Pathophysiology and Clinical Presentation:



GN Teaching Module Facilitator Guide1 Introduction2 Minimal Change Disease (MCD)3 Focal Segmental Glomerulosclerosis (FSGS)3. Lupus Nephritis (LN)4. Diabetic Nephropathy5. IgA Nephropathy (IgAN)6. Membranoproliferative Glomerulonephritis (MPGN)7. Infection-Related GN (IRGN)8. HIV Associated Nephropathy (HIVAN)9. C3 Glomerulopathy (C3GN)10. ANCA-associated Vasculitides (AAV)11. Anti-Glomerular Basement Membrane Disease (Anti-GBM Disease)12. Fibrillary and Immunotactoid GN13. AL- Amyloid and Light Chain Deposition Disease (LCDD)14. Fabry Disease15. C1Q Nephropathy16. Alport Syndrome17. Thin Basement Membrane Disease18. Membranous Nephropathy (MN)19. Thrombotic Microangiopathy (TMA)IntroductionDemystifying Glomerular Disease: A Worksheet Teaching ToolThis is the Facilitator’s Guide - a detailed answer key for the Glomerular Worksheet. The instructor should read this resource prior to the teaching session. This resource may be provided to the learners at the conclusion of the teaching session. The instructor is typically a physician or other health professional in the field of internal medicine or nephrology. The learner includes students of medicine, nursing, or allied health, internal medicine residents, or nephrology fellows. The ideal setting is a classroom with a chalk or dry erase board. The Glomerular Worksheet may be given to the student before the session to encourage a flipped classroom model, which is a proven modality to increase knowledge retention. Example of how to use this resource in the classroom:The first disease (Minimal Change Disease) from the resource file is shown in row format below. Disease ProcessHistology (Light Microscopy, Immunofluorescence, Electron Microscopy)Clinical Presentation (physical signs & symptoms)TreatmentPrognosis Minimal ChangeDiseaseThe learner begins by understanding the pathophysiology and histology of Minimal Change Disease. This disease is likely autoimmune to a podocyte target marker and the resultant disruption of the glomerular basement membrane results in an efflux of albumin out of the bloodstream and into the urinary space. The Light Microscopy (LM) is normal – the glomerular structure has little to no change. The Immunofluorescence is negative. The Electron Microscopy (EM) shows diffuse podocyte effacement. The learner will scratch out the foot processes on the podocyte to demonstrate effacement, and may take notes in the space to the side. The learners’ take notes in the empty space, and the facilitator adds from this Facilitator’s Guide for completeness. Next, the learners review the clinical presentation of Minimal Change Disease. The learner may describe physical or clinical symptoms such as edema, anasarca, thrombosis, nephrotic syndrome, heavy proteinuria, or acute kidney injury. This disease typically occurs in children, but when it occurs in adults, the etiology may be secondary to Hodgkin’s Lymphoma or NSAID use. Next, the facilitator will prompt the learner to discuss the treatment and prognosis for Minimal Change Disease. Here, the learner may state that the disease can be classified as Steroid Sensitive or Steroids Dependent – this is a critical point because the Steroid Sensitive forms rarely progress to chronic kidney disease. The first line treatment is corticosteroid therapy. The prognosis is generally good with very few patients experiencing loss of the glomerular filtration rate. The facilitator may utilize extra time to pose a clinical question about this particular disease in the PICO format. This follows the prompts: P – Patient / Problem, I – Intervention / Exposure, C – Comparison, O - Outcome. This would promote the learner to apply evidence-based medicine and self-directed learning principles to this worksheet. For this disease, one EBM style question may be: Your patient is a 6-year old child with Nephrotic Syndrome. You promptly initiate high dose corticosteroid therapy. You are concerned about steroid-induced gastric ulceration. In patients on high dose corticosteroid therapy, what is the evidence to support addition of prophylactic medication such as a PPI? Or, what is the evidence to support anti-coagulation in the prevention of venous thrombo-embolism in Nephrotic Syndrome?Educational Objectives:To become comfortable (reduce anxiety) with approaching glomerular diseaseTo create a worksheet that can be used as a study guideTo understand the pathophysiology and histologic representation of glomerular diseases with illustrationTo synthesize the clinical presentation, histology, treatment and prognosis of common or uncommon glomerular diseases that appear on examinations.Conceptional background for this curriculum:Even practicing nephrologists struggle with learning glomerular diseases. The apprehension may begin with an inadequate understanding of the pathophysiology of the disease process and the resulting histologic appearance of the glomerulus. Hence, trainees feel the need to memorize a constellation of symptoms that are associated with a particular disease pattern. This curriculum enhances active learning and is broadly applicable to students, residents, and fellows. Feedback received after implementation of this resourceThis worksheet has been extremely effective as a teaching tool at a single institution. The primary audience is Nephrology fellows. A colleague at another academic institution piloted this teaching tool; feedback has been implemented in the submitted iteration. Common themes from learners include: “Glomerular disease finally makes sense.” “This will be an excellent resource to use for board preparation.” “This session succinctly covered 15 diseases in one hour – this used to involve numerous boring power point lectures!”Advice to the instructorPlease allow one or more learners to think about each box before providing the answer. Since this module does not require a computer, a chalkboard or whiteboard is an extremely helpful tool for teaching and case discussion. There is an icebreaker activity at the end of the worksheet that has been fun!Limitations and areas for improvement1. This resource was created by and primarily used by a nephrologist. Hence, a non-nephrologist instructor may not have as robust a discussion with each case. This limitation may be overcome by diligent preparation and reviewing the answer file before the initial classroom session. 2. This facilitator guide may require updating, as novel treatment or tests become available for these diseases. The primary source of information is the Kidney Disease: Improving Global Outcomes (KDIGO) non-profit organization. Reference to this source is imperative because this collaborative work-group meets periodically to update guidelines on Glomerulonephritis and these publications are available free-of-charge online. This guide was created in June 2018 and information is current through this date. Minimal Change Disease (MCD)Pathophysiology and Clinical Presentation: Idiopathic Nephrotic Syndrome (NS)90% cases in children 10-15% cases in adultsSecondary MCD- Associated with malignancy, infections, drugs and systemic diseasesSymptomsMost common-edema, sudden onset may occurMicroscopic hematuria- 10-30% of individualsAKI due to tubular injury from sudden hemodynamic alterationOnset and relapses may be triggered by antecedent infections, typically respiratoryPatients with severe hypoalbuminemia (<2.5 g/L) are at high risk for thromboembolismPathology:Light Microscopy: NormalIF: Typically negative but may show low-level focal staining for C3 and IgMEM: Diffuse effacement and fusion of a majority of podocyte foot processesTreatment and PrognosisSupportive care i.e. low-sodium diet and diureticsInitial therapy for presumed or biopsy-proven MCD:PO prednisone daily (1mg/kg/d) or every other day (2mg/kg/day)Response determines prognosis-steroid responsive vs. steroid resistant MCDImmediate steroid responsiveness is a marker of good long-term prognosis20%- refractory to steroids10% - completely free of relapses after initial treatment30% - infrequent relapses requiring re-treatment with corticosteroids30% - > 2 episodes in 6 months treated with intermittent steroid therapy30% - frequently relapsing/steroid dependent and are candidates for 2nd line therapy due to side effects from chronic steroid use Second line therapy options:Cyclophosphamide (2-2.5mg/kg/d) x 8-12 weeks. Results in prolonged remission in 70% of patientsMycophenolate Mofetil (1-1.5g BID)Results in 50% reduction in relapse rateTacrolimus (0.05-0.3mg/kg/d in divided doses)Associated with higher remission rate of 80-90%, but relapses shortly after cessation of therapyRituximab (375 mg/m2 weekly x 4 weeks) Used for steroid-dependent or frequently relapsing MCD in steroid sensitive patients, along with TacrolimusRare cases of presumed MCD in childhood, who have a poor outcome and progressive GFR loss, may actually represent unidentified FSGSFocal Segmental Glomerulosclerosis (FSGS)Pathophysiology and Clinical Presentation: Represents 35% of cases of nephrotic syndrome in adults and a major cause of ESKD in certain populations Clinical Presentation-Proteinuria is usually non-selective (including albumin and higher-molecular weight macromolecules)Microhematuria is found in 25-75% of patientsHTN is found in 30-50% of patientsOccasionally patients can have glycosuria, aminoaciduria, phosphaturia, or a concentrating defect indicating functional tubular damageAPOL1 gene= major risk gene for FSGS and chronic hypertensive arterionephrosclerosis among African AmericansIn patients < 25 years of age, genetic screening for mutations in podocin, nephrin, or other podocyte genes may be useful. Tip variant and cellular variant present with greater proteinuria and higher incidence of nephrotic syndrome. Primary FSGSMore common in males and African Americans50-70% of adults present with asymptomatic proteinuria or nephrotic syndromeLikely mediated by circulating/permeability factor e.g. suPAR (solube urokinase plasminogen activator receptor) or CLC1 (cardiotrophin-like cytokine) Secondary FSGSFamilial/Genetic – mutations in nephrin, podocin, risk alleles for APOL1, etc. Virus Associated – HIV, Parvovirus B 19, CMV, etc. Drug Induced – Heroin, Interferon, Lithium, etc. Mediated by adaptive structural/functional responses - unilateral renal agenesis, HTN, obesity, reflux nephropathy, very low birth-weight, etc. Pathology: Earlier- pattern of glomerular injury involves a minority of glomeruli (focal) and only a portion of glomerular tuft (segmental)As disease progresses, more diffuse glomerulosclerosis resultsAs the defining lesion is focal and may be confined to deeper juxtamedullary glomeruli in early disease, it can be missed on renal biopsyPodocyte injury, glomerular hypertrophy and increased intracapillary glomerular pressures have pathogenetic significanceClassic FSGS (NOS – Not otherwise specified): Requires exclusion of more specific subtypes. There is accumulation of ECM that occludes glomerular capillaries, forming discrete segmental solidifications. There may be hyalinosis, endocapillary foam cells, and wrinkling of GBMAdhesions to Bowman capsule are commonOverlying visceral epithelial cells often appear swollen and form a cellular “cap” over the sclerosing segment. IF: focal and segmental granular deposition of IgM, C3 and occasionally C1 in the distribution of segmental glomerular sclerosisEM: Obliteration of glomerular capillaries with increased ECM matrix with wrinkled and retracted GBM. Overlying podocytes are detached, with complete effacement of foot processes. Perihilar Variant:More than 50% of glomeruli with segmental lesions display lesions involving vascular poleRequires exclusion of cellular, tip and collapsing variantParticularly frequent in secondary forms of FSGS mediated by adaptive responses glomerulomegaly (glomerular hypertrophy) and mild foot process effacementCellular Variant: Characterized by focal and segmental endocapillary hypercellularityGlomerular capillaries are segmentally occluded by endocapillary hypercellularity, including foam cells, infiltrating leukocytes and debris. EM: There may be hyperplasia of visceral epithelial cells. Foot process effacement is typically severe. Requires exclusion of tip lesions and collapsing lesionsUsually primaryCollapsing Variant:> 1 glomerulus has global collapse and overlying visceral cell hypertrophy and hyperplasia. Occlusion of glomerular capillary lumen by implosive wrinkling and GBM collapse. Glomerular epithelial cells often contain prominent intracytoplasmic protein resorption droplets and may fill Bowman space, forming pseudo-crescents. There is prominent tubulointerstitial disease (Interstitial fibrosis, tubular atrophy, interstitial edema, and inflammation.EM: Severe foot process effacement affecting both collapsed and non-collapsed glomeruli. Can be seen in primary or secondary FSGS caused by HIV, parvovirus B19 infection, interferon therapy, or pamidronate toxicity. Presence of endothelial tubuloreticular inclusions is helpful to identify collapsing FSGS secondary to HIV or interferon therapy. Tip Variant: Presence of > 1 segmental lesion involving the outer 25% of the tuft next to the origin of the proximal tubuleThere is either adhesion between the tuft and Bowman capsule or confluence of swollen podocytes with parietal or tubular epithelial cells at the tubular lumen or neck. Presence of perihilar sclerosis or collapsing sclerosis rules out tip variant. Most cases are primaryTreatment: Only primary FSGS should be treated with immunosuppressive therapy-Prednisone daily (1mg/kg/d) or every other day (1.5-2mg/kg/d) for a minimum of 4 weeks and maximum of 16 weeks, with a slow taper over 6 months after achieving complete remission. Options for steroid-resistant patients:Oral cyclosporine 3-5 mg/kg/day for 4-6 months (many clinicians extend to one year with slow taper due to high relapse rate)Tacrolimus in patients who are intolerant of cyclosporineOral MMF 1-1.5g bid plus dexamethasone for 4-6 months for patients who do not tolerate CNIsOral cyclophosphamide 2mg/kg/day for 2-4 monthsPatients with secondary FSGS- Treat underlying causePrognosis:Without therapy or response to therapy, majority will progress to renal failureOnly 5-25% of patients undergo spontaneous remission of proteinuria50% of patients develop ESKD in 10 years from presentationAfrican Americans experience a more rapid progression to renal failureOutcomes are best for tip variant and worse for collapsing variant of primary FSGSTransplantation: Approximately 40% of patients with primary FSGS develop recurrent FSGS in the allograftThose with prior allograft loss due to recurrent FSGS = highest risk of recurrencePlasma exchange has been used successfully to induce remission of proteinuria associated with recurrence Results more favorable in children > adults.Lupus Nephritis (LN)Pathophysiology and Clinical Presentation: Immune complex GN that is a common feature of Systemic Lupus Erythematosus (SLE)Peak incidence of lupus is from 15-45 years with female predominance (10:1)In people affected by SLE, LN affects both genders equally. Both SLE and LN are more common in African Americans, Hispanics and Asians compared to CaucasiansClinical Presentation100% of patients with LN have proteinuria80% have microhematuriaOn urine microscopy- dysmorphic erythrocytes and red-cell casts may be present45-65% of patients present have nephrotic syndrome. In many cases, nephritic syndrome develops in association with proliferative GN and a decline in GF40-80% patients can have reduced renal function10-20% can develop rapidly progressive GN15-50% of patients have hypertensionAutoantibodies are crucial to pathogenesis of LN and a hallmark of LN is accumulation of immune complexes in the glomeruliImmune complexes in glomeruli complement activation complement mediated damage. Renal disease in lupus can also present as Type 1 or type 4 RTA, thrombotic disorders due to anti-phospholipid syndrome and fibrillary GN.ANA- sensitive but not specificAnti-dsDNA Ab- more specificIn ANA negative lupus-like patients, anti-phospholipid Ab may be +Anti-C1q antibody is more closely associated with activity of LN than anti-dsDNASerum level of total hemolytic complement and complement components (C3, C4) are often depressed in LN. Pathology: Systematic classification systems for LN are based on glomerular involvement, although LN can affect all structures of the kidneyInterstitial and vascular injury are predictors of renal outcome. In active disease, tubulitis (infiltration/invasion of tubules) is foundIn chronic disease, interstitium is expanded by fibrosisLight MicroscopyElectron MicroscopyClass I (Minimal Mesangial LN)Normal glomeruliClass II (Mesangial Proliferative LN)Pure mesangial hypercellularity – More than 3 mesangial cells in areas away from the vascular pole.Class III (Focal LN)*Focal segmental or global, endocapillary or extracapillary GN, affecting less than 50% of the total sampled glomeruli.Sub-endothelial depositsClass IV (Diffuse LN)*Diffuse segmental or global, endocapillary or extracapillary GN, affecting 50% or more of the total sampled glomeruli. Sub-endothelial depositsClass V (Membranous LN)Defined by sub-epithelial immune deposits. Membranous changes may be present alone or on a background of mesangial hypercellularity and mesangial immune deposits. Patients with additional features of class III and IV are classified as V+III or V+IV respectively. sub-epithelial depositsClass VI (Advanced Sclerosing LN)Global glomerular sclerosis, affecting > 90% glomeruli.