Glomerular and Vascular Disorders



Glomerular and Vascular Disorders


Sharon G. Adler

Cynthia C. Nast

Tiane Dai

Phuong-Thu T. Pham

Phuong-Chi T. Pham



GENERAL PRINCIPLES IN THE MANAGEMENT OF GLOMERULAR DISEASES


Kidney Biopsy



  • Kidney biopsy should be performed when results will change management and/or refine prognosis. See Fig. 7.1 for kidney biopsy indications.


  • Repeat kidney biopsy indications:



    • Initial biopsy is inadequate for diagnosis.


    • Biopsy results will change management and/or refine prognosis.



      • Poor response to therapy


      • Unexpected deterioration of kidney function


      • Clinical or laboratory findings suggesting a change in severity of same disease (e.g., conversion of membranous to active diffuse lupus nephritis [LN])


      • Clinical or laboratory findings suggesting a new disease process






        FIGURE 7.1 Kidney biopsy indications.

        aA kidney biopsy may also be performed at the discretion of the nephrologist (e.g., new unexplained active urinary sediment or worsening proteinuria).

        bIn the presence of positive anti-GBM antibodies and classic presentation.

        cPositive genetic analysis; Low α-galactosidase A activity in leukocytes of males with history in Fabry disease.

        Abbreviations: ANCA, antineutrophil cytoplasmic antibody; eGFR, estimated glomerular filtration rate; FSGS, focal segmental glomerulosclerosis; GBM, glomerular basement membrane; GN, glomerulonephritis; MN, membranous nephropathy; MPO+, myeloperoxidase positive; PLA2R, phospholipase A2 receptor; PR3+, proteinase 3 positive.



      • Unclear cause of glomerular filtration rate (GFR) deterioration, chronic progression versus active disease


      • Determination of disease chronicity for treatment decisions (stop, continue, or intensify therapy)


  • Kidney biopsy adequacy:



    • Defined by sample size and location submitted for each microscopic method used (Fig. 7.2)


    • In general, a minimum of 8 to 10 glomeruli/biopsy; diffuse diseases can be diagnosed with one glomerulus (membranous nephropathy [MN], immunoglobulin A [IgA] nephropathy [IgAN]).


    • However, activity, chronicity, and other findings require more biopsy tissue.


    • Focal and/or segmental disease diagnosis requires more glomeruli (may need 20 glomeruli for focal segmental glomerulosclerosis [FSGS]).


General Management Considerations for Glomerular Diseases


Hypertension (HTN)



  • Goal systolic blood pressure (SBP) is <120 mm Hg using standardized office BP measurement in adult patients and <140/90 mm Hg in pregnant patients with glomerular disease and proteinuria.


  • Lifestyle modifications: salt restriction, weight optimization, exercise, smoking cessation


  • Clinical data support angiotensin-converting enzyme inhibitor (ACEI) or angiotensin-receptor blocker (ARB) as first-line therapy if safely tolerated:



    • Educate discontinuation for volume depletion (vomiting, diarrhea, sweating from high fever/strenuous exercise).


    • Monitor serum creatinine (SCr) and K+ frequently: Discontinue if SCr rises >20% from baseline.


    • K+-lowering medications may be considered if hyperkalemia limits ACEI/ARB tolerability. See Chapter 2.






      FIGURE 7.2 Kidney biopsy adequacy.

      aWhile a limited diagnosis can be made, additional information (activity, chronicity, presence of secondary FSGS or crescents) will not be available when the specimen is suboptimal.

      Abbreviations: AA, amyloid A; AL, amyloid light chain; DNAJB9, DnaJ homolog subfamily B member 9; FSGS, focal segmental glomerulosclerosis; H&E, hematoxylin and eosin; LECT2, leukocyte chemotactic factor 2; MN, membranous nephropathy; PAS, periodic acid-Schiff; PLA2R, phospholipase A2 receptor; THSD7A, thrombospondin type 1 domain containing 7A.



  • Second-line medical therapy:



    • Mineralocorticoid-receptor antagonist (e.g., spironolactone, eplerenone):



      • Useful antihypertensive and antiproteinuric agents, particularly in ACEI/ARB intolerant patients


      • May require discontinuation if hyperkalemia develops


      • Salvage therapy with K+ binders may be feasible.


  • Additional strategies:



    • Reducing BP with antihypertensive agents without angiotensin blocking activity also reduces proteinuria.


    • Loop and thiazide diuretics improve BP control, reduce hyperkalemia, and enhance the antiproteinuric effect of renin-angiotensin-aldosterone system inhibitor (RAASi).


Proteinuria



  • First-line medical therapy:



    • ACEI or ARB may reduce proteinuria by 40% to 50%. ACEI/ARB may be delayed in normotensive patients with podocytopathy expected to be easily responsive to immunosuppression (e.g., minimal change disease [MCD], primary FSGS, or steroid-sensitive nephrotic syndrome [NS]).


    • Combination may result in additive antiproteinuric effect, but hyperkalemia and acute kidney injury (AKI) may also be additive and unacceptable.


  • Others:



    • For patients who cannot tolerate ACEI or ARB, consider nondihydropyridine calcium channel blockers (e.g., diltiazem).


    • Intensify dietary sodium restriction (<2 g sodium) and consider using mineralocorticoid-receptor antagonists in patients who fail to achieve proteinuria reduction despite maximal medical therapy.


  • Dietary protein intake in patients with proteinuria (emphasize plant sources):



    • For patients with nephrotic-range proteinuria, advise 0.8 to 1 g/kg ideal body weight/d; add an additional 1 g/g of urinary protein losses (up to 5 g/d).


    • For those with non-nephrotic-range proteinuria and estimated GFR (eGFR) < 60 mL/min/1.73 m2, advise 0.8 g/kg/d.


Hyperlipidemia



  • Statin (HMG-CoA reductase inhibitors) use should be per standard guidelines for those with increased atherosclerotic cardiovascular disease (ASCVD) risks. Note that reduced eGFR < 60 mL/min/1.73 m2 not on dialysis and albumin to creatinine ratio (ACR) > 30 µg/mg are independently associated with increased risk of ASCVD.


  • Statins have not been proven to reduce cardiovascular events (CVEs) in NS (particularly MCD).


  • The renoprotective effect of statins in slowing GFR decline is not established.


  • The role for nonstatins (e.g., ezetimibe, fibrates, or PSCK9 inhibitors) in NS remains to be defined.


Nephrotic edema



  • Intravenous (IV) loop diuretics should be considered if anasarca is present because bowel wall edema limits oral medication absorption. Twice-daily administration is preferred.



  • Furosemide-resistant edema:



    • Consider switching furosemide to torsemide or bumetanide for better bioavailability.


    • Add thiazide, thiazide-like diuretics (e.g., metolazone), and/or mineralocorticoid antagonists to loop diuretics.


    • For diuretic-resistant edema, consider amiloride, acetazolamide, IV loop diuretics, ultrafiltration, or hemodialysis. In particular, consider adding amiloride in patients with high degree of proteinuria. Patients with proteinuria may have increased urinary plasmin level that directly stimulates sodium epithelial channel (ENaC) activity, thus sodium reabsorption.


    • Consider albumin infusion with diuretics, although benefit remains unproven.


  • Dietary sodium restriction < 2.0 g (<90 mmol) daily


Hypercoagulability



  • Increased thromboembolism (TE) risk in patients with NS with serum albumin <2.5 g/dL


  • Anticoagulation with heparin or warfarin (target international normalized ratio [INR] 2 to 3) if known arterial or venous thrombosis or pulmonary embolism for 6 to 12 months and/or for the duration of the NS


  • Consider prophylactic full-dose anticoagulation if serum albumin <2.0 to 2.5 g/dL and one or more of the following: proteinuria >10 g/d, body mass index > 35 kg/m2, family history of TE with documented genetic predisposition; New York Heart Association functional class III or IV congestive heart failure, recent abdominal or orthopedic surgery, or prolonged immobilization.


  • During heparin anticoagulation, a higher-than-average dose may be required because part of heparin action depends on antithrombin III, which may be lost in urine in nephrotic patients.


  • Aspirin may be used in lieu of heparin or warfarin in patients with high bleeding risk.


  • Aspirin may also be used in patients with serum albumin between 2.5 and 3.2 g/dL and increased estimate arterial TE risk of > 20/1,000 person-year.


  • Neither the efficacy nor safety of direct thrombin and factor Xa inhibitors has been systematically studied in patients with nephrotic-range proteinuria.


Risk of infection



  • Spontaneous bacterial peritonitis (SBP) may occur in nephrotic patients with ascites. Empiric antibiotics should include benzylpenicillin (pneumococcal infection).


  • In recurrent SBP, consider monthly IV Ig 400 mg/kg daily × 4 days to keep serum IgG >600 mg/dL (limited evidence).


