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]).
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).
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):
May require discontinuation if hyperkalemia develops
Salvage therapy with K+ binders may be feasible.
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.
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).
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.
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.
Intravenous (IV) loop diuretics should be considered if anasarca is present because bowel wall edema limits oral medication absorption. Twice-daily administration is preferred.
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
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.
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).
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
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).
Normal circulating IgA1
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.
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.
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
Occasionally with concomitant kidney biopsy findings consistent with MCD
Slowly progressive chronic kidney injury
Rapidly progressive (crescentic) glomerulonephritis (RPGN)
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)
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 is by kidney biopsy.
Currently, there are no validated surrogate diagnostic or prognostic markers.
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
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.
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
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.
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.
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.
Patients with IgAN who have persistent proteinuria ≥1 g/d despite ≥ 90 days of optimal supportive care are at high risk for progressive CKD.
Risk stratification for disease progression based on the IgAN International Prediction Tool:
This risk-stratification tool does not predict responses to any particular treatment.
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
Usually occurs in adults and without mucocutaneous lymph node (MCLN)
Microaneurysms may resemble “beads on a chain” on angiogram (Fig. 5.3).
Typically occurs in children in association with MCLN syndrome
Table 7.2 Large-sized vasculitis: Giant cell versus Takayasu arteritis
Table 7.3 Medium-sized vasculitis: Polyarteritis nodosa versus Kawasaki arteritis
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 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
Cytoplasmic (c-ANCA) and perinuclear (p-ANCA) refer to the ANCA staining pattern in ethanol-permeabilized neutrophils exposed to patient serum.
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:
May be fortuitous coexistence of anti-GBM and ANCA
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.
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
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
Table 7.5 summarizes management strategies for AAV.
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
Renal limited vasculitisa 10%-20% PR3,70%-90% MPO, 10% negative ANCA
Fifth to eighth decade of life with MPO-ANCA in the older age range; slight male predominance; more common in white than black.
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
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
50% of patients with MPA, GPA, or EGPA may have abdominal pain, bloody stool with mesenteric ischemia/intestinal infraction/perforation, pancreatitis, hepatitis.
Nodular cutaneous lesions are rare
Skin nodules due to dermal or subcutaneous arteritis and necrotizing granulomatous infiltration
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.
RTX may be preferred in the following cases:
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.
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
New Diagnosis or Relapse AAV Non-rapidly Progressive
Rapidly Progressive AAVa
Induction regimen depends on the severity of initial presentation.
Consider PLEX,f particularly if diffuse pulmonary hemorrhage is present (see text regarding PLEXIVAS trial results published in 2020)
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
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.
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):
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:
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
Multiple organ involvement, particularly upper respiratory tract
History of relapse
Persistence of ANCA titer following induction
RTX and corticosteroids are preferred if SCr < 4 mg/dL.
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.
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
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.
Delay transplantation for at least 6 months after complete clinical remission
It is not necessary to delay transplantation in patients with persistently positive ANCA.
20% to 60% of patients with SLE will develop clinically significant LN in the course of the disease.
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.
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.
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(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
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
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).
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.
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:
Benign, no long-term adverse effect on kidney function
Disease-specific therapy is not necessary.
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
Cyclophosphamide (CYC) NIH regimen
IV therapy should be considered for patients who cannot comply with oral therapy for whatever reason.
CYC Euro-Lupus regimen
CYC oral regimens
PO CYC: 1.0-1.5 mg/kg/d (maximum 150 mg/d) for up to 6 mo
Mycophenolate mofetil (MMF)
1,000-1,500 mg twice daily for 6 mo
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
CSA: 4-5 mg/kg/d
Nephrotoxicity limits use in patients with elevated SCr.
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.
AZA: 1.5-2.5 mg/kg/d
IV Ig or plasmapheresis
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.
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
For subnephrotic proteinuria: Initiate immunosuppression based on extrarenal indications.
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
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
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
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.
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.
Delay pregnancy until at least 6 months after complete remission
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.
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
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.”
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.
Disease develops over weeks to months.
May have mild respiratory symptoms or incidental microscopic hematuria with disease progressing over months to years
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.
Specific binding to GBM
Anti-GBM disease with kidney involvement only
Alport syndrome after kidney transplantation
Methylprednisolone 500 to 1,000 mg/d IV for 3 days, followed by prednisone, 1 mg/kg/d based on ideal body weight (maximum 80 mg/d) with slow taper to off by 6 months, plus
CYC: 3 mg/kg/d orally for 2 to 3 months. For patients older than 55 years, reduce dose to 2.5 mg/kg/d × 2 to 3 months
Corticosteroids should be started prior to tissue diagnosis if high suspicion due to rapidly progressive disease. Following diagnosis confirmation, add CYC and PLEX.
RTX may be considered in refractory anti-GBM disease.