Rapidly progressive glomerulonephritis oxford ebook pdf free download

Histologically, RPGN is characterized by a crescentic glomerulonephritis CGN , which is due to severe glomerular injury, resulting in rupture of the glomerular capillary loops Figure 1 , with accumulation of leucocytes and blood constituents in Bowman's space, which in turn induces visceral epithelial cell proliferation, together forming a cellular crescent. However, this cut-off is arbitrary and clearly severe glomerular injury can occur and result in a rapid decline of renal function with a lower proportion of crescents.

There are other conditions that can lead to a clinical syndrome of RPGN, which are not caused by severe glomerular. These include thrombotic microangiopathies and rarely cases of tubulointerstitial nephritis, making it important to make a firm diagnosis based on clinical, haematological, serological and renal biopsy data Table 1. Courtesy of Professor Alexander Howie.

CGN is commonly categorized based on the pattern of immunoglobulin deposition by immunohistochemistry, and is most frequently caused by: The relative likelihood of each of these is dependent on the age of the patient, with pauci-immune ANCA associated GN being more common in older patients and immune complex disease predominating in younger subjects, as a result of the propensity for IgA nephropathy IgAN post-infectious GN and lupus nephritis LN to affect younger patients.

Anti-glomerular basement membrane GBM disease with linear immunoglobulin deposition. Pauci-immune glomerulonephritis most often associated with anti-neutrophil cytoplasm antibody ANCA. Management of these conditions is based on the underlying aetiology; however, in many instances, due to lack of data, treatment strategies are extrapolated from one indication to another, based on the common clinical presentation and pathology with CGN.

In addition, for many of the conditions, clinical trials have specifically excluded patients with RPGN, and again extrapolations regarding management in this group have to be made. As a result, various conditions that present with RPGN may be treated with a similar type of regimen, using combinations of immunosuppressive agents, and adjunctive therapies; however, specific dosing protocols may vary.

Historically, the standard of care has been glucocorticoids, delivered as pulsed therapy and followed by oral treatment, in combination with cyclophosphamide; however, there remains much uncertainty about the most efficacious and least toxic steroid doses and how they may be best used in combination with other newer agents. In addition, the desire to minimise cumulative doses of cyclophosphamide, especially in younger patients, has led to the trialling of other induction therapies.

This review will highlight the most recent developments in the management of RPGN, with emphasis on the different approaches in particular clinical settings.

Standard induction therapy has been with cyclophosphamide, given orally or pulsed intravenously, with glucocorticoids. Recent trials have investigated alternative induction therapies. However, many of these studies have included patients without renal involvement, or with less severe renal impairment, limiting their utility to translate for patients with RPGN. Rituximab is now firmly established as an option in the management of AAV, and offers a viable alternative for patients with a contraindication to cyclophosphamide.

Two landmark trials demonstrated non-inferiority in comparison with cyclophosphamide and glucocorticoids in remission induction. Outcomes with regard end-stage renal disease ESRD , death, improvement in renal function and infectious complications were equivalent in these two small cohorts.

A larger cohort analysis is clearly required; until then, the long-term benefit of using rituximab without cyclophosphamide in patients with RPGN or advanced renal failure is uncertain. However, preliminary reports suggest that the international MYCYC study has failed to demonstrate non-inferiority of MMF and a standard glucocorticoid taper in comparison to intravenous cyclophosphamide in patients with MPA and granulomatosis with polyangiitis [ 7 ]; although a secondary end point of MMF regardless of glucocorticoid dosing did demonstrate non-inferiority, suggesting that MMF and more liberal steroid dosing may be equivalent to pulsed cyclophosphamide.

The landmark MEPEX trial, which included patients with severe renal AAV, demonstrated a significant benefit from therapeutic plasma exchange TPE in comparison with intravenous glucocorticoid [ 8 ]. Although mortality did not differ between the two groups, renal survival in patients who received TPE was more favourable at 3 and 12 months.

However, subsequent follow-up of this cohort found no difference in patient or renal survival after an average of nearly 4 years; the overall mortality rate was also unexpectedly high in both groups [ 9 ].

