Chapter 6: Glomerular Diseases And Cancer
Chapter 6: Glomerular Diseases and CancerDivya Monga* and Kenar D. Jhaveri†*Nephrology Division, University of Mississippi Medical Center, Jackson, Mississippi; and †Nephrology Division,Northwell Health, Hofstra Northwell School of Medicine, Great Neck, New YorkINTRODUCTIONGlomerular diseases are associated with many solidand hematologic malignancies. Additionally, many chemotherapeutic agents and post–stem cell transplant–associated glomerular lesions have been described.These glomerular lesions are most likely due toabnormal products produced by tumor cells, although the exact pathogenesis is unclear. The treatment of these cancer-associated glomerulopathiesis primarily targeted at treating the underlyingmalignancy. This chapter will review glomerulardiseases associated with cancer, chemotherapy,and hematopoietic stem cell transplantation(HSCT).SOLID TUMOR–ASSOCIATEDGLOMERULAR DISEASESMembranous nephropathyMembranous nephropathy (MN) is the most common glomerular pathology (Figure 1, A and B)described in patients with solid tumors (1,2).In a review of 240 patients with biopsy provenMN, Lefaucheur et al. (3) reported a prevalenceof malignancy of 10%. Only about half of thesepatients had symptoms related to cancer at thetime of their kidney biopsy. Also, most of thesepatients were diagnosed with malignancy withina year of MN diagnoses. Review of case seriesshows a reported prevalence of as low as 1% to ashigh as 22% (2).Classically, the solid tumors most commonlyassociated with MN are lung, bronchus, and gastriccancers, followed by renal cell, prostate, andthymoma (2). Other cancers reported with MNare colorectal, pancreatic, esophageal, and hepaticcarcinomas.Differentiating primary MN from secondaryMN associated with malignancy can be difficult.Our suspicion for a secondary glomerular diseaseAmerican Society of Nephrologyshould be high in a patient with known cancer whohas presence of proteinuria or nephrotic syndrome.Also development of proteinuria within a year ofdiagnosis of cancer should raise the suspicion ofsecondary form of glomerulopathy. Studies havereported risk factors like age .65 years and historyof smoking for .20 pack-years for paraneoplasticMN (3). Review of relevant studies (3–7) has suggested certain parameters, which can help differentiate primary from secondary MN, the latter beingassociated with cancer. These features are summarized in Table 1 (8).In addition to these findings, one should have ahigh index of suspicion for malignancy when apatient with MN is evaluated. It is reasonable toperform routine age- and sex-appropriate screening for malignancy, once other known causes ofsecondary MN have been excluded. In patients withhigh risk of lung cancer, low-dose chest computedtomography should be considered. The risk ofcancer persists for 5 years from the time of kidney biopsy (9). This is most likely due to slowgrowing malignancy, use of cytotoxic therapy forMN, or increased surveillance. Therefore, closemedical follow-up is needed even if the cancer isnot detected on initial screening at the time ofMN diagnosis.The possible mechanisms by which solid tumorsmay be associated with MN include the following(10):1) In situ immune complex formation: Antibodiesare formed against a tumor antigen, which islocalized in the sub epithelial location or to apodocyte antigen that is identical or similar tothe tumor antigen.Correspondence: Divya Monga, Division of Nephrology, University of Mississippi Medical Center, 2500 N. State St., Jackson,Mississippi 39216.Copyright 2016 by the American Society of NephrologyOnco-Nephrology Curriculum1
