Extrarenal manifestations in inherited kidney diseases

ABSTRACT

Monogenic kidney diseases result from an abundance of potential genes carrying pathogenic variants. These conditions are primarily recognized for manifesting as kidney disorders, defined as an impairment of the structure and/or function of the kidneys. However, the impact of these genetic disorders extends far beyond the kidneys, giving rise to a diverse spectrum of extrarenal manifestations. These manifestations can affect any organ system throughout the body, leading to a complex clinical presentation that demands a comprehensive understanding and interdisciplinary management of affected persons. The intricate interplay between genetic variants, molecular pathways, and systemic interactions underscores the importance of exploring the extrarenal aspects of inherited kidney diseases. This exploration not only deepens our comprehension of the diseases themselves but also opens avenues for more holistic diagnostics, treatment strategies, and improved interdisciplinary patient care. This article delves into the intricate realm of extrarenal manifestations in inherited kidney diseases, shedding light on the far-reaching effects that these genetic conditions can exert beyond the confines of the kidney system.

INTRODUCTION

Inherited kidney diseases (IKD) are rare, but range from relatively common conditions to ultrarare syndromes [1]. While some instances of IKD manifest with only mild symptoms, others can cause severe health problems leading to kidney failure and other morbidities [2, 3]. IKD comprise a very diverse group of clinically and genetically heterogeneous kidney disorders (Table 1). A common feature of IKD are extrarenal manifestations caused by ubiquitous expression of the respective gene product, qualifying many IKDs as syndromes. In a medical context, a “syndrome” refers to a collection of signs, symptoms, and clinical features that commonly occur together and are indicative of a particular underlying condition, disease, or disorder (https://www.genome.gov/genetics-glossary#S). Syndromes often have recognizable patterns that aid in diagnosis and medical understanding, assisting healthcare professionals in identifying and treating the underlying causes of the observed clinical manifestations. Nevertheless, it should be noted that not all the extrarenal symptoms experienced by individuals with disease-causing variants can be attributed to the causal gene. Rather, they are indicative of a general impairment in overall well-being. Initiating referrals for individuals with suspected IKD is therefore crucial for a timely diagnosis of extrarenal manifestations and their management. In this mini review, we will give a broad overview of some of these extrarenal manifestations observed in individuals with IKD (Fig. 1) and give thorough details in a tabular form (Table 2  https://doi.org/10.6084/m9.figshare.25982284.v1). Drawing on information mostly from the Online Mendelian Inheritance in Man (OMIM) database, Table 2 (https://doi.org/10.6084/m9.figshare.25982284.v1) presents extrarenal manifestations of IKD systematically sorted by organ systems, including other valuable information.

CONGENITAL ANOMALIES OF THE KIDNEY AND URINARY TRACT

Congenital anomalies of the kidney and urinary tract (CAKUT) are the main cause of kidney replacement therapy in children. The prevalence is ∼3–6 per 1000 live births [4]. Individuals with CAKUT show a broad spectrum of kidney malformations ranging from mild symptoms such as vesicoureteral reflux to severe forms such as bilateral kidney agenesis (Table 2  https://doi.org/10.6084/m9.figshare.25982284.v1) [5]. In addition to multifactorial causes, hereditary (monogenic) forms play an important role in its development. Up to now, more than 50 different monogenic disorders resulting in CAKUT have been described with different modes of inheritance (Table 1) [6]. Genes associated with monogenic CAKUT usually encode transcription factors involved in kidney development (e.g. HNF1B, PAX2, SALL1) [6]. Disease-causing variants in HNF1B are a frequent cause of CAKUT with a broad clinical spectrum including maturity-onset diabetes of the young type 5, pancreas atrophy, genital malformations, and CAKUT (Table 2  https://doi.org/10.6084/m9.figshare.25982284.v1) [7]. This demonstrates that CAKUT can be present in an isolated form and therefore limited to the kidney and urinary tract, or can be part of a syndromal disorder. In addition to syndromal forms, which will not be discussed in detail in this review due to quantity, individuals with CAKUT often present with single or multiple extrarenal manifestations (Fig. 1). These include, but are not limited to, the central nervous system, ears, eyes, heart, and limbs (Fig. 1) [8]. Further information can be found in Table 2 (https://doi.org/10.6084/m9.figshare.25982284.v1).

