Conventional and Biological Disease-Modifying Antirheumatic Drugs in Chronic Kidney Disease and Hemodialysis
https://doi.org/10.46856/grp.10.e181
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Santacruz Devia JC, Mantilla MJ, Pulido S, Varela DC, Agudelo CA, Londoño J. Conventional and Biological Disease-Modifying Antirheumatic Drugs in Chronic Kidney Disease and Hemodialysis. Global Rheumatology. Vol 5/ Ene - Jun [2024] Available from: https://doi.org/10.46856/grp.10.e181
Diagrama de flujo 1. Diagrama de búsqueda
Tabla 1. Modificaciones de las dosis de los FARMES sintéticos convencionales sugerida según los niveles de evidencia
Tabla 2. Modificaciones de las dosis de los FARMES sintéticos convencionales dirigidos y biológicos sugerida según los niveles de evidencia
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Conventional and Biological Disease-Modifying Antirheumatic Drugs in Chronic Kidney Disease and Hemodialysis
Advanced chronic kidney disease and the different modalities of renal replacement therapies have been a great limitation when prescribing the different conventional and biological therapies used for the treatment of different autoimmune diseases. Many of them persist with great activity, requiring the use of other types of medications such as glucocorticoids or non-steroidal anti-inflammatory drugs, further perpetuating their adverse effects. Addditionally, most clinical studies have excluded patients with chronic kidney disease and the evidence for continuing biological treatments in this scenario is based on pharmacokinetic properties or case reports where the outcomes have been favorable. The lack of knowledge and the absence of clear guidelines for decision-making regarding starting conventional or biological therapy in this context generate a lack of continuity in the prescription of treatments, which decreases the therapeutic response and negatively affects the quality of life. from the patients. For this reason, a narrative review is carried out with the aim of establishing a practical consensus that unifies the recommendations for each of the treatments most frequently used in the control of various autoimmune diseases in patients with advanced chronic kidney disease.
The kidney has often been affected by various prevalent autoimmune diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and systemic sclerosis (SSc) (1). This may be due both to damage associated with disease activity and to chronic deterioration linked to the use of certain immunosuppressive drugs (2). In addition, the frequent use of nonsteroidal anti-inflammatory drugs (NSAIDs) has also been identified as a contributing factor to the progression of kidney disease, associated with other comorbidities such as diabetes and hypertension (3). Historically, chronic kidney disease has represented a significant limitation for the use of disease-modifying antirheumatic drugs (DMARDs), both synthetic and biologic, due to the increased risk of toxicity posed by some of them, making their use unsafe in this context. It is also relevant to highlight the notable scarcity of clinical studies investigating the efficacy and safety of DMARDs in patients with chronic kidney disease (CKD) and undergoing dialysis (4). It is well known that CKD is characterized by a chronic inflammatory state, supported by the increased levels of several growth factors and inflammatory mediators, such as C-reactive protein, tumor necrosis factor, and monocyte chemoattractant protein-1 (5). This suggests that systemic inflammation plays a crucial role in the deterioration of kidney function, highlighting the need to block these mediators to mitigate kidney damage (6). This phenomenon is evident in cases of secondary amyloidosis, especially in rheumatoid arthritis (RA) and ankylosing spondylitis, where the use of tumor necrosis factor inhibitors (TNFi) is required despite the preexisting established kidney damage (7). Since this paradox remains, the current prescription of DMARDs in CKD is based on the pharmacokinetic and pharmacodynamic characteristics of each drug, rather than on evidence derived from clinical trials (8). Furthermore, several questions remain, such as: the great discrepancy in the recommendations regarding dose adjustment of several DMARDs based on glomerular filtration rate (GFR); the lack of knowledge about whether the dose adjustments and metabolism of DMARDs differ depending on each autoimmune disease; the uncertainty about whether there are variations in plasma concentrations due to frequent drug interactions; and to what extent the benefit of continuing each DMARD can be defined if kidney disease progresses (9).