Figure 1. Membranous nephropathy. (A) Light microscopy showing immune complex deposits. Note the thickened basementmembrane, which stains black while deposits within it stain pink, giving a variegated appearance to the capillary wall. Silver [periodicacid silver methamine (PASM)] stain; 603, original magnification. (B) Electron microscopy showing immune complex deposits in asubepithelial location, between effaced podocyte foot processes (top) and the basement membrane (bottom).2) Tumor antigens may form circulating immune complexes that are subsequently trapped in glomerularcapillaries.3) External factors such as infections with oncogenic viruses oraltered immune function that can cause both the malignancy and MN.Other glomerular diseasesMinimal change disease (MCD) has been reported in association with solid tumors like lung, colorectal, renal cell cancers,and thymoma. Rarely, pancreatic, bladder, breast, and ovariancancers have also been associated (2). Focal segmental glomerular sclerosis (FSGS) has been observed with renal cell carcinoma, thymoma, and rarely with lung, breast, and esophagealcancers (2). A membranoproliferative glomerular nephritis(MPGN) pattern of injury has been described with lung, kidney, and stomach cancer (2).Mustonen et al. (11) reported the first known associationbetween IgA nephropathy and solid tumors of the respiratorytract, buccal mucosa, and nasopharynx. Renal cell carcinomais the most frequently reported solid malignancy associatedwith IgA nephropathy (12). Treatment of underlying cancerimproved the IgA nephropathy (11).Rarely, both solid and hematologic malignancies have beenassociated with adult Henoch-Schönlein purpura (HSP)(13,14). Endocapillary glomerulonephritis is the most commonly seen lesion on kidney biopsy in adults with HSP (15).Older age and male sex were identified risk factors for cancerassociated HSP (14).Crescentic glomerulonephritis (CGN) has been associatedwith renal cell, gastric, and lung cancers (2).Thrombotic microangiopathy (TMA) has been associatedwith mucin-producing gastric, lung, and breast cancers (16).In these patients, ADAMTS13 activity is not impaired, andthey respond poorly to plasmapharesis (17).The exact mechanism of these solid tumor malignancyassociations with glomerular disease is poorly understood.There have been animal studies (18) done to help us understand the pathomechanisms involved.This animal study suggested that T-cell response might becritical in the development of paraneoplastic glomerulardisease. Th1 (T-helper type 1)-predominant responses havebeen associated with proliferative and crescentic forms of GNand Th2 (T-helper type 2) type responses with a membranouspattern of injury (19). Cancer-associated MCD might be relatedto vascular endothelial growth factor (VEGF) production(20). Overexpression of VEGF leads to a collapsing variantof FSGS, and underexpression is associated with a TMA patternof injury (21,22).Thymoma-associated glomerular diseaseMCD is the most common glomerular disease associatedwith thymoma (23). The prevalence of thymoma associatedglomerulopathy is ;2% (23). Other glomerular lesionsTable 1. Differences between primary and tumor-associated secondary MNCompared featureHistorySerologic markersHistopathologic clues on kidneybiopsyPrimary MNYounger age, no history of smokingPresence of circulating anti-PLA2R autoantibodiesin serumPredominance of glomerular IgG4 depositionEnhanced glomerular PLA2R stainingPresence of less than eight inflammatory cellsper glomeruliSolid tumor–associated MNAge .65 years, smoking .20 pack-yearsAbsence of anti-PLA2R autoantibodiesPredominance of glomerular IgG1/IgG2 depositionNormal glomerular PLA2R stainingPresence of greater than eight inflammatory cellsper glomeruliIgG, immunoglobulin G; MN, membranous nephropathy; PLA2 R phospholipase A2. Reprinted with permission from reference 73.2Onco-Nephrology CurriculumAmerican Society of Nephrology
Table 2. Glomerular diseases associated with solid tumorsand hematologic malignancies (23)MalignancyLung canceraColon cancerStomach cancerPancreas cancerBladder cancerRenal cell cancerProstate cancerBreast cancerEsophageal cancerGastrointestinal stromaltumorGastric cancerSpleen sarcomaHead and neck cancerWilms’ tumorTeratomaOvarian cancerCervical cancerEndometrial cancerTongue cancerMesotheliomaMelanomaSkin cancers (basal andsquamous cell)PheochromocytomaThymomaHodgkin diseaseNon-Hodgkin’s diseaseCLLAMLCMLMGUST-cell leukemiaHEMATOLOGIC MALIGNANCIES–ASSOCIATEDGLOMERULAR DISEASESGlomerular diseases reportedMN, MCD, MPGN, IgAN, FSGS, CGN,TMAMN, MCD, CGNMNMN, MCD, IgANMCDAAA, CGN, IgAN, MCD, FSGS, MPGNMN, CGNMN, FSGS, MPGN, TMAMPGN, FSGSAAAMPGN, CGN, TMAAAAMN, IgANMN, MPGNMNMN, MCDMNMNIgANMCDMN, MPGNMNMNMCD, FSGS, CGN, MPGNMCD, MN, MPGN, IgAN, FSGS, CGN,AAA, Anti-GBMMN, MCD, MPGN, IgAN, FSGSMN, MCD, MPGN, FSGS, CGNMN, FSGSMN, MCD, MPGNMPGNFSGSaIncludes