As the population worldwide ages, the epidemic of kidney disease will also increase. Anti-neutrophil cytoplasmic antibodies (ANCA) positive rapidly progressive positive glomerulonephritis (RPGN) is the most common etiology for biopsied patients among the very elderly. Its pathological features and clinical course are well described, though there is still debate about the mechanism of injury involved in individual patients. From very ancient times, the cornerstone of treatment historically has been high-dose cyclophosphamide and a lengthy course of high-dose corticosteroids. Although this regimen has diminished the immediate mortality rate of RPGN, its intermediate and long-term adverse effects are not insignificant. Attempts to minimize toxicity and improve efficacy have been made through the years to allow physicians some options for therapy. Lower cumulative cyclophosphamide regimens, shorter corticosteroid courses, and the introduction of rituximab have modified the armamentarium for treatment of ANCA positive RPGN. As progress is made in understanding the molecular pathogenesis of this disease, new targets will be found for potential therapeutic attack. The complement system is an area of active interest for all glomerular diseases at this time. Indeed, animal studies and preliminary human studies suggest that targeting the complement system can ameliorate the course of ANCA-positive RPGN. Hopefully, as the population ages, we will see more and safer therapeutic options to treat this once rapidly fatal disease.

The elderly population in the United States is growing. The US census projects that by 2030, approximately 20% (72 million) of the US population will be older than 65 years of age and 2.3% (9 million) will be older than 85 years of age [1]. More elderly patients are surviving longer with acute and chronic diseases, including those of the kidneys. According to recent data from the National Health and Nutrition Examination surveys, the largest increase in prevalent chronic kidney disease patients over the past decade was in those over 70 years of age, among whom CKD rates rose by nearly 30% [2]. While much of the disease burden can be explained by chronic conditions such as diabetes, hypertension, and atherosclerotic vascular disease [3-6] and a general age-associated decline in renal function [7, 8], a significant proportion of this rising renal epidemic may be due to potentially treatable diseases. In a series of 235 very elderly patients (80 years and older) who had undergone renal biopsy, a pathological diagnosis that could lead to change in treatment course was found in 67% of the cases [9].

The 2 largest series of renal biopsies in patients over 80 years of age to date are from the United States [9] and -Japan [10]. In the US study, the number one indication for renal biopsy was acute kidney injury, accounting for 46% of the 235 subjects studied. Progressive CKD accounted for 23.8% and nephrotic syndrome accounted for 13.2%. In the Japanese study, the top indication for renal biopsy was nephrotic syndrome, accounting for 50.7% of the 276 subjects studied, with acute kidney injury (AKI) second at 22.5%. In the US study, the top renal biopsy diagnosis was pauci-immune rapidly progressive glomerulonephritis (RPGN), seen in almost 20% of the patients. In Japan, membranous glomerulonephropathy was the number one finding, seen in about 31% of the series. RPGN (anti-GBM, myeloperoxidase, PR3 and immune complex glomerulonephritis [IC GN]) comprised about 16% of the pathological findings.

Most biopsy registries report a complication rate of about 10%, with most of them considered minor, such as transient gross hematuria or a hemodynamically insignificant drop in hemoglobin. Major side effects such as bleeding severe enough to require transfusion, vascular intervention, or nephrectomy are far rarer [11-14]. The few retrospective studies that have examined complication rates in the elderly (age >75 years) have reported low risk rates that do not differ from that of younger patients [15, 16]. One small prospective study comparing 26 patients >60 years of age with 184 younger subjects undergoing ultrasound-guided renal biopsy with a 16 gauge automated gun, reported a higher risk of gross hematuria post biopsy in the elderly group. But this did not lead to any significant difference in hemodynamic stability, perinephric hematoma formation, and/or need for vascular intervention [17].