Methodology
A non-systematic narrative review of the literature was conducted in English, French, Spanish, and German. It is important to note that no clinical studies were identified to justify a systematic review or meta-analysis. The purpose of this review was to gather the most representative available information from articles referenced in primary databases such as PubMed, Embase, and Google Scholar. The MESH (Medical Subject Headings) terms used were: “Chronic kidney disease,” “Conventional synthetic disease-modifying antirheumatic drugs,” “Tumor necrosis factor inhibitors,” “JAK inhibitors,” “Cyclophosphamide,” and “Rituximab”; these were combined using Boolean operators (AND, OR). The search was extended to include other commonly used drugs such as secukinumab, ixekizumab, guselkumab, and abatacept, but no representative data were found to support a recommendation. Below is a flow diagram detailing the search strategy (Diagram 1).
Conventional synthetic disease-modifying antirheumatic drugs
Methotrexate
Methotrexate (MTX) is a prodrug that becomes active once polyglutamated within the cell. This process occurs gradually and can take up to 27.5 weeks to reach a steady state. This time frame explains the delay in achieving the plateau of therapeutic response (10). The drug is mainly eliminated via the renal route, with approximately 80–90% excreted unchanged in the urine. This characteristic explains why any reduction in GFR leads to increased serum levels of the drug and, consequently, a higher risk of myelotoxicity (11). MTX is contraindicated when GFR is below 30 ml/min; if GFR is between 30–59 ml/min, a lower starting dose (7.5–10 mg weekly) is recommended. Other authors suggest contraindicating the drug when GFR is below 45 ml/min, as the drug’s elimination half-life doubles from 11 to 22.4 hours compared to patients with normal renal function, whereas at a GFR of 45–60 ml/min, it only doubles to 13.5 hours (12). Cases of methotrexate toxicity (including death) have been reported in patients receiving hemodialysis, even at low doses, and higher doses have required the use of leucovorin or extended dialysis with high-flux membranes to facilitate elimination (13)(14). It is also contraindicated in patients requiring peritoneal dialysis, although it may be prescribed (with a 50% dose reduction) in cases requiring continuous renal replacement therapy (15).
Leflunomide
The pharmacokinetics of leflunomide in CKD are largely unknown. Some studies have shown that teriflunomide (the active metabolite of leflunomide) was similar after administration of 100 mg of leflunomide in three patients undergoing peritoneal dialysis and reduced in patients on hemodialysis compared to healthy controls. Despite this, the free fraction of the drug in dialysis patients was higher (1.51%) compared to the 0.62% observed in controls. This finding suggests the need for closer monitoring when considering leflunomide administration in cases of advanced renal insufficiency (16). Leflunomide is positioned as the first-line drug in cases of advanced renal insufficiency due to its favorable pharmacokinetic properties. It is important to consider other possible side effects, such as poor blood pressure control, delayed wound healing, and an increased risk of infections (17).
Sulfasalazine
Nephrotoxicity associated with sulfasalazine (SSZ) is predominantly attributed to interstitial nephritis, whether acute or chronic. This complication may manifest within the first 12 months of treatment or even after several years. It is important to note that interstitial nephritis is idiosyncratic and is not usually directly related to the administered dose (18). Drug-induced acute kidney injury secondary to crystalluria has also been reported; therefore, discontinuation of the medication in patients presenting with nephrotoxicity is considered necessary.
Supportive measures such as hydration or the prescription of glucocorticoids will depend on the underlying mechanism causing the acute kidney injury (19). It is important to emphasize that 5-aminosalicylic acid (5-ASA) preparations, such as SSZ and mesalazine, may rarely induce allergic interstitial nephritis. This condition shows recovery in up to 85% of cases following drug discontinuation. A study conducted in patients with inflammatory bowel disease showed a decrease in GFR among those treated with 5-ASA preparations. In this regard, the loss was more pronounced in the group receiving SSZ (−19.5±24.3 ml/min) compared to mesalazine (−7.5±24.7 ml/min), possibly attributable to longer treatment duration in the former group (20). In patients with autoimmune diseases and CKD, it is recommended to start treatment with the lowest dose within the usual range when GFR is below 60 ml/min. Although there is limited data on the safety of SSZ use in patients with end-stage renal disease, it is known that SSZ is not dialyzable, as it binds to plasma proteins in more than 99%. A daily dose of 1 gram has been shown to be well tolerated in patients requiring hemodialysis. However, there is insufficient data on the efficacy or safety of higher doses. There is a need to gather more information to assess the suitability of SSZ treatment in this specific population (21).
