Background: Autoinflammatory diseases (AIDs) were first proposed 20 years ago and caused by dysregulation of the innate immune system, leading to episodes of systemic inflammation. Advances in next-generation sequencing and biological technology have resulted in the identification of new monogenic diseases and the corresponding signaling pathways that may guide us in targeted therapy. The kidney is a major target organ of various inflammatory processes. Summary: During systemic inflammation, increased pro-inflammatory cytokines, such as IL-6, IL-1β, and TNF, lead to over-transcription and release of acute phase reactant serum amyloid A (SAA). Sustained high SAA levels promote a cascade of pathophysiological events, including protein misfolding, protein fragmentation, and aggregation into highly ordered amyloid fibrils. Amyloid fibril deposition in the kidney cause progressive glomerular and vascular damage. Renal AA amyloidosis is a common and severe complication of AIDs, including familial Mediterranean fever, cryopyrin-associated periodic syndromes, TNF receptor-associated periodic fever syndrome, mevalonate kinase deficiency/hyper-IgD and periodic fever syndrome, and deficiency of adenosine deaminase 2. Amyloidosis may even be the first clinical manifestation in some patients, presenting with asymptomatic proteinuria, nephritic syndrome, progressive renal insufficiency, or end-stage kidney disease. In addition, major dysregulated pathways in different AIDs lead to endogenous inflammation, which is due to direct endothelial cytotoxicity caused by IL-1β, type I interferon, or possibly immune complexes. The kidney is frequently affected by various vasculitis, and kidney involvement is a major determinant of treatment options and outcomes. The renal vasculitis involved in AIDs includes renal artery Takayasu vasculitis, polyarteritis nodosa, and IgA vasculitis. Moreover, other kidney diseases, such as glomerulonephritis, lupus nephritis, and renal tubular dysfunction, were also reported in AIDs. Key Messages: Kidney manifestations can be a coexisting disease seen with AIDs. They may also be one of the characteristics of AIDs. Clinicians should be aware of the possibility that amyloidosis, vasculitis, or other kidney diseases may be associated with AIDs in order to make appropriate diagnosis and treatment. Kidney biopsy may be of great significance. Biologics, which switch off the underlying cytokine-mediated inflammatory process, have the potential to restore organ damage and improve the outcome in the very early stage of the disease.

© 2023 The Author(s). Published by S. Karger AG, Basel

Introduction

Autoinflammatory diseases (AIDs) were proposed in 1999 by Dr. Daniel Kastner and defined as unprovoked episodes of systemic inflammation in the absence of high-titer autoantibodies and antigen-specific T cells [1]. These unique episodes generally occur periodically with fever and other systemic manifestations such as skin rashes, arthritis, serositis, lymphadenopathy, hepatosplenomegaly, inflammatory bowel disease, central nervous system, and kidney complications. The innate immune system plays the predominant role in the pathogenesis of AIDs, in contrast to the adaptive immune system, a central player in autoimmune diseases. Genetically, monogenic AIDs are caused by highly penetrant genetic mutations and follow a pattern of Mendelian inheritance. Since its initial definition, more than 40 genes associated with AIDs have been identified, affecting different parts of the innate immune system.

The molecular mechanisms underlying AIDs relate to aberrant inflammasome activation, leading to overproduction of pro-inflammatory cytokines, especially IL-1β, abnormal nuclear factor-κB (NF-κB) signal, constitutive activation of type I interferon axis, inappropriate complement activation, and other cytokine signals [2–4]. Increased pro-inflammatory cytokine secretion is responsible for most of the systemic features of such disorder and for the persistent acute phase response. Table 1 summarizes the genetic background and mechanisms of AIDs mentioned in this review.

Table 1.

Genetic background and mechanisms of AIDs

DiseasesOMIM numberGeneProteinInheritanceGOF/LOFMechanism of diseaseFMF#249100MEFVPyrinARGOFActivation of pyrin inflammasome; IL-1β and IL-18↑MWS#191900NLRP3CryopyrinADGOFActivation of NLRP3 inflammasome; IL-1β and IL-18↑FCAS#120100NLRP3CryopyrinADGOFActivation of NLRP3 inflammasome; IL-1β and IL-18↑NOMID/CINCA#607115NLRP3CryopyrinADGOFActivation of NLRP3 inflammasome; IL-1β and IL-18↑TRAPS#142680TNFRSF1ATNFR1ADGOFMisfolding of mutant protein; NF-κB↑; ROS↑; IL-1β↑MKD/HIDS#260920MVKMVKARLOFDeficient/reduced MVK activity, RhoA prenylation inhibition resulting in activation of pyrin inflammasome; IL-1β↑DADA2#615688ADA2ADA2ARLOFDefect in macrophage differentiation; TNF↑; type I IFN↑VEXAS syndrome#301054UBA1UBA1SomaticLOFDefective in ubiquitylation; TNF↑; IL-6↑; IFN-γ↑BS#186580NOD2NOD2ADGOFActivation of NOD2; NF-κB↑; MAPK↑; multiple cytokines↑SAVI#615934TMEM173STINGADGOFConstitutive activation of STING; type I IFN↑HA20#616744TNFAIP3A20ADLOFDefect in hydrolysis of Lys63-linked ubiquitin chain; NF-κB↑; p38↑; JNK↑; IL-1β↑GRADDDX58RIG-IADGOFActivation of type I IFN pathway; type I IFN↑COPA syndrome#616414COPACOPAADLOFAccumulation and activation of STING at the Golgi; type I IFN↑SIFD#616084TRNT1TRNT1ARLOFDefect in tRNA maturation, protein synthesis; multiple cytokinesH syndrome#602782SLC29A3SLC29A3ARLOFGH deficiency, polyclonal lymphohistiocytic and plasma cell infiltration

