GOODPASTURE DISEASE

The anti-GBM disease is a rare small vasculitic disease affecting glomerular capillaries, pulmonary capillaries, or both.

 

Goodpasture disease

 

 

Literature review current through: Jul 2021. | This topic last updated: Feb 11, 2021.

Abbreviations (to facilitate your reading, read twice lease):

o   AB: antibody

o   AKI: acute kidney injury

o   ANCA: Anti-neutrophil cytoplasmic autoantibodies

o   Anti-GBM: Anti-glomerular basement membrane disease

o   ATI: acute tubular injury

o   ATN: acute tubular necrosis

o   Aza: azathioprine

o   CBC: complete blood count

o   Cph: cyclophosphamide

o   Ctr: citrate

o   Dgx: diagnosis

o   DX: dialysis

o   ESKD: end-stage kidney disease

o   FFP: fresh frozen plasma

o   GI: Gastrointestinal

o   Glccd: Glucocorticoids

o   GN: glomerulonephritis

o   HDX: hemodialysis

o   Hge: hemorrhage

o   IaD: Immunoadsorption

o   IF: immunofluorescence

o   im/m: immunosuppression/immunosuppressive.

o   IVIG: IV immunoglobulins.

o   KTx: kidney transplantation

o   MMF: Mycophenolate mofetil

o   MN: membranous nephropathy

o   MR: mortality

o   Mthyprd: methylprednisolone

o   O/An: oligoanuria

o   PE: plasma exchange

o   Pl Cr: plasma creatinine concentration

o   Pph: plasmapheresis

o   Pred: prednisone

o   RCT: randomized controlled trials

o   RF: Renal failure

o   RI: Renal impairment

o   RRT: Renal replacement therapy

o   Rtx: Rituximab  

o   Sns: signs

o   ttt: treatment

o   Tx: transplantation

o   UO: urine output

 

The anti-GBM disease is a rare small vasculitic disease affecting glomerular capillaries, pulmonary capillaries, or both. Most ptns show a rapidly progressive (crescentic) GN, despite certain ptns may show a relatively mild RI. Generally, this disease is typically presenting with severe AKI that may progress rapidly to ESKD. I will discuss the ttt and prognosis of the anti-GBM disorder.

EARLY INTERFERENCE

The early Dgx with proper intervention are the vital determinants of therapeutic response and long-term outcome of the anti-GBM disease ptns. A direct correlation has been observed between the presenting Pl Cr and the % of glomerular crescents; the latter are usually found in > 75 %of glomeruli if the Pl Cr > 5 mg/dL (442 micromol/L). Moreover, a direct relation between the magnitude of the anti-GBM AB levels and the Pl Cr level at presentation has been observed. Avoiding maintenance DX is uncommon in ptns requiring DX within 72 h.s of presentation, particularly ptns showing crescents affecting ALL the glomeruli. On the other hand, preventing ESKD can be achieved with less intense disease, despite some pts may show progressive course. Less % of intact glomeruli with an associated O/An may be the best determinant of a poor prognostic recovery. A crucial proposed question is whether commencing an empirical therapy in ptns with suspected Dgx of anti-GBM disorder before confirming the Dgx via serologic testing or obtaining tissue biopsy. Currently, we should NOT postpone therapy in such ptns, as the results of tests may not be available before several days, and ttt delay may trigger the risk of irreversible renal tissue damage.

PTNS TYPE

Ptns with anti-GBM disorder are mostly recommended to commence therapeutic Pph + Pred & Cph, including the following:

o   Pulmonary Hge (hemoptysis), regardless the presence and/or intensity of RI.

o   All ptns with renal affection NOT requiring immediate DX.

Treating ptns with DX-dependent RF with no pulmonary Hge is quite challenging setting. Some physicians advise not to treat such ptns, considering the very low possibility of renal recovery, particularly with ptn showing 100 % crescents on renal biopsy. Other clinicians may consider a short trial (2-3 wks) of Pph and im/m therapy, especially among the following ptns (Hopeful criteria):

(1)  Very acute illness where irreversible kidney damage is less likely.

(2)  Young aged-ptns with better tolerability to the aggressive im/m.

(3)  The finding of focal crescentic glomerular damage with ATI in kidney biopsy.

(4)  The finding of associated ANCA + clinical Sns of systemic vasculitis e.g., purpuric rash & arthralgia (uncommon in anti-GBM disorder). 