Outcome data will not be available for another few years NCT, protocol in [ 11 ]. No current trials of infliximab in AAV are registered. No further studies have been published using this agent. The authors suggest that this may be a viable steroid-sparing agent, but this would need to be confirmed in a larger trial. Complement antagonists: C5a, a cleavage product of C5, is a powerful anaphylatoxin and chemoattractant.

The C5a receptor, also known as CD88, is expressed on the surface of monocytes and neutrophils; its importance in the mediation of MPO-induced CGN has been demonstrated in animal studies [ 16 ]. Tocilizumab is an anti-IL 6 receptor monoclonal antibody. The clinical outcomes of adults with HSPN are worse than those of children [ 23 ].

Differences in disease severity, as well as treatment duration, between the MMF and cyclophosphamide groups may limit the generalisability of these findings.

There is one published report of successful use of rituximab in a patient with drug-induced HSP and crescentic IgAN who was resistant to glucocorticoids cyclophosphamide and plasmapheresis. After an average of 6 years follow-up, two patients died, one of whom developed ESRD. One randomised open-label trial of cyclophosphamide in HSPN has been published recently [ 28 ].

Fifty-four patients with severe HSPN were randomized to treatment with glucocorticoids alone or in combination with intravenous cyclophosphamide. The primary end point was complete remission at 6 months defined as BVAS 0. Improvement in renal function, renal survival and adverse events were secondary end points. The authors concluded that the addition of cyclophosphamide provided no benefit in these patients.

However, the two groups differed at baseline, with patients in the cyclophosphamide group being younger, less hypertensive and with lower disease activity than those in the steroid-only group.

Additionally, the study was underpowered, with an estimated sample of patients needed to detect a significant difference. Anti-GBM disease is essential to diagnose and treat rapidly as more advanced disease is associated with a worse renal recovery.

Standard therapy is with cyclophosphamide, glucocorticoids and TPE. Evidence for the use of rituximab in the treatment of anti-GBM disease is limited to case reports. In the past 5 years, successful use of rituximab has been reported in seven cases, who were either resistant to or intolerant of conventional treatment [ 29—32 ].

Improvement in renal function has been reported in three published cases. Shah et al. Bandak et al. MMF has also been successfully used in refractory or relapsing anti-GBM disease, but the evidence base for this agent does not extend beyond single case reports [ 33—35 ]. The efficacy of TPE in anti-GBM disease was first suggested by an observational study of seven patients in [ 36 ]. The largest case series of patients treated with TPE was published by Levy et al.

More recently, a large retrospective study of patients in China reported more favourable clinical outcomes in patients treated with a combination of TPE, cyclophosphamide and glucocorticoids, compared with those who received either cyclophosphamide and glucocorticoids or glucocorticoids alone [ 38 ]. There were differences between the groups at baseline, and less than half of the patients in the study underwent renal biopsy.

Immunoadsorption has been proposed as a more efficient method for removing anti-GBM antibodies. A comparison of DFPP with immunoadsorption found similar patient and renal survival, and a similar efficacy of antibody removal, in 28 patients with severe anti-GBM disease in China [ 40 ]. Combination haemodialysis and plasma exchange offers a possible benefit of reducing therapy time and manpower in patients who require both treatment modalities due to the severity of their disease as is often seen in anti-GBM disease.

The largest case series of this combination therapy was published last year [ 41 ]. These patients may have fewer extra-renal symptoms and more frequently are also positive for ANCA [ 42 ] and anti-C1q antibodies [ 43 , 44 ]. There are many studies in progress or recently published on LN, some of which report promising findings. However, most trials specifically exclude patients with RPGN or severe renal impairment. The evidence base for this subset of patients is therefore relatively small.

A retrospective study in China examined the clinical characteristics and outcomes of 33 patients with crescentic LN, using patients with non-crescentic LN as a comparator group [ 42 ]. All patients received combinations of glucocorticoids cyclophosphamide and MMF, in an uncontrolled manner. Unsurprisingly, the presence of crescents was associated with more severe renal injury, less favourable response to therapy, higher relapse rates and lower renal survival; patient survival was unaffected.

