RESUMO
Onconephrology focuses on management of kidney disease in cancer, which manifests itself in a variety of clinical syndromes, including acute kidney injury, chronic kidney disease, hypertension, proteinuria, and electrolyte disorders. Many of these syndromes result from cancer treatments including chemotherapy, immunotherapy, chimeric antigen receptor T cells, and stem cell transplant. Others are due to kidney-specific effects of the cancer, as seen with monoclonal gammopathy or glomerular diseases associated with malignancy. Further, cancer risk itself is heightened in patients with kidney disease, particularly kidney transplant recipients, and their care requires specific considerations. In this installment of AJKD's Core Curriculum in Nephrology, we review these and other core concepts in onconephrology, using a case-based approach to highlight clinical decision making.
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Injúria Renal Aguda , Neoplasias , Insuficiência Renal Crônica , Humanos , Neoplasias/tratamento farmacológico , Rim , Insuficiência Renal Crônica/terapia , Injúria Renal Aguda/terapia , CurrículoRESUMO
BACKGROUND: Despite increasing recognition of the importance of immune checkpoint inhibitor-associated AKI, data on this complication of immunotherapy are sparse. METHODS: We conducted a multicenter study of 138 patients with immune checkpoint inhibitor-associated AKI, defined as a ≥2-fold increase in serum creatinine or new dialysis requirement directly attributed to an immune checkpoint inhibitor. We also collected data on 276 control patients who received these drugs but did not develop AKI. RESULTS: Lower baseline eGFR, proton pump inhibitor use, and combination immune checkpoint inhibitor therapy were each independently associated with an increased risk of immune checkpoint inhibitor-associated AKI. Median (interquartile range) time from immune checkpoint inhibitor initiation to AKI was 14 (6-37) weeks. Most patients had subnephrotic proteinuria, and approximately half had pyuria. Extrarenal immune-related adverse events occurred in 43% of patients; 69% were concurrently receiving a potential tubulointerstitial nephritis-causing medication. Tubulointerstitial nephritis was the dominant lesion in 93% of the 60 patients biopsied. Most patients (86%) were treated with steroids. Complete, partial, or no kidney recovery occurred in 40%, 45%, and 15% of patients, respectively. Concomitant extrarenal immune-related adverse events were associated with worse renal prognosis, whereas concomitant tubulointerstitial nephritis-causing medications and treatment with steroids were each associated with improved renal prognosis. Failure to achieve kidney recovery after immune checkpoint inhibitor-associated AKI was independently associated with higher mortality. Immune checkpoint inhibitor rechallenge occurred in 22% of patients, of whom 23% developed recurrent associated AKI. CONCLUSIONS: This multicenter study identifies insights into the risk factors, clinical features, histopathologic findings, and renal and overall outcomes in patients with immune checkpoint inhibitor-associated AKI.
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Injúria Renal Aguda/induzido quimicamente , Antígeno B7-H1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Injúria Renal Aguda/mortalidade , Injúria Renal Aguda/terapia , Idoso , Feminino , Humanos , Rim/patologia , Masculino , Pessoa de Meia-Idade , Nefrite Intersticial/induzido quimicamente , Estudos Retrospectivos , Fatores de RiscoRESUMO
Immune checkpoint inhibitors have dramatically improved cancer therapy for many patients. These humanized monoclonal antibodies against various immune checkpoints (receptors and ligands) effectively treat a number of malignancies by unleashing the immune system to destroy cancer cells. These drugs are not excreted by the kidneys or liver, have a long half-life, and undergo receptor-mediated clearance. Although these agents have greatly improved the prognosis of many cancers, immune-related end organ injury is a complication that has come to light in clinical practice. Although less common than other organ involvement, kidney lesions resulting in acute kidney injury and/or proteinuria are being described. Acute tubulointerstitial nephritis is the most common lesion seen on kidney biopsy, while acute tubular injury and glomerular lesions occur less commonly. Clinical findings and laboratory tests are suboptimal in predicting the underlying renal lesion, making kidney biopsy necessary in the majority of cases to definitely diagnose the lesion and potentially guide therapy. Immune checkpoint inhibitor discontinuation and corticosteroid therapy are recommended for acute tubulointerstitial nephritis. Based on a handful of cases, re-exposure to these drugs in patients who previously developed acute tubulointerstitial nephritis has been mixed. Although it is unclear whether re-exposure is appropriate, it should perhaps be considered in patients with limited options. When this approach is taken, patients should be closely monitored for recurrence of acute kidney injury. Treatment of cancer in patients with a kidney transplant with immune checkpoint inhibitors risks the development of acute rejection in some patients and requires close surveillance.
