Background: Rapidly progressive glomerulonephritis (RPGN) is characterized by a rapid deterioration of renal function and by extracapillary proliferation in >50% of glomeruli. The most common type of RPGN is “pauci-immune” glomerulonephritis caused by anti-neutrophil cytoplasmic antibodies-associated vasculitis (AAV). Summary: The incidence of AAV increases with age and pauci-immune glomerulonephritis is the most common diagnosis found in renal biopsies in the elderly population. Age was identified as an independent negative risk factor for both death and end-stage renal disease in AAV, and the mortality of older patients was uniformly higher than in younger patients in all retrospective studies. Early diagnosis may be difficult particularly in elderly patients with renal-limited disease but is important for the good outcome of the patients. Immunosuppressive treatment options include cyclophosphamide or rituximab combined with corticosteroids with or without plasma exchange in case of severe disease. Data from randomized trials are completely missing for patient aged >75 years. Based on retrospective studies, elderly patients seem to respond to immunosuppressive drugs just as younger patients are able to, but they are at a higher risk of adverse events. Key Messages: RPGN is relatively common in the elderly patients. Immunosuppressive treatment in older patients with AAV or RPGN may be useful but needs to be strictly individualized with all the risks taken into consideration. Further studies are needed to examine the role of novel therapeutic options in the elderly population with RPGN.

Rapidly progressive glomerulonephritis (RPGN) is clinically characterized by a nephritic syndrome with rapid deterioration of renal function, progressing to end-stage renal disease (ESRD) within 3 months from the onset. Renal biopsy reveals so-called crescentic glomerulonephritis, characterized by extracapillary proliferation in >50% of glomeruli [1].

The etiology of RPGN differs, but the presence of crescents is always a marker of severe glomerular injury that requires prompt diagnosis and early initiation of adequate treatment.

There are 3 types of RPGN recognized based on the immunofluorescent pattern in the biopsy. Type I (about 10% of all RPGN cases) is associated with linear deposits of antibodies along the glomerular basement membrane (GBM), and is typical for anti-GBM (Goodpasture’s) disease. Type II (15–20%) is characterized by granular deposits of immunoglobulins and complement fractions and may be caused by a heterogenous group of primary or secondary glomerulonephritides (e.g., IgA nephropathy or lupus nephritis). Type III (60–80%) is the most common form of RPGN with no or very few immune deposits (“pauci-immune” glomerulonephritis), and is caused by anti-neutrophil cytoplasmic antibodies(ANCA)-associated small-vessel vasculitis [1, 2].

This mini-review focuses on ANCA-associated vasculitis, as it is by far the most common cause of RPGN in the elderly population. Anti-GBM disease will also be briefly mentioned, whereas the topic of type II RPGN has been omitted due to the heterogeneity of this group and lack of data from larger trials.

ANCA-associated vasculitis (AAV) comprises a group of diseases that include granulomatosis with polyangiitis (GPA, formerly Wegener’s), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) [3]. They are relatively rare, with the overall incidence rates in Europe reported in the range from 13 to 20 new cases per million population [4]. The incidence of AAV generally increases with age [4], with the peak incidence reported in the age group of 65–74 years (GPA 31.4/million; MPA 20.6/million) [5], even though the peak age differed in different studies [4]. It has been noted repeatedly that myeloperoxidase-ANCA-associated vasculitis (or MPA respectively) is relatively more common in higher age groups compared to PR3 (proteinase-3)-ANCA-associated vasculitis that prevails in the younger patients [6]. In keeping with predominant diagnosis of MPA in the elderly patients, renal involvement and RPGN are very common in this group, and may occur without any signs of extra-renal involvement in a significant proportion of patients, which makes the early establishment of the diagnosis challenging.

Although relatively rare in the general population, among elderly patients (≥80 years) who underwent renal biopsy, pauci-immune glomerulonephritis (GN) was the most frequent diagnosis (19%), with an even higher percentage among patients with acute kidney injury (33%) in the same cohort [7]. Similarly, in a study on 430 Chinese patients aged ≥65 years with renal biopsy performed, AAV was the leading secondary GN (44%) as well as the most common cause of acute kidney injury [8]. In another report from a national registry of renal biopsies, crescentic GN was present in 5% of patients under 60 years, but the number increased to over 11% in patients aged above 60 years [9].

Unlike AAV, anti-GBM disease typically displays bimodal age distribution with the peak incidence reached in the third decade (often presenting as pulmo-renal syndrome) and then in the sixth and seventh decades (when isolated kidney involvement is more common) [10].

The originally poor prognosis of untreated AAV has dramatically improved after the introduction of cyclophosphamide (CYC) into immunosuppressive treatment of vasculitis in the 1970s, with the current overall 1-year patient survival of almost 90% [11] and 5-year survival of about 75–80% [12]. Thus, the character of AAV has changed from a fatal disease into a chronic illness with remitting-relapsing disease course. Nevertheless, apart from mortality, severe morbidity, both disease and treatment related, remains a concern.