Another study in China reported that renal outcomes in patients with Class IV LN correlated with the percentage of histological crescents [ 43 ]. Statistical significance was not reported in this study, and treatment protocols varied. Although earlier case series and pilot studies suggested that rituximab might be effective in the treatment of LN, well-designed RCTs subsequently failed to demonstrate a benefit. The proportion of patients in this study with crescentic LN was not reported, but it is likely to be low.

Davies et al. Although the overall response rate was good 13 out of 18 responded by 6 months , the patients with RPGN fared relatively poorly.

All patients in this study had received standard immunosuppression prior to rituximab initiation, consisting of cyclophosphamide, glucocorticoids and MMF. Three patients had evidence of RPGN.

In summary, there does not appear to be sufficient published evidence supporting a beneficial effect of rituximab in crescentic LN. Both groups received pulsed glucocorticoids at induction, followed by maintenance therapy with low-dose oral prednisolone and Tripterygium wilfordii a traditional Chinese herbal-derived medication.

Adjunctive therapy was not reported in this study, so it is difficult to draw firm conclusions about the relative merits of the drugs studied. Morimoto et al. The patient went on to receive glucocorticoids and tacrolimus, and successful disease remission was achieved.

Ocrelizumab is an anti-CD20 monoclonal antibody with some evidence of efficacy in rheumatoid arthritis. A placebo-controlled trial of its use in type III—V LN was terminated early due to serious infections in the intervention arm; outcome data did not demonstrate a clear benefit of this agent [ 55 ].

Daha MR, van Kooten C. Role of complement in IgA ne- Experimental glome- phropathy. J Nephrol Nov J Exp The MEST score provides dx. Kidney Int McIntosh RM. Floege J, Feehally J. The al. Intensive Supportive Care plus Immunosuppression in IgA alternative pathway of complement activation may be involved Nephropathy. N Engl J Med ; PLoS One ;9:e J Am Soc Ne- of anti-glomerular basement membrane antibody disease trea- phrol ; Ann Intern ASN.

New treatment for IgA nephropathy: enteric Therapy of anti-glomerular basement membra- nuria. Nephrol Dial Transplant ; Medicine Baltimore Recurrent glomerular disease in ; Front Biosci Elite Ed ; Jennette JC. Rapidly progressive crescentic glomerulonephritis. Ne- Hellmark T, Segelmark M. Diagnosis and classification of phrol Dial Transplant ;30 5 Goodpasture's disease anti-GBM.

KDIGO clinical practice guideline Cui Z, Zhao MH. Advances in human antiglomerular base- for glomerulonephritis. Kidney Int Suppl ; Radhakrishnan J, Cattran DC. J Immunol ; Clin Kidney J Kambham N. Crescentic Glomerulonephritis: an upda- ; Adv Anat Pathol ; The cli- basement membrane nephritis. BMC Nephrol ; Benharkou A, et al. The HLA complex in Goodpasture's di- munoadsorption.

Rituximab in anti-glomerular base- QJM ; Ann Rheum cells specific to a glomerular basement membrane antigen me- Dis ; J Clin Invest ; Anti-glomerular base- Circulating anti-glomerular basement membrane case-based review. Semin Arthritis Rheum ; Am J Kidney Dis ; PMID: et al. J Autoimmun ; Autoimmunity to the alpha 3 chain of type IV Sprangers B, Kuypers DR. Recurrence of glomerulone- collagen in glomerulonephritis is triggered by 'autoantigen phritis after renal transplantation.

Transplant Rev Or- complementarity'. Natural autoantibodies against F, et al. Arthritis Rheum dx. Complement activation Genetically distinct subsets within ANCA- anti-glomerular basement membrane disease. J Clin Immunol -associated vasculitis. Chen M, Kallenberg CG. ANCA-associated vasculitides-advances Treatment of ANCA- in pathogenesis and treatment. Nat Rev Rheumatol ; -associated vasculitis: new therapies and a look at old entities. Kallenberg CG.