*Both class III and class IV may have active (proliferative), inactive (sclerosing), or combined active and inactive lesions, subclassified as A, C, and A/C, respectively. Both classes have sub-endothelial deposits. Transformation from one histologic class to other may occur, with worsening disease (e.g. class II may deteriorate to class IV) or with treatment (e.g. class IV may improve to class V). IF: IgG is the dominant immunoglobulin, and C4 and C1q are usually present along with C3.“Full-house Staining” – Presence of IgG, IgA and IgM, along with C3 and C1q highly suggestive of LN. Strong C1q staining is also suggestive of LN. May show aggregates of C3 in tubular basement membrane (found in 60-65% of biopsy specimens). EM: Some electron dense deposits have organized microtubular or fibrillar sub-structure, known as “fingerprinting”Tubuloreticular inclusions may be found in endoplasmic reticulum of renal endothelial cells, and are thought to reflect increased interferon expression. Treatment: Unless contraindicated, all should be treated with hydroxychloroquineTreatment is divided into initial phase and maintenance phase-Initial therapy-guided by ISN/RPS histological classificationISN class I and II no therapy indicated ISN Class III (A and A/C), Class IV (A and A/C) and Class V combined corticosteroid and immunosuppressive therapy Corticosteroids are started at high dose (1mg/kg/day orally or 1g IV daily for 3 days) and then tapered to 10 mg/day by 3-6 months. Steroids + PO cyclophosphamide daily or IV monthly pulses (0.5-1g/m2) for 6 months can be used.Mycophenolate Mofetil (MMF) + steroids for 6 months can be used for initial therapy and are at least as effective as cyclosphosphamide + steroid regimens. Optimum dose remains unclear, but 2-3 g/d of MMF orally can be used for initial therapy. Azathioprine can be used if MMF or cyclophosphamide is contraindicatedCNIs- tested as an alternative to cyclophosphamide and have favorable short-term responseMaintenance Therapy PO prednisone- continue at 5-15mg/dayAzathioprine or MMF are effective maintenance drugs and improve survivalFor most patients, MMF > AZA but AZA can be used in appropriate clinical settings, e.g. a patient who wants to get pregnant. CNIs can be used for patients who cannot tolerate MMF and AZA. Treatment for Membranous Lupus Nephropathy:For patients with sub-nephrotic proteinuria, reno-protective and anti-proteinuric therapies should be used. Short course of steroids or a CNI can be considered.Immunosuppressive regimens should be considered for all patients with nephrotic range proteinuria. MMF, AZA, or CNI is preferredCyclophosphamide = reserved for refractory cases. Membranous nephropathy can exist in association with class III and IV LN. In these patients, treatment is directed at the proliferative component. Remission only occurs in 30-40% of LN patients by 12 months. Defined as reduction in proteinuria to less than 0.5g/24h, absence of glomerular hematuria/RBC casts and stabilization/normalization of GFR. Prognosis: 8-15% of patients with LN will progress to dialysis Class IV diffuse proliferative disease carries the worse prognosis10 year renal survival rates are 75-85% for class VPrognosis is poor if biopsy shows extensive glomeruolsclerosis or interstitial fibrosis. Persistent inflammation with subendothelial and mesangial deposits on repeat renal biopsy is a strong predictor of development of renal failureBlack race, male gender, younger age (<24 years) and lower socio-economic status = associated with worse prognosis, independent of careTransplantationMost centers defer transplantation until lupus is quiescent for 6 monthsIf anti-DNA antibody levels, transplant immunosuppressive medications can be started few weeks before living donor transplantationPatients with Anti-phospholipid antibody are at high risk for allograft thrombosis. Recurrent LN occurs in 2-11% of transplanted kidneysDiabetic NephropathyPresentation:Leading cause of ESRD in adults and constitutes half of patients initiating dialysis. Moderately increased albuminuria = UACR between 30 and 300 mg/g. Severely increased albuminuria = UACR > 300 mg/day Long-term deleterious impacts of hyperglycemia and insulin resistance are central to development and progression of diabetic nephropathy. Characterized not only by glomerular disease but also by tubulointerstitial injury. Pathology:Light Microscopy: Progressive diffuse mesangial expansion, seen mainly on PAS stain. Areas of extreme mesangial expansion called Kimmelstiel-Wilson nodules (50% of patients)Arteriolar hyalinosisGBM and Tubular BM (TBM) thickening may be seen Changes in type II diabetes are more heterogeneous than type 1 DM.IF: in linear staining of GBM, TBM and Bowman capsule, mainly for IgG (IgG4) and albumin.EM: Thickening of GBM and TBM, and in mesangial matrix from 20% (normal) of glomerular volume to 40% when proteinuria begins to 80% in stage 3 CKDTreatment: Goals- slowing the rate of kidney disease progression as well as primary and secondary prevention of CV disease. In type 1 diabetes patients who receive pancreas transplant, normoglycemia for ~ 10 years: see reversal and disappearance of abnormalities on LM, including Kimmelstiel-Wilson nodular lesionsTarget hemoglobin A1C < 7% reduces risk of kidney disease progressionMetformin can safely be used even for patients even with a severely reduced eGFR Although there is lack of consensus, BP target of < 130/80 is reasonable1st choice for patients with diabetes and HTN and for patients with albuminuria even if they are normotensive: RAAS blocking medications (ACE-I/ARBs2nd line agents: CCB or Diuretics Lipid lowering therapy reduces CV outcomes but effects on renal outcomes are debatableSGLT-2 inhibitors (e.g. Empagliflozin) have shown kidney and CV protective potential beyond their effect in reducing A1CPrognosis/Transplantation: mortality in both type 1 and type 2 diabetic patients. 20-200-fold in patients with proteinuriaPatients with diabetes have mortality after kidney transplantation compared to non-diabetic patients. CV disease is the leading cause of death in diabetic patientsUrinary albumin excretion = good predictor of CV eventsIgA Nephropathy (IgAN)Pathophysiology and Clinical Presentation: Previously named Berger diseaseDefined by the presence of immune reactant rather than any other morphologic feature on kidney biopsySerum IgA level is increased in 1/3rd patients with IgA and HSPPathogenesis involves poorly galactosylated IgA1 O-glycoforms in the circulation generation of autoantibodies against such IgA1 O-glycoforms mesangial deposition and/or in-situ formation of IgG-IgA1 immune complexes mesangial cell proliferation, extra-cellular matrix overproduction.Polymeric IgA deposition in the mesangium is followed by mesangial proliferative GN. Mesangial IgA probably represents a common immune response to a variety of antigens. Complement deposits are usually C3 and properdin without C1q and C4IgA Vasculitis (previously called Henoch Schonlein Purpura; HSP) is a IgA Nephropathy with systemic symptoms, including palpable purpura and abdominal pain. It primarily occurs in children and treatment is supportive care, though corticosteroids may be used in severe disease. IgA Vasculitis rarely recurs. Patients with IgA Vasculitis who receive a renal transplant may have recurrent disease in the form of IgANIn Caucasians, IgAN male: female ratio is 3:1 whereas in Asians, its 1:1Clinical Presentation: 40-50% of patients have episodic macroscopic hematuria, most frequently in the 2nd decade of lifeUsually resolves spontaneously over a few days whereas microscopic hematuria persists between attacksThere may be flank pain caused by renal capsular swelling. Hematuria usually follows upper respiratory or GI tract infectious symptoms in 24 hours. 