The kidney is a major target organ of the inflammatory process. Kidney damage may be mediated through the deposition of the acute phase reactant serum amyloid A (SAA) as amyloidosis, which causes progressive glomerular and vascular damage and leads to organ failure. Moreover, the kidney can be affected by inflammasome activation and IL-1β-mediated vasculitis/vasculopathy. It is still not clear if kidney injury represents a clinical feature or only a manifestation of other disease processes. In this review, we focus on the multiple kidney manifestations of AIDs (Fig. 1 and Table 2), especially pay close attention to the mechanism of renal amyloidosis and vasculitis.

Fig. 1.

Overview of kidney involvement in AIDs. GN, glomerulonephritis.

Table 2.

Kidney involvement in AIDs

DiseasesPhenotypeKidney involvement clinicalKidney involvement pathologicalEffective treatmentAmyloidosis FMFFever, serositis, rash, AA amyloidosisProteinuria, nephrotic syndrome and/or renal insufficiency, ESKDAA amyloidosisColchicine, anti-TNF, anti-IL-1, anti-IL-6 MWSFever, rash, hearing loss, arthritis/arthralgia, abdominal pain, conjunctivitisProteinuria, nephrotic syndrome and/or renal insufficiency, ESKDAA amyloidosisAnti-IL-1 FCASCold-induced rash, arthralgia, conjunctivitis, feverLower extremity edema, massive proteinuria, renal insufficiency, hypertensionAA amyloidosisAnti-IL-1 NOMID/CINCARash, arthropathy, CNS inflammationProteinuria, impaired kidney functionAA amyloidosisAnti-IL-1 TRAPSFever, serositis, migratory rash and myalgia, periorbital edemaProteinuria, nephrotic syndrome, progressive kidney failure, requiring dialysis or kidney transplantation, hypertensionAA amyloidosisAnti-IL-1 MKD/HIDSFever, abdominal pain, vomiting, diarrhea, lymphadenopathy, rash, gangrenosumNephrotic syndrome, ESKDAA amyloidosisAnti-IL-1, anti-TNF, anti-IL-6, kidney transplantation DADA2Early-onset lacunar strokes, fever, livedo, vasculitis, immunodeficiencyNephrotic syndromeAA amyloidosisAnti-IL-1 VEXAS syndromeFever, chondritis, neutrophilic dermatosis, vasculitis, arthritis, pulmonary infiltrate, venous thromboembolism, macrocytic anemia, bone marrow vacuolesProgressive chronic kidney injury, high proteinuriaAA amyloidosisGlucocorticoids, anti-IL-1Vasculitis DADA2Early-onset lacunar strokes, fever, livedo, vasculitis, immunodeficiencyHematuria, proteinuria, renal insufficiency, hypertension, renal artery aneurysm, stenosis, and infarctsPANAnti-TNF, HSCT FMFFever, serositis, rash, AA amyloidosisHematuria, proteinuria, renal insufficiency, hypertension, perirenal hematomasIgAV, PAN, Behcet's disease, granulomatous vasculitisCorticosteroid, cyclophosphamide, colchicines, azathioprine, plasmapheresis TRAPSFever, serositis, migratory rash and myalgia, periorbital edemaMassive proteinuria, deterioration of kidney functionIgAVCorticosteroid, cyclosporine, anti-IL-1 NOMID/CINCARash, arthropathy, CNS inflammationMild proteinuria, renal insufficiencyVasculitis, pauci-immune cGNCyclophosphamide, anti-IL-1 BSGranulomatous polyarthritis, dermatitis, and uveitisHypertension, renal insufficiencyRenal artery Takayasu's-like vasculitisResistant to currently available therapy SAVIFever, vasculopathy, interstitial lung diseaseHematuria, proteinuriaANCA-associated vasculitisRituximab, glucocorticoids, and azathioprine VEXAS syndromeFever, chondritis, neutrophilic dermatosis, vasculitis, arthritis, pulmonary infiltrate, venous thromboembolism, macrocytic anemia, bone marrow vacuolesMicroscopic hematuriaGPA, pauci-immune GN, renal peritubular capillaritisNAOthers FMFFever, serositis, rash, AA amyloidosisNon-nephrotic range proteinuriaGlomerulonephritis (FSGS/IgAN/MCD)NA MKD/HIDSFever, abdominal pain, vomiting, diarrhea, lymphadenopathy, rash, gangrenosumGross hematuria, slight proteinuria, acute kidney failurecGNAnti-TNF HA20Fever, oral and genital ulcers, ocular inflammation, arthritisHematuria, proteinuria, relapsed nephrotic syndrome, hypertensionLN-III; LN-VAnti-TNF, anti-IL-1, JAK inhibitor GRADSLEAcute nephritis syndrome, RPGN, nephrotic syndrome, AKI, malignant hypertensionLNJAK inhibitor COPA syndromeInterstitial lung disease, arthritis, immune-related kidney involvementAcute kidney failure, hematuria, proteinuriaLNNA BSGranulomatous polyarthritis, dermatitis, and uveitisAlbuminuria, microscopic hematuriaGranuloma formation, tubulointerstitial nephritisResistant to currently available therapy SIFDSideroblastic anemia, B-cell immunodeficiency, fever, developmental delayRenal calculi, renal tubular Fanconi syndromeNARBC transfusions, IVIg, BMT H syndromeSymmetrical hyperpigmentation, hearing lossUrethral dilation and distension of calycesNANARenal Amyloidosis in AIDsPathogenesis of AA Amyloidosis in AIDs