RPGN is the most common clinical syndrome of AKI seen in the elderly. It is characterized clinically by rapid loss of renal function along with hematuria and proteinuria. Progression to end-stage renal disease can happen in a matter of days to weeks if left untreated. The most ominous pathological finding is that of glomerular extracapillary inflammation in Bowman’s space, crescent formation. The pathology of rapidly progressive or crescentic glomerulonephritis comprises 3 major categories: anti-glomerular basement membrane glomerulonephritis, immune complex glomerulonephritis, and Anti-neutrophil cytoplasmic antibodies (ANCA) positive pauci-immune glomerulonephritis. At the University of North Carolina, where detailed records of biopsies are routinely analyzed, approximately 80% of crescentic GN in patients over the age of 60 years is pauci-immune disease with no deposition of immunoglobulins or other evidence of immune complex disease. Immune complex GN is seen mainly in younger adults and children. Anti-GBM disease is rare in any age [18]. ANCA-positive glomerulonephritis often presents with severe histopathologic findings and large numbers of crescents of biopsy. Likewise, many patients have major elevations of their serum creatinine levels. These ominous findings often make a compelling argument to biopsy octogenarians and even nonagenarians. In the Columbia University series, there were 235 patients over the age of 80 years biopsied in only a 3-year period. Moreover, ANCA-positive vasculitis and glomerulonephritis is often associated with systemic involvement. Approximately three-fourths of patients with -ANCA-positive glomerulonephritis have associated systemic small vessel vasculitis (microscopic polyangiitis or granulomatous polyangiitis) [19]. In a recent large series of patients that included many patients over the age of 60 years , pulmonary involvement was found in 50% of patients; of these, 25% had hemoptysis, which can be life threatening [20]. These ANCA-positive RPGN patients (along with Goodpasture’s disease), comprise ‘pulmonary-renal’ syndromes, which if left untreated, bear the highest mortality rates.

In over 80% of pauci-immune glomerulonephritis patients, there is associated circulating antineutrophil cytoplasmic auto-antibody (ANCA) directed against myeloperoxidase or proteinase 3 in the azurophilic granules of leukocytes [21, 22] In the mentioned large US series of very elderly patients [9] who underwent renal biopsy with diagnosis of pauci-immune glomerulonephritis, a positive p-ANCA by immunofluorescence or myeloperoxidase by enzyme linked immunoabsorption assay was found in 63% of the cases. Hence, serological testing for ANCA is helpful in corroborating with pathologic diagnosis. Unlike anti-GBM glomerulonephritis which, once treated, has a low recurrence rate, pauci-immune GN tends to have a relapsing behavior and often requires maintenance therapy to prevent relapses. The clinical value of following ANCA titers longitudinally remains controversial [23, 24]. Values are best interpreted not in isolation but with clinical correlation.

Before the advent of immunosuppressive therapy, the prognosis of pauci-immune GN was poor. Untreated, Wegener’s Granulomatosis (now called granulomatous polyangiitis) at any age typically runs a rapidly fatal course with a mean survival of 5 months, with 82% of patients dying within 1 year and >90% dying within 2 years [25]. Despite improved treatment, the disease in patients of all ages is still associated with about 20% mortality in the first year of diagnosis and result in ESRD in up to 25% of surviving patients within 4 years [26]. Immunosuppressive treatment is generally agreed to be efficacious in inducing remission of disease in patients irrespective of age, but the complications of treatment are considerable and the risks of adverse effects rise with patient age [27]. In 2011, Bomback et al. [28] retrospectively looked at 61 very elderly patients (age >80 years) with pauci-immune GN, mean creatinine at presentation was 4 mg/dL. Fifty patients were treated with a variety of regimens (corticosteroids, cyclophosphamide – used both orally (58%) and intravenously, mycophenolate, azathioprine, plasma exchange) versus only 11 patients not treated with immunosuppression. Despite the predictable trend to a higher incidence of infection in the treated group, data analysis beyond the 1 year mark showed that treatment was associated with a significantly lower risk of ESRD and/or death compared to the untreated group [28]. While this was not a randomized controlled trial, it does indicate that most clinicians favor immunosuppressive therapy even in elderly patients with ANCA-positive vasculitis and that in many patients treatment is feasible and successful.