small-cell, non–small-cell, squamous cell, and bronchogenic cancers.AAA, AA amyloidosis; AML, acute myelogenous leukemia; CGN, Crescenticglomerulonephritis; CLL, chronic lymphocytic leukemia; CML, chronic myelogenous leukemia; FSGS, focal segmental global sclerosis; GBM, glomerular basement membrane; IgAN, IgA nephropathy; MCD, minimal changedisease; MGUS, monoclonal gammopathy of unclear significance; MN,membranous nephropathy; MPGN, membranoproliferative glomerular nephritis; TMA, thrombotic microangiopathy. Reprinted with permission fromreference 23.described are MN, FSGS, CGN, and lupus-like nephritis(24). MN is associated with thymoma of epithelial origin.MCD is associated with thymoma with lymphocyte predominance. The pathogenesis of thymoma-associated MN seemsto be similar to solid tumor–associated MN, and thymomaassociated MN is likely related to T-cell dysfunction (24).Studies (25–27) have suggested a major role of T cells, especially the Th2 subtype, in thymoma-associated nephroticsyndromes.Table 2 summarizes the various solid tumors seen withsolid tumors.American Society of NephrologyMinimal change diseaseMCD is classically associated with Hodgkin lymphoma (HL),more so in the mixed cellularity and nodular sclerosing types.MCD usually presents around the time of diagnosis of themalignancy (28). One case series does report diagnosis ofMCD preceding the diagnosis of lymphoma by several months(29). A poor response to the treatment of MCD with corticosteroids should raise suspicion of underlying lymphoma. Inthe case series by Audard et al., (29), the simultaneous diagnosis of HL and MCD was associated with the remission ofproteinuria in response to chemotherapy.Th2-related cytokines such as interleukin (IL)-13 have beenreported to cause inflammatory response in Hodgkin disease(30), and rat studies have shown that overexpression of IL-13induces proteinuria, hypoalbuminemia, and hypercholesterolemia (31). These kidney biopsies showed fusion of footprocesses, suggesting MCD like pathology.Membranoproliferative glomerulonephritisDa’as et al. (32) reviewed 42 cases of glomerular disease withchronic lymphocytic leukemia (CLL); of these, 36 had nephrotic syndrome. The most common glomerular lesion wasMPGN, followed by MN. Another case series of 13 patientswith glomerular disease and either CLL or well-differentiatedlymphocytic lymphoma (33) showed that the majority had anMPGN pattern of injury. Most MPGN patients had an associated cryoglobulinemia.An MPGN pattern on kidney biopsy (Figure 2) may also be a clueto a developing of undiagnosed lymphoplasmacytic malignancy(8). Sethi et al. (34) reported an association between MPGN andmonoclonal gammopathy of uncertain significance. They showedthat patients with monoclonal gammopathy with normal bonemarrow biopsies had granular immune deposits on their kidneybiopsy, which correlated with their serum and urine monoclonalproteins. This study (34) also demonstrated that monoclonalgammopathy can be seen in the setting of other lymphoplasmacyticdiseases, including low-grade B-cell lymphoma, CLL, and multiplemyeloma. Although this direct relationship is not proven, the current observation suggests this possibility (34). More of this is discussed in the paraproteinemia chapter of the curriculum.Glomerular diseases associated with myeloproliferativedisordersMyeloproliferative disorders include chronic myelogenousleukemia (CML), polycythemia Vera (PCV), and essentialthrombocythemia. A recent study (35) of 11 patients withmyeloproliferative disorders with proteinuria and renal failureshowed mesangial sclerosis with hypercellularity in all patients, segmental sclerosis in eight patients, features of TMAin eight patients, and intracapillary hematopoietic cells in fourpatients. Glomerular disorders associated with myeloproliferative disorders are usually late complications and tend toOnco-Nephrology Curriculum3