Antimalarials (Chloroquine/Hydroxychloroquine)
After oral administration, chloroquine (CQ) and hydroxychloroquine (HCQ) are rapidly and almost completely absorbed. They distribute to tissues in variable concentrations due to their large volume of distribution. Peak blood levels are reached after approximately 4 hours for CQ and between 2 to 6 hours for HCQ. In the blood, about 50% of CQ/HCQ binds to plasma proteins. In solid organs such as the heart, lungs, kidneys, and liver, tissue levels are significantly higher (10 times greater) compared to plasma. The active ingredient has a high affinity for melanin-containing tissues (mainly the skin and eyes) (22). The half-life of CQ and HCQ ranges from 40 to 50 days, and their main metabolites are monodesethyl chloroquine and monodesethyl hydroxychloroquine. It is advised to reduce the dose of HCQ and CQ by 50% when GFR is below 30 ml/min. The incidence of ocular adverse effects tends to increase as renal function declines. In cases of renal insufficiency, HCQ is preferred due to its lower renal elimination, as monodesethyl hydroxychloroquine is primarily excreted through feces, with less renal elimination. Some authors suggest reducing the dose by 50% only when GFR is below 10 ml/min and when prolonged use is anticipated. This adjustment is also recommended for patients undergoing hemodialysis and peritoneal dialysis. However, in patients on continuous renal replacement therapy, dose reduction is not necessary (23).
Azathioprine
Azathioprine is converted into the active metabolite 6-mercaptopurine in the liver and erythrocytes. Most of its metabolites are biologically inactive, with the exception of 6-mercaptopurine, which is partially excreted renally, and 6-thioinosinic acid, which is formed from 6-mercaptopurine and remains intracellular (24). For this reason, when the GFR is in the range of 10–50 ml/min, the azathioprine dose should be reduced to 75% of the standard dose. Other authors suggest administering 75% of the dose in situations where the GFR ranges between 10–30 ml/min (24). In cases of GFR below 10 ml/min or when the patient is undergoing hemodialysis, it is recommended to reduce the dose to 50% and to take it after each session, since approximately 48% of the drug is eliminated by dialysis over an 8-hour period (25).
The following table presents the suggested dose modifications of conventional synthetic drugs according to levels of evidence (Table 1).
Tumor Necrosis Factor Inhibitors
Etanercept
The exact clearance mechanism of etanercept is unknown, although metabolism is believed to occur through peptide pathways, likely mediated via the Fc binding in the reticuloendothelial system (26). The resulting amino acids from metabolism are recycled or eliminated through bile or urine. The immunoglobulin structure gives the drug a half-life of 3 to 4.8 days. A case report in renal failure showed that the half-life of etanercept was slightly prolonged, whereas another study including 6 patients on hemodialysis found that the pharmacokinetics were unchanged compared to controls (27). Small case series addressing treatment with etanercept at a dose of 25 mg once or twice weekly in end-stage renal disease have not documented adverse effects (28)(29).
Golimumab, Adalimumab, and Certolizumab
There are no pharmacokinetic data on the use of golimumab, adalimumab, or certolizumab in advanced renal failure, but it has been proposed that antibodies are hydrolyzed by lysosomes, undergoing intracellular catabolism without requiring renal involvement. Clinical data exist only for adalimumab from a retrospective study that showed no serious infections or other side effects in patients with a GFR of 41.6 ml/min (n=39) compared to a control of 83 ml/min (n=26), including 2 patients on dialysis (30).
Janus Kinase Inhibitors
Tofacitinib
Tofacitinib is a Janus kinase (JAK) inhibitor that is primarily metabolized in the liver via cytochrome P450 enzymes 3A4 and 2C19. Seventy percent of clearance occurs through the hepatic route, and the remaining 30% is excreted renally (31). In RA studies, patients with an eGFR < 40 or 50 mL/min were excluded. There is limited data on the use of tofacitinib in patients with an eGFR < 40 mL/min; therefore, it should not be used in advanced renal insufficiency, and if necessary, the dose should be reduced by 50%. Additionally, if it is absolutely necessary to continue treatment in end-stage renal disease, it is recommended to administer the drug after each dialysis session, as part of it is dialyzable (31).
