Decline of UA excretion may occur after KTx, leading to Hur and, sometimes gout. This complication is more commonly seen among CNI treated ptns
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Decline of UA excretion may occur after KTx, leading to Hur and, sometimes gout. This complication is more commonly seen among CNI treated ptns (esp. CyA). Other contributing comorbidities that’re common among KTR, e.g., allograft dysfunction, HT, DM, & CVS disease, may also trigger the risk of gout. The pharmacological control of comorbid disorders after Tx may induce the potential for drug interaction compromising the safety & efficacy of pharmacological agents provided for gout therapy. So, using A/I drugs and steroids to treat and/or prevent a gout flare and ULT for long-term control of gout are not entirely without risk in KTR. Consequently, gout in these ptns should primarily be dealt by physician experienced in addressing these clinical issues. I will discuss the ttt/prevention of gout among KTR.
EPIDEMIOLOGY & RISK AGENTS
Hur & gout are commonly seen in KTR, especially TR on the CNI, CyA to impede graft Rj. Most reports assessing Hur and gout in the KTx cohort were conducted in an era while most im/m strategies included Pred + either CyA or Aza:
Fewer reports have assessed the risk of Hur and gout in ptns on Tac and/or MMF, that have largely been replaced CyA & Aza, resp. One study: 121 KTR ttt with a Tac- & MMF-based regimen, incidence of Hur at one y post-Tx was %. Some, but not all, studies have reported a decline in Surate with switching from CyA to Tac. Retrospective study of Medicare TR given above, the incidence of NOG at 3 ys post-Tx was lowered with Tac as compared to CyA (6.1 vs 7.9 %).
The lowered GFR induced by CyA & Tac mostly contributing to urate retention, but tubular damage may also be crucial via deficient urate secretion. Concurrent diuretic use, allograft dysfunction due to Rj, higher BMI, older age, and male gender are other risk factors for Hur & gout. Whilst Hur has been complicated with higher rates of CVS morbidity & MR in the general population, this link has not been shown in KTR. Another analysis of KTR in the FAVORIT trial, showed Surate were not independently complicated with CVS events, MR, or Tx failure. Another study showed: gout was not associated with higher risk of all-cause MR after adjustment for any baseline confounder e.g., age, time post-Tx, and graft function.
Gout may be developed de novo (NOG) in ptns after organ Tx or recur in TR in whom a Dgx of gout was already settled. In KTR, salient features of gout are mostly similar to those observed in non-Tx gout ptns. However, gout could be more intense in TR with more frequently seen gout flares and tophi.
DGX OF GOUT IN TR:
Dgx of gout in KTR can be settled via similar way to that utilized in non-Tx ptns. In KTR presenting with new-onset Sms & Sns suggestive of a 1st gout flare, arthrcn & synovial fluid analysis (with red-compensated polarized LM for monosodium urate crystal recognition) & culture should be proceeded to settle the Dgx and exclude alternate one. Excluding septic arthritis is particularly crucial in Tx ptns receiving im/m with increasing risk of infection. However, feasibility of arthrcn can be limited by clinician inexperience, needle aspiration inaccessibility of the involved joint, or ptn location. In TR with a 1st presentation of inflammatory arthritis and with difficult arthrcn, radiologically guided arthrcn or ptn shifting to a center where arthrcn can be proceeded. In the latter option, we avoid starting A/I therapy with steroids (oral or parenteral) or an iL1i, but we may start NSAID or Clch if the ptn is candidate for any of them. In KTR with a given history of gout flare with experience or recurrence of acute arthritis, we usually start flare ttt without prior arthrcn if the ptn's Sms & Sns are simulating those seen before gout flares and not including fever, chills, or other Sms/Sns of local/regional infection. In these ptns, arthrcn and synovial fluid analysis/culture may unnecessarily postpone ttt, and arthrcn is not lacking risk of iatrogenic infection, albeit little. However, ptns with fever, chills, and/or Sms/Sns of concurrent infection, despite A/I therapy for gout flare, arthrcn & synovial fluid analysis with culture should be proceeded, as gout & septic arthritis may coexist simultaneously.