Figure 2. Membranoproliferative glomerulonephritis. Lightmicroscopy showing basement membrane duplication and increased cells in capillary lumens. Silver (PASM) stain; 603, originalmagnification.have a poor renal prognosis, with progressive kidney injuryoccurring in most patients (35).Essential thrombocythemia and PCV have been associated with FSGS and mesangial proliferative glomerulardisease. The prevalence of glomerular disease in PCV andessential thrombocythemia is approximately 3%–4% (36).CML is least likely to have an association with glomerularpathology (36).FSGS has also been reported with Hodgkin’s lymphoma(28) with good response to chemotherapy.Other glomerular diseases associated withlymphoproliferative disordersMN has also been reported with CLL, but less commonlycompared with MPGN (32). A case of IgA nephropathy hasbeen described with cutaneous T-cell lymphoma (37).Fibrillary glomerulonephritis (FGN) and Immunotactoidglomerulopathy (ITG) are rare groups of disorders characterized by formation of organized glomerular deposits (Figure 3,A and B). These diseases can either occur as primary conditionor be secondary to systemic diseases, mainly lymphoproliferativedisorders. ITG is more strongly associated with neoplasms,typically paraproteinemias and CLL, compared with FGN(38). ITG on kidney biopsy should warrant an investigationof an underlying hematologic malignancy. Treatment is directed toward underlying malignancy.Glomerular diseases have also been associated with hemophagocytic syndrome. This syndrome is most commonly associated with Epstein-Barr virus; however, it has also beendescribed with T-cell lymphoma (39,40). Thaunat et al. (40)described 11 patients with hemophagocytic syndrome whodeveloped nephrotic syndrome. Renal biopsy showed glomerular lesions consisting of MCD, FSGS, and TMA. In the absence of a causative viral infection, hemophagocytic syndromeis often treated with immunosuppressive therapy with uncertain renal outcomes.HEMATOPOIETIC STEM CELL TRANSPLANT–RELATED GLOMERULAR DISEASESIn HSCT patients, the kidney biopsy findings in patientswith nephrotic range proteinuria include MN, MCD, andFSGS (41). Although we discuss briefly here, an entirechapter is devoted to HSCT-related kidney disease in theCurriculum.Chronic graft-versus-host diseaseMN accounts for a majority of cases of HSCT-associatedglomerular disease, followed by MCD (41). When MCD occursin such patients, it is prudent to rule out recurrence of theprimary hematologic malignancy.Figure 3. Fibrillary and immunotactoid glomerulonephritis. (A) Electron microscopy view of fibrillary glomerulonephritis. (B) Electronmicroscopy view of immunotactoid glomerulonephritis.4Onco-Nephrology CurriculumAmerican Society of Nephrology
A review of literature by Brukamp et al. (41) showed a closetemporal relationship between development of nephrotic syndrome shortly after cessation of immunosuppression and thediagnosis of chronic graft-versus-host disease (GVHD). Luoet al. (42) investigated the etiology and pathogenesis of nephrotic syndrome after allogenic HSCT. Nephrotic syndromeafter allogenic SCT was associated with the occurrence ofchronic GVHD.Autologous HSCT can also develop glomerular diseases(43), although in these patients, GVHD does not occur. It ispossible that there is an immune dysregulation that might becausing nephrotic syndrome secondary to induction agents orthat these glomerular diseases are de novo. T cell–depletedHSCT recipients are highly unlikely to develop glomerulardiseases. However, our knowledge about glomerular diseasesin HSCT patients is incomplete, and more research is neededfor complete understanding.Thrombotic microangiopathy after HSCTTMA after HSCT is also known as bone marrow transplantnephropathy or, in some specific cases, radiation nephropathy.A diagnosis criteria for HSCT-related TMA included .4%schistocytes in blood, de novo prolonged or progressivethrombocytopenia, sudden persistent increase in lactate dehydrogenase, and a decrease in serum haptoglobin (44). Studies have suggested that acute GVHD grade 2–4, hepaticGVHD, veno-occlusive disease, adenovirus infection, olderage, being female, and total body irradiation of .12 Gy arerisk factors for the development of TMA (45,46). TMA can alsooccur in T cell–depleted group of patients where calcineurininhibitors (CNIs) and GVHD do not exist (47). Treatmentof HSCT-related TMA is usually supportive, with control ofhypertension and proteinuria. Plasma