  • Screening and treatment for latent diseases should optimally be performed prior to or concomitant with the initiation of immunosuppression.



    • For most patients, screen for hepatitis B and C, human immunodeficiency virus (HIV), syphilis, and tuberculosis (TB).


    • For patients from a tropical climate, screen for Strongyloides.


  • Latent TB should be treated concomitantly with immunosuppression. Four months of rifampin has been suggested to be noninferior to 9 months of isoniazid and pyridoxine. Note however, rifampin may decrease the bioavailability of corticosteroids.



  • Prophylactic trimethoprim-sulfamethoxazole (dapsone or atovaquone if sulfa-allergic) should be considered as prophylactic therapy against Pneumocystis jirovecii (previously known as Pneumocystis carinii pneumonia) when high-dose corticosteroids or other immunosuppressive agents are used.


  • Pneumococcal vaccination with both heptavalent conjugate vaccine (7vPCV) and 23-valent polysaccharide vaccine (23vPPV), annual influenza vaccination, and recombinant herpes zoster vaccine should be given.



    • The effectiveness of the recombinant zoster vaccine may be diminished in patients taking corticosteroids.


    • Vaccination with both a meningococcal conjugate vaccine (MenACWY) and a serogroup B meningococcal vaccine (MenB) should be provided to patients receiving complement inhibitor medications (i.e., eculizumab). Since these may confer only partial protection, the Centers for Disease Control also recommends additional concomitant meningococcal antibiotic prophylaxis (cdc.gov/meningococcal/clinical/eculizumab.html).


NEPHRITIC GLOMERULAR DISORDERS AND VASCULITIS/VASCULOPATHY


Immunoglobulin A Nephropathy


Background



  • Most common glomerulonephritis (GN) worldwide


  • Highest incidence in Eastern Asians; common in South Indians, Native Americans, and Mediterranean Europeans; very low incidence in African Americans


  • 15% to 25% reach end-stage kidney disease (ESKD) within 10 years, and 20% to 40% by 20 years


  • Comprises 10% to 20% of ESKD due to high prevalence


Pathogenesis (multistep model, steps 1 to 5)



  • Initial mucosal inciting event/pathogen exposure:



    • Naïve mucosal B cells switch class to become IgA antibody-secreting cells through T-cell-dependent (cytokine-mediated) and T-cell-independent (Toll-like-receptor ligation) pathways.


    • Mucosal types IgA are IgA1 with galactose deficient at hinge region (Gd-IgA1).













      image


      Normal circulating IgA1


      image


      Mucosal type galactose deficient at hinge region of IgA1 (Gd-IgA1)



  • Due to genetic and/or other undetermined factors, some mucosal Gd-IgA1 secretory B cells “mis-home” or “mis-traffic” and enter systemic compartments while continuing to secrete Gd-IgA1 systemically.


  • Antibodies directed against the underglycosylated hinge region of Gd-IgA1 are produced, likely driven by molecular mimicry.











    image


    IgA or IgG antibodies directed against Gd-IgA1 are produced.



  • The immune complexes [ICs] deposit in the mesangium in the kidneys



    • ICs are preformed in circulation or formed in situ when circulating IgA or IgG antibodies bind to previously deposited IgA1 in the mesangium.



    • ICs deposition in the mesangium is likely driven by mesangial trapping and increased affinity for Gd-IgA1 by mesangial matrix.


  • Deposited ICs activate complement and other pathways and lead to mesangial cell proliferation, matrix deposition, glomerular injury, and tubulointerstitial fibrosis.


Clinical manifestations

IgAN may present as primary GN, a GN secondary to a systemic disease, or a systemic vasculitis.


Primary IgAN



  • May present at any age


  • Organ involvement is restricted to the kidneys.


  • Presents with diverse clinical patterns



    • Episodic macroscopic “gross” hematuria



      • More common in children


      • Associated with upper respiratory tract infection or gastroenteritis



        • Gross hematuria occurs concurrently (synpharyngitic) or within 3 days of onset of infection.


        • Typically resolves by 3 days (different than postinfectious glomerulonephritis [PIGN])


        • Hematuria may be accompanied by flank or loin pain.


    • Asymptomatic hematuria and proteinuria (incidental finding):



      • More common in adults


      • Prolonged remission of clinical signs is common.


    • HTN and impaired kidney function


    • Gross hematuria with concurrent AKI


    • Nephrotic-range proteinuria



      • Occasionally with concomitant kidney biopsy findings consistent with MCD


      • May have concomitant FSGS and present with or without NS


    • Slowly progressive chronic kidney injury


    • Rapidly progressive (crescentic) glomerulonephritis (RPGN)


Secondary IgAN



  • Generally, secondary IgAN presents in association with conditions involving organs that produce or clear IgA, conditions that stimulate IgA production, or autoimmune diseases.


  • Conditions associated with IgAN:



    • Skin: dermatitis herpetiformis, psoriasis, psoriatic arthritis


    • Liver: alcoholism, primary biliary cirrhosis, cirrhosis; hepatitis B, chronic schistosomiasis. Cirrhotic liver has reduced capacity to metabolize/clear IgA.


    • Gastrointestinal (GI) tract: inflammatory bowel disease, celiac disease, ulcerative colitis, Crohn


    • Pulmonary: sarcoidosis, idiopathic hemosiderosis, cystic fibrosis, bronchiolitis obliterans, antineutrophil cytoplasmic antibody (ANCA) disease involving upper respiratory tract


    • Neoplasia: lung, larynx, pancreas, mycosis fungoides



    • Infection: HIV, leprosy


    • Systemic or immunologic disorders: systemic lupus erythematosus (SLE), rheumatoid arthritis, cryoglobulinemia, ankylosing spondylitis, Sjögren, Behçet, Reiter, familial immune-mediated thrombocytopenia, autoantibody IgA-mediated Goodpasture


    • Infectious: IgA-dominant infection-related GN (IgADIRGN)


Systemic IgA Vasculitis (i.e., Henoch-Schönlein Purpura)



  • IgA vasculitis (IgAV) usually occurs in the first decade of life but may occur at any age.


  • Children: Ankara 2008 composite IgAV classification requires:



    • Purpura or petechiae with lower limb predominance, and


    • At least one of the following four criteria: (1) abdominal pain, (2) histopathology, (3) arthritis or arthralgia, (4) renal involvement


    • 100% sensitivity and 87% specificity for IgAV


  • Adults: American College of Rheumatology (1990) published criteria for IgAV



    • Requires at least two of the following: (1) age ≤20 years at disease onset, (2) palpable purpura, (3) acute abdominal pain, (4) skin or bowel wall biopsy showing granulocytes in the walls of small arterioles/venules


    • 87.1% sensitive and 87.7% specific for IgAV


  • Patients with IgAV should be screened for malignancy and other secondary causes.


Diagnosis of IgAN



  • Diagnosis is by kidney biopsy.


  • Currently, there are no validated surrogate diagnostic or prognostic markers.


Histopathology (Fig. 7.3)



  • Light microscopy (LM): mesangial expansion and hypercellularity, may be segmental and/or global glomerulosclerosis, endocapillary hypercellularity, crescents


  • Immunofluorescence (IF): dominant or co-dominant mesangial IgA deposits



    • IgG, IgM, and/or C3


    • Staining for λ is typically greater than κ.


“MEST-C” OXFORD Classification for primary IgAN



  • Definition:



    • Mesangial hypercellularity: >50% glomeruli = M1, otherwise M0


    • Endocapillary hypercellularity: ≥one occluded glomerular capillary = E1, otherwise E0


    • Segmental sclerosis: ≥one segment of sclerosis or adhesion = S1, otherwise S0


    • Tubular atrophy and interstitial fibrosis: T0 = 0% to 25%, T1 = 26% to 50%, T2 >50%


    • Crescents: C0 = no crescent



      • C1 = active (cellular/fibrocellular) crescent in at least one glomerulus but <25% of glomeruli


      • C2 = active crescents in ≥25% of glomeruli







        FIGURE 7.3 Immunoglobulin A (IgA) nephropathy. A. Global mesangial hypercellularity (M1 lesion) (periodic acid-Schiff ×400). B. Endocapillary hypercellularity with luminal occlusion (arrows) (E1 lesion) (periodic acid-Schiff ×400). C. Mesangial hypercellularity and segmental glomerulosclerosis (M1 and S1 lesions) (periodic acid-Schiff ×400). D. Global mesangial IgA (×275). E. Mesangial electron-dense deposits, prominent in the paramesangial region (arrow) with a single subepithelial deposit (×14,000).


  • MEST-C scoring predicts renal outcome.



    • M1, S1, ≥T1, and ≥C1 are associated with worse prognosis.


    • M1, S1, and T1 are additive.


    • E1 and C1 may be improved with immunosuppression.