GOUT FLARES THERAPY:
Gout flare is painful and disabling but self-limited. Early ttt may limit the pain and shorten flare timing. Essentials of gout flare ttt in non-Tx population may also apply to ttt of gout flares in TR. These include ttt with A/I agents at full A/I (as opposed to analgesic) doses as soon as possible after flare initiation with additive measures e.g., icing of the involved joint, and joint protection/immobilization. These maneuvers are mostly of unproved efficacy. Specific considerations in gout flares therapy in KTR may include:
1) Ptn comorbidities may affect the safety and/or efficacy of A/I agents in TR; careful assessment of these comorbid disorders is crucial with appropriate ttt selection for gout flares. The following states have been incriminated:
2) As KTR receiving im/m to impede graft Rj, the possibility of current joint infection as an alternate or concomitant Dgx should be considered in all Tx ptns seen with Sms of gout flare.
3) Ptns receiving ULT to prevent gout flare should not hold this therapy if a gout flare developed, considering lack of benefit from temporary withdrawal, and later re-starting may invite another flare.
Initial anti-inflammatory(A/I) options:
Multiple varieties of A/I agents have been shown to be effective in ttt of gout flares including systemic/intraarticular steroids, oral NSAIDs, oral Clch, and, IL1 beta antagonists. There’s no single best agent for all ptns, but the variability of several agents and approaches may widen the clinician options, according to individual ptn criteria and the gout flare past history, which agent is most likely to provide more benefits and minimizing the risk of the adverse events and drug interactions that’s particularly crucial in ttt gout flare in organ TR. There’s no high-quality evidence(s) particularly directed to KTR guiding the optimal ttt of gout flare. Available approach is based mainly upon the clinical experience & data about the gout flare ttt in non-Tx ptns. The evidence is generally conforming gout recommendations/guidelines provided by the ACR, the ACP, & EULAR. Ptns with NOG: In KTR with NOG (i.e., history lack of gout before Tx) and who do not have associated joint infection (as identified by arthrcn & synovial fluid analysis/culture), a suggested approach to gout flare ttt include:
Ptns with 1st gout flare having one or 2 actively inflamed joints, > arthrcn & joint fluid aspiration with intraarticular steroids injection. Once the aspirated fluid is not clearly purulent, it should be microscopically examined, gram stained with culture, and prompt ttt of septic arthritis accordingly. These steps are depending upon the availability of expert clinician in such facilities and if the joint is currently accessible for injection. Using triamcinolone acetonide (40 mg for large joint, e.g., knee, 30 mg for medium one, wrist, elbow, & 10 mg for a small one) or equivalent of methyl-prednisolone acetate. Ptns with > 2 inflamed joints or having one or 2 actively inflamed joints but with inaccessible intraarticular steroids injection > oral A/I agents:
o Oral steroids (Pred or prednisolone) as 1st-line, given their safety with moderate/ severe graft dysfunction. Pred (or equivalent) 5 ds, then gradual taper over a week to either dosing used in maintenance mg once/d./im/m or total hold in TR not maintained on Pred. Steroids should be cautiously used considering risk of HF, poorly controlled HT, or glucose intolerance.
o Steroid intolerance or contraindicated, low-dose Clch + NSAID are alternates. Low-dose oral Clch in ptns starting A/I ttt within 24 h.s of Sms onset. The effective impact of Clch is less likely if ttt is started between 24 & 36 hs after onset. Clch should NOT be provided to KTR with:
In TR receiving Tac (rather than CyA), the approach to Clch dosing is like to that applied in non-Tx ptns with renal dysfunction. Ptns cannot receive Clch, we may provide potent oral NSAID, e.g., naproxen (500 mg twice/d.) or indomethacin (50 mg 3-times/d.). A shortened course NSAIDs ( ds) can be provided in KTR without noticed adverse effects as long as kidney graft function and ptn well-being are wisely monitored. NSAIDs are mostly efficacious if ttt is provided within 48 hs of Sms starting. Dosage can be declined gradually after a significant improvement in Sms, but dose frequency should be kept for additional days for optimized A/I action. NSAID can be hold within 2 d. after total flare resolution. NSAIDs should be avoided in elderly (>60 ys) and ptns with active peptic ulceration, kidney dysfunction (eGFR <50 mL/min/1.73 m2), active CVS disorders, or NSAID allergy. NSAIDs should not be used for Prox measure against gout flare in KTR.