exchange has not provento be effective.CHEMOTHERAPY-ASSOCIATED GLOMERULARDISEASEThrombotic microangiopathyMitomycin C, an alkylating agent, used to treat breast, gastric,and pancreatic cancer, can cause TMA-like syndrome. Itsnephrotoxicity is dose dependent and usually appears after acumulative dose of .40–60 mg/m2 given over a period ofseveral months (48).Gemcitabine, commonly used for pancreas, urothelial, andovarian cancers, has been shown to cause TMA (49). Cessationof these medications is shown to improve TMA. Carfilzomibis a second-generation proteasome inhibitor used for thetreatment of relapsed or refractory multiple myeloma. Therehas been recent case reports (50,51) that reported TMA associated with the use of this agent. One of them (51) had kidneybiopsy evidence of TMA (Figure 4). Treatment options includecessation of the drug with uncertain importance of therapeuticplasma exchange. Kidney biopsy–proven renal TMA has beenAmerican Society of NephrologyFigure 4. Thrombotic microangiopathy. Light microscopy viewshowing red cell thrombi in the afferent arteriole and two glomerular capillaries. Some basement membrane duplication, butwithout increased intracapillary cells, is also visible. Silver (PASM)stain; 603, original magnification.reported by Kwa et al. (52) in patients receiving years ofpegylated liposomal doxorubicin for recurrent ovarian cancer.Bisphosphonate-induced glomerular injuryPamidronate is used to treat malignancy associated bonedisorders in myeloma. Markowitz et al. (53) showed thatpamidronate causes biopsy-proven collapsing FSGS. MCDhas also been reported with this agent (54).Interferon-induced glomerular injuryInterferons (IFN)-a, -b, and -g have been associated with moderate proteinuria (55). Markowitz et al. (56) reported 11 cases ofcollapsing FSGS that developed during treatment with IFN. IFNa developed significant proteinuria and renal failure after a shortduration of treatment. Patients treated with IFN-b developedproteinuria after a prolonged course of treatment. The authors(56) also reviewed 21 additional cases of IFN-associated glomerular disease. Thirteen of these patients had FSGS, and the rest hadMCD. The mechanism of this injury is not fully understood.There is a direct effect of IFN on the podocyte by altering thecellular proliferation and cell metabolism (56). The indirect effectsof IFN might be due to adaptive immune mechanism that increasemacrophage activation or via 1L-6 or 1L-13 production (56).IFN-a, when used for treatment of CML, has been reportedto be associated with TMA (57,58).Calcineurin and mammalian target of rapamycininhibitorsCNIs can cause a rare manifestation of TMA with glomerularchanges. The histology is indistinguishable from other causesof TMA (59). The only consensus on treatment is to withdrawthe CNIs (60).Mammalian target of rapamycin (mTOR) inhibitors suchas sirolimus, tensirolimus, and everolimus can developOnco-Nephrology Curriculum5
Table 3. Glomerular toxicity associated with chemotherapeutic agentsType of cells involvedGlomerular epithelial cells (podocytes)Minimal change diseaseFocal segmental glomerular sclerosisOther glomerular diseasesGlomerular endothelial cellsThrombotic microangiopathyChemotherapy agentsInterferon-a and -b, pamidronate, tyrosine kinase inhibitors,anthracyclines, mTOR inhibitorsInterferon-a and -g, pamidronate, tyrosine kinase inhibitors, clofarabine,anthracyclines, mTOR inhibitorsIpilimumab, mTOR inhibitorsMitomycin-c, gemcitabine, cisplatin, carboplatin, cytarabine, lomustine,tamoxifen, bleomycin, bortezomib, carfilzomib, anthracyclines, hydroxyureacomplications including TMA and FSGS in renal transplantpatients (61–63). MCD, MN, FSGS, MPGN, and IgA nephropathy have also been associated with sirolimus in thekidney transplant literature (64–66). There is speculation thatsirolimus-induced proteinuria is related to collapsing FSGS associated with VEGF overexpression in podocytes.Antiangiogenesis agentsAntiangiogenic agents are used primarily for advanced stage solidtumors, including renal cell carcinoma, non–small cell lung carcinoma, colorectal carcinoma, and gastrointestinal stromal tumors. Monoclonal antibodies against VEGF and tyrosine kinaseinhibitors (TKIs) (67,68) have been observed to cause hypertension, proteinuria, and renal vascular injury, manifested by proteinuria and TMA (69). VEGF maintains normal functioning ofglomerular endothelial cells, podocytes, mesangium, andperitubular capillaries. Hence, inhibition of VEGF can lead todose-dependent proteinuria, swelling and detachment of glomerular endothelial cells, vacuolization of endothelial cells,disruption of slit diaphragms, and down-regulation of nephrin(70). Examples of anti-VEGF therapy include bevacizumab,and TKIs include sunitinib and sorafenib. In the majority ofcases, proteinuria and hypertension resolve or significantly improve with cessation of this therapy (69). VEGF inhibitors aremore likely to present as TMA or renal-limited TMA and TKIsas MCD or MCD/FSGS on kidney biopsy (71).New chemotherapeutic agent–associated glomerulardiseaseSeveral new chemotherapies are now available in clinical practice. Renal toxicity of these novel agents has been increasinglyreported in the last decade. Clofaribine is a purine nucleosideanalog used to treat relapsed or refractory pediatric acute lymphoblastic leukemia and adult acute myelogenous leukemia.Nephrotoxicity most commonly manifests as elevation in serumcreatinine. Kintzel et al. (72) reported AKI following exposure ofclofaribine along with nephrotic range proteinuria. Unfortunatelya kidney biopsy was not available. Extrapolating from animalstudies, Jhaveri et al. (73) postulated that inhibition of ribonucleotide reductase by clofarabine might be the cause of collapsingglomerulopathy and/or kidney injury seen with this agent.Ipilimumab is a monoclonal antibody against humancytotoxic T-lymphocyte antigen 4. It is US Food and Drug6Onco-Nephrology CurriculumAdministration (FDA) approved for unresectable or metastaticmelanoma. Renal biopsy in a patient with ipilimumabassociated AKI with nephrotic range proteinuria revealedlupus nephritis with positive anti–double-stranded DNA antibodies (74). There are also case reports of acute granulomatous interstitial nephritis by this agent (75).Anthracyclines like daunorubicin and doxorubicin have beenknown to cause nephrotic syndrome with renal lesions consistent with MCD, FSGS not otherwise specified (NOS), or collapsing glomerulopathy (76).Table 3 summarizes the glomerular toxicities associatedwith chemotherapy agents.Ongoing education and heightened physician awarenessregarding these negative associations is central to earlyrecognition and their successful management.CONCLUSIONSeveral cancers are associated with various glomerular diseases.Membranous nephropathy remains the most common glomerular pathology reported in patients with solid tumors.Although MCD disease has been classically associated with HL,MPGN has been recognized in patients with CLL. Severalreports and studies in the literature suggest that treating thecancer leads to resolution of the glomerular disease.TAKE HOME POINTSc Many solid and hematologic malignancies are associated with differentglomerular diseases.c Several case reports and case series of cancer-associated glomerulardiseases have shown that treating the cancer may lead to resolution ofthe glomerular process.cAlthough membranous nephropathy has been classically associated withsolid malignancies, minimal change disease has been commonly describedwith hematologic malignancies, especially Hodgkin lymphoma.c Membranoproliferative glomerulonephritis is increasingly beingrecognized to be associated with chronic hematologic malignanciessuch as chronic lymphocytic leukemia.c Chemotherapy agents can also lead to glomerular diseases, the mostcommon being TMA associated with targeted therapies.American Society of Nephrology