30-40% patients may have microscopic hematuria with <2g/24 h proteinuriaFull-blown nephrotic syndrome is uncommon (~ 5% of patients)AKI is uncommon but may occur due to: 1) necrotizing GN and crescent formation, 2) tubule occlusion by RBCs or 3) incidental renal insults in older patients. Pathology: Light Microscopy: in mesangial cells and mesangial matrix with normal appearing capillary loops, although endocapillary hypercellularity may occurFocal segmental or global glomerular sclerosis indicates disease has been going on for a whileNecrotizing GN and cellular crescent formation may be seen in severe cases.IF:Diffuse mesangial IgA is the defining hallmark of IgANC3 is co-deposited in up to 90% of cases, IgG in 40% of cases, and IgM in 40% of casesC5b-9 is found with properdin, indicating alternative complement pathway activationDeposits of secretory IgA in the mesangium are characterized by more severe diseaseEM: Electron dense deposits are seen in mesangial and paramesangial areas; 1/3 patients can have focal thinning of GBMTreatment and Prognosis: Supportive therapy- anti-hypertensive and anti-proteinuric medications. ACE-inhibitors: 1st choice Weak evidence for benefit of fish-oil.Steroids may be considered if proteinuria > 1g/day after optimum supportive care for 3 to 6 months AND GFR is > 50ml/min. Start with 1mg/kg/day for 2 months and then reduce by 0.2mg/kg/day/month. Cyclophosphamide, MMF and Azathioprine are not recommended for intermediate risk patientsTonsillectomy can be considered in patients with recurrent macroscopic hematuria in the setting of recurrent tonsillitisEnteric corticosteroid preparation use (budesonide 16mg/day) has shown reduction in proteinuria in a Phase 2b trial in EuropeRisk of progression decreases if proteinuria is reduced to <1g/dayGood prognosis: minor urinary abnormalities (i.e. isolated hematuria), normotensive and normal GFR Close follow-up needed to detect 40% of patients who will develop worsening proteinuria and 5% of patients who will lose GFR over 7-10 yearsIntermediate prognosis: significant proteinuria, hypertension and slow reduction in GFRPoor prognosis: rapidly progressive renal failure associated with crescentic IgAN.Treatment often needs combination of plasma exchange, prednisolone and cyclophosphamide? of patients reach ESKD in 12 monthsTransplantation: Transplant outcome is not affected for the first 10 years if IgAN is the primary renal disease. Mesangial IgA deposits recur in the donor transplant kidney in up to 60% of patients with IgANDeposits seem benign in the short term. Membranoproliferative Glomerulonephritis (MPGN)Pathophysiology and Clinical Presentation: Characterized by circulating immune-complexes due to persistent antigenemia, diffuse proliferative lesions involving mesangium and capillary walls and often double-contoured capillary walls due to remodeling A histologic pattern of injury: similar in primary and secondary diseaseOccurs when host cannot eliminate a foreign antigen despite humoral response, (i.e. chronic hepatitis C, bacterial endocarditis, etc)Can occur in chronic immune-complex diseases such as lupusCan also occur when immune complexes cannot be cleared, e.g. due to deficiencies in classical complement pathway (C1q, C2, C4) or C3Mixed cryoglobulinemias (Type II and III) are associated with MPGN 80-90% of patients have chronic HCV infectionPresentation: weakness, arthralgias and purpura. MPGN can be associated with HCV infection in the absence of cryoglobulinemiaAffects males and females equally and relatively more common in CaucasiansClinical Presentation:Microhematuria, non-nephrotic or nephrotic range proteinuria, or nephritic syndrome with rapidly progressive GNHypertension is present in 50-80% of patients. Classical pathway is activated and see depressed levels C3, C4 () and CH50C3 nephritic factor (C3Nef) activity - strongly associated with Dense Deposit Disease (DDD). Prompts genetic analysis of complement factors. Pathology: Light Microscopy: Hypercellularity and intrinsic glomerular cell proliferation- typically mesangial cells, leading to accentuation of normal glomerular lobular structureSilver staining shows a double-contouring of the GBM. In cryoglobulinemic MPGN: cryoprecipitates can be observed as hyaline-like globules. IF: Deposition of IgG, IgM and C3 in a granular capillary wall distribution. Staining for classical pathway complement components (C1q, C4) may be seen. EM: Immune deposits in sub-endothelial portions of capillary wall and mesangial regionsDeposits can be small and sparse or large and numerousSeparation of GBM from endothelial cell can be seen with deposition of new basement membrane under the endothelial cell15% of cases demonstrate both subendothelial and subepithelial deposits associated with minute disruption of lamina densaMicrotubular or fine fibrillary structures consisting of precipitated cryoglobulins can be seenTreatment: Idiopathic MPGN:Normal renal function and asymptomatic non-nephrotic range proteinuria supportive treatment and close follow-upNephrotic syndrome and progressive decline in renal function oral cyclophosphamide or MMF + low-dose daily or alternate-day steroids. Rapidly progressive crescentic GN Cyclophosphamide or MMF + high dose pulse steroids. Rituximab and Eculizumab used in few patients successfully Hepatitis B virus associated MPGN: use anti-viral agents. Immunosuppressive agents are discouraged. Hepatitis C virus associated MPGN: In patients with mixed cryoglobulinemia corticosteroids, cytotoxic drugs or Rituximab, and anti-viral therapy. Rituximab (375 mg/m2/week x 4 weeks) as efficient as cyclophosphamide (2mg/kg/day for 2-4 months) in blocking cryoglobulin production and does not enhance HCV replicationIf nephrotic range proteinuria or progressive renal failure plasma exchange and methylprednisolone pulses may be included Secondary MPGN of other etiology: Treat the underlying cause (i.e. treat SLE, treat underlying infection, treat lymphoma etc.)Prognosis/Transplantation50% of patients with idiopathic MPGN either die or need RRT 5 years after diagnosisPatients with nephritic syndrome and high C1q staining have poor prognosisSeverity of crescent formation in native kidney biopsy has predictive value for recurrence of disease in allograftGraft loss has been reported in up to 40% of those with recurrence, and the risk of recurrence in subsequent grafts ~ 80%Infection-Related GN (IRGN)Pathophysiology and Clinical Presentation: Variable presentation: ranging from asymptomatic to rapidly progressive GN. Hematuria (microscopic or gross), proteinuria (subnephrotic but may be nephrotic) and variable degrees of HTN and edema may be presentIn classic post-streptococcal GN (PSGN), urinary sediment = activeHypocomplementemia is extremely common in children with C3 in 90% of cases and C4 to a lesser extent. In adults, Hypocomplementemia ~ 30-80% of patients. Adults more commonly present with kidney failure and complications of hypervolemia (e.g. decompensated heart failure)Latent period may be 7-10 days after oropharyngeal infections and 2-4 weeks after skin infectionsASO, anti-DNase B, antihyaluronidase and anti-streptokinase = serologic markers of recent streptococcal infection. In adults, most cases of IRGN no longer follow streptococcal infection and GN co-exists with the triggering infection. In the developed world, IRGN due to staphylococcus and gram-negative bacteria: more common. Pathology: Biopsy findings influenced by organism, site and duration of infectionLight Microscopy:Wide range of proliferative glomerular lesions- most common is diffuse endocapillary proliferation with infiltrating neutrophils. A membranoproliferative pattern can be seen when infection is long-standingSubacute or remote cases may show focal endocapillary proliferation or mesangial proliferative appearanceNecrotizing and crescentic GN: a pattern associated with endocarditisIF: Dominant or co-dominant staining for C3, with lesser degree of Ig stainingIn classic PSGN, IgG is seen in a similar distribution to C3In