Ptns unable to receive oral drugs and not candidates for intraarticular steroids, we may start parenteral (IV/IM) steroids. Dosing & duration of parenteral steroids for a gout flare in KTR are similar to that in non-Tx ptns. IV Clch should not be given considering the risk of serious adverse impacts, including death. A therapeutic alternate in this setting is anakinra, a short-acting IL-1 receptor antagonist, provided as 3 (or more, as needed by ptn response) daily SC injections of 100 mg each dose. Canakinumab, an IL-1 B monoclonal AB, approved by EU authorities for ttt only in gout ptns with 3 or more annual flares resistant to other A/I agents. However, we are not recommending canakinumab in organ TR considering the prolonged inhibition of IL-1 B action in these im/m ptns.
Ptns with previous history of gout: In KTR with previous history of gout, therapeutic inlet to the gout flare is similar to that in ptns with NOG. However, specific features of the ptn's previous gout history, i.e., total flare quantities, recent rate of flaring, and experience with certain agents, impacting the choice/duration of an A/I agent:
Ptns on ULT at the timing of a gout flare (e.g., Allop, Febux, Pbd, benzbromarone, or pegloticase), the ULT should be stabilized with no interruption. There’re no benefits of transient withdrawal, and subsequent resumption that may trigger another gout flaring.
Gout flare resistant to the standard A/I: Gout flare is usually self-limited, not persist > 2 weeks. Considering gout flare resistance despite the current use of A/I agents and other measures, we should revise the Dgx to assure that there’s no other cause(s) for the acute inflammatory arthritis. Especially, gout Dgx needs to be confirmed by the finding of mono-Na+ urate crystals, and septic arthritis should be excluded via arthrcn. If gout has been confirmed, options for ttt may include combined A/I agents (e.g., added steroid, oral/parenteral, to a ptn already on Clch or NSAID) or off-label addition of a short-acting IL-1 B inhibitor, e.g., anakinra.
Concomitant infection: In TR with a gout flaring with associated systemic infection not including inflamed joint(s), we should avoid using steroids (by any route) and IL-1 beta inhibitors. So, we may provide Clch or an NSAID, unless there’re CI.
Overview of prevention: In gouty ptns, the disease can be obviously controlled over time by targeting/maintaining Surate via pharmacological agents. The ULT are indicated in ptns with recurrent gout flares (≥2 flares/y.) or having tophi or joint damage attributed to gout. While ULT are usually indicated in KTR, it’s often more challenging. As in general populations, the recommended target Surate in KTR with gout is <6 mg/dL (<357 micromol/L). In KTR, a Sm-free ("intercritical") intervals after gout flare are an opportunity to assess long-term ttt options for further flares Prox and evolution/progression of tophi and/or joint damage, including:
Pharmacological urate-lowering therapy (ULT): several classes may include:
While ULT, alone or combined, can settle/maintain target Surate and consequently decline/prevent gout flare and prevent/resolve tophi, their use is not entirely risk-free in KTR. So, asymptomatic Hur is NOT considered an indication for urate-lowering use in KTR. Considering the risk for complex/serious drug interaction, ULT and associated gout flare Prox in KTR should ideally be managed by physicians with experience in these clinical problems. In contrary to gout flare therapy, starting ULT and flare Prox rarely requires urgent decision. Physicians managing gout in a TR but not included in the ptn's Tx team are advised to keep contact with ptn's Tx team to maximize safety and effectiveness of therapy.
Start & duration of ULT: In KTR, ULT should be instituted at a lowered dose. Ptns commencing these agents, we provide also lowered A/I doses, if possible, to limit the risk of a gout flare during early stages of urate lowering. Once we decided to start these agents, therapy is provided indefinitely/continuously to still effective.