Clin Exp Rheumatol ;S Understanding the role of ri- J Am plasmic autoantibody-mediated disease. Nat Rev Rheuma- Soc Nephrol ; Fussner LA, Specks U. Can antineutrophil cytoplasmic antibody T, et al. J Am Soc Nephrol ; Note that the capillary walls are not outlined, since the deposits are primarily limited to the mesangium. EM typically reveals electron-dense deposits that are primarily limited to the mesangium, but may also occur in the subendothelial and subepithelial spaces.

The number and size of these deposits generally correlates well with the severity of changes seen on light microscopy. Low power electron micrograph in IgAN. The primary finding is electron dense deposits that are limited to the mesangial regions D.

The glomerular basement membrane GBM is normal and there are no glomerular capillary wall deposits. Higher power EM with significant expansion of mesangial matrix and presence of large mesangial dense deposits arrow. Scores for all glomeruli are averaged and the resulting assigned hypercellularity score is either M0 if the mean score is less than 0. E0 if no hypercellularity is present within lumina. A score of T0, T1 or T2 is given if the percentage of involved cortical area is ; or.

Based on the histological features of cases of IgAN over a 14 year period at one institution: Class I 39 cases : minimal or no mesangial. In one trial, 44 patients with proteinuria 0. Blood pressure control was similar in the two groups. Praga et al. JASN, p, Patients with more severe or rapidly progressive disease e. The potential benefit of glucocorticoid therapy alone in IgAN has been examined in uncontrolled studies, retrospective observations, and a few relatively small, randomized controlled trials.

A prospective trial from Italy included 86 adults with proteinuria 1 to 3. The patients were randomly assigned to supportive therapy alone, or glucocorticoids 1. Several trials have suggested a possible benefit from combined immunosuppressive therapy in these patients, however, most did not include a comparison group treated with prednisone alone. Rx Combined Immunosuppressive Therapy In a randomized control trial of 38 patients with rapidly progressive disease without crescents combined treatment with prednisone and oral cyclophosphamide for 3 months, followed by azathioprine for two years or more, resulted in better preservation of renal function.

A lower degree of proteinuria was also observed in treatment group compared to controls. Uncontrolled reports in patients with IgAN causing crescentic RPGN suggest possible benefit from regimens similar to those used in other forms of crescentic GN: IV pulse methylprednisolone followed by oral.

After two months of therapy, there was substantial clinical improvement characterized by reductions in Cr and proteinuria. A more prolonged course of aggressive immunosuppressive therapy was evaluated in 12 patients with CIgAN who had a mean serum Cr of 2. Monthly IV cyclophosphamide 0. Tumlin et al. NDT, p, After the six month course, there was significant improvement in the serum Cr concentration from 2.

Repeat biopsy at six months revealed the absence of cellular crescents and endocapillary proliferation in all patients. Throughout a three-year follow-up, all patients continued prednisone 0. A study reviewed renal biopsies over a period of 14 years and found 33 cases of glomerulonephritis with crescents 1.

Of these 33 cases, 8 had the diagnosis of IgAN 0. Despite intensified therapy, 4 patients developed renal failure and returned to hemodialysis within 1 year.

Another retrospective study reviewed allograft biopsies over a period of 9 years at a Chinese University hospital and found 18 cases with crescent formation, of which 10 patients 0. Over a 15 year period, 42 patients with biopsy proven IgAN received kidney transplants, they were followed for a mean 9 year period and had sequential allograft biopsies.

The 2 patients with diffuse crescentic IgAN in their native kidneys, experienced acute graft dysfunction at 15 and 47 months post transplant. No crescentic proliferation was observed during follow up in any other case. The authors suggest that only diffuse crescentic IgAN in the native kidneys was associated with occurrence of crescents in the kidney transplants. Open navigation menu.

Close suggestions Search Search. User Settings. Skip carousel. Carousel Previous. Carousel Next. What is Scribd? Recently, a meta- analysis of available trials involving treatment of AAV was performed evaluating the effect of different corticosteroid dosing regimens in relapse prevention. Rheumatology Oxford ;48 12 —5; with permission. Recent investigations have shown that intravenous IV pulse cyclophosphamide is equally effective as oral cyclophosphamide, with lower cumulative cyclophosphamide dose and fewer episodes of leukopenia, but no reduction in infectious complica- tions.

