Efficacy of Therapeutic Apheresis for Cryoglobulinemic Vasculitis Patients with Renal Involvement: A Systematic Review Free

Cryoglobulins refer to immunoglobulins (Igs) that have the property of precipitating when exposed to temperatures <37°C, and then redissolve at temperature >37°C. There are three types of cryoglobulinemia (CG) based on the compositions of Igs or cryoproteins in the blood. Type I CG is characterized by single monoclonal Igs, primarily IgM (occasionally IgG or IgA). The other two types are mixed (usually IgG and IgM). Type II is characterized by a combination of monoclonal and polyclonal Igs, usually IgMκ plus IgGκ or IgGλ. Type III comprises both polyclonal IgM and IgG [1, 2]. Mixed CG is characterized by cryoglobulins that exhibit rheumatoid factor activity against IgG, allowing them to form immune complexes.

Cryoglobulinemic vasculitis (CV) is a type of systemic vasculitis where cryoglobulins are deposited in small and medium-sized blood vessels, causing immune-mediated damage and inflammation [2‒4]. The kidney is frequently affected in 30–60% of the cases, especially those with type II CG. Renal manifestations usually vary, from more frequently hematuria or proteinuria, to nephritic or nephrotic syndromes (NS), acute kidney injury (AKI), and acute renal failure (ARF) [5‒7]. Other specific clinical features of CV include weakness, cutaneous involvement, and vasomotor symptoms (e.g., purpura, skin ulcers, Raynaud), musculoskeletal involvement (e.g., arthralgias and myalgias), peripheral neuropathy, and pulmonary and cardiac disease [4, 8]. Treatment for CV typically involves treatment targeting the causative disease (such as hepatitis C and hematological malignancy), and the use of steroids and cytotoxic or immunosuppressive drugs (such as rituximab, azathioprine, cyclophosphamide, and methotrexate), which can improve the prognosis in many cases but may have limited success in some patients [8].

The excessive production of abnormal Igs is thought to be the fundamental mechanism underlying the disease [2]. Therapeutic apheresis (TA) can rapidly remove circulating cryoglobulins, albeit transiently. When used in combination with immunosuppressive therapy, TA has been suggested to effectively reduce CV-associated morbidities in patients with life-threatening systematic inflammatory syndrome. The American Society of Apheresis categorizes severe and/or symptomatic CG as category II and recommends TA as a second-line therapy [9]. There are various modalities of TA, such as plasma exchange (PE), plasmapheresis (PP) or double filtration PP (DFPP), immunoadsorption apheresis, lymphocytapheresis, low-density lipoprotein apheresis, and cryofiltration (CF) [10]. PE involves non-selectively removing plasma components from the blood, and replacement fluid like albumin is typically used [10]. On the other hand, PP involves extracorporeal removal, return, or exchange of blood plasma or components, which is accomplished by either centrifugation or filtration using semipermeable membranes [11]. Immunoadsorption Apheresis enables the selective removal of specific plasma components, such as Ig, antibodies, and immune complex, for targeted therapeutic interventions [12]. Lymphocytapheresis has been described in patients with lymphocyte abnormalities, such as rheumatoid arthritis, and also frequently employed in cases of focal segmental glomerulosclerosis where T lymphocytes-derived permeability factors might be involved [13]. Low-density lipoprotein apheresis is beneficial for reducing glomerular lipotoxicity by decreasing LDL levels and improving macrophage functions [10]. In addition, CF is another effective approach to remove cryoglobulins from a patient’s serum, leading to a rapid decline in the cryocrit [14, 15]. Each of these TA modalities plays a critical role in managing diverse medical conditions, providing clinicians with effective tools to address specific therapeutic needs.

It is worth mentioning that PE, PP, and CF have predominantly been reported in patients with CV [16]. However, substantial multicenter randomized controlled trials comparing the efficacy of TA versus placebo or other therapies are currently lacking. Consequently, the efficacy of these different TA modalities in CV patients with renal involvement remains uncertain. In light of this, we conducted this systematic review to assess TA’s efficacy in these patients and to offer a comprehensive overview of the existing evidence.

The protocol for this systematic review has been registered with PROSPERO (International Prospective Register of Systematic Reviews, No. CRD42023417727). We performed a comprehensive literature search of MEDLINE, EMBASE, and Cochrane Databases up to December 2022 to identify relevant studies reporting outcomes of TA in adult CV patients with renal involvement. Two investigators (J.M. and P.K.) independently conducted the literature review to assess the efficacy of TA in these patients and collected the data. The search strategy employed the terms “plasma exchange OR plasmapheresis OR extracorporeal blood purification” AND “cryoglobulinemia AND (vasculitis OR glomerulonephritis).” No language limitations were applied during the search process. In case of any differing decisions between the investigators, they reached a mutual consensus. This study adhered to the Preferred Reporting Items for Systematic Reviews (PRISMA) Statement guidelines [17].