CILIOPATHIES

Ciliopathies arise from disease-causing [(likely) pathogenic] variants in ciliary proteins often affecting the kidney and multiple other organ systems. Almost 1000 cilia-related genes and their respective ciliary proteins have been discovered so far [9]. The phenotypic spectrum is therefore broad ranging, from dysplastic kidney diseases with variable cyst formation (e.g. multicystic dysplasia), cystic kidney diseases with classic inheritance (e.g. autosomal dominant polycystic kidney disease, ADPKD), to polycystic kidney diseases with a syndromic appearance (e.g. Meckel–Gruber syndrome, Bardet–Biedl syndrome). The terms “ciliopathy” and “cystic kidney disease” are often used synonymously because their gene products are localized in the cilium–centrosome complex and disease-causing variants in these genes lead to functional and structural disorders of this complex presenting with cyst formation [10]. A large group within the ciliopathy group are cystic kidney diseases, such as ADPKD that is the most common IKD in adults to date. ADPKD is hallmarked by the progressive development of bilateral progressive kidney cysts [11]. Most cases of ADPKD (prevalence ∼1 in 1000 individuals) can be attributed to disease-causing variants in the PKD1 (∼78%) and PKD2 (∼15%) genes [12]. Well-known extrarenal affections include polycystic liver disease and intracranial aneurysms leading to a high morbidity and mortality rate if ruptured and even when unruptured (Table 2  https://doi.org/10.6084/m9.figshare.25982284.v1, Fig. 1) [13]. The advent of comprehensive sequencing techniques has led to the discovery of additional genes associated with ADPKD-like phenotypes making it a genetically heterogenous disease [12]. In turn, this may lead to other extrarenal manifestations dependent on the gene carrying the disease-causing variant (Table 2  https://doi.org/10.6084/m9.figshare.25982284.v1). Identified genes include GANAB, DNAJB11, ALG5, ALG9, and IFT140 [12]. Systematic characterization of extrarenal manifestations associated with disease-causing variants in these genes can be difficult because of the rarity of the disease (e.g. ALG5 and colonic diverticulosis/Hirschsprung's disease) [14]. Despite the large number of ciliopathies, improved molecular genetic diagnostics make it possible to classify cases clinically in up to 70% [15].

GLOMERULOPATHIES

Glomerular disease is an umbrella term comprising a broad spectrum of conditions affecting the glomeruli (Table 1). These conditions are characterized by multiple etiologies (e.g. hereditary causes, infections, immunologically mediated forms), clinical presentations, and histopathological findings leading to differential disease progression and clinical management depending on the underlying cause [16]. Affected individuals can present with, for example, nephrotic/nephritic range proteinuria and (microscopic) hematuria (e.g. in steroid resistant/sensitive nephrotic syndrome, focal-segmental glomerulosclerosis, and Alport syndrome). Glomerular diseases are often associated with chronic kidney disease leading to a high economic burden. So far, disease-causing variants in >50 genes with different modes of inheritance (e.g. autosomal dominant and recessive, X-linked) are known (Table 1) [17]. Depending on the underlying (monogenic) cause, a variety of extrarenal manifestations can be observed (Table 2  https://doi.org/10.6084/m9.figshare.25982284.v1). Clinical management in proteinuric kidney disease can therefore be challenging with frequent changes in pharmacotherapy leading to prolonged courses of immunosuppression. However, many studies have shown that genetic testing can also determine the best treatment option for every manifestation posttransplant and aid counseling for family planning or living-related donor options. This has been shown especially for Alport syndrome and focal-segmental glomerulosclerosis [18–20].