Since the above retrospective study was published in 2011, most treatment data revolved around the use of cyclophosphamide, an alkylating agent. The usage of cyclophosphamide has inherent risks of adverse effects, such as infection and malignancy. Alternative regimens have been used in attempts to lower the cumulative induction dose by using intermittent intravenous pulse therapy as opposed to a daily oral regimen. De Groot et al. [29] proved similar efficacy in remission attainment. There were more frequent relapses in the pulse group but on long-term follow-up (4 years). This was not associated with increased morbidity or mortality [30]. The total cumulative dose in the IV pulse group was about 8 g vs. almost 16 g of cyclophosphamide in the oral daily group at the 6-month mark of the study. Pagnoux et al. [31] in the 2015 CORTAGE trial (CORTicosteroid and cyclophosphamide induction treatment for systemic necrotizing vasculitis patients AGEd >65 years) looked at the efficacy of using even lower cumulative doses of cyclophosphamide. There were 104 patients with a mean age of 75 and baseline GFR of 40 mL/min. Systemic vasculitis was seen in 20% of the total group. Fifty-three were randomized to the experimental arm of 6 fixed doses of cyclophosphamide 500 mg to be given IV every 2–3 weeks. Corticosteroids were given for 9 months. This was followed by maintenance therapy with azathioprine, mycophenolate mofetil, or methotrexate. The control arm was cyclophosphamide 500 mg/m2 IV pulse given every 2–3 weeks until remission, along with corticosteroids for 26 months. At 3 years follow-up, there was comparable attainment of remission with both regimens but lower rates of adverse effects (including death) in the experimental arm. However, relapse rates were high in both arms [31].

The desire to further decrease cyclophosphamide usage heralded the use of rituximab by Jones et al. [32] Rituximab is a B-cell depleting anti-CD20 monoclonal antibody. In this trial of 44 subjects, the median age was 67 years, the mean GFR at baseline was 18 mL/min and systemic vasculitis was present in at least two-thirds of the patients in each study arm. Thirty-three received rituximab (375 mg/m2/week for 4 doses) along with 2 IV pulses of cyclophosphamide 15 mg/kg followed by no maintenance. Eleven patients received IV cyclophosphamide 15 mg/kg every 2–3 weeks until remission (max 10 doses), followed by maintenance therapy with azathioprine. All patients were on CS with taper to 5 mg/day by the 6-month mark. Follow-up was for 12 months. Remission attainment was similar in the 2 arms, but the rituximab-based regimen was not associated with a decrease in adverse effects. There were 8 deaths total (6/33 in the rituximab [RTX] arm and 2/11 in the control arm), all of them were over the age of 62 with poor GFR at entry (mean 9 mL/min). Causes of death were infection, cardiovascular disease, and complications of dialysis [32]. At the same time, the initial results of the RAVE trial in 197 patients with ANCA-positive vasculitis were published [20]. The mean age of the study group was 53 years with an average GFR of 60 mL/min at baseline. Although no patient could be intubated or have an entry creatinine >4 mg/dL, half the patients had pulmonary involvement and two-thirds had renal disease. Patients were randomized to 4 weekly doses of rituximab versus oral cyclophosphamide (3–6 months) followed by azathioprine therapy (12–15 mos). Both groups got tapering doses of steroids. Rituximab and steroids with no follow-up immunosuppression proved equivalent in complete remissions of disease (64%) to cyclophosphamide and steroids followed by azathioprine maintenance therapy (53%). Serious infections were also equivalent in the 2 groups. This pivotal trial provided the evidence for FDA approval of rituximab in the United States. Subsequent follow-up at 18 months confirmed the equivalent sustained remission rate in both arms of the study [33].

In terms of maintenance therapy after induction, rituximab is also strongly considered. Guillevin et al. [34] randomized 115 patients who just completed induction therapy with corticosteroids and IV pulse cyclophosphamide to either maintenance with rituximab or azathioprine. Follow-up was 28 months. The rituximab regimen was fixed at 500 mg doses given at days 0, 14, then at months 6, 12, and 18. Azathioprine was 2 mg/kg/day for 12 months, then 1.5 mg/kg/day for 6 months, and then 1 mg/kg/day for 4 months. The number of major relapses were significantly fewer in the RTX arm, and the frequency of severe adverse effects was similar in both arms [34].

