromised patients.
  American Journal of Kidney Diseases 03/2012; 59(6):886-90. · 5.43 Impact Factor