The merit to treat all ptns with renal affection not requiring immediate DX is depending upon the current evidence that im/m therapy may be beneficial to ptns presenting with a higher Pl Cr. Retrospective analysis: 71 ptns with anti-GBM disease exposed to Pph, Pred, & Cph, ptn and kidney outcome varied with disease intensity at presentation:

o   Ptns presenting with Pl Cr: < 5.7 mg/dL (500 micromol/L), ptn & kidney survival: 100 & 95 % at one y and 84 & 74 % at median of 90 mo, resp...

o   If Pl Cr > 5.7 mg/dL (500 micromol/L), and not requiring urgent DX (within 72 hs), ptn & kidney survival: 83 & 82 % at one y and 72 & 69 % at last follow-up, resp.

o   Ptns requiring urgent DX, ptn/kidney survival: 65 & 8 % at one y and 36 & 5 % at last follow-up, resp. All ptns having crescents in ALL glomeruli on biopsy requiring to be maintained on DX. On contrary, 2 ptns with significant ATN + crescents on biopsy have recovered long-term independent renal function.

o   42 ptns showing pulmonary Hge, bleeding was held in almost 90 %.

 

PRIMERY THERAPY

Plasmapheresis (Pph) + im/m: If we decided to treat the ptn, {Pph + im/m} therapy is recommended, rather than im/m alone. Pph will eliminate the circulating anti-GBM AB with other inflammatory mediators, and the im/m agents will control new AB production. Inpatient admission is mostly advised to commence therapy. Currently, there’re no large RCT supporting this approach, and many studies have been mostly uncontrolled.

Generally, the current data may suggest that almost 30-45 % of ptns managed with Pph + im/m will benefit by preventing the progress to ESKD or death. However, the expected recovery is much more likely to occur in ptns commencing ttt prior to O/An development and it is uncommonly observed in ptns requiring DX or having 100 % crescents on tissue biopsy.

The only given RCT evaluating the outcomes of 17 ptns managed with Pred + Cph with/without Pph. By the end of ttt, 2 of 8 ptns in the Pph g., compared with 6 of 9 in the im/m-alone g., became DX-maintained (25 vs 67 %, resp). This report concluded that, despite the presence of some benefit of Pph, the % of crescents on the 1^st renal biopsy and the presented Pl Cr are well-correlated to ptn outcome.

Regardless of therapy, ptns with < 30 % crescents & Pl Cr < 3 mg/dL (265 micromol/L) did well, while those with severe crescentic involvement & Pl Cr > 4 mg/dL (354 micromol/L) exhibit poor outcome. However, in observational trials, the advent of Pph has been associated with better ptn and kidney survival. Despite the lack of clear evidence of benefit, Pph is currently recommended for the ttt anti-GBM disease ptns.

Two factors may justify this concept:

o   Better morbidity/MR in the Pph era as compared with the historical findings.

o   Biological reasonability of ameliorated disease sequelae with fast elimination of anti-GBM AB, as compared with the slower reduction with im/m alone

Pph regimen: The preferable initial Pph regimen = daily 4 L exchanges/ 2-3 wks. Pph via either centrifugal or membrane separation can be considered equally effective. Generally, albumin can be provided as a replacement fluid. If, however, the ptn has had a recent kidney biopsy or showed pulmonary Hge, then 1-2 L of FFP should be substituted for albumin by the end of ttt for the coagulating factors repletion that could be depleted via Pph.

 

By the end of the 2–3-week plan, the requirement for more Pph sessions can be recognized by the ptn's clinical settings and the magnitude of anti-GBM AB titers. Additional Pph may not be required if the ptn has been improving with evident decline in serum anti-GBM AB levels. On contrary, continued Pph may be warranted:

1)    With active pulmonary illness (e.g., hemoptysis),

2)    if AB titers are had not been diminished, or

3)    AB titers rebound after withdrawal of Pph.

A suspected potential complication related to FFP therapy (14 % Ctr by volume) is the metabolic alkalosis. The metabolized Ctr may generate HCO₃, the elimination of which may be impeded via renal failure. Ctr-induced metabolic alkalosis may be corrected by HDX if required. With intense infection in the setting of Pph, a single infused IVIG; 100-400 mg/kg) can be administrated after a Pph session for Ig levels repletion.

 

 

 

Im/m therapy

Glccd + Cph: Pph should be augmented by Glccd + im/m agents, better, Cph.