Selection of agents: There’s no high-quality evidence guiding the optimal ULT in TR with gout. Selection of ULT in KTR is mainly based on reports in non-Tx ptns, TR cohorts, and the clinical experience.
1st-line (Allop monotherapy): In KTR, XOI Allop are mostly the 1st-line therapy. Allop is preferred over the alternate XOI Febux considering the greater cost of Febux and, particularly, concerns regarding the higher frequency of CVS events (esp. CVS death) with Febux as compared to Allop in ptns at higher risk for these events. Allop is preferred over uricosuric agents considering the ease of Allop intake and the limited efficacy of some of uricosuric agents with renal dysfunction. Tx ptns of Chinese, Thai, or Korean ethnicity considered for Allop should be examined before start for the HLA-B*58:01 allele that’s associated with severe Allop hypersensitivity; positive ptns for this allele should not receive Allop.
●Ptn with eGFR >60 mL/min/1.73 m2, we often initiate Allop ttt at 100 mg/d. titrating the dose upwardly by 100 mg every weeks to the level required to keep target Surate <6 mg/dL (<357 micromol/L). Starting dose of 100 mg or less of Allop may show lowered risk of rare but SCAR or Allop hypersensitivity syndrome and gout flares development that’s commonly seen with the start ULT.
● Ptns with eGFR of 30 to <60 mL/min/1.73 m2, we start Allop at 50 mg once/d. titrated upward in 50 mg increments every weeks to keep the dose required to reach /maintain a target Surate <6 mg/dL (<357 micromol/L).
● Ptns with an eGFR of <30 mL/min/1.73 m2, we start Allop at a dose equivalent to ≤ mg/d/mL/min eGFR (e.g., for ptn with eGFR of 17 mL/min/1.73 m2, daily Allop dose would be 25 mg that can be provided more readily as 50 mg every 2 d.), then titrating the dose up warding in 50 mg increments every wks to the minimal dose required to keep/ maintain a target Surate <6 mg/dL (<357 micromol/L).
Maximum dosing of Allop provided to ptns with renal dysfunction is not usually limited (considering the regulating agency-approved dosing limits). Although kidney dysfunction does mean an increasing risk of severe/life-threatening but rare serious impacts with Allop, there’s no evidence that the incidence of the uncommon but life-threatening effects has been declined after the advised Allop dose-reduction. Several reports have showed that target Surate can be safely reached with stepwise Surate-monitored titration of Allop dosage in ptns with allograft function from normal to severe dysfunction. XOI (Allop & Febux) should be prohibited in ptns on Aza therapy as the metabolized 6-mercaptopurine, the active metabolite of Aza, involves conversion of 6-mercaptopurine to 6-thiouric acid, a reaction catalyzed by XOI.
So, accumulated 6-mercaptopurine with severe BM toxicity may result due to combined use of Aza and an XOI. However, if the ptn on Aza has intense gout and an XOI should be started, Aza dose reduction (by at least 50-75 %) with careful monitoring of WBCs. However, holding Aza is commonly required in many ptns. An alternate option is to switch ptn from Aza to MMF, if possible, as MMF has no interaction with Allop or Febux.
2nd-line therapy (Febux monotherapy): Ptns not tolerating or reaching target Surate with Allop, ULT with the XOI Febux is an alternate option, provided that ptn is not on Aza & not having established high CVS risk. Febux has been proved to effectively control Hur in KTx ptns; however, the results of one large trial compared Febux with Allop raised concerns about CVS safety of Febux among ptns at higher risk for CVS events.
Starting Febux dosing is 40 mg once/d & measure Surate after weeks of ttt. If target Surate has not been reached, we may raise dosing in 40 mg increments with Surate monitoring weeks after each dose rising. Regulating agency-approving the dosing limits differ by country (e.g., 80 mg/d. in US & Canada, 120 mg/d. in the EU). Febux dose reduction with renal dysfunction is not required in ptns with an eGFR >30 mL/min/1.73 m2; however, in ptns with an eGFR from mL/min per m2, Febux dose should not > 40 mg/d.