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Injúria Renal Aguda/prevenção & controle , Antineoplásicos Imunológicos/efeitos adversos , Rejeição de Enxerto/prevenção & controle , Inibidores de Checkpoint Imunológico/efeitos adversos , Proteinúria/prevenção & controle , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/imunologia , Injúria Renal Aguda/fisiopatologia , Rejeição de Enxerto/induzido quimicamente , Rejeição de Enxerto/imunologia , Humanos , Glomérulos Renais/efeitos dos fármacos , Glomérulos Renais/imunologia , Glomérulos Renais/fisiopatologia , Transplante de Rim/efeitos adversos , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Proteinúria/induzido quimicamente , Proteinúria/imunologia , Proteinúria/fisiopatologiaRESUMO
Nephrotoxicity from cancer therapies is common and increasingly encountered in clinical practice, such that the subfield of "onco-nephrology" has emerged. Conventional chemotherapeutic drugs and novel agents targeting specific genes/proteins are effective cancer therapies but suffer from a number of adverse kidney effects. An effective avenue of cancer treatment is immunotherapy, which uses drugs that augment immune system-mediated recognition and targeting of tumor cells. As such, leveraging the immune system to target malignant cells represents an important modality in eradicating cancer. IFN and high-dose IL-2 are older immunotherapies used in clinical practice to treat various malignancies, whereas new cancer immunotherapies have emerged over the past decade that offer even more effective treatment options. The immune checkpoint inhibitors are an exciting addition to the cancer immunotherapy armamentarium. Chimeric antigen receptor T cells are also a new immunotherapy used to treat various hematologic malignancies. However, as with the conventional and targeted cancer agents, the immunotherapies are also associated with immune-related adverse effects, which includes nephrotoxicity.
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Injúria Renal Aguda/induzido quimicamente , Imunoterapia/efeitos adversos , Interferon-alfa/efeitos adversos , Interleucina-2/efeitos adversos , Neoplasias/terapia , Injúria Renal Aguda/epidemiologia , Injúria Renal Aguda/imunologia , Feminino , Previsões , Humanos , Imunoterapia/métodos , Imunoterapia/tendências , Interferon-alfa/uso terapêutico , Interleucina-2/uso terapêutico , Masculino , Neoplasias/imunologia , Neoplasias/patologia , Medição de Risco , Resultado do TratamentoRESUMO
Acute kidney injury due to high-dose methotrexate (HDMTX) is a serious, life-threatening toxicity that can occur in pediatric and adult patients. Glucarpidase is a treatment approved by the Food and Drug Administration for high methotrexate concentrations in the context of kidney dysfunction, but the guidelines for when to use it are unclear. An expert panel was convened to provide specific, expert consensus guidelines for the use of glucarpidase in patients who develop HDMTX-induced nephrotoxicity and delayed methotrexate excretion. The guideline provides recommendations to identify the population of patients who would benefit from glucarpidase rescue by more precisely defining the absolute methotrexate concentrations associated with risk for severe or life-threatening toxicity at several time points after the start of an HDMTX infusion. For an HDMTX infusion ≤24 hours, if the 36-hour concentration is above 30 µM, 42-hour concentration is above 10 µM, or 48-hour concentration is above 5 µM and the serum creatinine is significantly elevated relative to the baseline measurement (indicative of HDMTX-induced acute kidney injury), glucarpidase may be indicated. After a 36- to 42-hour HDMTX infusion, glucarpidase may be indicated when the 48-hour methotrexate concentration is above 5 µM. Administration of glucarpidase should optimally occur within 48-60 hours from the start of the HDMTX infusion, because life-threatening toxicities may not be preventable beyond this time point. IMPLICATIONS FOR PRACTICE: Glucarpidase is a rarely used medication that is less effective when given after more than 60 hours of exposure to high-dose methotrexate, so predicting early which patients will need it is imperative. There are no currently available consensus guidelines for the use of this medication. The indication on the label does not give specific methotrexate concentrations above which it should be used. An international group of experts was convened to develop a consensus guideline that was specific and evidence-based to identify the population of patients who would benefit from glucarpidase.