staphylococcus infections, IgA is commonly the dominant immunoglobulinEndocarditis associated IRGN may have pauci-immune appearanceEM: Classic finding is hump-shaped subepithelial electron-dense depositsMesangial deposits and subendothelial deposits are also present Treatment: Mostly supportive and treat underlying symptom/infection In select cases with aggressive crescentic GN and rapidly progressive disease-immunosuppression with IV methylprednisolone may be of benefitPrognosis/Transplantation: Prognosis in children: > 95% experience full recoveryPrognosis of epidemic PSGN in adults: Up to 50% of adults with sporadic IRGN may require dialysis and mortality ~ 20%Patients with DM have worse prognosis after IRGN: high rates of progression ESKDPost-infectious GN is rare in renal allografts, likely due to immunosuppression. HIV Associated Nephropathy (HIVAN)Pathophysiology and Clinical Presentation: The classic kidney disease related to HIV: form of collapsing focal segmental glomerulosclerosis (FSGS), referred to as HIVANWith widespread use of cART (combined anti-retroviral therapy) decline in incidencePatients of African descent are more susceptible due to high frequencies of APOL1 genetic polymorphisms on chromosome 22, specifically G1 and G2 Direct viral effects and immune complexes in the kidney may also be culprits in kidney damage Kidney infiltrates in HIV-ICD (Immune-complex disease): B-lymphocytesKidney infiltrates in HIVAN: T-lymphocytes and macrophagesBesides HIVAN and HIV-ICD, HIV can cause non-collapsing FSGS, TMA as well as disorders associated with nephrotoxic HIV therapies. Classic presentation of HIVAN: nephrotic syndrome, GFR loss, bland urine sediment, and large, often densely echogenic kidneys. Patients with HIV at risk: viral load, CD4 count < 200 cell/L Pathology:Light Microscopy: Collapse of glomerular capillaries involving entire glomerulus, visceral glomerular epitheliosis, podocyte hypertrophy and proliferation surrounding shrunken glomerulus, and mesangial prominence and hypercellularityTubular injury is marked by tubular dilation, tubular atrophy, and proteinaceous castsModest interstitial inflammation may be present with lymphocytes, plasma cells, and monocytesHistology of HIV-ICD includes MPGN types I and II, IgA nephropathy, membranous nephropathy, lupus-like GN, TMA and post-infectious GN. IF: Generally non-specific in HIVAN. EM: diffuse foot process effacement and possible endothelial tubuloreticular inclusions (TRIs) without immune-complex deposits. Treatment: Initiation of cART regardless of the CD4 count. Prognosis/Transplantation: Untreated HIVAN ESKD in a few months. HIV patients on dialysis, who are receiving cART have comparable survival to non-HIV patients. Outcome of kidney transplantation in HIV-positive patients is similar to HIV-negative recipients, regardless of the HIV-status of the donorClassic HIVAN doesn’t recur in allografts but HIV-ICD recurrence has been reported. C3 GLOMERULOPATHY (C3GN)Pathophysiology and Clinical Presentation: Abnormal control of the alternative complement pathway accumulation of C3 in glomeruliAbsence of staining for immunoglobulins or for components of classical pathway of complement activation, C1q and C4. May show a variety of appearances on LM, including MPGN pattern and most cases previously called MPGN are examples of C3 glomerulopathy. On EM, a common presentation is dense-deposit disease (DDD) – most cases of DDD do not have MPGN morphology on LMPathogenesis is failure of Circulating Factor H (CFH) to control alternative pathway activation uncontrolled consumption of C3 serum C3 level in most patients. C3 Nephritic factor (C3NeF) stabilizes C3 convertase by preventing normal action of CFH. C3 glomerulopathy without the characteristic appearance of DDD is called C3 Glomerulonephritis (C3GN). DDD affects males and females equally and is a disease of children and young adults. All have proteinuria (mostly nephrotic range) usually with hematuria. Nephritic presentation is also possible. Half of patients have a preceding URI with ASO titer. They may develop ocular drusen (accumulation of C3 in retina) or acquired partial lipodystrophy. C3GN clinical presentation: microhematuria, nephrotic range proteinuria, and hypertension serum C3 levels in 80% of patients with DDD and 50% of patients with C3GNIn familial cases of C3 glomerulopathy, search for genetic mutations may be importantPathology: Light Microscopy: Presence of membranoproliferative changes is typical in both C3GN and DDD. Some cases show mesangioproliferative pattern or endocapillary hypercellularityCrescent formation may be presentIF: Widespread C3 staining of capillary walls and focal granular mesangial staining with absence of C1q and C4 and immunoglobulins. EM: DDD shows presence of typical osmiophilic, dense transformation of the GBM, with similar features often seen in tubular basement membrane and large densities in the mesangiumC3GN: electron dense material that expands the GBM similar to changes in DDD, but without such marked electron densityIn both DDD and C3GN, subepithelial hump-shaped deposits are frequently seen. More common in infectious exacerbations of the diseaseTreatment/Prognosis/Transplantation: Treatment=undefinedKDIGO recommendations for idiopathic MPGN can be used for C3 glomerulopathy with MPGN patternA recent study described a favorable response to MMF In the presence of CFH mutations or anti-CFH antibodies, plasmapheresis is recommendedNumber of case reports and a small trial for use of Eculizumab DDD and C3 glomerulopathy frequently recur and associated with poor graft survival, although newer therapies such as Eculizumab may alter the prognosis45-50% of patients have allograft failure at 5 yearsANCA-associated Vasculitides (AAV)Pathophysiology and Clinical Presentation:Divided into MPA, GPA and EGPA based on clinical, lab and path differences.Microscopic Polyangiitis (MPA): Necrotizing vasculitis, few or no immune deposits (pauci-immune), affects small vessels predominantly. Necrotizing GN and pulmonary capillaritis is often present. Granulomatous inflammation is absent. Granulomatosis with Polyangiitis (GPA): Necrotizing granulomatous inflammation that involves upper and lower respiratory tract, necrotizing vasculitis affects small to medium vessels. Necrotizing GN is common. Eosinophilic Granulomatosis with Polyangiitis (EGPA): Necrotizing granulomatous inflammation rich in eosinophils, involving the respiratory tract and necrotizing vasculitis affecting small to medium vessels. ANCA more common when GN is presentAll share a pattern of GN– necrosis and crescent formation and an absence/paucity of immunoglobulin deposition, hence pauci-immune crescentic GN. If absence of systemic vasculitis called renal-limited vasculitis. ANCA titers usually correlate with disease activity but this correlation is not very strong and conventional serologic testing can be negative in patients with clinically and pathologically typical MPA or GPA. Administration of certain drugs (e.g. hydralazine) and cocaine adulterated with levamisole can induce AAV associated with high titers of MPO-ANCA and PR3-ANCAANCA-activated neutrophils release factors that activate the alternative complement pathway C5a Neutrophil chemotaxis further activation of neutrophils by ANCAUsually begins in the 5th, 6th and 7th decade of life but may occur at any ageClinical Presentation: Constitutional symptoms often presentRenal involvement often occurs with GPA and MPA but less common with EGPA: hematuria, proteinuria and renal failure (usually characteristics of RPGN)Purpura (usually on lower extremities) is a common manifestation of all of them. Nodular lesions can be present in GPA and EGPA. Patients can have pulmonary hemorrhage in all of themUpper respiratory tract involvement (rhinitis, sinusitis, otitis media, ocular inflammation) is most common in GPA. When patients with saddle nose have ANCA, it is almost always PR3-ANCA (MPA does not cause granulomatous inflammation)Cardiac disease (transient heart block, infarction, myocarditis, pericarditis, endocarditis) is present in 50% of patients with EGPA but 20% of patients with GPA or MPAPeripheral neuropathy (usually mononeuritis multiplex) is most frequent in EGPAANCA testing has 80-90% sensitivity for AAVc-ANCA and p-ANCA are patterns seen on IFA and need to be confirmed