The systematic review included case reports, case series, clinical trials, and observational studies, comprising cross-sectional, case-control, or cohort studies that provided data on the outcomes of TA in adult patients (>18 years) with CV and renal involvement. Studies lacking renal involvement, without TA treatment, with unclear TA effects, or possessing poor methodological quality were excluded. Renal involvement pertains to patients displaying renal manifestations, such as proteinuria, hematuria, NS, AKI, ARF, and/or glomerulonephritis. Different studies presented varying definitions or descriptions for assessing TA efficacy and renal outcomes (online suppl. Table 1, 2; for all online suppl. material, see https://doi.org/10.1159/000534102). Across most investigations, the response to TA treatment was evaluated by monitoring enhancements in proteinuria, serum creatinine (sCr), albumin, Ig, complement, and/or cryoglobulins/cryocrit levels. Furthermore, some studies assessed renal outcomes following TA therapy through criteria such as complete/partial remission of proteinuria and/or recovery/improvement of renal function.

Conference abstracts and non-English articles were excluded from the review. Two investigators (J.M. and P.K.) independently assessed the retrieved articles for eligibility, with any discrepancies resolved through consensus among all authors. The quality of each study was evaluated by the investigators using the validated methodological index for non-randomized studies (minors) quality score [18].

For data collection from each included article, a standardized data collection form was utilized. The following information was gathered: study title, author names, publication year, study type, number of patients, patient gender and age, whether kidney biopsy was performed, specifics of any immunosuppressive treatment (including duration before, during, and after TA), TA protocol details (including modality, session, and duration), concomitant treatments alongside TA, duration of follow-up, response to TA, and long-term renal outcomes (defined as those persisting for at least 3 months after TA). In our analysis, we compiled and summarized the data on sex, age, number of sessions, and follow-up duration as well as laboratory examinations from the original studies, considering any missing information. For example, in case report studies, individual ages were reported, whereas some case series studies presented age as an average or mean value. In such cases, we reported the age range based on the mean to provide a summary. Regarding the number of sessions and follow-up duration, we calculated the averages for case report and case series studies, respectively. The ranges of these averages were then summarized and reported in our analysis. In certain case series studies, we conducted statistical analyses illustrate the variances in laboratory data (such as proteinuria, sCr, Ig, complement, and cryocrit) before and after TA therapy administration.

Various studies have used different criteria to measure the response of TA and its impact on renal outcomes. The data pertaining to the response to TA and renal outcomes were extracted directly from the original study (online suppl. Table 1, 2). In most researches, improvement in proteinuria, sCr levels, Ig, complement, and cryoglobulins or cryocrit levels after TA treatment are used to define TA response, and long-term renal outcomes are defined as complete/partial remission of proteinuria or recovery/improvement of renal function that persists for more than 3 months after TA treatment. In general, complete remission was characterized as having proteinuria of less than 0.5 g per 24 h, while partial remission was defined as a reduction in proteinuria ranging from 0.5 to 3.5 g per 24 h, along with a >50% decrease from the baseline level. Certain studies used alternative criteria to assess the renal outcomes, including metrics such as renal remission, clinical response, and clinical condition. Renal remission was considered achieved when there was a >50% reduction in urinary protein levels and the absence of hematuria. Clinical response was identified by the resolution of vasculitis ulcers (if present), improvement in neuropathy, enhanced renal function, and/or resolution of skin rash. The clinical condition was graded on a scale from zero (normal) to 4 (indicative of life-threatening disease or loss of function). Statistical analysis was employed in certain case series studies to demonstrate the significance of alterations in proteinuria, sCr, Ig, complement, and cryocrit or cryoglobulin levels.

Most of the presented data are descriptive. With regard to statistical analysis of laboratory data, mean ± standard deviation or median (interquartile range, IQR) was presented, and the Kruskal-Wallis test was performed using JMP Pro 14 (SAS Institute Inc.). All p values were 2-tailed and were considered statistically significant at ≤0.05.

The initial literature search yielded 1,008 potentially relevant articles (Fig. 1). After eliminating 178 duplicate articles and excluding 578 articles that clearly did not meet the inclusion criteria based on article type, 262 articles underwent a thorough full-length review. Out of these, 186 articles were further excluded as they did not meet the specified inclusion criteria. Ultimately, 76 articles were included in this systematic review, consisting of 63 case reports (online suppl. Table 1) and 13 case series with three or more cases per study (online suppl. Table 2). The methodological quality of these 76 studies was comprehensively assessed (online suppl. Table 3).