Though the risk of malignancy with rituximab-based immunosuppressive regimens appears similar to that of the general population, there are concerns regarding the risk of infectious complications. In addition to leukopenia, hypogammaglobuminemia is a concern, increasing the risk for bacterial infections. Because there is cross-talk between the B and T cells, there is also increased risk for viral infections as well [35]. It is important to attempt to vaccinate patients at least 4 weeks before starting treatment with rituximab, and of course, avoiding live vaccines. Clearly this is not always possible in a disease like RPGN. Screening for hepatitis B infection is important and obtaining hepatology consultation and using anti hepatitis B virus medications in patients when indicated are equally important. Accessing risk for latent TB is also important. Progressive multifocal leukoencephalopathy is a rare demyelinating disease of the brain that results from lytic infection of oligodendrocytes caused by the reactivation of JC polyomavirus. By the year 2011, the World Health Organization retrieved 182 cases of progressive multifocal leukoencephalopathy (PML) of which 114 were associated with the use of RTX. Although the majority of the cases were seen in hematological malignancies with confounding effects of other immunosuppressants, there were 6 cases in patients with rheumatoid arthritis. The conclusion is that RTX may increase the risk of developing PML, but absolute risks are probably low [36].

Attempts are being made to lower the exposure to corticosteroids in the treatment of ANCA-associated renal disease. There is growing evidence to suggest the role of complement activation in glomerular disease in general. Avacopan, previously called CCX168, is an orally administered small-molecule C5aR antagonist that blocks the effects of C5a and prevented the development of GN induced by anti-myeloperoxidase antibodies in a murine model of ANCA associated vasculitis (AAV) [37]. Jayne et al. [38] recently studied the drug as a potential steroid-sparing agent in the treatment of this disease. Sixty-seven patients (mean age 58, GFR at baseline 50 mL/min; patients with severe systemic involvement like pulmonary hemorrhage or cerebral vasculitis were excluded) were randomized into 3 arms. One consisted of standard prednisone starting at 60 mg daily with taper, the second consisted of avacopan administered with low dose prednisone at 20 mg daily with taper, and the last arm was avacopan without any prednisone. All patients received either cyclophosphamide (followed by azathioprine maintenance) or rituximab. Follow-up at 6 months showed similar treatment response in all 3 arms with a greater decrease in proteinuria seen in the avacopan arms. Adverse effects were lower in the experimental arms. Better quality of life scores and less new onset or worsening diabetes was seen as well with avacopan [38]. The ongoing ADVOCATE study (NCT 02994927) will look at using this drug to completely replace glucocorticoids in patients with more severe renal ANCA disease. Finally, the PEXIVAS study (NCT 00987389) examines the merit of adding plasma exchange to standard of care in patients with AAV who present with eGFR <50 mL/min, even if without pulmonary hemorrhage.

Rao et al. [39] examined the mortality rates in 5,667 patients aged 70 years and older who were either waitlisted on dialysis or had received a kidney transplant. The mortality risk was 56% lower for the transplant recipients. In an analysis looking at the organ procurement and transplant network/United Network of Organ Sharing database, Huang et al. [40] showed that kidney transplant recipients aged >80 years have a higher perioperative mortality and a lower 2-year patient survival compared with recipients aged between 60 and 69 years. However, the death-censored graft survival was comparable. In addition, comparable graft survival was observed in recipients of standard criteria donor kidneys and extended criteria donor kidneys. This suggests that transplantation may actually be a reasonable alternative to dialysis for those -ANCA-positive patients who eventually reach ESRD.

ANCA-associated vasculitis is the most common cause of RPGN with acute kidney injury in our aging population. Although the mortality has decreased since the advent of immunosuppression, the morbidity that goes along with treatment is not to be dismissed. Stratifying the severity of illness at presentation helps us to weigh the risk benefit ratio of treatment. The biopsy itself is of value in telling us the chronicity of damage: that of the acute illness as well as from concomitant disease like diabetes, hypertension, and arteriolosclerosis. At present, many of the elderly patients with this disease will benefit from immunosuppressive therapy. Aside from the traditional cyclophosphamide and steroid regimens, we now have the option of using rituximab, lower dose cyclophosphamide, some combination of the 2 (as in RITUXIVAS) or possibly in the near future, a steroid sparing complement blocker. This is clearly a disease that will become more common as our population ages. The therapeutic challenge is to reduce side effects and improve survival. At present, given the many number of newer therapies and better usage of older medications, many of these patients will benefit from treatment.

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