Glucocorticoids (Glccd): We give pulse IV Mthyprd (15-30 mg/kg, maximum 1000 mg/20 min)/d./3 doses followed by daily oral Pred (1 mg/kg/d., maximum 60-80 mg/d) that could be tapered once remission has been achieved. However, no available evidence of benefits of the pulse Mthyprd over other Glccd doses and other regimen, and many ptns have been managed only with oral Glccd with no IV pulse. On Pph days, we provide Pred after Pph, despite this drug is minimally eliminated via Pph. Glccds are usually continued for almost 6 mo.

Cph: Starting oral Cph dose is 2 mg/kg/d. We should decrease the dose by 25 % for elderly (>60 ys) and frail ptns with adjusting the dosing for impaired renal function. On Pph days, we provide Cph after Pph and continue Cph for 3 mo in most ptns; if anti-GBM AB levels are not declined by 3 mo, we can continue Cph administration for maximum 6 mo. Most anti-GBM disease ptns showing remission may not require to be maintained on im/m therapy. Excepted from this is the ptn showing double-positive for anti-GBM AB + ANCA; such ptns having greater risk of relapse of vasculitic disease and should be maintained on im/m therapy similar to that applied for ANCA-associated vasculitis. Despite the general use of oral Cph, the relative benefits of oral & IV Cph in anti-GBM disease is not clear.

Retrospective study: 122 ptns with anti-GBM disease managed with PE, 32 received oral & 71 received IV Cph: No significant improvement in ptn survival with oral Cph. IV administration may be used in ptns who cannot receive oral form.

Cph (oral or IV) can be complicated with P. jirovecii pneumonia, amenorrhea, alopecia, and bladder toxicity (hemorrhagic cystitis & bladder carcinoma). Complications with higher doses of Glccd include oropharynx fungal infection, gastritis (that may cause GI bleeding in ptns at nigher risk), and bone losses. Both Cph and Glccd are associated with a higher risk of infection.

Alternatives to Cph: Rtx & MMF are alternate agents that can be given to ptns cannot tolerate Cph. However, we do not usually use these agents as 1^st-line therapy due to lack of evidence:

Rituximab (Rtx): If Rtx administrated, we can give 1 g/2 doses. If ptn on daily Pph, the 1^st of the 2 Rtx doses can be provided after the initial 7 successive d. of Pph & Glccd, as simultaneous Rtx & Pph will induce elimination of Rtx from the circulation. After 48-h, another 7 days of Pph can be provided, after that the 2^nd of the 2 doses of Rtx is given. If the ptn was on alternative-d., Pph, Rtx should be provided immediately after the Pph exchange, permitting a period of time for binding of Rtx to B cells prior to the next Pph ttt.

MMF: If MMF is given, we provide an initial dose of 500 mg twice/d and titrate up as tolerated to a dose of 1000 mg twice/d. We monitor the WBCs count for Sns of leukopenia. Dose decline is warranted in ptns with leukopenia or intense GI SE.

Many case-reports have reported successful ttt of anti-GBM disorder with these agents; however, evidence via RCT still lacking. Review: 22 ptns managed with  Rtx, 15 were treated for relapsed/refractory disease, and 7 received the drug as initial therapy (rather than Cph). No ptns had simultaneous ANCA positivity. Pulmonary Hge resolved and anti-GBM titers declined in mostly all ptns, but none of the ptns with refractory disease recovered renal function.

Supportive measures: added to Pph and im/m therapy, ptns with intense disease may require additive supporting care. Ptns showing life-threatening hemoptysis, may need intubation with mechanical ventilation in addition to measures to manage the bleeding tendencies. Ptns developing advanced RF in spite of ttt may require commencing DX therapy. The RRT therapy indicated similarly to other causes of RF.

Monitoring response to treatment: All ptns with anti-GBM should be closely monitored as following:

1)    Clinical status: During the acute phase (1^st 2-3 wks), with most ptns being hospitalized for ttt, we may monitor the SCr, CBC, and UO on daily bases. With pulmonary Hge, serial chest radiographs could be enough to observe any deterioration in the alveolar Hge. With ptn's discharge, we may schedule him on weekly follow-up visiting for the 1^st 2-4 wks. With persistent ptn stability, the duration between visiting could be extended to every 2-4 wks.

2)    Anti-GBM AB levels: We monitor anti-GBM AB on weekly bases for the 1^st 6 wks until they’re undetectable on 2 successive occasions, then monitor the anti-GBM AB levels every other wk for 4 weeks, and if still undetectable, we check the levels once/month/6 mo. Moreover, we check AB levels if the ptn showed clinical Sns of recurrence. In ptns receiving Pph combined with Glccd and Cph, clearance of anti-GBM AB typically seen within 4 wks of ttt; the continued presence of AB after 8 weeks is uncommon. If AB levels still persistently high, the im/m strategy should be modified. 