AA amyloidosis is a common and severe complication of several AIDs, especially periodic fever syndromes. During systemic inflammation, SAA can increase up to 1,000-fold under the stimulation of IL-6, IL-1β, and TNF [5]. Prolonged inflammation can cause long-term elevation of SAA. Sustained high SAA levels are a prerequisite for the formation of pathological amyloid fibrils, which promote a cascade of pathophysiological events, including protein misfolding, protein fragmentation, and aggregation into highly ordered amyloid fibrils [6].

There are three types of regulatory elements in the 5’-flanking promoter region of the SAA gene, including the recognition sequences of NF-κB and NF-IL6 transcription factors and an SAA-activating sequence for SAA-activating sequence-activating factor [7–9]. SAA gene transcription significantly increases during inflammation, mainly under the stimulation of LPS and various pro-inflammatory cytokines, including IL-6, IL-1β, and TNF (Fig. 2a). IL-6, IL-1β, TNF, and LPS binding to the IL-6 receptor (IL-6R), IL-1 receptor (IL-1R), tumor necrosis factor receptor (TNFR), toll-like receptors 2 and 4 (TLR2/4), respectively, results in the NF-IL6 or NF-κB translocation to the nucleus and transcription of the SAA genes (Fig. 2b). In addition, SAA gene transcription can undergo positive feedback by its products, i.e., the SAA proteins can bind and activate the TLR2 and TLR4 signaling pathways during acute phase reaction [10].

Fig. 2.

Mechanisms of renal amyloidosis in AIDs. a Mechanisms of overproduction of various cytokines in AIDs. Gain-of-function mutations in MEFV and NLRP3 activate the pyrin and NLRP3 inflammasome and lead to increased IL-1β secretion. Loss-of-function mutations in MVK lead to deficiency of mevalonate kinase activity, abnormal processing of RhoA GTPase, and ultimately, activation of pyrin inflammasome. Mutations in TNFRSF1A lead to misfolded TNF receptors accumulating in the endoplasmic reticulum, which further enhances NF-kB activation, and overproduction of cytokines. Loss-of-function mutations in ADA2 lead to abnormal macrophage differentiation and activation of type I interferon. Loss-of-function mutations in UBA1 lead to defect in ubiquitylation and overproduction of cytokines. bSAA gene transcription significantly increases during inflammation, mainly under the stimulation of LPS and various pro-inflammatory cytokines, including IL-6, IL-1β, and TNF. c Deposition of highly ordered amyloid fibrils in the kidney.

The generation of the AA proteins is responsible for the pathogenesis of AA amyloidosis. AA protein, which is typically the 76 amino acids of the N-terminal of SAA, folded into oligomers aggregated from hydrophobic β-sheets. These oligomers form insoluble fibrils and deposit in multiple organs, such as the kidneys, spleen, and liver (Fig. 2c). The deposition of these amyloid fibrils in organs impairs normal function and eventually leads to death [11, 12].

Familial Mediterranean Fever (OMIM #249100)

Familial Mediterranean fever (FMF) is the most common monogenic AIDs with an autosomal recessive transmission, which is characterized by recurrent attacks of fever; abdominal, thoracic, and articular pain; pericarditis; and amyloidosis [13]. Rare manifestation of FMF includes protracted febrile myalgia, erysipelas-like erythema, vasculitides, reduced fertility, decreased atopy, chronic ascites, and peritoneal malignant mesothelioma [13]. Biallelic gain-of-function mutations in MEFV gene encoding pyrin protein result in activation of pyrin inflammasome and subsequently activation of caspase-1 and release of active IL-1β and IL-18, which play major roles in the pathogenesis of FMF [14].

AA amyloidosis due to chronic inflammation is the major and most severe complication of FMF. Amyloidosis may even be the first clinical manifestation of FMF in some patients [13]. In the absence of treatment, about 50% of FMF patients would develop amyloidosis [15]. Amyloidosis associated with FMF mainly affects the kidneys and gastrointestinal tract. Renal amyloidosis presents with asymptomatic proteinuria, nephritic syndrome, and progressive loss of kidney function to end-stage kidney disease (ESKD). Hematuria and hypertension almost never occur. The main risk factors for amyloidosis are male gender, arthritis, Met694Val and SAA a/a homozygosity, and family history of amyloidosis [16]. Colchicine is a highly effective treatment for FMF patients, which decreases the attacks and prevents renal amyloidosis even if the FMF attacks do not respond to the drug [17]. Thus, colchicine should be started once clinical diagnosis is established. Anti-TNF agents are the first biologics used in FMF amyloidosis and have shown beneficial effect [18, 19]. Anti-IL-1 agents are also well tolerated and effective in controlling proteinuria and improving kidney function, including patients on dialysis and kidney transplantation [20–23]. Moreover, patients with FMF amyloidosis treated with tocilizumab, a humanized monoclonal IL-6 inhibitor, showed significant decrease in proteinuria [24].