This is concordant with the data from a previously performed meta-analysis on the same subject. It is already known that patients positive for PR3-ANCA who remain ANCA positive after induction of stable disease remission are at increased risk for relapse of disease; therefore immunosuppression for a longer period might be considered in these patients. Controversies exist on how to treat patients with end-stage renal disease ESRD at the time of diagnosis.

Current dogma is that patients with ESRD without any active inflammatory lesions within the kidney will not benefit from immunosuppressive therapy and will not regain independent renal function. Are there conditions in which treatment is definitely futile?

In such cases, plasma exchange treatment with concomitant standard therapy increases the risk of therapy-related death more than it raises the likelihood of attaining independence from dialysis.

In patients with ESRD patients, maintenance immunosuppressive therapy prevents relapse of extrarenal manifestations. They showed that relapse rates of patients on dialysis were signifi- cantly lower than in the same patients before onset of ESRD, and were lower than patients not on dialysis.

Moreover, patients on maintenance immunosuppressive therapy were at increased risk for infectious complications and death. In general, relapse should be managed similar to new-onset disease, taking into account the acquired disease- and treatment-related damage. Repeat kidney biopsy can be helpful in differentiating patients with poor treatment response as a result of chronic damage from those who might benefit from intensified treatment.

In a small study, it was shown that relapse could be prevented when patients were treated with cyclophosphamide after an increase in ANCA titer.

Cumulative cyclophosphamide dosage was lower in patients on preemptive treat- ment than in a control group of patients who were untreated except in cases of clinical relapse after an increase in titer. Cycles Three open-label studies50—52 in refractory cases. The initial high dose should be maintained for 4 weeks, after which the dose is tapered according to various tapering schedules. Abbreviation: IVIG, intravenous high-dose immunoglobulin. EULAR recommendations for the management of primary small and medium vessel vasculitis.

Ann Rheum Dis ;68 3 —7. Diagnostic predictive value of ANCA serology. Kidney Int ;53 3 —8; with permission. Longer follow-up data will have to show the clinical relevance of this finding. Pauci-Immune Necrotizing Glomerulonephritis relapse is lower after transplant compared with before transplant. They concluded that the presence of circulating ANCA at the time of transplantation was associated with the development of vascular lesions in the graft, but was not significantly correlated with graft survival.

Also, in multivariate analysis, patients were more likely to die when transplantation was performed within 12 months after reaching disease remis- sion compared with transplantation after 12 months. Nomenclature of systemic vasculitides. Proposal of an international consensus conference. Arthritis Rheum ;37 2 : — Predictors of treatment resistance and relapse in antineutrophil cytoplasmic antibody-associated small-vessel vasculitis: comparison of two independent cohorts.

Arthritis Rheum ;58 9 — Renal involvement in Churg-Strauss syndrome. Am J Kidney Dis ;47 5 —9. Antineutrophil cytoplasmic autoantibodies and associated diseases: a review. Am J Kidney Dis ;15 6 — Anti-neutrophil cytoplasmic autoantibody- associated glomerulonephritis and vasculitis. Am J Pathol ; 5 — Wegener F. Uber die eigenartige rhinogene Granulomatose mit besonderer Betei- ligung des Arteriensystems unde der nieren. Beitrage zur Path Anat ; 36—68 [in German].

Coexistence of anti-glomerular basement membrane antibodies and myeloperoxidase-ANCAs in crescentic glomerulone- phritis. Am J Kidney Dis ;46 2 — Renal histology in ANCA- associated vasculitis: differences between diagnostic and serologic subgroups.

Prognostic markers in patients with antineutrophil cytoplasmic autoantibody-associated microscopic polyangiitis and glomerulonephritis. J Am Soc Nephrol ;7 1 — Clinical and histo- logic determinants of renal outcome in ANCA-associated vasculitis: a prospective analysis of patients with severe renal involvement.