RECURRENCE

Disease relapse can be around 2 % in some center's experience, but data are insufficient to recognize how often it can be seen. Clinical relapse is more common in ptns with associated ANCA +ve, where the vasculitis and not the anti-GBM disease is currently re-activated.  A greater rate of recurrence can be seen with smokers or ptn exposed to occupational hydrocarbon. All ptns with anti-GBM disease should quit smoking avoiding such exposure.

With potential recurrence with renal affection, repeat renal biopsy to confirm the Dgx and exclude associated pathology e.g., ANCA-associated vasculitis & MN. With confirmed recurrent anti-GBM disease, repeat Pph with Glccd and Cph with similar regimen as above. Rtx or MMF can be tried as an alternate therapy to Cph in ptns developing disease recurrence/relapse while on Cph therapy or cannot tolerate this medication.

 

PERSISTING ANTI-GBM AB:

Uncommonly seen, ptns with anti-GBM disease have persistently higher anti-GBM AB levels, with/without disease activity, despite of ttt with daily Pph + im/m therapy for at least 2 weeks. The optimal management of such ptns is not certain, and data are confined to case report (s) and small series. However, not all ptns with residual anti-GBM AB titers requiring modification in the therapeutic plan and ttt should be individualized based upon the ptn's clinical setting. The following scenarios may help clarification of the decision varieties:

[1] Ptns with a persistently higher AB titer (absolutely defined as 3 times the upper limit normal or higher) that’s not declining despite the provided daily Pph and Cph -based therapy for at least 2-3 wks and ptn having evidence of current disease activity (i.e., ongoing pulmonary Hge and/or active GN [persistently found or new urinary RBCs casts and/or worsened renal function]), certain experts provide Rtx (1 g initially followed 14 ds later by another 1 g dosing). The need for additional daily Pph beyond 4 wks should be reevaluated, especially ptns having no recovering renal function after one mo of initial intervention and not having pulmonary Hge.  

[2] Ptns with a persistently higher AB titer, starting DX, have no pulmonary Hge, and have a kidney biopsy with high % of crescents or glomerulosclerosis and interstitial fibrosis, we taper off ttt and continue anti-GBM AB monitoring.

[3] Ptns with a persistently intermediate AB titer (absolutely defined as 1-3 times upper limit normal) after 3-4 mo of Cph-based protocol and having recovered renal function and overall doing fine, we may shift Cph to Rtx (1 g initially followed 14 ds later by another 1 g dosing). If Rtx is not available, we shift to Aza (1-2 mg/kg/d.) or MMF (MMF; 1000 mg twice/d), both of them are less toxic than Cph, and continue ttt for 6-9 mo. We continue monitoring such ptns for Sns of clinical recurrence or increasing anti-GBM AB levels.  

SPECIAL POPULATIONS

Double +ve anti-GBM & ANCA-associated disorders: Ptns with double +ve for anti-GBM AB & ANCA should be managed primarily as for anti-GBM disease considering that is the more intense lesion. However, unlike ptns with single +ve anti-GBM disease, double +ve ptns still requiring maintaining on im/m agents for ANCA disease considering their tendency to relapse the vasculitis. Revising the reports that double +ve ptns may be more likely to recover from DX as compared to single +ve anti-GBM disease, ttt with Pph + im/m agents should be considered for ptns presented with DX-requiring RF.

Observational reports: have observed that double +ve ptns have similar outcome to those with single +ve anti-GBM disease but showing frequent rates of relapse considering they have ANCA-associated vasculitis, e.g., one study: 41 ptns with single +ve anti-GBM disorder and 37 double +ve ptns reported 12-mo kidney survival rates of 44 & 53 %, resp. Renal recovery at one y was greater among double +ve ptns than those with anti-GBM disorder (29 vs 17 %). However, while no single +ve anti-GBM disease ptns showed disease relapse, about one-½ of double +ve ptns had recurrent disease over a median of 4.8 ys that suggests maintaining im/m agents may be of benefits in these ptns, as in those with ANCA-associated vasculitis.

Anti-GBM disease with MN: Multiple series of ptns with anti-GBM disorder and MN have been reported. We manage such ptns with the same plan as that is applied for ptns with anti-GBM. Response to therapy appears to be simulating that of ptns with anti-GBM disorder with not MN, and, sometimes, proteinuria related to MN has been improving.  