  • There are insufficient data to support the use of MEST-C scoring to guide treatment or predict response in patients with IgAN.


Management



  • Table 7.1 summarizes management strategies for patients with IgAN.


Supportive care



  • Provide supportive care as tolerated for all patients with any variant of IgAN


  • ACEI or ARB, but not both, is recommended in all patients with proteinuria > 0.5 g/d with or without HTN.


  • Aldosterone blockers may also be considered for antiproteinuric and antifibrotic effects.


  • Healthy lifestyle modifications per routine American College of Cardiology/American Heart Association (ACA/AHA) HTN guidelines


  • Consider tonsillectomy only if recurrent tonsillitis









Table 7.1 Management strategies for primary IgAN and variants





























All patients with any form of IgAN




  • BP control with goal systolic pressure < 120 mm Hg using standardized office BP as safely tolerated



  • ACEI or ARB is recommended if proteinuria > 1 g/d, otherwise ACEI/ARB is suggested.



  • Aldosterone blockers may also be considered for antiproteinuric and antifibrotic effects.



  • Healthy lifestyle modifications per routine ACA/AHA hypertension guidelines



  • IST is not recommended if eGFR < 30 mL/min/1.73 m2 (not reflecting AKI) and/or kidney biopsy evidence of chronic disease.


Primary IgAN




  • Consider IST for persistent proteinuria > 1g/d despite maximal routine care above for 6 mo



  • Suggested IST (data on optimal therapy are still lacking):




    • Oral prednisone at 0.8-1.0 mg/kg/d × 2 mo, then reduce by 0.2 mg/kg/d per month for the next 4 mo, or



    • Intravenous bolus of 1 g methylprednisolone × 3 d at months 1, 3, and 5, followed by oral prednisone at 0.5 mg/kg/d on alternate days × 6 mo



  • Alternative:




    • Low-dose corticosteroid + MMF (Chinese study)



    • MMF was not beneficial in a study involving Caucasians.



  • Other considerations:




    • Tonsillectomy: only consider in patients with recurrent tonsillitis



    • Not recommended due to lack of evidence: anticoagulants, antiplatelets, AZA, CYC, fish oil


Secondary IgAN




  • Treat underlying etiology if possible


Nephrotic IgAN with MCD



Rapidly progressive/crescentic IgAN




  • Rule out and treat secondary causes (e.g., acute inflammatory disorders or ongoing infections)



  • Treat with CYC and corticosteroids analogous to ANCA-associated vasculitis if clinical safe


IgA vasculitis (HSP)




  • Consider corticosteroids course above


Pregnancy




  • Consider 6-mo course of IST prior to conception if high progression risk


Children




  • Most pediatric nephrologists treat children with proteinuria > 1g/d and mesangial hypercellularity (Oxford M1) with RAASi + corticosteroids.



  • Children with rapidly progressive IgAN have a poor outcome, corticosteroids and oral CYC may be considered.


Abbreviations: ACA/AHA, American Cardiology Association/American Heart Association; ACEI, angiotensin-converting enzyme inhibitor; AKI, acute kidney injury; ANCA, antineutrophil cytoplasmic antibody; ARB, angiotensin-receptor blocker; BP, blood pressure; eGFR, estimated glomerular filtration rate; IgAN, IgA nephropathy; MCD, minimal change disease; MMF, mycophenolate mofetil; RAASi, renin-angiotensin-aldosterone system inhibitor.



Immunosuppressive therapy for primary IgAN



  • Consider treatment for patients with high risk of chronic kidney disease (CKD) progression, for example, persistent proteinuria > 1 g/d despite maximal supportive care for 6 months.



  • Consider enrollment in clinical trial if applicable.


  • Otherwise, consider a 6-month course of corticosteroid (weak evidence). Mycophenolate mofetil (MMF) may be considered as a steroid-sparing agent in Chinese patients. Data for non-Chinese are insufficient.


  • Agents not recommended at this time: azathioprine (AZA), cyclophosphamide (CYC) (unless rapidly progressive IgAN [RP IgAN]), calcineurin inhibitor (CNI), rituximab (RTX), fish oil; data on Acthar gel remain scant.


Considerations for IgAN variants



  • Nephrotic IgAN with minimal change on biopsy: treat as minimal change


  • IgAN with AKI in the absence of common reversible causes: Repeat kidney biopsy if AKI persists for ≥ 2 weeks to rule out rapidly progressive (RP) IgAN.


  • RP IgAN: treat with CYC and corticosteroids similar to the treatment of ANCA-associated vasculitis (AAV). RTX has not been shown to be effective in this IgAN subset. (RP IgAN is defined as a kidney biopsy with mesangial and endocapillary hypercellularity, many crescentic glomeruli, often with segmental focal necrosis. Clinically, RP IgAN is defined as ≥50% decline in eGFR over 3 months or less after excluding reversible causes [e.g., pre- and post-kidney causes]. Having crescents without a concomitant decline in kidney function does not define RP IgAN.)


  • Secondary IgAN: evaluate and treat secondary causes


  • IgAV: for patients at high risk for CKD progression despite maximal supportive care: treat with corticosteroids as described above for primary IgAN.


  • IgAN in pregnancy planning: For patients with high CKD progression risk, consider a 6-month course of immunosuppression to optimize proteinuria prior to conception.


  • IgAN in children:



    • Most pediatric nephrologists treat children with proteinuria > 1 g/d and mesangial hypercellularity (Oxford M1) with RAASi + corticosteroids.


    • Children with RP IgAN have a poor outcome. Treatment with corticosteroids and oral CYC may be considered (limited data).


Caveats regarding immunosuppressive therapy for patients with IgAN



  • For patients with non-nephrotic proteinuria, the benefits of corticosteroids have not been proven. Corticosteroids should be avoided in patients with relative contraindications, including diabetes mellitus (DM), obesity, latent infections (e.g., viral hepatitis, TB), secondary IgAN, uncontrolled psychiatric illness, and a history of upper GI bleeding.


  • Immunosuppressive therapy is not recommended for patients with eGFR <30 mL/min/1.73 m2 that does not reflect AKI and/or those with a high-quality (good sampling) kidney biopsy consistent with chronic disease.


  • Risks and benefits of using immunosuppression must be discussed in patients with eGFR < 50 mL/min/1.73 m2 due to the increased likelihood of adverse effects.


  • The presence of crescents in a kidney biopsy is not an automatic indication for starting immunosuppression in the absence of concomitant functional change.


Prognostic indicators



RENAL AND SYSTEMIC VASCULITIDES


Classification of Vasculitis


Large-sized vessels: aorta → renal artery



  • Granulomatous arteritis: giant cell or Takayasu arteritis (Table 7.2)


  • Patients >50 years of age: giant cell arteritis


  • Patients <50 years of age: Takayasu arteritis


Medium-sized vessels: renal artery → interlobar artery → arcuate artery



  • Necrotizing arteritis: polyarteritis nodosa (PAN) or Kawasaki disease (Table 7.3)


  • Polyarteritis nodosa



    • Usually occurs in adults and without mucocutaneous lymph node (MCLN)


    • Microaneurysms may resemble “beads on a chain” on angiogram (Fig. 5.3).


  • Kawasaki disease



    • Typically occurs in children in association with MCLN syndrome








Table 7.2 Large-sized vasculitis: Giant cell versus Takayasu arteritis































Giant Cell Arteritis


Takayasu Arteritis


Age of onset


Typically > 50 y old


10-20 y old; very rare after age 50


Gender


Female:Male: 4:1


Female:Male: 9:1


Pathogenesis


Unclear: thought to involve genetics, sex, and age-related alterations of the immune and arterial systems


Unclear: presumed autoimmune disease triggered by bacteria, viruses, or tuberculosis followed by an autoimmune process driven by molecular mimicry


Clinical manifestations


Headaches, temporal artery tenderness, blindness, deafness, jaw claudication, tongue dysfunction, reduced pulses, extremity claudication; >50% have polymyalgia rheumatica (stiffness and aching of the neck, hips, shoulders); renal involvement is rare compared with Takayasu; hypertension possible


Reduced pulses, vascular bruits, claudication, renal ischemia due to renal artery stenosis or aortic coarctation; hypertension possible


Pathology


Renal arteries may be involved, but significant disease is rare.


Ischemic renal disease relatively common; glomerular lesion possible; nodular mesangial matrix expansion, mesangiolysis


Treatment


Same for both conditions: corticosteroid (prednisolone 1 mg/kg/d for 1 mo, followed by slow taper over several months. Persistent disease requires prolonged corticosteroid and/or cytotoxic agents (e.g., cyclophosphamide); patients with giant cell arteritis should also be on low-dose aspirin to reduce thrombotic risks. Surgical bypass or angioplasty may be required when disease is quiescent.










