Inborn errors of immunity with kidney and urinary tract disorders: a review

Human inborn errors of immunity (IEIs), previously referred to as primary immunodeficiency disorders (PIDs), are a heterogeneous spectrum of inherited abnormalities of the immune system with different organ involvement. The number of identified IEIs is rapidly increasing, highlighting the non-negligible role of an interdisciplinary approach in clinical diagnosis. Kidney disorders are one of the important comorbidities in some of the affected patients and play a significant role in the diagnosis and course of disease. According to recent studies, 22 types of human IEI with renal manifestations have been identified so far, including immunodeficiency with congenital thrombocytopenia, thymic defects with additional congenital anomalies, complement deficiencies, type 1 interferonopathies, immunity related to non-hematopoietic tissues, congenital neutropenia’s, common variable immunodeficiency disorder (CVID) phenotype and immuno-osseous dysplasia. Based on this classification, we herein review IEIs with renal features and explain the genetic defect, inheritance, and type of renal manifestations.


Introduction
Inborn errors of immunity (IEI) comprise a group of 485 inherited disorders.Damage to the germinal variants of genes is the cause of these hereditary disorders (1).Indeed, deletion or reduction of the protein expression or function (null/hypomorphic) or protein modification to acquire gainof-function (GOF) result in altering the encoded gene product and cause IEI, on this basis they divided into dominant or recessive, autosomal, or X-linked, and with complete or incomplete penetrance.IEIs are clinically manifested with a wide spectrum of mild to severe symptoms, including recurrent infections, autoimmunity and autoinflammatory diseases, allergy, bone marrow failure, and often malignancy.
Manifestations are related to variant type and its inheritance (2).Although IEIs are considered rare disorders and affect 1 in every 10,000 to 50,000 births based on the type, the recognition of new phenotypes can change its prevalence as the estimated prevalence rate is 1 in every 1000 to 10,000 births [3].In the past few years, several novel gene defects have been found, and more case reports of these patients have been published [2,4].In a number of these studies, the role of kidney disorders in the onset, duration, and end of the disease was reported, and the main cause of death in some of them was related to kidney disease [5][6][7][8].In this study, we review kidney disorders among these patients and discuss the related renal manifestations.To identify relevant articles, we performed an advanced search in PubMed, using the following combination of keywords; nephropathy, renal disorder, renal abnormality, proteinuria, nephrocalcinosis, glomerulonephritis, nephrotic syndrome, autoimmunity, lupus nephritis, hemolytic uremic syndrome (HUS) and Inborn errors of immunity.Based on recent studies 22 types of IEI were described to have kidney disorders as their manifestations, which are listed in Table 1 according to the type of mutation, IEI classification, and the type of kidney disease.

IEIs with renal manifestations
IEIs are classified into 10 groups in the last update of The International Union of Immunological Societies (IUIS) in 2022 [1], and in this study, most renal manifestations were related to the complements.In Table 1, these diseases are given and in the section below, diseases with more evidence in the literature were reviewed.

Factor H-related protein deficiencies
The five Complement Factor H-related proteins (FHR1-5) are structurally related to factor H, an important regulator of complement alternative pathways [9].Mutations in FHR by creating duplicated dimerization domains lead to C3 glomerulopathy (C3G), which is a heterogeneous group of chronic kidney diseases [10].Renner et al. (2022) In a study on murine, reported that variation in genes or expression of FHRs can be associated with glomerular damage by disrupting the regulation of complement binding to mesangial, glomerular endothelial, podocytes, and tubular epithelial cells [11].Medjeral-Thomas et al. [12] and Zhu et al. [13] identified the increased level of FHR-5 in patients with Immunoglobulin A nephropathy (IgAN) as a risk factor for disease progression.

Thrombomodulin deficiency
Thrombomodulin is a membrane protein and cofactor for thrombin which has a strategic role in coagulation, innate immunity and complement regulation [14].This protein is encoded by the THBD gene and variants including A43T (Impaired binding of Complement factor H (CFH) and C3b) [15], P495S and P501L (Moderate reduction of thrombomodulin expression on the cell surface) [16] and D486Y (Less common in patients with venous thrombosis) [17] are identified.It seems that, these variants can cause endothelial damage and microvascular thrombosis and manifest atypical hemolytic-uremic syndrome (aHUS) clinically.Microangiopathic hemolytic anemia in association with thrombocytopenia and acute kidney injury are features of typical aHU.Raina et al. (2022) in a systematic review showed that C3; CH50; AH50; and CFB were lower in aHUS as compared with the reference range [18].