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Injúria Renal Aguda/tratamento farmacológico , Antimetabólitos Antineoplásicos/efeitos adversos , Metotrexato/efeitos adversos , Neoplasias/tratamento farmacológico , Guias de Prática Clínica como Assunto/normas , gama-Glutamil Hidrolase/uso terapêutico , Injúria Renal Aguda/induzido quimicamente , Antimetabólitos Antineoplásicos/administração & dosagem , Consenso , Relação Dose-Resposta a Droga , Seguimentos , Humanos , Metotrexato/administração & dosagem , Neoplasias/patologia , Proteínas Recombinantes/uso terapêuticoRESUMO
Immune checkpoint inhibitors that target the programmed death 1 (PD-1) signaling pathway have recently been approved for use in advanced pretreated non-small cell lung cancer and melanoma. Clinical trial data suggest that these drugs may have adverse effects on the kidney, but these effects have not been well described. We present 6 cases of acute kidney injury in patients with lung cancer who received anti-PD-1 antibodies, with each case displaying evidence of acute interstitial nephritis (AIN) on kidney biopsy. All patients were also treated with other drugs (proton pump inhibitors and nonsteroidal anti-inflammatory drugs) linked to AIN, but in most cases, use of these drugs long preceded PD-1 inhibitor therapy. The association of AIN with these drugs in our patients raises the possibility that PD-1 inhibitor therapy may release suppression of T-cell immunity that normally permits renal tolerance of drugs known to be associated with AIN.
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Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais/efeitos adversos , Antineoplásicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Nefrite Intersticial/induzido quimicamente , Doença Aguda , Idoso , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Proteínas Reguladoras de Apoptose/antagonistas & inibidores , Morte Celular/efeitos dos fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , NivolumabeRESUMO
Extracorporeal modalities for the removal of drugs and toxins are indicated for the treatment of overdoses and intoxications. Well-established modalities include hemodialysis (HD), high-flux HD (HfD), and charcoal hemoperfusion (HP). Recently, there have been increasing reports on the use of continuous renal replacement therapy (CRRT), such as continuous veno-venous hemodialysis (CVVHD), continuous veno-venous hemofiltration (CVVH) or CVVH combined with dialysis (CVVHDF). In the present article, we will discuss the various factors that determine the clearance of drugs and toxins and accordingly, we will propose that with few exceptions, CRRT does not have a role in the routine management of intoxications.
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Overdose de Drogas/terapia , Nefrologia/métodos , Diálise Renal/métodos , Hemofiltração , Hemoperfusão , HumanosRESUMO
Pneumococcal infections remain a leading cause of death in persons ≥ 65 y of age. Recent reports have illustrated detrimental changes in the endoplasmic reticulum stress response or unfolded protein response in aging and age-related diseases; however, the relationship between aging, the unfolded protein response, and innate immune responses to Streptococcus pneumoniae has not been fully elucidated. Our results illustrate that stimulator of IFN genes-mediated production of IFN-ß during S. pneumoniae infection is decreased in aged hosts. Enhanced endoplasmic reticulum stress in response to S. pneumoniae augmented inositol-requiring protein 1/X-box binding protein 1-mediated production of autophagy-related gene 9 (Atg9a). Knockdown of Atg9a or treatment with gemcitabine HCl resulted in enhanced stimulator of IFN genes-mediated production of IFN-ß by aged macrophages. Consecutive treatments with gemcitabine during in vivo S. pneumoniae infection decreased morbidity and mortality in aged hosts, which was associated with decreased Atg9a expression, increased IFN-ß production, and improved bacterial clearance from lung tissue. Taken together, data presented in this study provide new evidence as to why older persons are more susceptible to S. pneumoniae, and provide a possible mechanism to enhance these responses, thereby decreasing morbidity and mortality in this population.