Table 7.3 Medium-sized vasculitis: Polyarteritis nodosa versus Kawasaki arteritis


































Polyarteritis Nodosa (PAN)


Kawasaki


Age of onset




  • Age 40-60 y old




  • Young children, peaks at age 1, typically < 5 y old


Epidemiology




  • No gender preference




  • Asians and Polynesians > Caucasians and blacks



  • Sporadic; occasional endemic or endemic pattern


Pathogenesis




  • Unknown; immune-complex trigger (e.g., HBV, other infections) suggested, but not confirmed



  • Absence of ANCA




  • Not clear



  • Possible precipitating factors: agent or environmental toxin



  • Both cell- and antibody-mediated mechanisms possible


Clinical manifestations




  • ACR criteria: having a radiographic or pathologic diagnosis of vasculitis and ≥three of the following: (1) weight loss ≥ 4 kg, (2) livedo reticularis, (3) testicular tenderness, (4) myalgia or leg weakness/tenderness, (5) mononeuropathy or polyneuropathy, (6) DBP > 90 mm Hg, (7) elevated BUN or SCr unrelated to dehydration or obstruction, (8) HBsAg or HBsAb, (9) arteriogram with aneurysms or occlusions of visceral arteries, (10) positive polymorphonuclear neutrophils in biopsy of small- or medium-sized artery



  • No mucocutaneous lymph node involvement




  • Mucocutaneous lymph node syndrome: fevers, mucosal inflammation, swollen red (strawberry) tongue, polymorphous erythematous rash, indurative edema of extremities, erythema of palms/soles, desquamation from tips of digits, conjunctival injection, lymphadenopathy, coronary arteritis (possible myocardial infarction).



  • Renal arteritis is uncommon.



  • Disease is typically self-limited.


Histopathology




  • Renal artery, interlobar, arcuate, interlobular arteries; involvement of capillaries, arterioles venous beds exclude PAN



  • Nodular inflammatory lesions and aneurysms in arteries



  • Acute arterial lesion: segmental transmural fibrinoid necrosis and/or leukocyte infiltration; chronic changes: arterial wall erosions from necrotizing inflammation into surrounding perivascular tissue leading to appearance of enlarged lumen, hence “pseudoaneurysm” and propensity for thrombosis and rupture



  • Note: Light microscopy changes of involved vessels are indistinguishable from ANCA-associated GN.




  • Small and medium arteritis with necrotizing inflammation, frequently involving coronaries and renal arteritis (interlobar > arcuate > interlobular arteries)



  • Pseudoaneurysm formation and thrombosis may occur.


Treatment




  • Corticosteroid alone may be adequate if benign (younger age, no cardiac, gut, or renal involvement).



  • If no hepatitis B: corticosteroid and/or cytotoxic agent (e.g., cyclophosphamide)



  • If hepatitis B+ and severe disease: consider a short course of corticosteroid + plasma exchange pending response to antiviral therapy.




  • Aspirin and intravenous Ig therapy and/or corticosteroids



  • Recurrence is rare if promptly treated.


Abbreviations: ACR, American College of Rheumatology; ANCA, antineutrophil cytoplasmic antibody; BUN, blood urea nitrogen; DBP, diastolic blood pressure; GN, glomerulonephritis; HBsAb, hepatitis B surface antibody; HBsAg, hepatitis B surface antigen; HBV, hepatitis B; SCr, serum creatinine.




Small-sized vessels: interlobar artery → arcuate artery → interlobular artery → arterioles → glomerular capillaries



  • Immune complexes in vessel walls:



    • Cryoglobulins: cryoglobulin deposits often affecting both skin and glomeruli


    • IgA-dominant deposits (IgAV): vasculitis involving skin, gut, and glomeruli, with associated arthritis/arthralgias


    • SLE or rheumatoid arthritis


    • Others: postinfectious, hypocomplementemic urticarial (anti-C1q) vasculitis


  • Circulating ANCAs with paucity of vascular or glomerular Ig staining:



    • Lung granulomas and no asthma: granulomatous polyangiitis (GPA)


    • Eosinophilia, asthma, and lung granulomas: eosinophilic granulomatosis with polyangiitis (EGPA)


    • No asthma or lung granulomas: microscopic polyangiitis (MPA)


ANCA Vasculitis


Definition of ANCA



  • ANCA are antineutrophil cytoplasmic autoantibodies directed against various lysosomal enzymes that “serve” as antigens.



    • Some ANCA are directed against proteinase 3 (anti-PR3).


    • Some ANCA are directed against myeloperoxidase (anti-MPO).


    • Other (atypical) ANCA are directed against other antigens/proteinases (e.g., human neutrophil elastase [HNE], lysozyme).



      • The pathogenic roles of atypical ANCAs are unclear.


      • Cystic fibrosis: ANCA directed against bactericidal/permeability-increasing protein


      • Cocaine adulterated with levamisole:



        • Most if not all patients appear to have MPO-ANCA, 50% also with PR3-ANCA.


        • ANCA may also be directed against HNE.


        • Affected patients may present with purpuric to necrotic skin lesions, often earlobes and nose


        • Renal manifestations may include crescentic GN or renal infarction


      • Inflammatory bowel disease: atypical ANCA directed at high mobility groups (HMG) 1 and/or 2


c-ANCA and p-ANCA



  • Cytoplasmic (c-ANCA) and perinuclear (p-ANCA) refer to the ANCA staining pattern in ethanol-permeabilized neutrophils exposed to patient serum.



    • All antigens (including MPO) are cytoplasmic in vivo.


    • c-ANCA is typically directed against PR3.


    • p-ANCA is typically directed against MPO.


    • Atypical ANCAs are directed at antigens other than MPO or PR3.


    • c-ANCA and p-ANCA can bind to proteinases other than PR3 and MPO that are not necessarily pathogenic.


    • Initial testing for ANCA should include indirect immunofluorescence microscopic assay (IFA) for c-ANCA or p-ANCA pattern followed by enzyme immunoassay (EIA) for specificity against PR3, MPO, or other antigens.



Notes regarding ANCA



  • Classic PAN is usually ANCA negative.


  • 30% of patients with anti-glomerular basement membrane (anti-GBM)-positive sera, 25% of patients with SLE, and 25% of patients with idiopathic IC crescentic GN have concurrent ANCA.


  • 5% of patients with ANCA-positive sera also have anti-GBM antibodies.


  • Patients with concurrent anti-GBM and ANCA antibodies:



    • Rare occurrence


    • May be fortuitous coexistence of anti-GBM and ANCA


    • Anti-GBM may develop following GBM injury from ANCA-associated GN.


    • Disease course is similar to anti-GBM GN in early disease, but relapse pattern is similar to ANCA disease.


Proposed pathogenesis of AAV



  • Priming of neutrophils by cytokines (e.g., from a viral infection) leads to:


  • Increased neutrophil expression/trafficking of cytoplasmic ANCA antigens (e.g., PR3 or MPO) onto cell surfaces, where they are accessible to ANCA.


  • The ANCAANCA antigen interaction in cytokine-primed neutrophils leads to:



    • Neutrophil release of enzymes from granules, toxic oxygen metabolites, inflammatory mediators into surroundings and


    • Adherence of activated neutrophils to endothelial cells, both leading to:


  • Endothelial cell injury, vascular thrombosis, and downstream ischemia


Clinical manifestations



  • See Table 7.4 for well-characterized ANCA syndrome specific clinical manifestations.


  • ANCA-associated GN may present with non-nephrotic proteinuria and hematuria, acute nephritis with necrosis and new crescents, rapidly progressive nephritis with crescentic GN, or slowly progressive nephritis.


  • Nonspecific signs and symptoms of necrotizing vasculitis: cutaneous purpura, papular/ulcerated lesions, peripheral neuropathy (mononeuritis multiplex), nonspecific muscular/joint pain, evidence of GI bleed, tendency for venous thrombosis


Histopathology



  • ANCA-associated (pauci-immune) crescentic GN often has crescents in different stages simultaneously (acute, subacute, and chronic lesions) due to the relapsing nature of the disease (Fig. 7.4).


Management



  • Table 7.5 summarizes management strategies for AAV.


Induction therapy



  • Corticosteroids plus either CYC or RTX is recommended for new-onset AAV with renal involvement.


  • Considerations to select CYC versus RTX:



    • CYC is the preferred agent for the following:









      Table 7.4 Clinical manifestations of ANCA-associated vasculitis syndromes









































      ANCA-associated vasculitis syndromes


      MPA 30%-40% PR3, 50%-60% MPO, 10%-30% negative ANCA


      GPA 75%-90% PR3, 10%-20% MPO, 5%-10% negative ANCA


      EGPA 5%-10% PR3, 40%-60% MPO, 30%-50% negative ANCA


      Renal limited vasculitisa 10%-20% PR3,70%-90% MPO, 10% negative ANCA


      Patient characteristics


      Fifth to eighth decade of life with MPO-ANCA in the older age range; slight male predominance; more common in white than black.