ACKNOWLEDGMENTSPathology images are courtesy of James Pullman, Albert EinsteinMedical Center, NY.19.20.REFERENCES1. Ronco PM. Paraneoplastic glomerulopathies: New insights into an oldentity. Kidney Int 56: 355–377, 19992. Bacchetta J, Juillard L, Cochat P, Droz JP. Paraneoplastic glomerulardiseases and malignancies. Crit Rev Oncol Hematol 70: 39–58, 20093. Lefaucheur C, Stengel B, Nochy D, Martel P, Hill GS, Jacquot C, RossertJ, Group G-PS. Membranous nephropathy and cancer: Epidemiologicevidence and determinants of high-risk cancer association. Kidney Int70: 1510–1517, 20064. Beck LH, Jr., Bonegio RG, Lambeau G, Beck DM, Powell DW, CumminsTD, Klein JB, Salant DJ. M-type phospholipase A2 receptor as targetantigen in idiopathic membranous nephropathy. New Engl J Med 361:11–21, 20095. Qin W, Beck LH, Jr., Zeng C, Chen Z, Li S, Zuo K, Salant DJ, Liu Z. Antiphospholipase A2 receptor antibody in membranous nephropathy. JAm Soc Nephrol 22: 1137–1143, 20116. Hoxha E, Kneissler U, Stege G, Zahner G, Thiele I, Panzer U, Harendza S,Helmchen UM, Stahl RA. Enhanced expression of the M-type phospholipase A2 receptor in glomeruli correlates with serum receptor antibodies in primary membranous nephropathy. Kidney Int 82: 797–804, 20127. Ohtani H, Wakui H, Komatsuda A, Okuyama S, Masai R, Maki N, KigawaA, Sawada K, Imai H. Distribution of glomerular IgG subclass deposits inmalignancy-associated membranous nephropathy. Nephrol DialysisTransplant 19: 574–579, 20048. Jhaveri KD, Shah HH, Patel C, Kadiyala A, Stokes MB, Radhakrishnan J.Glomerular diseases associated with cancer, chemotherapy, and hematopoietic stem cell transplantation. Adv Chronic Kidney Dis 21: 48–55, 20149. Bjorneklett R, Vikse BE, Svarstad E, Aasarod K, Bostad L, Langmark F,Iversen BM. Long-term risk of cancer in membranous nephropathy patients. Am J Kidney Dis 50: 396–403, 200710. Beck LH Jr. Membranous nephropathy and malignancy. Semin Nephrol30: 635–644, 201011. 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diseases,including low-gradeB-celllymphoma,CLL,andmultiple myeloma. Although this direct relationship is not proven, the cur-rent observation suggests this possibility (34). More of this is dis-cussed in the paraproteinemia chapter of the curriculum. Glomerular diseases associated with myeloproliferative disorders
Part One: Heir of Ash Chapter 1 Chapter 2 Chapter 3 Chapter 4 Chapter 5 Chapter 6 Chapter 7 Chapter 8 Chapter 9 Chapter 10 Chapter 11 Chapter 12 Chapter 13 Chapter 14 Chapter 15 Chapter 16 Chapter 17 Chapter 18 Chapter 19 Chapter 20 Chapter 21 Chapter 22 Chapter 23 Chapter 24 Chapter 25 Chapter 26 Chapter 27 Chapter 28 Chapter 29 Chapter 30 .
TO KILL A MOCKINGBIRD. Contents Dedication Epigraph Part One Chapter 1 Chapter 2 Chapter 3 Chapter 4 Chapter 5 Chapter 6 Chapter 7 Chapter 8 Chapter 9 Chapter 10 Chapter 11 Part Two Chapter 12 Chapter 13 Chapter 14 Chapter 15 Chapter 16 Chapter 17 Chapter 18. Chapter 19 Chapter 20 Chapter 21 Chapter 22 Chapter 23 Chapter 24 Chapter 25 Chapter 26
an active urine sediment (nephritic syndrome) or with proteinuria (nephrotic syndrome) and hematuria, the site of glomerular injury— particularly, which glomerular cells are targeted. There are three major types of re
DEDICATION PART ONE Chapter 1 Chapter 2 Chapter 3 Chapter 4 Chapter 5 Chapter 6 Chapter 7 Chapter 8 Chapter 9 Chapter 10 Chapter 11 PART TWO Chapter 12 Chapter 13 Chapter 14 Chapter 15 Chapter 16 Chapter 17 Chapter 18 Chapter 19 Chapter 20 Chapter 21 Chapter 22 Chapter 23 .
8 Sleep-wake disorders 2 1 1 9 Diseases of the eye and adnexa 117 93 24 10 Diseases of the nervous system 257 232 25 11 Diseases of the ear and mastoid process 22 21 1 12 Diseases of the circulatory system 107 93 14 13 Diseases of the respiratory system 107 95 12 14 Diseases of the digestive system 264 236 28 15 Diseases of the skin 341 284 57 .
metabolic diseases O99.3: Mental disorders and diseases of the nervous system O99.4: Diseases of the circulatory system O99.5: Diseases of the respiratory system O99.6: Diseases of the digestive system O99.7: Diseases of the skin and subcutaneous tissue O99.8: Other specified diseases and conditions
Types of Glomerular Disease 1/2 Proteinuria and blood in urine (hematuria) are the most common manifestations of glomerular diseases. Proteinuria can be classified by the amount of protein that leaks into the urine: Nephrotic: 3.5 grams of protein in 24 hour collection of urine-severe Sub nephrotic: 0.5-3.5 grams of protein in 24 hour collection of urine-moderate
Susannah G Tringe*‡, Andreas Wagner† and Stephanie W Ruby* Addresses: *Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA. †Department of Biology, University of New Mexico, Albuquerque, NM 87131, USA. ‡Current address: DOE Joint Genome Institute, 2800