In general, vasculitis population, advancing age and impaired renal function have been commonly identified as independent negative prognostic factors, as was, for instance, also described in the report on outcomes of patients included in previous randomized trials performed in AAV [13]. On the other hand, elderly patients aged above 75 years were typically excluded from these trials. There is therefore relatively little data on the prognosis of elderly (and very elderly) patients with AAV [14-17].

Hoganson et al. [14] found an elevated risk for mortality (hazard ratio = 2.69) in patients with AAV aged more than 75 years (n = 22) compared to younger patients. Interestingly, about a half of the deceased elderly patients died early, that is, within 6 months from diagnosis. The other risk factors for death in this cohort included higher S-creatinine and higher Birmingham Vasculitis Activity Score (BVAS). Similarly, Weiner et al. [15] also confirmed worse prognosis for 151 elderly (≥75 years) patients with AAV, with 1- and 2-year survival rates being 71.5 and 64.6%, respectively. In contrast to the study of Hoganson et al. [14], however, lower BVAS was associated with higher mortality in the latter study [15]. The explanation for this difference between studies is not entirely clear, but as the authors of the more recent study discuss [15], lower BVAS may suggest that there were no extra-renal symptoms, and in patients with isolated renal disease, the diagnostics may be more difficult and treatment somewhat delayed, causing worse prognosis.

Very elderly patients with biopsy-proven pauci-immune GN aged ≥80 years were included in another study by Bomback et al. [16]. In this cohort, the morbidity and mortality were very high, with nearly 70% of patients reaching the combined end-point of ERSD or death within the first year. In another report, Haris et al. [17] defined elderly patients as those aged 65 years or more and also found higher mortality in the older than in the younger patients with AAV, even though the percentage of deaths within the first year did not significantly differ (37 vs. 27%, p = 0.22).

The key to the successful treatment of AAV is the early diagnosis. Nevertheless, this may be particularly difficult in the elderly, as these patients often develop atypical or hardly any clinical symptoms, with, for example, fatigue being ascribed to advanced age. Furthermore, they are often affected by many comorbidities that may mask the symptoms of systemic vasculitis or cause misdiagnosis.

It is believed that in the context of appropriate clinical symptoms, (rapidly) worsening renal function and positivity of autoantibodies (either ANCA or anti-GBM) the immunosuppressive treatment should be initiated as soon as possible [18]. Even though renal biopsy is not strictly necessary to make the diagnosis, it is highly recommended not only for the confirmation of diagnosis but also for the evaluation of the chronicity of the pathological process in the kidney and to assess the prognosis [19]. The presence of more than 50% globally sclerotic glomeruli in the biopsy specimen (i.e., so-called sclerotic class according to recent histopathological classification of ANCA-associated glomerulonephritis) has been linked to the poorest outcome [20]. In the elderly population, the confirmation of the diagnosis using renal biopsy is particularly useful to prevent unnecessary and potentially toxic treatment. On the other hand, nephrologists may be reluctant to perform renal biopsy in this population due to, for example, existing comorbidities, shorter life expectancy, uncertainty concerning the use of immunosuppressive treatment, or patient’s preference [21]. However, given the urgency, clinically suspected RPGN is one of the most common indications for biopsy in the elderly patients.

Immunosuppressive treatment may help to prevent not only ESRD but also mortality from alveolar haemorrhage in cases of pulmo-renal syndrome in systemic vasculitis. According to the current guidelines [19], the induction treatment of systemic generalized AAV should consist of either CYC or rituximab (RTX) with corticosteroids (CS), with the addition of plasma exchange (PLEX) recommended in patients with severe renal involvement (S-creatinine ≥500 µmol/L) and/or alveolar haemorrhage. In the maintenance treatment, azathioprine or methotrexate (with low-dose corticosteroids) are most commonly used, but RTX has been also increasingly used in this setting and successfully tested as a maintenance agent in a clinical trial [22].

The recommendations for the treatment of AAV are based on results of a number of randomized trials performed in the last 2 decades but, in fact, there is little evidence for patients aged 75 years or more, as these patients have been excluded from the trials. In general, immunosuppressive treatment needs to be given in the elderly population with caution. In patients with AAV treated in randomized trials, adverse events were accountable for more than a half of deaths in the first year while active vasculitis only attributed to 19%, suggesting that the toxicity of the current treatment remains significant [11].

On the other hand, both Bomback et al. [16] and Weiner et al. [15] concluded that elderly patients with AAV who received immunosuppressive treatment had better prognosis (lower mortality and/or lower number of ESRD) than those left untreated or not treated in the standard way. Nevertheless, the selection of patients who received immunosuppression is likely to be biased, as those in an a priori better condition are more likely to be treated [23]. In another retrospective study [24], the response to immunosuppressive treatment in elderly patients (over 65 years) did not differ from the younger ones as also the relapse rate. However, the older patients were more likely to develop infection, particularly if leukopenia was present.