by EIA (Lupus can give false + pattern, especially p-ANCA).By EIA, most c-ANCA is PR3-ANCA and most p-ANCA is MPO-ANCA. In some patients: not possible to differentiate between GPA, EGPA and MPA Pathology: LM:Acute vascular lesion is segmental fibrinoid necrosis, accompanied by leukocyte infiltration and leukocyte fragmentation. Early vasculitic lesions have infiltrating neutrophils replaced later by mononuclear leukocytes.Acute necrotizing lesions sclerotic lesions. In kidney necrotizing GN crescent formationPatients with GPA have necrotizing granulomatous inflammation of respiratory tractPatients with EGPA have necrotizing granulomatous inflammation with conspicuous eosinophils but its not pathognomonicTreatment:GN severe enough to cause renal impairment = indication for immunosuppressionTreatment involves induction and maintenance of remission and treatment of relapse. Induction: Combined treatment with PO prednisone )1mg/kg/day tapered to 0.25mg/kg/day by 3 months) + cyclophosphamide (2mg/kg/day oral or 0.5g/m2 per month adjusted upward to 1g/m2 based on leukocyte count after 2 weeks) Induces remission in 75% patients @ 3 months and 90% @ 6 monthsRituximab is approved for induction based on RAVE and RITUXVAS trials, as remission rate was similar to cyclophosphamide. Adverse events = no different in the two groupsPlasma exchange results in resolution of pulmonary bleeding and reduced risk of progression to ESKDMaintenance:Cyclophosphamide can be replaced by Azathioprine (2mg/kg/day) after 3-6 months (CYCAZAREM trial)Methotrexate can be used for maintenance but should not be used in patients with low GFRAlternative approach is to stop induction therapy after 6-12 months in patients with lower risk of relapse, especially with MPO-ANCA Relapse Therapy:Risk of relapse: 10-15% even with remission maintenance therapyHigher in patients with PR3-ANCA and respiratory tract diseaseRelapse- diagnosed based on clinical and pathologic evidence of recurrent disease, not just ANCA titer aloneRituximab or cyclophosphamide can be used (growing evidence that rituximab may be superior to cyclophosphamide for relapse)MMF, Azathioprine, Methotrexate or combination of drugs can be used. Prognosis/Transplantation: With adequate immunosuppression, 5 year renal and patient survival is 65 to 75%Older age, serum creatinine, pulmonary hemorrhage and ESKD poor outcomeHigher proportion of globally sclerotic glomeruli worse renal prognosisPatients with MPO-ANCA slightly better renal outcome than those with PR3-ANCA Renal transplantation is not contraindicated in patients with ESKD caused by AAVA positive ANCA titer at the time of transplantation doesn’t increase the risk of recurrent disease in the transplantAnti-Glomerular Basement Membrane DiseasePathophysiology and Clinical presentation:Usually secondary to autoimmunity against non-collagenous domain (NC1) of a type IV collagen chain, α3 (IV) NC1, also known as Goodpasture antigen. Some patients also have antibodies to other basement membrane constituents. Goodpasture disease is rare – 1 case per 1 million population/year. Clinical Presentation50-75 % of patients present with acute symptoms of lung hemorrhage and have advanced renal failureCough and hemoptysis are signs of lung hemorrhage, but can have iron-deficiency anemia and dyspnea on exertion in the absence of hemoptysisIn 1/3 to 1/2 of patients, GN occurs in the absence of lung hemorrhageOnce renal impairment has occurred, deterioration in renal function is rapidUrinalysis always reveals hematuria and usually modest proteinuriaPathology: Negative lung biopsy (open or bronchoscopic) is unhelpful in excluding the diagnosisLight Microscopy: Diffuse proliferative GN with variable degree of necrosis, crescent formation, glomerulosclerosis and tubular loss. Degree of crescent formation and tubular loss correlates with renal prognosis. IF: Linear deposition of immunoglobulin IgG (sometimes IgA or IgM) along the GBM is pathognomonic in the setting of glomerular inflammation. C3 deposition= detected in ~ 75% of biopsies. Treatment: Plasma exchange, cyclophosphamide and steroids PO Prednisone-1mg/kg/d orally, reduced at weekly intervals to achieve 1/6th of this dose by 8 weeks- maintain by 3 months and then taper to stop by 4 months Cyclophosphamide: 3mg/kg/d orally. If older than 55-2.5mg/kg/d. Discontinue if leukopenia below 3.5x109/L or neutropenia develops. Resume once counts recoverPlasma exchange: Daily exchange of one volume of plasma for 5% human albumin for 14 days or until circulating antibody is suppressedIn the presence of pulmonary hemorrhage, 300-400 ml of FFP is given at end of each treatmentMonitoring of anti-GBM titers during and 24-hours after the last plasma exchange treatment is useful to confirm effective suppression of antibodiesOnce disease is controlled, immunosuppression can be tapered off in 3 months and subsequent relapse is uncommonIn RPGN with no evidence of infective cause, immunosuppressive therapy can be started immediately, sometimes before renal biopsy findings are availablePrognosis/Transplantation: Once RPGN has developed, renal function is rapidly and irreversibly lostRenal recovery is unlikely if, at initiation of treatment, patient is oliguric, has a very high proportion of glomeruli with circumferential crescents, or has a serum Cr of > 5.5mg/dL.Recurrence is more common if anti-GBM antibodies are still detectable at the time of transplantationTransplantation should be delayed until antibodies are negative for 6 monthsFibrillary and Immunotactoid GNA. Fibrillary GN: Clinical Presentation: Rare disorderPatients present with nephrotic syndrome and varying degrees of kidney disease Screen for plasma cell dyscrasia- occasionally present DDX to include cryoglobulinemia and Hepatitis C Pathology: IF: + IgG (typically IgG4) and C3; Fibrils: negative for congo red and Thioflavin T EM: presence of amyloid-like, randomly arranged fibrillary deposits (18-22nm) in the capillary wallTreatment/Prognosis: No standardized treatment available. Progression to ESKD is the ruleB. Immunotactoid Glomerulopathy: Clinical Presentation: More rare than fibrillary GNUsually associated with a plasma cell dyscrasia or lymphoproliferative disorderDDX should include cryoglobulinemia Pathology:EM: Deposits contain thick (greater than 30 nm) organized microtubular structures that are located in mesangium and along capillary wallsTreatment: Treat underlying plasma cell dyscrasia. AL- Amyloid and Light Chain Deposition Disease (LCDD)Pathophysiology:Immunoglobulin light-chain deposition is directly responsible for most of the kidney pathologic alterations that occur with paraproteinemias (with the exception of AH-amyloid and Heavy chain deposition disease)In the setting of monoclonal gammopathy, light chain production increases, and proximal tubule receptors become saturated, allowing light chains to appear in the urine as Bence Jones ProteinIn the evaluation of kidney disease, the ideal screening test for an associated plasma-cell dyscrasia include immunofixation electrophoresis of serum and urine and quantification of serum free and light chainsA. AL-TYPE AMYLOIDOSISPathophysiology and Clinical Presentation:~20% of patients exhibit overt multiple myeloma or other lymphoproliferative disorder Systemic disease that typically involves multiple organs (Kidney, Heart, GI, Lung, Liver and CNS). Proteinuria (non-nephrotic to nephrotic range) and kidney function are the major kidney manifestations More commonly associated with members of family Pathology: Light Microscopy: Mesangial nodules that enlarge and cause progressive effacement of glomerular capillaries IF: Light chain deposits in mesangium, subepithelial space of capillary loops and may penetrate GBM in advanced stages. + congo red stain that produces apple-green birefringence under polarized light and with thioflavin T and S. EM: Randomly oriented, non-branching fibrils: 7-10 nm in diameter.Treatment/Prognosis:For AL-amyloidosis without features of MM, high-dose chemotherapy with autologous peripheral stem-cell transplantation (HDT/SCT) are an optionMore conservative approaches = patients age > 80 years, LVEF < 40%, SBP < 90 mmHg, oxygen saturation < 95% on room air, or overall significant functional impairmentPatients who undergo HDT/SCT have a median survival of 4.6 years compared to patients ineligible for