Cryopyrin-Associated Periodic Syndromes

Cryopyrin-associated periodic syndromes (CAPS) are inherited as an autosomal dominant condition. The spectrum of CAPS includes three syndromes, which are from the mildest to the most severe phenotype, familial cold autoinflammatory syndrome (FCAS, OMIM #120100), Muckle-Wells syndrome (MWS, OMIM #191900), neonatal-onset multisystem inflammatory disease (NOMID), or chronic infantile neurological cutaneous and articular (CINCA) syndrome (OMIM#607115) [2]. CAPS are caused by gain-of-function mutations in NLRP3 gene encoding cryopyrin protein. The mutations result in activation of NLRP3 inflammasome and caspase-1, which in turn causes overproduction of active IL-1β and IL-18, switching on the inflammatory cascade in an uncontrolled manner [2].

At least 25% of MWS patients develop progressive amyloidosis in addition to recurrent episodes of fever, skin rash, sensorineural hearing loss, arthritis/arthralgia, abdominal pain, and conjunctivitis [15]. The kidney, liver, and spleen are the main target organs of AA amyloid deposits. Proteinuria, nephrotic syndrome, and/or renal insufficiency have been reported to be the predominant disease manifestations [25]. Renal amyloidosis invariably leads to ESKD if not effectively treated. Increased SAA concentrations significantly correlated with the worse kidney disease prognosis and mortality. The risk of death was reported to be 17.7 times as high among patients with highest SAA concentrations [25]. Thus, serum AA testing is essential during follow-up. The genetic defect involving the NLRP3 gene leads to an abnormal production of IL-1β. Therefore, anti-IL-1 treatment represents an effective therapy in MWS patients. Successful anti-IL-1 treatment of renal amyloidosis in patients with MWS has also been reported [25, 26].

Renal amyloidosis rarely occurred in <2% of patients with FCAS, which is characterized by cold-induced rash, arthralgia, conjunctivitis, and fever [27, 28]. One patient with FCAS who presented with fever, rash, malaise, conjunctivitis, and arthralgia after cold exposure since birth was reported in 2006 [29]. During the course of the disease, the patient developed hypertension, lower extremity edema, and massive proteinuria. Colchicine treatment did not improve proteinuria. Kidney biopsy was performed due to worsening proteinuria and an increase of creatinine level and revealed the deposition of amyloid in the glomeruli and arterioles. After treatment with anakinra, the patient’s symptoms of FCAS improved significantly and proteinuria decreased to less than 1 g/d.

NOMID/CINCA, the most severe form of CAPS, is characterized by the triad of skin rash, arthropathy, and severe central neurological manifestations such as brain atrophy, intellectual disability, and hearing loss [30]. Amyloidosis may develop in NOMID/CINCA patients, although not as much as MWS. Neven et al. [31] reported that amyloidosis presented in 2 of 10 patients with NOMID/CINCA. The first patient presented with mild impaired kidney function without proteinuria. Kidney biopsy revealed intense AA amyloid deposition and major glomerular sclerosis. After anakinra treatment, kidney function of this patient did not improve; however, no proteinuria developed in at least 6 months of follow-up. The other had significant proteinuria but normal kidney function. Kidney biopsy revealed AA amyloid deposition. Proteinuria gradually decreased from 8.5 g/24 h to 0.45 g/24 h at 1 year of anakinra treatment.

TNF Receptor-Associated Periodic Fever Syndrome (OMIM #142680)

TNF receptor-associated periodic fever syndrome (TRAPS), first defined in 1999, is an autosomal dominant AID caused by gain-of-function mutations in the TNFRSF1A gene encoding TNF receptor 1 (TNFR1) [1]. The mutations of TNFRSF1A gene lead to misfolded receptors accumulating in the endoplasmic reticulum, which further enhances NF-κB activation, ROS production, impaired autophage, and overproduction of cytokines [2, 32]. TRAPS manifests as intermittent fever, migratory rash, myalgia, non-peritonitic abdominal pain, arthralgia/arthritis, and periorbital edema. In a case series of TRAPS patients, up to 60% (25/41) developed renal AA amyloidosis, which is the most serious long-term complication, usually presenting with proteinuria, nephrotic syndrome, progressive kidney failure and requiring dialysis or kidney transplantation [33]. Uncontrolled hypertension has also been reported [34]. Mutations in cysteine residues are generally associated with a more severe disease phenotype and carry the greatest risk of amyloidosis [35]. However, no Asian patients with TRAPS have been reported with amyloidosis [36]. Colchicine is ineffective, while the effect of steroids is inconsistent in TRAPS [34]. Anti-IL-1 therapy can effectively control inflammation and prevent flares in TRAPS with or without amyloidosis [37, 38], indicating that IL-1 signaling plays a role in the pathogenesis of TRAPS. Also, anti-IL-1 drugs are reported to be safe and effective in patients with TRAPS on dialysis [39].