Membrane cofactor protein (CD46) deficiency
It has been shown that deficiency in soluble or membranebound proteins of the complement system is mainly associated with systemic lupus erythematosus, infection, aHUS, and angioedema [19].Membrane cofactor protein (MCP; CD46) is an inhibitor of complement activation, whose role in immune complex syndromes has recently been noticed [20].This protein is involved in inactivating C3b and C4b by serine protease factor I (FI).More than 80 mutations associated with aHUS phenotype are identified in MCP [21][22][23][24], accounting for ∼10 − 15% of aHUS cases [25].It seems necessary to perform related genetic evaluations in children with HUS who develop kidney failure.

CD19 & CD81 deficiency
Mutation in CD19 gene causes symptoms similar to common variable immunodeficiency disorder (CVID) due to strong reduced in antibody production [26].Recent case-reports presented kidney involvement in children with CD19 defect in the early years of their lives.Primary manifestations may include recurrent hematuria or meningitis and frequent respiratory infections as a result of antibody response to vaccination [26].Findings such as IgA, IgG and IgM deficiencies and a kidney biopsy result of endocapillary proliferative glomerulonephritis and intense mesangial IgA deposits, can indicate IgA nephropathy in these patients [26].It seems IgA nephropathy might not be attributable directly to CD19 deficiency since its functions accompany with CD21, CD81, and CD225 and they may also play a significant role [27][28][29].Further investigations are needed in this field.

RAC2 deficiency
The large family of guanosine triphosphatases (GTPase) enzymes are involved in the hydrolysis of GTP nucleotides to guanosine diphosphate (GDP).The Rac family consists of Rac1, Rac2 (GTPase, exclusively expressed in hematopoietic cells), and Rac3, RhoG, and Rac associated GTPase.Rac2 is the major isoform in human neutrophils that regulate them in neutrophil chemotaxis [6,30].RAC2 deficiency impact on wide spectrum of immunity system such as innate arm and B-and T-cell migration, activation, development.Indeed, genetic defect in RAC2 gene can be associated with a wide range of immune symptoms such as soft-tissue infections which presented few weeks after birth [30].W56X, D57N, P34H, E62K, N92T, G12R variants have been reported in the Rac2 subset [31].Alkhairyet et al. reported in 2014 the homozygous loss-of-function mutation in the RAC2 gene, (W56X) causes: CVID, glomerulonephritis, coagulopathy, multiple hormone deficiencies potentially on the autoimmune basis and abnormalities of neutrophil granules [32].Among patients reported to date due to RAC2 mutations [5,33], recurrent sinopulmonary infections was the major clinical manifestation during their first admission.Despite the presence of various types in these patients, only 2 family cases (sister/brother) with W56X diagnosed with post streptococcal glomerulonephritis (PSGN) [34].

Sphingosine phosphate lyase insufficiency (SPLIS)
Sphingosine phosphate lyase insufficiency syndrome (SPLIS), caused by defect in SGPL1 gene, is a childhood syndrome that mainly manifests with steroidresistant nephrotic syndrome (SRNS), primary adrenal insufficiency, rapid or insidious neurologic deterioration, immunodeficiency, and acanthosis [35].Sphingosine-1-phosphate lyase (SPL) enzyme is involved in irreversible degradation of sphingolipid into phosphoethanolamine and hexadecimal and its removal [36].Kidney involvement mainly manifests as steroid-resistant nephrotic syndrome, which can be congenital or occur during infancy, may progress into end-stage kidney disease in the first year of life, and seems to be correlated with a higher mortality rate [37].In these patients, nephrotic syndrome may be the primary or isolated manifestation, and the outcome of kidney transplantation is largely unknown [38].

Wiskott-Aldrich syndrome (WAS)
X-linked Wiskott-Aldrich syndrome (WAS), first recognized in 1937 by Dr. Alfred Wiskott, and then in 1957, confirmed by Robert Aldrich [39].it is estimated to involve 1-10 live births per million males.The WAS gene encodes a cytosolic protein known as WAS protein (WASp) and it expressed in myeloid, lymphoid, and hematopoietic stem cells (HSCs), which can lead to various clinical manifestations, but thrombocytopenia (X-linked thrombocytopenia [XLT]), eczema, and recurrent infections with increased risk of lymphoid malignancies, autoimmune disorders or congenital neutropenia (X-lined neutropenia [XLN]) are classic phenotype of WAS [40,41].The patients with thrombocytopenia show a different range of symptoms from a mild petechiae and purpura to serious intracranial and/or intestinal bleeding, which lead to death in 4-10%.
The mean platelet volume (MPV) in WAS is often < 5 fL, so it can reach < 2 fL in the patients with severe bleeding symptoms.In addition, this disease is usually misdiagnosed with immune thrombocytopenia (ITP), and it should be noted that the WAS hallmark is micro thrombocytopenia (small platelets) [41].Eczema can affect 75% of these patients, and usually shows itself as refractory and the patient is not able to treat it quickly [42].