Baricitinib
The recommended dose of baricitinib is 4 mg once daily. A dose of 2 mg per day is recommended for patients over 75 years of age and for those with a history of chronic or recurrent infections (32). The total body clearance of baricitinib is 8.9 L/h, with a half-life of nearly 12 hours. The drug's technical sheet recommends a 2 mg dose in patients with an eGFR between 30 and 60 mL/min. The use of baricitinib is not recommended in patients with a creatinine clearance < 30 mL/min (33).
Upadacitinib
Upadacitinib is a JAK inhibitor with greater selectivity for JAK1 than for JAK2, JAK3, or TYK (34). Weight, sex, race, age, mild to severe renal insufficiency, and mild to moderate hepatic insufficiency (Child-Pugh A or B) do not affect its safety (35). One study showed that the renal clearance of upadacitinib decreased progressively with increasing severity of renal insufficiency (5.6 L/h in subjects with normal renal function and 1.06 L/h in subjects with severe renal insufficiency). Population pharmacokinetic analyses of upadacitinib in patients with rheumatoid arthritis showed that those with mild to moderate renal insufficiency (with an average creatinine clearance of 40 mL/min) experienced a 16% to 32% increase in plasma concentrations compared to controls (36). Despite this, the overall renal clearance of the drug is very low and no dose adjustment is necessary, unless the eGFR is below 30 mL/min, in which case it is contraindicated (37).
Cyclophosphamide and Rituximab
Cyclophosphamide, which is itself inactive, is converted in the liver into the active metabolites 4-hydroxycyclophosphamide and aldophosphamide via CYP2B6 and CYP3A4. About 20-25% of cyclophosphamide is excreted unchanged in the urine. In the presence of renal insufficiency, its clearance significantly decreases. Cyclophosphamide binds slightly to plasma proteins, whereas its metabolites bind up to 50%. The metabolites are also primarily excreted renally (38). For this reason, a dose adjustment of 75% of the usual dose is necessary when eGFR is between 10–30 mL/min, and it should be reduced to 50% when eGFR is below 10 mL/min. Cyclophosphamide shows moderate dialyzability (20–50%), so maintaining a 50% dose adjustment is recommended in intermittent hemodialysis situations. In these cases, it is advised to administer the next dose during the following session, allowing at least 12 hours to pass before the subsequent application (39). Rituximab is not removed during hemodialysis, so it can be administered at standard doses in patients with advanced end-stage renal disease without requiring any adjustment (40).
Tocilizumab
A case report was identified of a 64-year-old Japanese woman with RA who achieved low disease activity as measured by DAS28-CRP and was able to reduce glucocorticoid use with the administration of tocilizumab while on hemodialysis at a dose of 8 mg/kg every 4 weeks, without any adverse effects reported from its use (41).
A table is presented below showing the suggested dose modifications for biologic DMARDs and targeted synthetic DMARDs according to levels of evidence (Table 2).
Although relevant pharmacological aspects of conventional synthetic DMARDs (csDMARDs) are known in daily clinical practice, the available information remains insufficient to issue recommendation grades with higher levels of evidence in patients with chronic kidney disease (CKD). Despite this, the currently available evidence was unified to provide safe and practical recommendations, based on pharmacological properties and, in some cases, on case reports with satisfactory outcomes. Leflunomide is the conventional synthetic drug that shows the greatest safety in patients with advanced-stage CKD, and most of these drugs require dosage adjustment according to glomerular filtration rate (GFR). TNF inhibitors, which undergo intracellular catabolism without depending on renal clearance, may be safe in this context. However, the reported cases with favorable outcomes have been mainly associated with etanercept and adalimumab. Regarding JAK inhibitors, upadacitinib does not require dose adjustment with GFR greater than 30 ml/min, while tofacitinib and baricitinib require adjustments in stage 3 CKD. Tofacitinib is the only JAK inhibitor that has been prescribed in some cases of patients undergoing hemodialysis. It is important to consider cyclophosphamide adjustment when GFR drops below 30 ml/min, due to the increased risk of adverse events, including bone marrow suppression, infections, increased malignancy risk, and hyponatremia. Rituximab, on the other hand, can be administered without contraindications at any stage of CKD.
As authors of this article, we certify that none of the materials in the manuscript (including tables and figures) have been previously published, nor are they included in any other document.
This article has not received specific funding from the public sector, commercial sector, or nonprofit organizations.
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