Assuntos
Envelhecimento/imunologia , Estresse do Retículo Endoplasmático/imunologia , Interferon beta/biossíntese , Proteínas de Membrana/imunologia , Infecções Pneumocócicas/imunologia , Animais , Proteínas Relacionadas à Autofagia , Western Blotting , Células Cultivadas , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Imunoprecipitação , Interferon beta/imunologia , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Infecções Pneumocócicas/metabolismo , RNA Interferente Pequeno , Reação em Cadeia da Polimerase em Tempo Real , Transfecção , Proteínas de Transporte VesicularAssuntos
Cobre/deficiência , Deficiências Nutricionais/diagnóstico , Transtornos Neurológicos da Marcha/etiologia , Sulfato de Zinco/efeitos adversos , Zinco/farmacologia , Cobre/metabolismo , Cobre/uso terapêutico , Deficiências Nutricionais/induzido quimicamente , Deficiências Nutricionais/complicações , Humanos , Falência Renal Crônica/complicações , Falência Renal Crônica/terapia , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Diálise Peritoneal , Medula Espinal/diagnóstico por imagem , Sulfato de Zinco/uso terapêuticoRESUMO
The NLRP3 inflammasome is activated in the lung during influenza viral infection; however, the impact of aging on inflammasome function during influenza infection has not been examined. In this study, we show that elderly mice infected with a mouse-adapted strain of influenza produced lower levels of IL-1ß during in vitro and in vivo infection. Dendritic cells from elderly mice exhibited decreased expression of ASC, NLRP3, and capase-1 but increased expression of pro-IL-1ß, pro-IL-18, and pro-IL-33 compared with dendritic cells from young infected mice. Treatment with nigericin during influenza infection augmented IL-1ß production, increased caspase-1 activity, and decreased morbidity and mortality in elderly mice. Our study demonstrates for the first time, to our knowledge, that during influenza viral infection, elderly mice have impaired NLRP3 inflammasome activity and that treatment with nigericin rescues NLRP3 activation in elderly hosts.
Assuntos
Envelhecimento/imunologia , Antivirais/farmacologia , Proteínas de Transporte/imunologia , Inflamassomos/imunologia , Nigericina/farmacologia , Infecções por Orthomyxoviridae/imunologia , Transferência Adotiva , Envelhecimento/metabolismo , Animais , Western Blotting , Proteínas de Transporte/metabolismo , Caspase 1/imunologia , Caspase 1/metabolismo , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Feminino , Inflamassomos/efeitos dos fármacos , Inflamassomos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Proteína 3 que Contém Domínio de Pirina da Família NLR , Infecções por Orthomyxoviridae/metabolismo , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Thrombotic microangiopathy (TMA) is a syndrome of microangiopathic hemolytic anemia and thrombocytopenia with end-organ dysfunction. Although the advent of plasma exchange, immunosuppression, and complement inhibition has improved morbidity and mortality for primary TMAs, the management of secondary TMAs, particularly drug-induced TMA, remains less clear. TMA related to cancer drugs disrupts the antineoplastic treatment course, increasing the risk of cancer progression. Chemotherapeutic agents such as mitomycin-C, gemcitabine, and platinum-based drugs as well as targeted therapies such as antiangiogenesis agents and proteasome inhibitors have been implicated in oncotherapy-associated TMA. Among TMA subtypes, drug-induced TMA is less well-understood. Treatment generally involves withdrawal of the offending agent and supportive care targeting blood pressure and proteinuria reduction. Immunosuppression and therapeutic plasma exchange have not shown clear benefit. The terminal complement inhibitor, eculizumab, has shown promising results in some cases of chemotherapy-associated TMA including in re-exposure. However, the data are limited, and unlike in primary atypical hemolytic uremic syndrome, the role of complement in the pathogenesis of drug-induced TMA is unclear. Larger multicenter studies and unified definitions are needed to elucidate the extent of the problem and potential treatment strategies.