Mevalonate Kinase Deficiency/Hyper-IgD and Periodic Fever Syndrome (OMIM #260920)

Mevalonate kinase deficiency (MKD)/hyper-IgD and periodic fever syndrome (HIDS) is an autosomal recessive AID caused by loss-of-function mutations in the mevalonate kinase (MVK) gene [32]. The mutation of MVK results in deficient or reduced activity of MVK, which inhibits the RhoA prenylation and thus activated the pyrin inflammasome and increased secretion of IL-1β [32]. The common symptoms are recurrent episodes of fever; gastrointestinal symptoms like abdominal pain, vomiting, and diarrhea; lymphadenopathy; aphthous ulcers; arthralgia; myalgia; and skin rash [32, 40]. Amyloidosis is rare in MKD/HIDS. 20 cases of amyloidosis secondary to MKD/HIDS have been reported in the literature [41]. The prevalence of AA amyloidosis is roughly estimated at about 6% of all MKD/HIDS cases. The main clinical signs of renal amyloidosis were nephritic syndrome and/or ESKD. Kidney biopsies showed deposition of AA amyloid, presenting in small arteries and kidney, also in the glomeruli [42]. The literature on the therapy of AA amyloidosis secondary to MKD/HIDS is very sparse. In contrast to FMF, colchicine was found to be invalid in MKD/HIDS-associated amyloidosis. Several biologics have been used effectively, including anti-IL-1 anakinra and canakinumab, anti-TNF protein etanercept and adalimumab, and anti-IL-6 tocilizumab [40–44]. Moreover, MKD/HIDS patients with renal amyloidosis can benefit from kidney transplantation [44]. About half of the reported MKD patients underwent kidney transplantation. However, it is noteworthy that AA amyloidosis relapses on one-third of kidney grafts if the disease is not controlled after transplantation [41, 44].

Deficiency of Adenosine Deaminase 2 (OMIM #615688)

Deficiency of adenosine deaminase 2 (DADA2) is inherited in an autosomal recessive manner and caused by biallelic loss-of-function mutations in ADA2 gene, which encodes the adenosine deaminase 2 (ADA2) protein [45, 46]. Deficiency of ADA2 causes skewed macrophage differentiation toward the M1 pro-inflammatory phenotype [45], which is known to produce IL-1β, IL-6, and TNF [47, 48]. Recent studies also demonstrated type I interferon activation in DADA2 patients, suggesting a possible role of interferon in disease pathogenesis [49–51]. Patients with DADA2 mainly present with early-onset lacunar strokes, recurrent fevers, hepatosplenomegaly, and livedo rash or with polyarteritis nodosa (PAN), a medium- and small-sized vessel necrotizing vasculitis [45, 46]. Some DADA2 patients may also manifest as immunodeficiency with recurrent infections, hypogammaglobulinemia, and lymphopenia or with hematologic symptoms including pure red cell aplasia or bone marrow failure [52, 53].

Amyloidosis in DADA2 patients is rarely reported. Only 3 cases with DADA2 and renal amyloidosis were reported in the literature [54–56]. The first patient suffered from fever attacks, abdominal pain, myelofibrosis, and renal and intestinal amyloidosis. Antinuclear antibody, rheumatoid factor, and lupus anticoagulant were also positive. The patient was resistant to immunosuppressives and died because of pneumonia 2 months after DADA2 diagnosis. The second patient was a 13-year-old girl, presenting with nephritic syndrome at the onset. Autoinflammatory features included arthritis and hepatosplenomegaly. Antinuclear antibody and anti-dsDNA were negative. Kidney biopsy revealed secondary AA amyloidosis without signs of vasculitis. She was successfully treated with canakinumab after unresponsive proteinuria treated with colchicine and methylprednisolone. The third patient presented with peripheral facial paralysis and renovascular hypertension at 3 months of age. Later, she developed recurrent fevers, polyarthritis, Raynaud’s phenomenon, gastrointestinal bleeding, and intracerebral hemorrhage. The poorly controlled inflammatory state ultimately led to the development of AA amyloidosis, presenting with nephrotic syndrome and progressive renal dysfunction [56].

Vacuoles, E1 Enzyme, X-Linked, Autoinflammatory, Somatic Syndrome (OMIM #301054)

Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) is an adult-onset treatment-refractory disease caused by somatic mutations in UBA1 gene, which affects only males [57]. The UBA1 gene encodes the major E1 enzyme, which is responsible for initiating nearly all cellular ubiquitin signaling. The Met41 variants result in reduction of the canonical catalytically proficient UBA1b and production of a novel, catalytically deficient UBA1c, which caused loss of ubiquitylation and dysregulation of innate immune pathways. Patients develop systemic inflammation and hematologic abnormalities, including recurrent fevers, chondritis, neutrophilic dermatosis, vasculitis, arthritis, pulmonary infiltrate, venous thromboembolism, macrocytic anemia, as well as bone marrow vacuoles [57, 58].

Euvrard et al. [59] reported the first case of VEXAS syndrome complicated by systemic AA amyloidosis. The patient, a 59-year-old man, suffered from recurrent fever, polyarthritis, maculo-papular rash, auricular chondritis, and macrocytic anemia. Then, he developed a progressive chronic kidney injury with high proteinuria. Kidney biopsy revealed glomerular, tubular, and vascular SAA deposits. Additionally, MRI scan showed cardiac amyloidosis. Bone marrow aspiration revealed vacuolization of granulocytic and erythroblastic progenitors. High-dose glucocorticoids and anti-IL-1 therapy were effective, with the fever and cutaneous signs disappearing and the cardiac function improving. Nevertheless, he was still undergoing regular dialysis due to the irreversible renal amyloidosis.