A total of 154 patients experiencing 170 episodes of serious events that necessitated TA, such as deteriorating renal function, severe skin lesions and neuropathy, pulmonary hemorrhage, or intestinal vasculitis, were included in the study. Among these patients, 51% were males, and the mean age ranged from 52 to 58 years (Table 1). The CV type was classified as 15 type I cases, 97 type II cases, and 13 type III cases, with the remaining patients having mixed (n = 17) or undetermined (n = 12) CV types. Out of the 154 patients, the etiology of CV remained unidentified in 85 cases (55.2%). Hematologic malignancy accounted for 53% (n = 8/15) of type I cases, while hepatitis C was the common cause in 27% (n = 26/97) of type II cases (Table 2).

PP or DFPP was documented in 40 studies, consisting of 3 case series and 37 case reports. Following this, PE was reported in 31 studies, comprising 8 case series and 23 case reports, while CF was mentioned in 5 studies, which included 2 case series and 3 case reports (online suppl. Table 4). Among the total of 154 patients, PE was performed in 85 cases (56%), PP/DFPP in 52 cases (34%), and CF in 17 cases (11%) (Table 1). Among the total of 170 episodes of serious events that necessitated TA, PE was utilized in 93 episodes (54.7%), PP/DFPP in 60 episodes (35.3%), and CF in 17 episodes (10%) (Table 1).

The protocols for TA treatment showed significant variations across studies (online suppl. Table 1, 2). On average, TA sessions ranged from 5 to 18 during the intensive treatment period, with most studies implementing a frequency of once or twice a week. Nearly all patients received a combination of steroids and/or immunosuppressants, along with treatment targeting the underlying causative disease, such as hepatitis C or blood cancer, both during the TA treatment and follow-up periods (online suppl. Table 1, 2).

The overall response rate for TA treatment was 78%. Type I, II, and III patients experienced response rates of 84%, 77%, and 75%, respectively. Regarding the treatment modalities, the response rates for PE and PP/DFPP were similar at 76% and 73%, respectively. However, both were lower compared to CF with a response rate of 100% (Table 1). The alterations of proteinuria, sCr, and cryoglobulins or cryocrit levels after intensive TA therapy are shown in Table 3.

Throughout an average follow-up period ranging from 5 months to 9 years, the overall renal outcome rate was 77%. The renal outcome rates for type I, II, and III patients were 89%, 76%, and 90%, respectively. Regarding the long-term renal outcome, patients receiving PE, PP/DFPP, and CF showed similar rates of 78%, 76%, and 81%, respectively (Table 1).

The findings from this systematic review demonstrate that TA therapy yields a favorable response rate of 78% in CV patients with renal involvement, and it is also associated with a noteworthy long-term recovery or improvement rate of 77% in renal function. These results strongly support the efficacy of utilizing TA in treating CV patients with renal involvement. Additionally, the study highlights the critical role of TA administration during severe events, as it can significantly influence renal outcomes.

CV conditions are often linked to elevated levels of cryoproteins in the blood, triggering systemic inflammation in multiple organs [2, 4]. Kidney injury is a common occurrence in CV patients, characterized by symptoms like proteinuria, hematuria, and renal failure. In a study involving 279 patients with hepatitis C-related CG, renal impairment/failure was observed in 205 patients (73%), with 47% of these patients exhibiting NS [24]. Based on the majority of reviewed studies, CV patients typical exhibit MPGN as the prevailing renal histopathological lesion, which aligns with findings from other researches [7, 25]. Additionally, the studies reviewed also reported cases of focal or diffuse proliferative glomerulonephritis, mesangio-capillary glomerulonephritis, and endocapillary proliferative glomerulonephritis [19, 20, 26‒29]. The presence of CV-related acute nephritic or nephrotic syndrome significantly increases the risk of severe cardiovascular events, while chronic renal failure or ESKD is associated with a substantial increase in mortality [30, 31]. Hence, it necessitated specific therapies that can achieve efficacy within short timeframes [16].