      Lungs


      Necrotizing vasculitis without granulomatous inflammation


      Necrotizing Granulomatous inflammation; sinusitis, rhinitis, otitis media, lung nodules/cavitation, saddle nose, ocular lesions more specific with PR3-ANCA; MPO-ANCA may present with chronic lung fibrosis


      Asthma; Eosinophil-rich and Granulomatous inflammation


      Kidneys


      Often rapidly progressive disease but can be indolent or chronic, PR3-ANCA tends to be more acute in presentation compared to the more indolent chronic presentation seen with MPO-ANCA.


      Kidney disease is less frequent and less severe than MPA or GPA.


      ANCA-positive glomerulonephritis without any classic systemic symptomology for MPA, GPA, or EGPA


      Gastrointestinal


      50% of patients with MPA, GPA, or EGPA may have abdominal pain, bloody stool with mesenteric ischemia/intestinal infraction/perforation, pancreatitis, hepatitis.


      Skin


      Nodular cutaneous lesions are rare


      Skin nodules due to dermal or subcutaneous arteritis and necrotizing granulomatous infiltration


      Neurological


      Peripheral neuropathy, usually mononeuritis multiplex pattern; up to 70% in EGPA, 50% GPA, 30% MPA


      Central nervous system involvement less common, may present as vasculitis within meninges


      Other organ involvement


      20% cardiac involvement (e.g., heart blocks, ventricular hypokinesis)


      20% cardiac involvement


      Eosinophilia: systemic infiltration


      50% cardiac involvement


      a Drug-induced AAV may also more commonly present with MPO-ANCA. Additionally, positivity for both PR3 and MPO-ANCA is not uncommon with drug-induced AAV.


      Abbreviations: AAV, ANCA-associated vasculitis; ANCA, antineutrophil cytoplasmic antibody; EGPA, eosinophilic granulomatous polyangiitis; GPA, granulomatous polyangiitis; MPA, microscopic polyangiitis; MPO, myeloperoxidase; PR3, proteinase 3.




      • Patients with SCr ≥ 4 mg/dL because data for other agents are limited in patients with severe kidney injury.


      • For patients with SCr < 4 mg/dL and one or more of the following:



        • Baseline serum total IgG is low.


        • Patient is hepatitis B surface antigen (HBsAg) positive.


        • RTX is not available.







          FIGURE 7.4 Glomerular crescents in antineutrophil cytoplasmic antibody-associated vasculitis. A. Necrotizing and cellular (active) crescent. There are segmental necrosis with capillary disruption and urinary space fibrin (arrow), and inflammatory and epithelial cells in the urinary space (arrowhead) (Masson trichrome ×400). B. Fibrotic (chronic) crescent. There is collagen in the urinary space (arrows) separating the obliterated glomerular tufts with a break in Bowman capsule (arrowhead) (Jones silver ×400).


    • RTX may be preferred in the following cases:



      • Patients with SCr < 4 mg/dL


      • Fertility concerns for children, men, or women


      • Frail elderly patients


      • Patients for whom leukopenia avoidance and/or a steroid-sparing protocol is a high priority


      • Relapsing disease


      • PR3 disease


  • Corticosteroids:



    • 2020 PLEXIVAS trial, total n = 704, reported that reduced-dose regimen of corticosteroids was noninferior to standard-dose regimen with respect to death or ESKD. Reduced-dose regimen consisted of: week 1: identical steroid dose to standard regimen; week 2: dose reduced by approximately 50% from standard dose while dose in standard group was gradually reduced starting in week 3; at 6 months, the cumulative dose of oral corticosteroids in the reduced-dose group was less than 60% of that in the standard-dose group; after 22 weeks, both groups received 5 mg daily of prednisone or prednisolone until week 52.


    • Recommendation for prednisone dosing: start at 1 mg/kg/d, for example, 60 mg/d (maximum 75 to 80 mg/d); taper to half dose by week 2, quarter dose by week 8, then 2.5 mg/d step decrease to reach 5 mg/d (or 7.5 mg/d in patients who start out at 75 to 80 mg/d) by week 16. Continue low dose for 52 weeks, then discontinue at the discretion of the treating physician.


Plasma exchange (PLEX)



  • Add PLEX in patients with concurrent anti-GBM disease and AAV


  • Consider PLEX in patients with rapid rise in SCr, requirement for dialysis at presentation, or diffuse alveolar hemorrhage









    Table 7.5 Management strategies for ANCA-associated vasculitis



































    Induction


    New Diagnosis or Relapse AAV Non-rapidly Progressive


    Rapidly Progressive AAVa


    Induction regimen depends on the severity of initial presentation.




    1. CYCb or RTXc plus



    2. Corticosteroidsd




    1. CYC or (CYC + RTX)e plus



    2. Corticosteroids



    No PLEX


    Consider PLEX,f particularly if diffuse pulmonary hemorrhage is present (see text regarding PLEXIVAS trial results published in 2020)


    Maintenance


    Options for maintenance therapy




    • Maintenance therapy may be started at 3-6 mo once remission is achieved.



    • There is no consensus on duration of maintenance (range of 18-48 mo per published studies).



    • 48-mo duration appears to confer lower relapse rates than 24-mo.




    • AZA 1-2 mg/kg/d × > 18 mo or



    • RTX (On demand OR fixed schedule for > 18 mog); fixed schedule; RTX 500 mg IV q 6 mo for up to 18 mo, tailored dosing based on CD19 counts, or



    • MMF may be prescribed, up to 1 g bid for ˜2 y, if intolerant of AZA, or



    • Methotrexate (initially 0.3 mg/kg/wk, maximum of 25 mg/wk) in patients intolerant of both AZA and MMF, but not if GFR < 60 mL/min/1.73 m2


    Relapse




    • Rituximab and corticosteroid are the preferred agents for SCr < 4 mg/dL.



    • CYC and corticosteroid are preferred if SCr is >4 mg/dL.



    • In non-life-threatening relapse, reinstitute or increase current corticosteroid dose, with or without AZA or MMF.


    Refractory Diseaseh




    • Change therapy




      • Switch to RTX if previously treated with CYC (especially if PR3-ANCA AAV) or vice versa



      • Oral CYC if previously treated with IV CYC and RTX is not available.



    • Consider PLEX.


    Note: Treatment outline is based on Rovin BH, Caster DJ, Cattran DC, et al. Management and treatment of glomerular diseases (part 2): conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int. 2019;95:281-295.


    a Rapidly progressive AAV is defined as serum creatinine > 4 mg/dL, crescentic glomerulonephritis, or diffuse pulmonary hemorrhage.

    b CYC (0.5-0.75 g/m2 IV q 3 to 4 weeks or 1.5 to 2.0 mg/kg/d orally); reduce dose if age > 60 years or eGFR < 20 mL/min/1.73 m2. Induction therapy with CYC should be discontinued after 3 months if patient remains dialysis dependent and free of extrarenal disease manifestations.

    c Rituximab (375 mg/m2 weekly × 4 or 750 mg/m2 [maximum dose 1,000 mg] biweekly × 2). Rituximab may be used as alternative initial treatment in combination with corticosteroids in patients without severe disease or in whom CYC is contraindicated.

    d Corticosteroids (methylprednisolone 500 to 1,000 mg IV pulse daily × 1 to 3 days for a maximum of 1 to 3 g, followed by 1 mg/kg/d of prednisone with taper over 16 weeks to 5 mg po daily). See PLEXIVAS trial in list of Suggested Readings.

    e Rituximab-based regimen per the international, randomized, open-label trial comparing a rituximab-based regimen with a standard cyclophosphamide/azathioprine-based regimen in the treatment of active, generalized ANCA-associated vasculitis (RITUXVAS) trial.

    f PLEX regimen: 60 mL/kg ideal body weight; replacement fluid is typically 5% albumin. Fresh-frozen plasma and/or cryoglobulins may be used at the end of apheresis session to replace coagulant factors, especially for patients with a recent renal biopsy and/or diffuse alveolar hemorrhage. Number of treatments: For vasculitis: seven treatments over 14 days if diffuse pulmonary hemorrhage (start with daily treatment until bleeding stops, then every other day, up to total of 7 to 10 treatments). For vasculitis in association with anti-GBM antibodies: Daily treatment for 14 days or until anti-GBM antibodies are undetectable. Must monitor daily prothrombin time and fibrinogen and replace volume with fresh-frozen plasma and 10 units of cryoprecipitate, respectively, as needed to correct coagulopathy associated with removal of coagulant factors with apheresis. Monitor electrolytes daily.

    g On-demand rituximab therapy is based on peripheral B-cell repopulation plus ANCA reappearance. Benefit of one over the other approach remains to be defined by the Comparison Study of Two Rituximab Regimens in the Remission of ANCA-associated Vasculitis (MAINRITSAN 2).

    h Refractory disease is defined as no improvement by 4 weeks, improvement of <50% in 6 weeks of treatments as measured by BVAS/WG, or chronic persistent disease after more than 12 weeks.