Renal Vasculitis in AIDs

Vasculitis is inflammation of the blood vessels, which can be either one of the features of AIDs or closely associated with them [60]. Comprehensive studies have highlighted new immune pathways that may guide us in targeted therapy of vasculitis. As shown in Figure 3, major dysregulated pathways in different AIDs lead to endogenous inflammation which is due to direct endothelial cytotoxicity due to IL-1β, type I interferon, or possibly immune complexes [61].

Fig. 3.

Mechanisms of renal vasculitis in AIDs. Dysregulated immune pathways in different AIDs lead to endogenous inflammation by direct endothelial cytotoxicity of IL-1β, IL-6, IL-18, TNF, or type I interferons.

The kidney is frequently affected by various vasculitis, and kidney involvement is a major determinant of treatment options and outcomes. The renal vessels involved in AIDs include the renal artery in Takayasu arteritis, medium-sized renal parenchymal artery in PAN, and glomerular involvement in IgA vasculitis. The clinical manifestations of renal vasculitis include renovascular hypertension, gross or microscopic hematuria, proteinuria, oliguria or anuria, progressive renal insufficiency, and occasional loin pain. Pathological manifestations include inflammatory lesions of vessels ranging in size from renal artery, interlobar, arcuate, and interlobular to glomeruli. Fibrinoid necrosis and perivascular infiltrate of neutrophiles, mononuclear leukocytes, and eosinophils are common. Aneurysm formation, thrombosis, rupture of the vessel with hemorrhage, crescent formation, focal mesangial glomerulonephritis, interstitial inflammation, and tubulitis can also be found [62].

Deficiency of Adenosine Deaminase 2

Vasculitis of small- and medium-sized arteries is a major clinical feature of DADA2 and strongly resembles that of classic PAN. The central nervous system and skin are most commonly involved manifesting as early-onset ischemic (lacunar) and/or hemorrhagic strokes or as cutaneous PAN. Other organs with dense vascularization such as the kidney and liver can also be affected. Meyts et al. [52] reported that arterial hypertension was found in 21%, renal artery aneurysm in 6%, renal artery stenosis and infarcts in 4% of 161 DADA2 patients. Clinical features include hematuria, proteinuria, renal insufficiency, and hypertension. Kidney histopathologic findings of DADA2-associated vasculitis are non-granulomatous, necrotizing vasculitis of small- and medium-sized vessels, kidney inflammation with dense lymphocytic infiltration, and glomerular scarring, similar to PAN [46, 63]. Anti-TNF treatment is suggested to be an effective treatment [64]. Bone marrow transplantation has also been reported to control both severe immunodeficiency, hematologic involvement, and vascular phenotype of DADA2 [52].

Familial Mediterranean Fever

The most common vasculitis in FMF is IgA vasculitis with a prevalence of 2.7–7.2% [65–67]. Abbara et al. [68] summarized the features of 46 patients with FMF and IgA vasculitis. All patients developed purpura. In addition, 71.7% had abdominal pain, 71.7% had joint involvement, and 52.2% had kidney involvement presenting as hematuria and/or proteinuria. Kidney biopsy showed mesangial cell proliferation with mesangial IgA and C3 deposition, without crescent, compatible with Henoch Schonlein purpura nephritis. Patients with IgA vasculitis associated with FMF had a more severe and protracted course with high fever and severe joint pain than those without FMF [69]. Corticosteroids were used in 53.3% of patients [68]. Other treatments included cyclophosphamide, azathioprine, colchicine, and plasmapheresis. IgA vasculitis associated with FMF is different from the typical isolated IgA vasculitis and should be considered as associated rather than coexisting as a separate clinical entity.

Another common vasculitis described in FMF is PAN-like vasculitis, which can be found in about 1% of FMF patients [66, 67, 70]. Among 61 patients with simultaneous occurrence of FMF and PAN, 49.2% of the patients had kidney involvement, characterized by hematuria and/or proteinuria and/or elevated creatinine [68]. Glomerular involvement, hypertension, and perirenal hematomas occurred in 32.8%, 49.2%, and 49.2% of patients, respectively. Abnormal renal arteriography, such as aneurysm or vascular occlusion, was reported in 57.4% of patients. Histological features were compatible with classic PAN defined as the presence of leucocytes in small- or medium-sized arteries. Patients with FMF and PAN had younger onset, more perirenal hematomas, more severe myalgia, and better overall prognosis than patients with PAN alone [71]. Corticosteroids were used in 96% of patients, cyclophosphamide in 60.8%, and azathioprine in 19.6%. 90.2% of patients achieved remission; in contrast, 9.8% of patients died due to PAN [68]. There is still no consensus on whether PAN observed in FMF is coincidental or directly associated.

Renal vasculitis other than IgA vasculitis and PAN was rarely reported in patients with FMF. Kidney involvement associated with FMF and Behcet’s disease was reported in 6 patients [68]. FMF with necrotizing crescentic glomerulonephritis (cGN) with granulomatous vasculitis was reported in one patient, as proven by kidney biopsy, who was treated with colchicine and azathioprine and showed a favorable response [72].

TNF Receptor-Associated Periodic Fever Syndrome

TRAPS can rarely present with features of vasculitis. Only 1 case with renal vasculitis and TRAPS has been reported [73]. The male patient with Thr50Met heterozygous mutation in TNFRSF1A gene suffered from recurrent fever, abdominal pain, eye manifestations, and myalgia with increased acute phase reactants since he was 6 months old. He also presented with massive proteinuria, deterioration of kidney function, and kidney biopsy-proven IgA vasculitis. He was treated with methylprednisolone and cyclosporine for kidney injury, thereafter with canakinumab for TRAPS, which achieved complete remission.