HDT/SCT whose median survival is 4 monthsThalidomide, Lenalidomide and Bortezomib based regimens can be used to reduce monoclonal plasma cell population and light chain productionB. Light Chain Deposition Disease (LCDD):Clinical Presentation: Systemic disease that typically presents initially with isolated kidney injury related to non-amyloid granular deposits of monoclonal light chains with or without heavy chainsLCDD presents with proteinuria, sometimes in nephrotic range, microscopic hematuria, and kidney failure. Albumin and monoclonal light chains are the dominant proteins in the urine 50-60% of patients with LCDD will not develop myeloma or other malignant lymphoproliferative diseasePathology:Light Microscopy: Nodular glomerulopathy and distortion of glomerular architecture by amorphous, eosinophilic material. (Appearance resembles diabetic nephropathy)IF: Monotypic light chains in the glomeruli. light chains usually compose granular deposits of LCDD. EM: Sub-endothelial light chain protein deposits along the glomerular capillary wall. Treatment/Prognosis:In patients with MM, therapy directed towards MMIn patients with LCDD without MM, randomized controlled trials are not available to guide therapy but same therapeutic approach as used for MM can be employedMelphalan/prednisone, HDT/SCT, Thalidomide regimens and Bortezomib have shown efficacy If underlying plasma cell dyscrasia is not addressed, disease will recur in the transplant. Fabry DiseasePathogenesis and Clinical Presentation: X-linked lysosomal storage disorder that results from absent or deficient activity of the enzyme -Galactosidase A (encoded by GLA gene on Xq22) progressive accumulation of glycosphingolipids, predominantly globotriaosylceramide (GB3) in all organsReduced activity of -Galactosidase A in leukocytes confirms the diagnosis in male patientsIn women, genetic testing is mandatoryClinical Presentation: Early childhood: pain, anhidrosis and GI symptomsLater: CKD ESRD, hypertrophic cardiomyopathy and cerebral events. Urine sediment may show red and white cells, hyaline or granular casts or lipid particlesDue to non-specific symptoms, often a delay of 10-20 years from earliest symptoms to diagnosisUrinary GB3 is increased in many casesRenal imaging may show cortical or para-pelvic cysts. Pathology:Light Microscopy: Vacuolated, foamy podocytes seen; inclusions appear empty as content is removed during processingWith methylene blue or Toluidine blue staining, stored material can be visualizedAccompanying mesangial sclerosis, tubular atrophy, interstitial fibrosis, and sclerosis of arterial blood vessels depending on the stage of CKDElectron Microscopy: Podocytes with lamellated membrane inclusion bodies in secondary lysosomes can be seen. They may consist of concentric rings or have a “zebroid” striped appearance. Treatment/Prognosis/Transplantation: Directed therapy for each organ system/symptomsSpecific enzyme replacement therapy (Fabrazyme) with IV recombinant human -Galactosidase is available (infused at 1mg/kg over several hours every other week)Consider for every adult male and symptomatic femalePatients receiving dialysis have a poorer 3-year survival as compared with non-diabetics5-year survival after kidney transplantation is also lower. However, kidney transplantation offers the best survival advantage and should be first-choice in patients with Fabry disease. C1q NephropathyPathogenesis and Clinical Presentation: Criteria for diagnosis: predominant C1q deposits on IF and no clinical or laboratory evidence of SLEMay be associated with MCD, FSGS or proliferative GNClinical presentation: Nephrotic range proteinuria, hematuria and renal insufficiency Pathology: Among ~9000 renal biopsies reviewed from 1994 to 2002 from Columbia University in New York, 19 were classified as C1q nephropathy. 17 patients had FSGS (six with collapsing and two with cellular forms) on renal biopsy, and two had MCD. Treatment/Prognosis: Treat the underlying light microscopic lesion (eg, MCD or FSGS). Patients who have C1q nephropathy and FSGS are more likely to progress to ESKDAlport SyndromePathophysiology and Clinical Presentation: Disease of collagen that affects the kidneys, ears, and eyes 85% of patients have X-linked disease and most cases results from a mutation of COL4A5, a gene located at Xq22, that codes for the 5 chain of type IV collagenAutosomal inheritance occurs in 15% of casesForms with early onset of kidney failure in affected males are called juvenile, and those with kidney failure in middle age are called the adult type. Extra-renal manifestations are more common in juvenile kidnredClinical presentation: Microscopic hematuria-which may become apparent after exercise or feverDysmorphic RBCs and red-cell casts can be found in affected malesOcular changes that are diagnostic: anterior lenticonus, posterior polymorphous corneal dystrophy, and retinal flecksX-linked disease can progress to ESKD without over hearing loss. Half of those with adult-type will have no overt hearing lossPathology: Light Microscopy: Initially may be normal or near-normalAs disease progresses, interstitial and tubular foam cells may become prominentEventually progressive glomerulosclerosis and interstitial scarring develops; may look like FSGS. IF: Routinely negativeStaining for 5(IV) chain by immunohistochemistry may be informative. Male and female patients with autosomal recessive Alport and most male patients hemizygous for COL4A5 mutation show no staining of GBM with the 5 antibody. EM: GBM is up to 3 times its normal thickness and split into several irregular layers- frequently interspersed with numerous electron-dense granules about 40 nm in diameter. Treatment/Prognosis: Treat hypertension, especially by using ACE to slow progression of kidney failure Some reports claim benefit of using cyclosporine in reducing proteinuria. Others found little benefit. Hemizygous males inevitably progress to ESKD1/4 heterozygous females develop ESKD, usually after the age 50In families with autosomal inheritance, females are affected as early and as severely as males, and kidney failure often occurs before the age of 20 in homozygous autosomal recessive Alport syndromeThin Basement Membrane DiseasePathophysiology and Clinical Presentation: Autosomal dominant BM glomerulopathyHeterozygous mutations of the COL4A3 or COL4A4 gene @ chromosome 2May present with microscopic hematuriaPathology: LM and IF: No abnormalities of glomeruli, tubules, interstitium or vessels. EM: GBM is uniformly thinned to one-half its normal thickness. No disruption or lamellation of the GBM. Treatment/Prognosis: No treatment neededKidney failure seldom occursLongevity- unaffected Membranous Nephropathy (MN)Pathophysiology and Clinical Presentation: Results from immune-complex deposits in the sub-epithelial surface of the glomerular capillary wall podocyte injury with resultant proteinuria and potential nephrotic syndromePrimary (Idiopathic) membranous nephropathy: occurs without any identifiable cause or initiating event (75-80% of patients)Predominant autoimmune system responsible is that associated with autoantibodies directed at the M-type phospholipase A2 receptor (PLA2R) on podocytes (present in 75-80% of patients)Secondary membranous nephropathy: Autoimmune diseases e.g. Class V lupus nephritis Infections e.g. Hepatitis B Malignancy (solid tumors) e.g. colon, kidney, lung are most common Drugs or Toxins e.g. NSAIDsClinical Presentation: More common in men (2:1) and rare in childrenPrimary MN has peak incidence during the 4th and 5th decade of lifeMost common cause of nephrotic syndrome in non-diabetic Caucasian adultsMN in childhood is more often secondary (e.g. caused by HBV).70-80% of patients present with nephrotic syndrome while remaining present with subnephrotic asymptomatic proteinuria. Microscopic hematuria is present in 30-40% patients but red-cell casts are rare.Serum complement levels are normal in primary MNOnly 10-20% patients have hypertension (HTN) at the time of diagnosis< 10% patients present with renal impairmentClinically relevant thromboembolic events occur in the range of 10% of Nephrotic MS patientsA positive test for Anti-PLA2R is strongly suggestive of MN but negative test doesn’t exclude the diagnosis of idiopathic MNPathology: Formation of immune complexes at the interface of podocytes and GBM changes