    Abbreviations: AAV, antineutrophil cytoplasmic antibody-associated vasculitis; AZA, azathioprine; CYC, cyclophosphamide; Ig, immunoglobulin; IV, intravenous; MMF, mycophenolate mofetil; PLEX, plasma exchange; PR3-ANCA, antineutrophil cytoplasmic antibody directed against proteinase-3; RTX, rituximab; q, every.




  • Note: Despite current practice/guideline in using PLEX as outlined above, the PLEXIVAS trial reported no reduction in the incidence of death or ESKD with PLEX in patients with severe AAV (defined as an eGFR < 50 mL/min/1.73 m2 or diffuse pulmonary hemorrhage). Future recommendations may change.


Maintenance therapy



  • For patients not on dialysis, maintenance therapy with RTX alone or AZA plus corticosteroids is recommended. There is no role for the addition of oral corticosteroid or other immunosuppressive agents with RTX maintenance.


  • The optimal duration of maintenance therapy remains undefined:



    • 18 to 48 months has been suggested.


    • 48-month duration appears to confer lower relapse rates compared with 24-month.


    • The optimal duration of RTX maintenance is undefined (18 months may be considered).


  • Choice of maintenance therapy (*preferred):



    • *AZA, * RTX, MMF, or methotrexate


    • The following should be considered in selecting AZA versus RTX as maintenance therapy:



      • AZA plus corticosteroids may be preferred if:



        • Total IgG is <300 mg/dL.


        • HBsAg is positive.


        • RTX is not available.


      • RTX alone may be preferred if:



        • PR3 disease


        • Treating a relapse


        • Patient is a slow metabolizer of AZA (i.e., patients with thiopurine methyltransferase [TPMT] deficiency—the diagnosis may be made with measuring TPMT activity or genetic testing).


        • Steroid avoidance is important.


      • Methotrexate may be considered if:



        • Methotrexate is used as induction therapy.


        • Intolerance of all other immunosuppressive agents


  • Duration of maintenance therapy may be prolonged if any of the following characteristics is present because they are associated with higher risk of relapse:



    • Diagnosis of GPA


    • Anti-PR3 positivity


    • Multiple organ involvement, particularly upper respiratory tract


    • History of relapse


    • Persistence of ANCA titer following induction


Other treatment considerations for AAV



  • Relapse:



    • RTX and corticosteroids are preferred if SCr < 4 mg/dL.


    • CYC and corticosteroids are preferred if SCr is ≥4 mg/dL.


    • In non-life-threatening relapse, reinstitute or increase corticosteroid dose, with or without AZA or MMF.



  • Resistant disease:



    • Increase in corticosteroid dose or addition of RTX or CYC is recommended, whichever is not already being used.


    • Suggested alternatives: IV Ig or PLEX may be considered.


  • Disease monitoring: Although changes in ANCA titers may be modestly predictive of future disease relapse, modification of immunosuppressive therapy (i.e., intensifying or reinitiating therapy) based on increasing ANCA titer alone is not recommended.


  • Avoid over-immunosuppression, provide P. jirovecii prophylaxis, and be vigilant with infectious complications in all patients receiving immunosuppressive therapy.


  • Discontinue immunosuppressive therapy in dialysis-dependent patients without extrarenal manifestations who show no kidney response after 3 months of treatment.


  • Future direction: Studies evaluating the efficacy of complement-targeted therapy involving the C5a-receptor inhibition with CCX168 avacopan to replace corticosteroid are ongoing.


Natural history/prognosis



  • 5-year kidney and patient survival are approximately 65% to 75%.


  • Poor prognostic risks: older age, higher presenting SCr or dialysis need at presentation, pulmonary hemorrhage




  • Others:



    • MPO-ANCA patients tend to present with worse kidney function and more chronic changes. However, if MPO-ANCA is diagnosed early, it may be associated with better renal outcome compared with PR3-ANCA.


    • Patients with EGPA more often have cardiac compared with kidney involvement.


Kidney transplantation



  • Delay transplantation for at least 6 months after complete clinical remission


  • It is not necessary to delay transplantation in patients with persistently positive ANCA.


Lupus Nephritis


Epidemiology



  • 20% to 60% of patients with SLE will develop clinically significant LN in the course of the disease.


  • Age:



    • Most patients who develop LN are younger than 55 years.


    • Severe nephritis is more common in children than elderly patients.


  • Gender difference (female-to-male ratio) is noted for female predominance and varies with age:



    • 2:1 in prepubertal children


    • 4:1 in adolescents



    • 8 to 12:1 in adults


    • 2:1 in adults age greater than 60 years


    • Renal outcome portends worse prognosis in males than females.


  • Race-related demographics:



    • SLE is more common in African Americans and Hispanics than whites.


    • Severe LN is more common in African Americans and Asians than in other ethnic groups.


    • Patients of African ancestry with APOL1 risk alleles are at increased risk for worse renal outcomes.


Pathogenesis



  • The pathogenesis likely involves multiple components including genetic susceptibility, epigenetic phenomena, immunoregulatory dysfunction, hormonal imbalances, and various environmental factors, among others.


  • For interested readers, see Appendix A for more details regarding pathogenesis.



Histopathology (Fig. 7.5)

International Society of Nephrology/Renal Pathology Society classification of LN






    • Class I: minimal mesangial LN: normal glomeruli by LM; mesangial immune deposits by IF and electron microscopy (EM) only


    • Class II: mesangial proliferative LN: mesangial hypercellularity on LM; mesangial immune deposits by IF and EM


    • Class III: focal LN (<50% of glomeruli involved)



      • Class III(A): active lesions (leukocytes, karyorrhexis, necrosis, cellular or fibrocellular crescents, large subendothelial deposits forming “wire loops” or “hyaline thrombi”)


      • Class III(A/C): active and chronic lesions


      • Class III (C): chronic lesions (segmental or global glomerulosclerosis, fibrotic crescents)


    • Class IV: diffuse LN (≥50% glomeruli involved)



      • Class IV(A): active lesions


      • Class IV(A/C): active and chronic lesions


      • Class IV(C): chronic lesions







        FIGURE 7.5 Lupus nephritis. A. Mesangial proliferative (class II) (periodic acid-Schiff ×400). B. Segmental proliferation with leukocytes and a necrotizing/crescentic lesion (Masson trichrome ×400). C. Active focal lupus nephritis (class III). There is segmental involvement of <50% glomeruli with proliferative features. In chronic focal lupus nephritis, there is focal scarring/sclerosis (periodic acid-Schiff ×200). D, E. Active diffuse lupus nephritis (class IV). In (D), there are large subendothelial deposits forming wire-loop lesions (arrows) and hyaline thrombi (arrowhead). In (E), there is more leukocytic infiltration with a segmental cellular crescent. F. Membranous lupus nephritis (class V). Capillary walls are thickened with subepithelial deposits and spikes, with mild segmental mesangial hypercellularity (D-F Jones silver ×200). G. Global mesangial and capillary wall staining for immunoglobulin G in mixed active diffuse and membranous lupus nephritis (class IV + V) (×400). H. Electron microscopy showing large subendothelial (wire loop) (arrow), mesangial, and segmental subepithelial electron-dense deposits (×6,000). I. Tubuloreticular inclusions (arrows) in endothelial cell cytoplasm beneath subendothelial deposits. Small subepithelial deposits are also present (×29,000).


    • Class V: membranous LN (>50% subepithelial deposits with or without mesangial hypercellularity)



      • Class V may occur with Class III or Class IV.


    • Class VI: advanced sclerosing LN (≥90% globally sclerosed glomeruli without residual activity)



  • IF: “Full-house” staining for IgG (strong), IgA, IgM, C1q (strong), and C3. Location depends on the LN class.


  • EM: mesangial, subendothelial, and/or subepithelial depending on disease class



    • Usually deposits in at least two glomerular locations, may have a “fingerprint” substructure


    • Endothelial cell tubuloreticular inclusions are usually present


Management



  • Table 7.6 summarizes current management strategies for LN.


For all LN classes



  • Antimalarials (hydroxychloroquine):



    • All patients with LN should be treated with antimalarial unless contraindicated. Yearly monitoring for retinopathy is advised with hydroxychloroquine. Other adverse effects: cardiotoxicity (congestive heart failure, prolonged QT/arrhythmias), drug accumulation in podocyte lysosomes with formation of multilamellar zebra bodies mimicking Fabry disease, and hemolysis associated with G6PD deficiency.