3rd -line therapy (combined XOI + uricosuric agent): In the infrequently failing ptns to reach the target Surate with XOIs at their highest dosing, combined therapy with both XOI + uricosuric agent (benzbromarone or Pbd) may be beneficial. Uricosuric agents should be prohibited in ptns at risk of nephrolithiasis or UA nephropathy, e.g., ptns with UA overproduction. Moreover, benzbromarone therapy should NOT be provided to ptns with hepatic dysfunction, and Pbd should NOT be given to hyperuricemic ptns with cystinuria or on D-penicillamine.
1) Benzbromarone: an efficient uricosuric agent that can be provided in a single daily dosing and has been tested in kidney & cardiac TR. This agent that’s not widely used owing to concerns regarding hepatotoxicity and should not be started in ptns with hepatic dysfunction, has been successfully used as monotherapy and combined with Allop in ptns with failed Allop titration to target Surate. The uricosuric action of benzbromarone has been proved to be preserved during ttt of kidney/cardiac TR with Kru as low as eGFR of mL/min/1.73 m2. In KTR, benzbromarone is initiated with initial dose of 25 mg/d., with dose titration by mg incrementing up to maximum 100 mg/d. to reach/maintain target Surate. Liver function and Surate should be currently monitored.
2) Probenecid (Pbd): is an effective ULT in most gouty ptns but mostly ineffective if the eGFR is <50 mL/min/1.73 m2. Pbd is instituted at 250 mg twice/d and titrated in 250 mg increments every wks according to Surate. Usual maintenance dosing necessary to reach the target Surate are mg twice or 3 times/d. The maximum effective dosing is 3 g/d.
Support for the combined therapy of XOI + uricosuric agent was suggested when Allop was approved in the US in 1966 and was involved in the 2012 ACR guidelines for Hur control in gouty ptns. However, this approach has rarely applied, as successful targeting Surate by titrated dosing of Allop seen in most ptns. For variable causes, clinicians are reluctant titrating Allop to > 300 mg/d, despite clear evidence that a minority of gouty ptns achieving target Surate with this dose. Monotherapy is usually preferred and we acknowledge the combined therapy of Allop + uricosuric agent for improving total outcome of ULT in gout.
Other options: In TR not tolerating Allop or febuxstat, or are at higher risk of adverse effects to Allop (e.g., ptns with HLA-B*58:01 allele), we may provide uricosuric agent monotherapy with benzbromarone, if found, or pbd if the eGFR is ≥50 mL/min per 1.73 m2. We do not advice uricases (pegloticase, rasburicase) as initial ULT in KTR. Generally, we keep using uricases for ptns with intensely severe gout with no other ttt options.
A/I Prox with commencing ULT: Gout flares are commonly seen early in the course of ULT. So, in ptns starting ULT, low-dose A/I agents (either Clch or oral steroids) for gout flare Prox are advised. Duration of flare Prox is often mo after the target Surate is achieved and confirmed in ptns free of tophi and for the same timing after tophi resolution in ptns with advanced gout. In KTR commencing ULT, the following approach to gout flare Prox is advised:
Monitoring ULT response: response to ULT is crucial to assure the target Surate achievement and sustainment. In KTR on ULT, we monitor:
o In all KTR starting ULT, we monitor Surate monthly with titrated therapy and after adding of drugs potentially impact Surate. Once the Surate target is achieved, we monitor Surate every 3 mo/1st y., and 6 monthly thereafter. Moreover, monthly monitoring of CBC, SCr, & electrolytes can be added.
o KTR on Allop or Febux, we monitor hepatic functions (AST/ALT & serum bilirubin) 3 mo after starting and then every mo. In KTR on benzbromarone, we monitor hepatic functions on monthly bases.
o In KTR on Clch as A/I Prox during commencing ULT, we monitor CK once or twice/y, esp. in ptns on interacting drugs, e.g., statins. Clinical benefits of ULT are not immediately seen even though a decline in Surate at a given dosing of oral ULT is commonly evident within weeks of starting or dose titration. Reducing flare frequency/severity are often not seen until after mo of ULT (even more with resolute tophus) and according to the baseline urate crystal levels and magnitude of Surate decline.