Interleukin 6 cytokine family signal transducer
Interleukin-6 signal transducer (IL6ST) encodes the GP130 protein.In pro-inflammatory conditions, GP130 signaling IL6 cytokine.IL-6 family cytokines are involved in the regulation of the hepatic acute-phase reaction, in B-cell stimulation, in the regulation of the balance between regulatory and effector T cells, in metabolic regulation, and in many neural functions [50].Biallelic loss-of-function IL6ST variants cause autosomal recessive hyper-IgE syndrome or a variant of the Stuve-Wiedemann syndrome (skeletal dysplasia, lung dysfunction, congenital thrombocytopenia, dermatitis, renal abnormalities, and defective acute-phase response) [34].Chen et al. (2020) reported a Saudi Arabic family with two fetuses with mutations in IL6S and were homozygous for c.841C > T; p.Arg281*.The first fetus had short femora (less than fifth centile), bowed tibia, multicystic dysplastic right kidney, dilated cisterna magna, and a small chest and died 3 h after delivery [34].

Schimke immuno-osseous dysplasia
Schimke Immuno-Osseous Dysplasia (SIOD) is an autosomal recessive multi-system disorder, with the genetic cause of biallelic loss-of-function mutation in SMARCAL1 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1) gene [8].The incidence rate of SIOD is 1 per 1-3 million live births and is clinically manifested by growth failure, spondyloepiphyseal dysplasia, lymphopenia, and proteinuria.Hypothyroidism, cerebral ischemia, and bone marrow failure were also reported in half of these patients [7].Nephropathy in SIOD children is described as progressive and steroidresistant [51].The pathophysiology of nephropathy in SIOD remained unknown but the role of the SMARCAL1 gene in the renal progenitor population is suggested in the study of Dekel et al. [52].In this study, according to the neonatal/adult murine kidney, it is explained that peak levels of SMARCAL1 and localization in glomerular podocytes can explain proteinuria and progressive nephropathy in SIOD children.

Pediatric systemic lupus erythematosus due to DNASE1L3 deficiency
The prevalence and incidence of lupus in children is not precisely known due to different age definitions [35].But since the role of gender and sex hormones in the occurrence of lupus is less prominent at a young age, the role of genetics in this field becomes more prominent.The disease usually involves skin, musculoskeletal system, and kidneys, of which the latter is the determinative manifestation for prognosis [53].Al-Mayouf et al. (2011) investigated six families with pediatric lupus and found a role for DNA-SE1L3 loss-of-function mutations in these patients [36].Loss-of-function mutations in DNASE1L3 cause high disease activity with variable degrees of renal involvement in children.Also, In the study by Kisla et al. (2021) a child with DNASE1L3 deficiency who suffered from urticarial skin lesions, frequent hemoptysis, and kidney involvement, was finally diagnosed as this rare monogenic lupus [53].

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED)
Mutations in the gene encoding immune regulatory (AIRE) protein cause autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) with recessive or dominant autosomal inheritance.In this syndrome, the patient suffers from chronic Candida infection in childhood and then autoimmune hypoparathyroidism and autoimmune primary adrenocortical failure [57].If there are two of these three components or a previous diagnosis in the patient's sibling, this disease is raised.Tissue-specific antibodies and cytokines created during this syndrome can rarely cause kidney involvement and autoimmune TIN [58].The symptoms of TIN are nonspecific and sometimes less clear, but unexplained fever is one of its notable features [59].Increased creatinine, ESR, abnormal urinalysis, proteinuria or decreased kidney function without abnormalities in urinalysis can be a clue to suspect this syndrome in susceptible patients (58).

Conclusion
Inborn errors of immunity are multi-system disorders and require interdisciplinary approach for optimal diagnosis and management.Among others, the characteristics of kidney and urinary system in IEIs have remained obscure and need more consideration by the pediatrics, nephrologists and immunologists.As illustrated in Fig. 1, a thorough evaluation of kidney and urinary system in patients with abnormal initial renal screening should be performed concomitantly with immunology workup.This evaluation is divided in primary and secondary steps and will be helpful in earlier clinical diagnosis of the underlying IEIs before the result of the genetic study become ready.
Fig. 1 Step-wise approach for evaluation of kidney and urinary tract disorders in patients with inborn errors of immunity In this review, we tried to summarize the IEIs reported to manifest renal abnormalities, however, the list provided here is according to the well-established IEIs and certainly in the future it will be extended.

Table 1
Inborn errors of immunity with renal features AR autosomal recessive, GOF gain-of-function, LOF loss-of-function, AD autosomal dominant, CVID common variable immunodeficiency, XL X-linked, AIRE; autoimmune regulator, SLE systemic lupus erythematosus