Neonatal-Onset Multisystem Inflammatory Disease/Chronic Infantile Neurological Cutaneous and Articular

Ebrahimi-Fakhari [74] described a case of renal vasculitis in a female with NOMID/CINCA syndrome. At age of 12 years, the patient developed a pauci-immune crescent glomerulonephritis with diffuse extra-capillary necrosis and vasculitis without amyloidosis. After 3 pulses of cyclophosphamide, her kidney function was stabilized, but mild proteinuria and reduced creatinine clearance remained. At age of 17 years, she was treated with anakinra, which significantly improved all symptoms. The occurrence of renal vasculitis and glomerulonephritis extends the spectrum of NOMID/CINCA syndrome.

Blau Syndrome (OMIM #186580)

Blau syndrome (BS) is a rare autosomal dominant monogenic AID associated with gain-of-function mutations of NOD2 gene. NOD2 is a type of pattern recognition receptor in innate immunity and is autoinhibited in unstimulated state. The mutations of NOD2 may result in activation of receptor-interacting protein kinase 2 and downstream signaling including NF-κB and mitogen-activated protein kinase, which ultimately results in production of inflammatory cytokines such as IL-1β, IL-6, TNF, and IL-18 [75]. However, there is still a significant knowledge gap between the canonical NOD2 signaling pathway and granuloma formation. BS is characterized by triad of granulomatous polyarthritis, dermatitis, and uveitis. Clinical manifestations beyond the typical triad included leukocytoclastic vasculitis; granulomatous in the liver, intestines, parotid glands, lymph nodes, and kidney; interstitial lung disease; pericarditis; and chronic kidney failure [75]. Vasculitis is rare in BS. Rose [76] reported a cohort consisting of 31 BS patients. Hypertension was observed in 5 patients. Two patients developed vasculitis, including one with cutaneous leukocytoclastic vasculitis and the other with large vessel vasculitis (Takayasu’s like) with involvement of renal artery.

STING-Associated Vasculopathy with Onset in Infancy (OMIM #615934)

STING-associated vasculopathy with onset in infancy (SAVI) is caused by gain-of-function mutations in TMEM173 gene encoding the STING protein, resulting in constitutive overproduction of type I interferon [77]. SAVI is characterized by vasculopathy resulting in ulceration, necrosis, even amputation, and interstitial lung disease. Kidney involvement has been sparsely documented [78–81]. Notably, half of the patients are positive for ANCA antibodies [80, 81]. Staels et al. [80] reported a kindred with SAVI, in which the proband and his father both suffered from ANCA-associated vasculitis with kidney involvement. A pauci-immune intra- and extra-capillary glomerulonephritis with hematuria and proteinuria was observed. Treatment with rituximab, followed by glucocorticoids and azathioprine, resulted in partial remission of kidney disease up to 16 months of follow-up. Given the good clinical response with conventional treatment, Janus kinase (JAK) inhibitor was not evaluated.

Vacuoles, E1 Enzyme, X-Linked, Autoinflammatory, Somatic

Nearly half of the patients with VEXAS syndrome presented with vasculitis, but ANCA-associated vasculitis affecting the kidney was atypical [58]. Only 2 cases with renal vasculitis have been reported. Ross et al. [82] described a case of refractory ANCA-negative granulomatosis with polyangiitis manifesting as pauci-immune glomerulonephritis in the context of microscopic hematuria and elevated serum creatinine. In another case with VEXAS, renal peritubular capillaritis and low titer-positive proteinase 3 antibody were found [83]. Both patients lack a prolonged response to therapies.

Other Kidney Manifestations in AIDsGlomerulonephritis

Various types of glomerulonephritis have been described in patients with FMF. Kukuy et al. [84] reviewed 25 patients with FMF who underwent kidney biopsy for urine protein exceeding 0.5 g/24 h. 10 (40%) of them displayed kidney pathological injury other than AA amyloidosis. Focal glomerulonephritis was the most common pathological manifestation, followed by focal segmental glomerular sclerosis, IgA nephropathy, minimal change disease [84, 85]. Compared with AA amyloidosis, these patients showed a milder phenotype, including proteinuria <3.5 g/24 h, normal blood pressure, and a less aggressive course of kidney disease. Additionally, in 2007, an 18-month-old boy presented with severe MKD and membranoproliferative glomerulonephritis was reported. He was treated successfully with anakinra [86].

Crescentic Glomerulonephritis

cGN was described as case reports in MKD. In 1999, M. Tsimaratos [87] reported a patient with MKD who experienced recurrent episode of gross hematuria, slight proteinuria, and acute kidney failure. Kidney biopsy showed a pauci-immune cGN with circumferential fibrous or fibrocellular crescents present in all glomeruli, diffuse interstitial fibrosis, and tubular atrophy. No amyloid deposits were detected. Finally, he underwent periodic hemodialysis and kidney transplantation. In 2006, Rainer Siewert [43] described another MKD patient who presented with acute kidney failure; the biopsy showed cGN and no evidence for renal amyloidosis. The patient was administered subcutaneous etanercept and had a favorable response. However, 3 months later, the patient died because of cardiac amyloidosis.