Assuntos
Antineoplásicos , Neoplasias , Microangiopatias Trombóticas , Humanos , Microangiopatias Trombóticas/terapia , Microangiopatias Trombóticas/tratamento farmacológico , Antineoplásicos/efeitos adversos , Neoplasias/tratamento farmacológico , Neoplasias/complicações , Gencitabina , Inibidores de Proteassoma/efeitos adversosRESUMO
Patients with cancer may develop kidney disease with a variety of different clinical manifestations including acute kidney injury, chronic kidney disease, hypertension, proteinuria and electrolyte disturbances. Onco-nephrology is the subspecialty of nephrology that diagnoses and manages kidney disease in patients with cancer. In this article, we review major topics in Onco-Nephrology that may be encountered by the general internist.
Assuntos
Injúria Renal Aguda , Neoplasias , Nefrologia , Insuficiência Renal Crônica , Humanos , Neoplasias/complicações , Neoplasias/terapia , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/terapia , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/terapiaRESUMO
Patients with malignancies have a high prevalence of kidney disease and are often treated with antineoplastic agents that undergo kidney metabolism or excretion or clearance via renal replacement therapies. Thus, the dosing of these agents, including classic chemotherapeutic drugs, targeted therapies, and immunotherapy, must take into account patients' kidney function. In this review, we will discuss the pitfalls of accurate measurement of kidney function and how kidney disease affects both pharmacodynamic and pharmacokinetic properties of drugs. Lastly, we will discuss specific agents and summarize current dosing strategies for use in patients with chronic kidney disease and end-stage kidney disease.
Assuntos
Antineoplásicos , Neoplasias , Insuficiência Renal Crônica , Antineoplásicos/uso terapêutico , Taxa de Filtração Glomerular , Humanos , Rim , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Diálise Renal , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/terapia , Terapia de Substituição RenalRESUMO
In the present report, we have described venous outflow banding as a technique to assist with maturation of a percutaneous arteriovenous fistula (pAVF) without sacrificing potential target veins for future access. A 47-year-old obese man had undergone pAVF creation between the right ulnar vessels with coil embolization of the brachial vein. Follow-up imaging demonstrated the median cubital vein briskly filling the cephalic and basilic veins. The basilic vein was banded with the patient under local anesthesia successfully. Banding of the superficial veins provides an alternative after creation of a pAVF to preserve veins that could be used as conduits for future access.
RESUMO
BACKGROUND: In patients receiving immune checkpoint inhibitor (ICI) therapy, acute kidney injury (AKI) is common, and can occur either from kidney injury unrelated to ICI use or from immune activation resulting in acute interstitial nephritis (AIN). In this study, we test the hypothesis that occurrence of AIN indicates a favorable treatment response to ICI therapy and therefore among patients who develop AKI while on ICI therapy, those with AIN will demonstrate greater survival compared with others with AKI. METHODS: In this observational cohort study, we included participants initiated on ICI therapy between 2013 and 2019. We tested the independent association of AKI and estimated AIN (eAIN) with mortality up to 1 year after therapy initiation as compared with those without AKI using time-varying Cox proportional hazard models controlling for demographics, comorbidities, cancer type, stage, and therapy, and baseline laboratory values. We defined eAIN as those with a predicted probability of AIN >90th percentile derived from a recently validated diagnostic model. RESULTS: Of 2207 patients initiated on ICIs, 617 (28%) died at 1 year and 549 (25%) developed AKI. AKI was independently associated with higher mortality (adjusted HR, 2.28 (95% CI 1.90 to 2.72)). Those AKI patients with eAIN had more severe AKI as reflected by a higher peak serum creatinine (3.3 (IQR 2.1-6.1) vs 1.4 (1.2-1.9) mg/dL, p<0.001) but exhibited lower mortality than those without eAIN in univariable analysis (HR 0.43 (95% CI 0.21 to 0.89)) and after adjusting for demographics, comorbidities, and cancer type and severity (adjusted HR 0.44 (95% CI 0.21 to 0.93)). CONCLUSION: In patients treated with ICI, mortality was higher in those with AKI unrelated to ICI but lower in those where the underlying etiology was AIN. Future studies could evaluate the association of biopsy-proven or biomarker-proven AIN with mortality in those receiving ICI therapy.