Anti-GBM disease with no detectable anti-GBM AB: There’re infrequently reported ptns with +ve linear staining for IgG on renal biopsy and -ve commercially tested circulating anti-GBM AB. Some ptns with no detected anti-GBM AB may show a variant known as "atypical anti-GBM nephritis" that’s an indolent type of anti-GBM disease with no pulmonary affection. Diffuse crescentic disease is uncommon in this type. In such ptns without significant crescentic GN, we do not administer ttt with im/m agents. However, rarely, in ptns developing Sns of progressive illness, we can manage with Glccd + Cph without Pph, as there’re no detected circulating AB to be removed via Pph.

Certain subset of ptns with biopsy-proved anti-GBM disease may show undetected circulating anti-GBM AB owing to false -ve testing. If the suspected anti-GBM disease is robust according to clinical presentation, we manage with similar approach to that applied in ptns with anti-GBM disease who have detected anti-GBM AB. Alternatively, techniques of detecting the circulating anti-GBM AB, e.g., indirect IF, Western blot, or biosensor system, should be applied whenever available. If the repeated tests with these tools still negative, we may hold Pph and continue ttt with Glccd + Cph.  

Recurrence after Tx: Recurrent anti-GBM disease after KTx is rarely observed.  

INVESTIGATIONAL THERAPIES: The following have been suggested for anti-GBM disease therapy:

(1)  Immunoadsorption (IaD): IaD, provided as a part of the Pph program, may be efficacious in some ptns with anti-GBM disease, even in ptns maintained on DX, e.g., the provided im/m + IaD in combination, via a sepharose-coupled, sheep-antihuman IgG column along 25 cycles induced recovered renal function, with stabilized Cr level of 2 mg/dL (177 micromol/L) in certain cases.

(2)  IgG-degrading enzyme of Streptococcus (IdeS): A series of 3 ptns showing refractory anti-GBM disease, ttt with IdeS induced a rapid decline in circulating anti-GBM AB. Renal biopsy showed negatively stained Fc IgG fragments. However, none of these ptns independently recovered renal function, probably because of the lately instituted ttt in their disease course. The clinical significance of this approach needs more evidence.

KIDNEY TRANSPLANTATION (KTx)

Ptns developing ESKD due to anti-GBM disease may be considered for KTx. There’re no current data guiding the optimal approach of KTx. Most Tx centers advise at least 6 mo of undetected anti-GBM AB values before commencing KTx. Recurrent anti-GBM disease after KTx is very rarely reported.

PROGNOSIS

Considering the self-limited criterion of anti-GBM disease, ptns surviving the 1^st y with preserved renal function generally doing fine. As mentioned before, renal and ptn outcome are correlating closely with the magnitude of RI at presentation. Ptns with moderate/severe disease and not requiring DX on presentation generally responding to therapy, with recovered kidney function is maintained along the long-term following-up. On the other hand, few ptns requiring urgent DX escape the need to be maintained on DX. Other clinical/pathological criteria have also been observed to be predicting kidney outcome:

1)    Large, multicenter series: 123 ptns diagnosed as anti-GBM disease between 1986 & 2015, 5-y kidney & ptn survival were 34 & 83 %, resp... Multi-variable analysis: DX dependency at presentation considered the most robust predictor of ESKD with following-up. Moreover, certain histopathologic criteria, e.g., % of normal glomeruli & the magnitude of interstitial infiltrates on renal biopsy were also considered as independent predictor (s) of ESKD.

2)    Multicenter series: 119 ptns with anti-GBM disease, with 78 % requiring DX at presentation and 46 % showed pulmonary Hge, 5-y ptn survival = 92 %. Mortality risk factors may include age at onset, HT, dyslipidemia, and the need for mechanical ventilation. Administration of Pph was accompanied with improving outcome. Renal survival at 3 mo = 31%. Among ptns requiring DX at presentation, only 16 % can recover kidney function.

3)    Study: 43 ptns with anti-GBM disease, O/An at Dgx was the strongest predictor of ptn MR, and both O/An and the % of glomerular crescents identified on biopsy were the best predictors of a poor renal outcome. Ptns longevity with recurrent lesions, whether ANCA +ve or -ve, is typically superior to that in the 1^st presentation of anti-GBM disease. Here, Dgx is the clearer, leading to the rapid starting of the proper therapy.