Lupus Nephritis

Haploinsufficiency of A20 (HA20, OMIM #616744) is an autosomal dominant disease caused by loss-of-function mutations of TNFAIP3 gene encoding the A20 protein, which is a potent anti-inflammatory molecule and can both remove the Lys63-linked ubiquitin chains and add Lys48-linked ubiquitin chains on substrates. Insufficiency of A20 protein leads to increasing NF-κB, p38, JNK signaling, and overproduction of IL-1β, TNF, IL-6. Patients with HA20 experience recurrent oral and genital ulcers, ocular inflammation, and arthritis [88]. Some patients with HA20 present with not only the autoinflammatory phenotypes but also several autoimmune diseases, including systemic lupus erythematosus, autoimmune hepatitis, or psoriatic arthritis [89]. Lupus nephritis (LN) has been reported in 5 patients with HA20. Li et al. [90] described a 14-year-old Chinese girl with HA20 presenting with hepatic fibrosis, pericardial effusion, hypothyroidism, systemic lupus erythematosus, and LN. Kidney biopsy displayed class III LN. The patient received anti-TNF etanercept in combination with hydroxychloroquine, prednisolone, and MMF, which displayed good efficacy. We recently also reported 3 patients with HA20 presenting with LN, including one adult and two children [91]. Kidney biopsy showed class IV LN in 2 patients and class V LN in one patient. Belimumab, a human monoclonal antibody targeting B-cell-activating factor, and the JAK inhibitor tofacitinib were used in two children, respectively. Both showed good response. Aeschlimann et al. [92] reported an HA20 patient with oral and genital ulcer, polyarthritis, rash, arterial hypertension, and proteinuria during pregnancy. Kidney biopsy was consistent with class V LN. The patient was treated with corticosteroids, etanercept, hydroxychloroquine, and anakinra.

LN has also been described in patients with a gain-of-function mutation Arg109Cys in DDX58 gene, which encodes the cytosolic dsRNA sensor retinoic acid-inducible gene I (RIG-I). The mutation disrupts RIG-I autoinhibition and results in constitutive activation of type I interferon pathway. Peng et al. [93] reported 5 patients carrying the DDX58 Arg109Cys mutation presented with LN. Kidney biopsy demonstrated class III LN in 2 patients, class IV in 2 patients, and class IV + V in one patient. One of the patients showed a good response to the JAK inhibitor baricitinib. We denoted the disorder caused by DDX58 mutation as gain-of-function mutation in RIG-I-associated disease.

Coatomer subunit alpha (COPA) syndrome (OMIM #616414) is an autosomal dominant multisystem AID that affects the lungs, joints, and kidneys [94]. It is caused by heterozygous loss-of-function mutations in COPA gene, encoding the alpha subunit of the coatomer protein complex I (COPI) which is required for retrograde transport of STING from the Golgi to endoplasmic reticulum [94, 95]. Mutant COPA induces accumulation and constitutive activation of STING at the Golgi, leading to enhanced type I interferon signaling and systemic inflammation [95]. Patients with COPA syndrome had an increased risk of heterogeneous kidney disease. Immune-related kidney involvement has been documented in 37% of patients [96, 97]. COPA syndrome has also been reported as a cause of LN. Siham Boulisfane-El Khalif et al. [98] reported a 10-year-old girl with kidney biopsy-proven LN and carried a known pathogenic mutation in the COPA gene. Steroid pulse, cyclophosphamide, hydroxychloroquine, and mycophenolate mofetil were introduced but without significant impact on the disease, and she developed kidney failure.

Granulomas in the Kidney

Renal granulomas are an uncommon and atypical manifestation of BS, but they have been reported in the literature. In 2019, Jindal et al. [99] reported a 3-year-old girl with BS who presented with early-onset polyarthritis without rash, granulomatous uveitis, and disseminated granulomas in the kidney and liver. At 21 years of age, she was found to have albuminuria and microscopic hematuria, persistent anemia, and thrombocytopenia. Kidney biopsy revealed diffuse interstitial lymphoplasmacytic infiltration with occasional lymphoid aggregation and granuloma formation, as well as immune complex deposition. Further, through literature search, they found unusual site granulomas in another 17 patients with BS, 6 of which occurred in the kidney. Another series of patients with BS showed kidney involvement in 2 out of 30 patients [100].

Renal Tubular Dysfunction

Sideroblastic anemia with B-cell immunodeficiency, periodic fever, and developmental delay (OMIM #616084) is caused by homozygous or compound heterozygous loss-of-function mutations in TRNT1 gene [101]. Renal tubular dysfunction is a common feature of sideroblastic anemia with B-cell immunodeficiency, periodic fever, and developmental delay patients, manifesting as early-onset renal calculi with marked hypercalciuria, renal tubular Fanconi syndrome, nephrocalcinosis, hypokalemia, hypophosphatemia, aminoaciduria, and high urinary NAG and RBP [102–104]. About half of the patients die early in life due to multiorgan failure or cardiac arrest [102]. Regular or intermittent RBC transfusions and IVIG replacement are common interventions. Early bone marrow transplantation has successfully reversed the hematologic and immunologic manifestations and prevented developmental delay in one patient [102].

Others

Rare renal anomalies are also seen in AIDs. In 2016, Bakhchane described a patient with H syndrome (OMIM #602782) which was caused by a mutation in the SLC29A3 gene and presented with symmetrical hyperpigmentation and hearing loss. At 12