    • Observational and cohort studies suggest that the use of antimalarial is associated with a reduction in the odds of developing LN in patients with SLE and improved likelihood of complete renal response to treatment and lower ESKD risk in those with LN.








      Table 7.6 Management strategies for LN



















      All patients with LN




      • Antimalarials (hydroxychloroquine): yearly monitoring for retinopathy is advised with hydroxychloroquine.



      • Manage and treat complications: prevent/treat edema, hypertension, dyslipidemia, proteinuria, thrombosis whenever indicated



      • Use prophylaxis therapy against Pneumocystis jirovecii if receiving high-dose immunosuppressive therapy


      Class I/II




      • Disease-specific therapy is not generally necessary due to relatively benign course.



      • If nephrotic-range proteinuria:




        • Evaluate for lupus podocytopathy (e.g., podocyte effacement) and, if present, treat as minimal change disease.



        • Otherwise, consider low-dose corticosteroids and one additional agent (e.g., MMF).


      Classes III/IVa


      Induction therapy: corticosteroids plus either intravenous CYC or MMF. Aim to taper and discontinue corticosteroids by 12 mo if complete response.


      Maintenance: MMF or AZA. MMF is the first choice for maintenance therapy since it decrease the risk of LN relapse compared to AZA.


      Class V


      For subnephrotic proteinuria: initiate immunosuppression based on extrarenal indications


      For nephrotic-range proteinuria: initiate glucocorticoids and one additional agent (MMF, CYC, AZA, CNI, RTX)


      a See Table 7.7 for more detailed management of LN classes III/IV.


      Abbreviations: AZA, azathioprine; CNI, calcineurin inhibitor; CYC, cyclophosphamide; LN, lupus nephritis; MMF, mycophenolate mofetil; RTX, rituximab.




  • Manage and treat complications: Prevent/treat edema, HTN, dyslipidemia, proteinuria, thrombosis whenever indicated.


  • Monitoring of LN:



    • Serial proteinuria and SCr


    • Hematuria may persist for months even with improved proteinuria and SCr.


    • Anti-dsDNA, complement, and anti-C1q autoantibody levels


  • Definitions of response to therapy:



    • Complete response:



      • Return of SCr to baseline (±10% to 15% of baseline), and


      • A decline in urine protein-to-creatinine ratio (uPCR) < 500 mg/g within 6 to 12 months


    • Partial response:



      • Stabilization (±10% to 15% of baseline) or improvement of SCr, and


      • ≥50% decrease in uPCR where final uPCR is <3,000 mg/g within 6 to 12 months


Class I/II LN-specific therapy



  • Benign, no long-term adverse effect on kidney function


  • Disease-specific therapy is not necessary.


  • If nephrotic-range proteinuria, evaluate for lupus podocytopathy, and if present, treat as MCD. Otherwise, consider treatment with a low dose of corticosteroids in combination with another immunosuppressive agent (e.g., MMF).


Class III/IV LN-specific therapy (Table 7.7)



  • Induction therapy:



    • Corticosteroids plus either IV CYC or MMF. MMF should be the preferred agent in patients who wish to preserve fertility or who have Asian, Hispanic, or African ancestry or prior CYC exposure approaching maximum cumulative lifetime dose (see Safety Notes regarding CYC below).


    • Alternative options for induction therapy to be used in combination with corticosteroids may be considered in the case of drug intolerability, lack of response

      to standard therapy, or lack of availability and/or high cost of standard drugs. These may include CNI, RTX, AZA, or leflunomide, among others.








      Table 7.7 Management strategies for lupus nephritis classes III and IV
























































      Inductiona


      Dosage


      Comments


      Cyclophosphamide (CYC) NIH regimen


      IV CYC: 0.5-1.0 g/m2 given monthly for 6 mo




      • IV therapy should be considered for patients who cannot comply with oral therapy for whatever reason.


      CYC Euro-Lupus regimen


      IV CYC: 500 mg every 2 wk for 3 mo




      • Study was limited to less severe patients and predominantly Caucasians.b



      • Unknown if efficacy of Euro-Lupus regimen is similar to that of NIH for LM class III/IV or in non-Caucasians.


      CYC oral regimens


      PO CYC: 1.0-1.5 mg/kg/d (maximum 150 mg/d) for up to 6 mo




      • PO CYC provides similar efficacy to IV CYC in prospective observational studies.



      • Some, but not all, investigators suggested more adverse effects with PO CYC compared with IV CYC.


      Mycophenolate mofetil (MMF)


      1,000-1,500 mg twice daily for 6 mo




      • MMF is preferred for fertility preservation, known history of high CYC exposure, and Hispanic, African American, or Asian ancestry.



      • ALMS trial: MMF had an equivalent response rate and similar incidence of adverse effects for induction compared with IV CYC at 6 mo.


      Maintenance


      Maintenance therapy should be continued for at least 36 mo.




      • First-line: MMF (1-3 g/d in divided doses) is the first choice for maintenance therapy since it decreases the risk of LN relapse compared to AZA (1.5-2.5 mg/kg/d). Maintenance therapy with AZA or MMF has been suggested to be superior to CYC based on the risk of death and development of CKD.



      • Alternative: Use if CNIs or mizoribine is suggested for patients who cannot tolerate MMF or AZA.



      • Unless corticosteroids are required for extrarenal lupus manifestations, gradual tapering of corticosteroids to aim for eventual discontinuation should be considered after patients have maintained a complete clinical kidney response for at least 12 mo.



      • If disease relapses during tapering period, go back to previous level of immunosuppression that controlled the disease or an alternative recommended first-line therapy.


      If disease worsens as evidenced by increasing SCr or proteinuria during the first 3 mo of therapy with either CYC or MMF




      • Assess for compliance



      • Switch therapy (e.g., from CYC to MMF or vice versa), or



      • Consider prolonged IV CYC course or alternative therapies listed below below (e.g., CNI [cyclosporine or tacrolimus], rituximab, AZA)



      • Consider IV Ig or plasmapheresis (in the setting of concomitant TTP or refractory APS)


      Consider repeating biopsy


      Cyclosporine (CSA)


      CSA: 4-5 mg/kg/d




      • Nephrotoxicity limits use in patients with elevated SCr.


      Tacrolimus (TAC)


      Combination TAC (4 mg/d) + MMF (1 g/d)




      • Comparable remission rates between combination TAC (4 mg/d) + MMF (1 g/d) and IV CYC (0.75 g/m2) for 6 mo (Chinese RCT).


      Rituximab (RTX)


      RTX: doses vary among trials


      RTX: 1,000 mg on days 1, 15, 168, and 182 (dose used in LUNAR trial)




      • LUNAR trial: Although RTX therapy led to more responders and greater reductions in anti-dsDNA and C3/C4 levels, it did not improve clinical outcomes after 1 y of treatment.


      Azathioprine (AZA)


      AZA: 1.5-2.5 mg/kg/d




      • AZA had similar induction response rate compared with that for IV CYC at 2 y. AZA had fewer adverse effects, but higher late relapse rate, risk of doubling of SCr, and more chronic changes on late follow-up biopsies.


      IV Ig or plasmapheresis





      • May be considered in the setting of concomitant TTP or refractory APS


      a Induction therapy should be used in combination with corticosteroids: oral prednisone 1 mg/kg (maximum 80 mg/d), to be tapered over 6 to 12 months per clinical response. Initial intravenous methylprednisolone (e.g., 5 to 10 mg/kg × 1 to 3 days) may be considered at induction for aggressive disease. Optimal dosing and duration of corticosteroid therapy remain to be defined.

      b Severe disease was defined as >50% segmental glomerular necrosis or crescents and rapidly progressive kidney failure.


      Abbreviations: ALMS, Aspreva Lupus Management Study (RCT involving patients with classes III, IV, and V LN); APS, antiphospholipid syndrome; CNI, calcineurin inhibitor; IV, intravenous; IV Ig, intravenous immunoglobulin; LN III/IV, lupus nephritis classes III and IV; LUNAR, Lupus Nephritis Assessment with Rituximab trial involving patients with LN III/IV randomized to receive either MMF + steroids or MMF + steroids + rituximab; MMF, mycophenolate mofetil; NIH, National Institute of Health; PO, per oral; RCT, randomized controlled trial; SCr, serum creatinine; TTP, thrombocytopenic thrombotic purpura.



    • Antibiotic prophylaxis should be used to prevent infections with P. jirovecii during induction therapy.


  • Maintenance therapy:



    • MMF is the first choice for maintenance therapy since it decreases the risk of LN relapse compared to AZA. AZA is an alternative to MMF.


    • Maintenance therapy should be continued for a minimum duration of 36 months.


    • AZA or MMF maintenance therapy has been suggested to be superior to CYC in terms of risk of death and development of CKD.