in podocytes deposition of new ECM between and around the immune deposits thickening of GBM (membranous change). In some cases, focal glomerulosclerosis, tubular atrophy and interstitial fibrosisLM:Earliest stage: Can be normal and diagnosis is made by IF and EM.Formation of sub-epithelial immune complexes of IgG and complement in which glomeruli appear histologically normal and can be mistaken for minimal changeNext stage: Homogeneous thickening of the capillary wall (PAS and H&E staining)Silver methenamine staining: Early projections of GBM between deposits may be detected in spike-like configurationLater: Lucencies may develop in the GBM as immune deposits are resorbed, resulting in craters within the thickened GBMLeukocyte infiltration is absent – No associated glomerular hypercellularityMesangial hypercellularity is suggestive of secondary MN, such as class V lupus nephritis. Tubulointerstitial Injury is common and correlates with both renal function and level of proteinuriaImmunohistology:Granular glomerular capillary wall staining for IgG (stains sub-epithelial deposits on the outer surface of all capillary walls)Predominant IgG subclass in primary MN is IgG4Positive staining for IgA, IgM, IgG1 or IgG3 or significant staining in the glomerular mesangium suggest lupus or other causes of secondary MNPositive C3 staining reflects active, ongoing immune deposit formationStrong C1q staining is more common in lupus-associated MNPLA2R staining in the immune deposits is present in anti-PLA2R-associated MNElectron Microscopy:Presence of sub-epithelial electron dense depositsEffacement of overlying foot processesIf disease persists, BM material is laid down between deposits spikes seen on LMOvert thickening of BM in later stages with less apparent spikesTreatment: Resolution depends on remission of the immune response, the extent of podocytes damage and expansion of the GBM. General management: RAS blockade, low-salt diet, diuretics, BP control (BP target < 125/75), dietary protein restriction, statins for treatment of hyperlipidemiaConsider anticoagulation for patients with proteinuria > 10g or albumin < 2.5 due to increased risk of thromboembolic events, especially in the first 2 years of presentationControl of proteinuria- associated with prolonged survival and slower rate of renal disease progression. Initiate treatment if patient has persistent nephrotic range proteinuria (>4g/day) that has not declined more than 50% over 6 months despite anti-hypertensive and anti-proteinuric therapyVery high levels of anti-PLA2R or rise in serum creatinine > 30% within 12 months due to disease progression might be an indication for early interventionMonitor 3 months (instead of 6) in patients with heavy proteinuria (>8g/day)Corticosteroid treatment alone is not sufficient for MN except in Japanese populationModerate risk of progression- use Ponticelli Regimen – Daily oral dose of cyclophosphamide alternating monthly with corticosteroids: methylprednisolone pulses (1g IV daily for 3 days at start of months 1,3 and 5) followed by oral prednisone (0.5mg/kg/day for 27 days) for 6 months. Likelihood of benefit is reduced and adverse effects increase in patients with impaired renal function, especially if GFR is < 30 ml/min) Calcineurin inhibitors (both cyclosporine and tacrolimus) reduce proteinuria in MNRelapses are common after short exposure (6-12 months) and a longer exposure at lower maintenance doses may help maintain partial remission. Treatment should be changed if there is no reduction in proteinuria in 3-4 monthsRituximab has shown to decrease proteinuria by 60-70% with remission continuing to occur after last infusionRelapse rate is less than the CNIs ACTH (1-2mg IM weekly for one year) showed a similar remission rate as cyclophosphamide+steroids in a small study Prognosis/Transplant: Spontaneous remissions in 30% of patients but less likely if proteinuria is severePatients with non-nephrotic proteinuria, no RBC casts, no hypertension, normal renal function and no systemic features of a secondary cause have a benign course25% ESRD rate by 8 years and 50% ESRD rate by 15 yearsPrognosis is worse if associated with superimposed renal conditions like drug-induce interstitial nephritis, superimposed crescentic GN or renal vein thrombosisPatients with primary MN are suitable candidates for transplant but disease may recur in 50% patientsPositive test for anti-PLA2R at transplantation predicts early recurrenceThrombotic Microangiopathy (TMA)Pathophysiology and Clinical Presentation: A group of diseases characterized by microangiopathic hemolytic anemia (MAHA), thrombocytopenia and kidney injuryThrombotic thrombocytopenic purpura (TTP) is caused by ADAMTS 13 deficiency Hemolytic Uremic Syndrome (HUS) usually occurs in pediatric patients who have infections with bacteria that produce Shiga-like toxin(Stx)Atypical HUS (aHUS): HUS that is not associated with Stx-producing bacterial infections and is due to defects in regulation of alternative complement pathway (also called complement-mediate TMA)An underlying defect in alternative complement pathway (70% of patients) Mutations in genes for factor H (most commonly affected gene), factor I, the CFHRs, MCP, C3 and MCP (better prognosis and may be self-limited)10% of patients have autoantibodies to factor HDiarrhea is the most common trigger for in children and pregnancy is the most common trigger in adultsSecondary HUS: Several systemic diseases (SLE, APS etc.), drugs (CNIs, cocaine etc.), Infections (E. Coli O157:H7, Hepatitis A, B and C etc.), and other systemic conditions (malignant hypertension, pregnancy etc.) are associated with TMAsClinical presentation-Triad of Anemia (Hemoglobin < 10g/dL), Thrombocytopenia (Platelet count < 150,000/L), and reduced kidney function with oliguria and hypertensionProteinuria and hematuria are observed with red-cell castsSchistocytes are present, LDH is and haptoglobin is ; Coombs test is negativeC3 may be low but is not pathognomonicNeurologic findings variable: ranging from drowsiness and slight confusion to seizures and coma TTP- diagnosed if ADAMTS 13 activity is <10%Complement analysis- measurement of circulating complement factors, anti-factor H antibodies, and screening for genetic mutations of CFH, CFI, MCP or CD46, C3, CFB and thrombomodulinPathology: LM: Endothelial damage and swelling with formation of double-contours along the glomerular capillary wallThrombi with schistocytes in glomerular capillaries, arterioles and small arteriesGlomeruli can appear shrunken with wrinkling of basement membraneThere may be evidence of cortical necrosis due to obstruction of microcirculationIF: Negative for immunoglobulin and complement factors and positive for fibrinogen in blood vesselsEndothelium of small arteries and arterioles may be positive for complement activation productsEM: Intracapillary fibrin and platelet aggregatesSubendothelial expansion with deposition of fluffy materialReduplication of GBMNo electron-dense depositsTreatment: aHUS-Eculizumab (monoclonal anti-C5 antibody that inhibits terminal complement pathway) normalizes hematologic parameters and kidney function and allows successful transplantation in patients who have already reached ESKDEffective complement inhibition is evaluated by measuring CH50, which is <10%Treatment discontinuation carries a risk of disease relapseWhen anti-factor H autoantibodies are present, plasma exchange is combined with immunosuppression (corticosteroids + azathioprine, MMF, cyclophosphamide or Rituximab)If eculizumab is not available or ADAMTS 13 activity is not readily available, plasma exchange therapy is started at 1.5 plasma volume, exchanging with FFPTTP- Treated with plasma exchange plus steroidsRituximab can be used for patients who fail to respond or relapse after initial treatment. If HUS is secondary to S.pneumoniae infection, therapy with plasma must be avoided as it worsens the disease. Prognosis/Transplantation: Untreated, natural history of full-blown clinical syndrome is severe, with 2-10% of patients dying and one-third progressing to ESKD? of patients experience disease relapsesExcept for patients with MCP mutations, all others have risk of post-transplant recurrenceAll patients with aHUS should be transplanted under Eculizumab therapy ................
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