Assuntos
Injúria Renal Aguda , Nefrite Intersticial , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/epidemiologia , Creatinina , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Rim , Nefrite Intersticial/induzido quimicamenteRESUMO
OBJECTIVE: We evaluated whether substrate reduction therapy with miglustat could alter the course of action myoclonus-renal failure syndrome (AMRF), a rare, progressive myoclonic epilepsy with early mortality caused by scavenger receptor class B member 2 (SCARB2) gene mutations. METHODS: We identified an AMRF patient with a biallelic combination of SCARB2 mutations determined by whole exome sequencing. SCARB2 encodes a protein that traffics ß-glucocerebrosidase to the lysosomal membrane. Mutations lead to a complex pattern of glucosylceramide accumulation and neurologic symptoms including progressive action myoclonus, seizures, and ataxia. We then evaluated the effect of inhibiting glucosylceramide synthesis, as is used in Gaucher disease. The patient was treated for 3 years with miglustat after several years of steady worsening. RESULTS: Progression of myoclonus halted, dysphagia resolved, some skills were reacquired, and seizures remained well controlled. CONCLUSIONS: The response suggests that neurologic symptoms of SCARB2-associated AMRF could be ameliorated, at least partly, by targeting glycosphingolipid metabolism with available medications.
Assuntos
Injúria Renal Aguda , Metotrexato/efeitos adversos , Diálise Renal/métodos , gama-Glutamil Hidrolase/uso terapêutico , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/epidemiologia , Injúria Renal Aguda/terapia , Relação Dose-Resposta a Droga , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Infusões Intravenosas , Rim/efeitos dos fármacos , Metotrexato/uso terapêutico , Neoplasias/tratamento farmacológico , Prognóstico , gama-Glutamil Hidrolase/administração & dosagemRESUMO
Since the discovery of the Toll-like receptors and their crucial role as modulators of innate immunity, there has been increasing appreciation of their role in human health and disease. Toll-like receptor signaling is critical in defending against invading microorganisms, but sustained receptor activation is also implicated in the pathogenesis of inflammatory diseases. Here we review the role of Toll-like receptors and their endogenous ligands in various renal diseases, particularly their activation in the inflammatory response of ischemic kidney injury, organ transplantation, and immune-mediated glomerulonephritis.
Assuntos
Nefropatias/metabolismo , Receptores Toll-Like/metabolismo , Animais , Doenças Autoimunes/metabolismo , Glomerulonefrite/metabolismo , Humanos , Transplante de Rim/imunologia , Ligantes , Estrutura Molecular , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais , Receptores Toll-Like/químicaRESUMO
PURPOSE OF REVIEW: Endogenous ligands are released during ischemia-reperfusion injury that occurs during organ transplantation. Evidence suggests that these ligands, such as hyaluronan, activate the innate immune system via Toll-like receptors. This review will highlight the studies on the role of hyaluronan in modulating alloimmune responses. RECENT FINDINGS: Within the last year, the role of hyaluronan as an endogenous activator of innate alloimmunity has been investigated. We have shown that hyaluronan activates dendritic cells and primes T-cell alloimmunity primarily via a toll like receptor 4/Tirap-dependent pathway. Recent studies have described that the hyaluronan receptor, CD44, modulates these innate immune responses by augmenting regulatory T-cell function, and augmenting the expression of negative regulators of Toll-like receptor signaling. SUMMARY: Hyaluronan activates innate alloimmune responses and subsequently influences adaptive alloimmunity. Improving our understanding of the nature of endogenous innate ligands that activate alloimmunity may lead to improved therapeutics in organ transplantation.