The potential pathogenesis of CV is thought to be related to excessive cryoprotein production. To address this, the use of TA proves to be a swift and efficient method to eliminate cryoglobulins, thereby saving valuable time for subsequent treatment options [8]. The studies in this systematic review revealed that most patients experienced severe or life-threatening manifestations, such as deteriorating renal function and/or ARF, severe skin lesions and neuropathy, pulmonary hemorrhage, and intestinal vasculitis [4, 32‒36]. Currently, there is no standardized protocol for TA treatment, including modality options, TA frequency, and total sessions. Most studies reviewed initiated treatment once or twice a week. Typically, a combination of TA and medications like steroids, immunosuppressants (e.g., rituximab, cyclophosphamide, azathioprine, and methotrexate), and/or specific targeted therapies against underlying causes (e.g., chemotherapy for blood cancers, direct-acting antivirals for hepatitis C) were employed in most patients. It is crucial to highlight that the timing of TA initiation is critical in some situations. For instance, supplementary TA treatment demonstrated a positive response in certain cases with relapses [37‒45]. In cases undergoing rituximab therapy, TA should be performed prior to or 7 days after rituximab infusion since it can effectively remove rituximab especially within 3–7 days after administration [46]. Additionally, TA should be administrated before the progression of serious events. A retrospective study of 159 CV patients demonstrated that those with life-threatening symptoms were less likely to respond to TA therapy (adjusted odds ratio 0.12, 95% CI 0.03–0.42; p = 0.001) and had a higher risk of mortality within the first year after the first TA session compared to patients without life-threatening symptoms [47]. However, several case series studies indicated that TA was more effective in patients with ARF compared to those with chronic renal failure or insufficiency [19, 21, 22, 48].

Although the renal outcomes in patients receiving PE, PP, and CF were comparable, our finding suggest that the response to CF was superior compared to PE and PP. In a case series study involving 16 patients with ARF and extrarenal symptoms, after an average 18 sessions of PE treatment, 24 h proteinuria, sCr, and cryocrit (%) levels significantly decreased from 3.5 ± 3.3 to 1.6 ± 2.6 g (p < 0.001), from 2.9 ± 1.8 to 1.6 ± 0.6 mg/dL (p < 0.01), and from 22 ± 20 to 11 ± 15 (p < 0.01), respectively [20]. In another case series, study involving 4 patients with NS and AKI, after an average of 7 sessions of DFPP, 24 h proteinuria, sCr, and cryocrit levels decreased from 3.0 ± 1.5 to 0.7 ± 0.6 g (p = 0.03), from 2.59 ± 0.81 to 0.61 ± 0.27 mg/dL (p = 0.05), and from 30 (IQR 18, 200) to zero mg/L (IQR 0, 3) (p = 0.05), respectively [16]. However, a case series study with 3 patients with NS and AKI demonstrated that an average of 3.3 sessions of CF treatment resulted in significant reductions in 24 h proteinuria, sCr, and cryoglobulin levels from 4.9 ± 0.7 to 0.6 ± 0.6 g (p < 0.0001), from 1.7 ± 0.4 to 1.1 ± 0.3 mg/dL (p = 0.02), and from positive to negative, respectively [23]. It is worth noting that the sample size in all these studies is limited, especially in the study with CF treatment. Therefore, the efficacy of CF treatment in CV patients with severe renal symptoms needs be further investigated.

It is essential to acknowledge the limitations of the current systematic review. First, the included studies span a considerable time range from 1982 to the present, potentially introducing variations in the efficacy of TA due to advancements in modern care, including the use of new medications. Second, this review relies on case report and case series studies, where different definitions or descriptions were utilized to assess TA efficacy and renal outcomes. As a result, the reported results may be influenced by inherent biases present in these study designs. Moreover, the findings presented in this review exclusively pertain to the efficacy of TA in CV patients with renal involvement. Further research is necessary to determine the extent to which these cases reflect the broader CV population and to gain a more comprehensive understanding of TA efficacy in this context. Finally, there is a lack of controlled or comparative randomized clinical trials on this topic, which further limits the scope of the review. Future studies should aim to refine and optimize the use of TA in CV treatment through controlled trials, standardized protocols, and exploration of combination therapies. These endeavors will enhance the understanding of TA’s role, improve treatment outcomes, and contribute to the development of evidence-based guidelines for the management of CV patients with renal involvement.

The findings from this systematic review highlight the success of incorporating TA alongside other treatments, such as immunosuppressive therapy, in effectively managing severe renal involvement in CV patients. Among the TA modalities assessed, including PE, PP, and CF, all proved to be effective, with PE being the most commonly utilized approach. However, further research is warranted to determine the optimal TA modality and treatment regimen for different subtypes of CV, as well as to explore long-term outcomes beyond renal function. Nonetheless, these results provide valuable insights into the application of TA in treating CV patients with renal involvement and emphasize the significance of a multidisciplinary approach in enhancing patient outcomes.

An ethics statement is not applicable because this study is based exclusively on published literature.

The authors have no conflicts of interest to declare.

This research was not funded by external sources.

Jing Miao, Charat Thongprayoon, and Wisit Cheungpasitporn designed research. Pajaree Krisanapan and Supawit Tangpanithandee performed literature search. Jing Miao and Pajaree Krisanapan reviewed the literature. Jing Miao analyzed data and wrote the manuscript. All authors proofread the final manuscript.

All relevant data are reported in the article. Further inquiries can be directed to the corresponding author.