    • Other alternatives: CNI, mizoribine (Japanese data)


    • Corticosteroids: aim to taper and discontinue by 12 months if complete response


  • Safety notes regarding CYC:



    • Maximum lifetime dose of 36 g of CYC is suggested to minimize risk of hematologic malignancies.


    • Maximum cumulative dose for those who wish to conceive should not exceed 10 g.


    • Dose reduction with reduced kidney function (20% and 30% reduction for creatinine clearance [CrCl] 25 to 50 and 10 to 25 mL/min, respectively)


    • Adjust CYC dose to keep nadir leukocyte count ≥ 3,000/µL (10 to 14 days for IV CYC and 1 week for PO CYC)


    • Use sodium-2-mercaptoethane (mesna) to minimize bladder toxicity


    • Fertility protection while on CYC treatment:



      • Women: leuprolide, ovarian tissue cryopreservation


      • Men: testosterone (efficacy poorly established), sperm banking


Class V LN-specific therapy



  • For subnephrotic proteinuria: Initiate immunosuppression based on extrarenal indications.


  • For nephrotic-range proteinuria: Initiate immunosuppression with corticosteroids and one additional agent (e.g., MMF, CYC, AZA, CNI, RTX).


Advances in SLE-targeted therapy



  • Belimumab: human monoclonal antibody that selectively neutralizes soluble B-cell activating factor (BAFF)



    • Food and Drug Administration (FDA) approved for treatment of ANA/anti-dsDNA positive adults with high disease activity on standard therapy


    • Short-term clinical trials suggest reduced SLE activity, flare rates, and corticosteroid need.


  • Obinutuzumab: a humanized anti-CD20 monoclonal antibody



    • Improved complete remission rates in patients with diffuse proliferative LN in a phase 2 clinical trial comparing standard therapy (MMF and steroids) versus standard therapy plus obinutuzumab (Nobility trial)


    • Obinutuzumab was awarded FDA “fast-track” approval based on Nobility. It is currently approved for B-cell lymphomas as Gazyva.


  • Omalizumab: recombinant humanized monoclonal antibody that blocks the binding of IgE to the FcεRI receptor



Poor prognostic indicators



  • Patient characteristics: African or Hispanic ancestry, male gender, pediatric onset, frequent relapses, incomplete remission, neuropsychiatric lupus, proteinuria > 4 g/d at diagnosis


  • Serologies: antiphospholipid syndrome (APS) or the presence of antiphospholipid antibodies (aPLs), persistent hypocomplementemia, elevated anti-dsDNA or anti-C1q antibodies


  • Histologic findings: crescentic GN, thrombotic microangiopathy (TMA), or extensive tubulointerstitial fibrosis


Lupus and pregnancy



  • Measurable SLE disease activity is present in 40% to 50% of pregnancies among patients with SLE, with LN occurring in up to 75% of these cases.


  • Active SLE during pregnancy is associated with:



    • Increased risk of preeclampsia to 30% compared to 5% in the general population


    • Increased risk of fetal death and preterm birth


  • Active LN during pregnancy is associated with:



    • Increased maternal adverse outcomes including increased risk of gestational HTN, preeclampsia, and maternal death. There is evidence to suggest that LN classes III/IV may be associated with higher risk for HTN/preeclampsia compared to other LN classes.


    • Possible increased risks of preterm birth, intrauterine growth restriction, stillbirth, and neonatal death (inconsistent findings in the literature)


  • Risk factors for adverse outcomes in pregnancy:



    • Active disease at conception


    • Positive aPLs


    • HTN, proteinuria, reduced GFR in the first trimester


  • Management of APS/NS during pregnancy:



    • Adverse outcomes of APS and positive aPLs include late fetal loss (after 10 weeks of gestation) and increased relative risk of preeclampsia


    • Women with APS and arterial thrombotic events are also at high risks for stroke and maternal morbidity and mortality.


    • Routine screening for aPLs is recommended.


  • Anticoagulation:



    • For women with known APS receiving chronic anticoagulation, convert warfarin to unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) during pregnancy.


    • For women with no known history of thrombotic events, but with obstetric criteria for APS of having either ≥ three pregnancy losses or late pregnancy loss, prophylactic anticoagulation consisting of a low-dose aspirin with either UFH or LMWH should be initiated.


    • For women with aPLs, but not meeting clinical criteria for APS, clinical surveillance with either antepartum aspirin or prophylactic UFH or LMWH is suggested.


    • For patients with NS, prophylactic anticoagulation should be considered.


  • Differentiating between lupus flare and preeclampsia in a woman with AKI:



    • Lupus flare: AKI may occur any time including prior to 20 weeks of gestation and postpartum, presence of hypocomplementemia, RBC casts, and leukopenia.



    • Preeclampsia: AKI only occurs after 20 weeks of gestation with absence of findings seen with lupus flare above.


  • Management of SLE/LN in pregnancy:



    • Delay pregnancy until at least 6 months after complete remission


    • Use of CYC, MMF, ACEI, and ARB is contraindicated due to potential teratogenicity.


    • Corticosteroids, hydroxychloroquine, AZA, and CNI are considered safe during pregnancy. LN patients who become pregnant while being treated with MMF should be switched to AZA.


    • Methotrexate is teratogenic and is contraindicated in pregnancy. Methotrexate should be discontinued ≥ 3 months prior to conception.


    • Hydroxychloroquine maintenance therapy should be continued during pregnancy. Discontinuation of hydroxychloroquine may lead to lupus flares including LN.


    • Low-dose aspirin should be started prior to 16 weeks of gestation to reduce risks of preeclampsia, intrauterine growth retardation, and fetal loss.


    • Patients with LN relapse during pregnancy should be treated with corticosteroids and, if necessary, AZA.


    • Patients receiving corticosteroids or AZA during pregnancy should not be tapered until at least 3 months postpartum.


ANTI-GLOMERULAR BASEMENT MEMBRANE DISEASE (ANTI-GBM)


Goodpasture’s syndrome

This is an autoimmune disease that predominantly affects both the kidneys and lungs. When only kidneys are involved, the condition is referred to as anti-GBM disease.


Epidemiology



  • Incidence: 0.5 to 1.0/million/y


  • Predominantly Caucasians, recognized in Asians, rare in other ethnicities


  • Peak age 20 to 30 years with slight male predominance; This group of patients more commonly present with pulmonary hemorrhage.


  • Smaller peak at age 60 to 70 years with female predominance; This group of patients more likely presents with isolated glomerular disease.


  • Predisposing factors: HLA-DR15 and DR4 at increased risk


Pathogenesis



  • Autoantibody formation against the GBM antigens:



    • Typical antigen involves the non-collagenous (NC1) domain of type IV collagen α3 chain [α3(IV)NC1], known as, the “Goodpasture antigen.”


    • Any other GBM constituents may also serve as antigens including the α3 to α5 type IV collagen chains of type IV collagen.


  • Type IV collagen chains are also present in alveolus, cochlea, parts of eye (corneal basement membrane and Bruch membrane), choroid plexus of brain, and some endocrine organs.


  • Presenting symptoms may be related to injury of these organs.



Clinical manifestations



  • Disease develops over weeks to months.


  • May have mild respiratory symptoms or incidental microscopic hematuria with disease progressing over months to years


  • Precipitating factors:



    • Exposures to hydrocarbons, cigarette smoking, pulmonary infection, and fluid overload may lead to:



      • Alveolar injury that allows anti-GBM antibodies to access and injure alveolar membranes resulting in pulmonary hemorrhage


      • Pulmonary hemorrhage appears as “fluffy, fleeting infiltrates of rapid onset and clearing on chest radiographs.


    • Prior kidney injury/inflammation may predispose to development of anti-GBM disease. GBM injury allows anti-GBM antibodies access to their antigenic site.


Histopathology (Fig. 7.6)



  • LM: glomerular crescents without mesangial hypercellularity. Crescents are in the same stage (all active, subacute, or chronic) due to “one-shot” anti-GBM antibody production.


  • IF: glomerular capillary wall IgG in a linear pattern


  • EM: no deposits


Differential diagnoses



  • Specific binding to GBM



    • Anti-GBM disease with kidney involvement only


    • Alport syndrome after kidney transplantation


  • Nonspecific binding to GBM: DM, light-chain disease






FIGURE 7.6 Anti-glomerular basement membrane antibody nephritis. A. Cellular crescent causing destruction of Bowman capsule segmentally (arrow) (Jones silver ×400). B. Linear capillary wall staining for immunoglobulin G (×200).



Prognostic indicators



  • Higher presenting SCr and higher percentage of crescents portend worse prognosis. Renal recovery is rare if SCr is >6 mg/dL.


  • Need for dialysis, particularly if in association with 100% crescents


Management


Immunosuppressive therapy

Jul 21, 2021 | Posted by in NEPHROLOGY | Comments Off on Glomerular and Vascular Disorders
Premium Wordpress Themes by UFO Themes