Taken together, immunosuppressive treatment in older patients with AAV or RPGN may be useful but needs be individualized as much as possible with life expectancy, comorbidities, risk of infection, drug toxicity, and patient preference taken into consideration. Frequent visits and careful monitoring for adverse events are fully justified.

Cyclophosphamide

CYC has long been the induction treatment of choice in AAV, but the cumulative dose of CYC has been substantially reduced, partly due to early switch from CYC to azathioprine and partly due to the use of intravenous CYC pulses. In an European Vasculitis Society study called CYCLOPS [25], the efficacy of intravenous pulses of CYC in the induction treatment was compared with that of oral CYC. Despite a much lower cumulative dose of CYC in the pulse limb compared to the oral one (8.2 vs. 15.9 g, p < 0.001) and lower rate of leukopenia there was no difference between both limbs in the time to remission and remission rate at 9 months (87.7 vs. 88.1%). Even though in the long-term follow-up of the CYCLOPS study [26] the risk of relapses was doubled in patients originally treated with intravenous CYC, the mortality and the risk of ESRD were not higher in CYC-sparing regimens. Thus, pulsed CYC has become increasingly used in the induction treatment in generalized AAV [27]. Later, Pepper et al. [28] have shown that intravenous CYC (in combination with plasma exchange) may be successfully used even in the treatment of dialysis-dependent patients, who were excluded from the CYCLOPS Trial.

In elderly patients, dose reduction of CYC is required with further adjustment of the dose based on renal function and leukocyte count. For intravenous CYC, the recommended dose of CYC (if no other dose adjustments are required) is 15 mg/kg in patients <60 years, 12.5 mg/kg in those aged 60–70 and 10 mg/kg in those over 70. Similarly, the dose of oral daily CYC needs to be reduced from 2 mg/kg/day to 1.5 or 1.25 mg/kg/day [25].

Rituximab

Owing to its success in randomized [22, 29, 30] trials, RTX now represents (at least) a comparable alternative for both induction and maintenance treatment of AAV, especially in relapsing vasculitis even though it has been increasingly used also as a first-line treatment option. The mean age of patients included in the RAVE trial was 54 years [30] and the median age in RITUXVAS [29] was 68 (range 56–75), so there is limited knowledge on the use of RTX in older patients. However, as these patients are particularly prone to adverse events of conventional immunosuppressive drugs, treatment with RTX seems to be a plausible alternative.

In a recent paper, Timlin et al. [31] used RTX as induction treatment in 31 elderly patients with AAV (mean age 71 ± 6 years, 22 patients [71%] with renal involvement). Remission was achieved in 97% of patients, and the safety profile of RTX in elderly patients seemed good, even though the incidence of infectious complications was relatively high. There is a need for further studies to evaluate the efficacy and safety of RTX in elderly patients.

An interesting concept of RTX used as steroid- and CYC-sparing agent was introduced in the CycLowVas Trial [32]. Patients with renal AAV received 2 × 1 g of RTX with 6 low-dose pulses of CYC and reduced dose of corticosteroids. The results were encouraging and the regime seems to be attractive for use in the elderly and often fragile patients, even though this needs to be further tested.

Plasma Exchange

The prognosis of patients with severe AAV (with S-creatinine ≥500 µmol/L or life-threatening vasculitis manifestations) is significantly worse compared to other vasculitis subgroups. There is no specific data regarding the use of PLEX in AAV in the elderly patients, but it has been used based on the data derived from studies in general AAV population.

Plasma exchange has been routinely used in the treatment of anti-GBM disease. In AAV, the MEPEX trial [33] compared the efficacy of PLEX versus methylprednisolone pulses as add-on treatment to standard therapy with oral CYC and corticosteroids in patients with severe renal vasculitis. At 3 months, significantly more patients treated with PLEX compared to those treated with methylprednisolone pulses (69 vs. 49%) were alive and independent of dialysis and this difference lasted at one year. However, the one-year mortality remained high in both limbs (25%). In addition, the difference in the rate of ESRD became non-significant during long-term follow-up casting doubt on the promising efficacy of PLEX in the (long-term) preservation of renal function [34, 27]. A meta-analysis of 9 small randomized controlled trials [35] in 387 patients with renal vasculitis and idiopathic RPGN including patients with serum creatinine <500 µmol/L demonstrated that PLEX had no effect on mortality but decreased the risk of ESRD by 36% and this effect seemed to be independent on baseline serum creatinine. PEXIVAS [36] is until now the largest trial in vasculitis having recruited already 700 patients with renal vasculitis with estimated GFR <50 mL/min and/or alveolar haemorrhage, which should provide clear answers on the remaining questions about indications of PLEX in AAV.

Both authors declare no conflict of interest related to the topic of this paper.

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