TUBULOPATHIES

The term tubulopathy refers to the disruption of the normal physiological function of kidney tubules, responsible for regulating acid-base balance, fluid, and electrolyte homeostasis through active and passive processes [21]. Tubulopathies are pathophysiologically mostly genetic in nature (>60 genes known to date, Tables 1 and 2), can affect any part of the kidney tubule, and often present with a spectrum of non-specific clinical features, making diagnosis challenging [22]. To diagnose a suspected tubulopathy a thorough workup of urine and serum samples is mandatory, but imaging techniques and genetic evaluation have become more important in the last decades [21]. Prominent aspects in these patients as a consequence of the kidney involvement are polyuria, polydipsia, irritability, growth impairment, variations in blood pressure, and nephrocalcinosis, thereby making an overlap with kidney stone diseases and metabolic kidney diseases already apparent (Table 2  https://doi.org/10.6084/m9.figshare.25982284.v1) [21, 22]. Despite the intrarenal impairment leading to tubulopathies, there are a multitude of extrarenal manifestations in these diseases, most of them unspecific (not directly related to the altered gene) [21]. More specific extrarenal manifestations may guide the clinician in diagnosing the underlying disease (e.g. sensorineural hearing loss, ophthalmologic issues, and developmental delay; Fig. 1). One important extrarenal manifestation of Bartter syndrome, which can also be classified as a kidney stone disease, is the complications of chronic hypokalemia including rhabdomyolysis and cardiac arrhythmias making a timely diagnosis a prerequisite in the management of individuals suffering from tubulopathies (Table 2  https://doi.org/10.6084/m9.figshare.25982284.v1) [21].

KIDNEY STONE DISEASES

Dependent on stone location, one can differentiate stone disorders into nephrocalcinosis (deposits of calcium salts in tubules/interstitium with two anatomical forms: medullary, diffuse), nephrolithiasis (stones in the kidney), and urolithiasis (stones in the urinary tract/bladder) [23–25]. Incidence rates for uro- and nephrolithiasis are rising in adult and pediatric populations probably due to mainly environmental factors [26, 27]. Nevertheless, in pediatric cohorts most stone diseases are inherited with fewer cases of monogenic stone disorders in the adult population [23, 26]. To date, >40 genes have been identified to be associated with these IKD following all three known Mendelian inheritance patterns (Table 1) [24]. Most associated genes belong to kidney transporter genes (e.g. SLC34A1, SLC34A3), but non-renal genes are also known (primary hyperoxaluria) [28]. Frequent monogenic causes of kidney stone diseases are cystinuria (77%) and primary hyperoxaluria (11%), both of which overlap phenotypically with other kidney disease categories such as metabolic disorders [29]. Since most genes carrying disease-causing variants in kidney stone disease are kidney solute transporters, chloride channels, tight junction proteins, and metabolizing enzymes, the primary defect is often located in the kidney's tubular system, also classifying them as tubulopathies [24]. Understanding the molecular and genetic mechanisms of primary hyperoxaluria has led to the development of an RNA-based therapeutic (lumasiran) designed to reduce hepatic production of oxalate. Clinical trials demonstrated the efficacy of the drug leading to its approval and the possibility of personalized therapy for affected individuals [30]. The occurrence of extrarenal manifestations in monogenic kidney stone diseases is dependent on the gene/pathway involved and may affect a vast number of organs ranging from the affection of the central/peripheral nervous system to skeletal deformities or skin lesions to name a few (Table 2  https://doi.org/10.6084/m9.figshare.25982284.v1) [28, 31].

METABOLIC DISORDERS

More than 1400 inherited metabolic disorders (IMD) are known so far as defined by the International Classification of Inherited Metabolic Disorders [32]. They can affect the body as a whole and may have multisystemic consequences, thereby often overlapping with other disease categories. A distinctive feature of IMD is that many of them can be treated causally, but significant therapeutic advancements will be realistic in the future [33]. In some cases, variant-specific molecular therapies are at the forefront [34]. Metabolic kidney diseases (MKD) make up ∼10% of all IMD, may affect any part of the kidney/urinary tract, and comprise ∼190 disorders so far (Table 1) [35]. An often overlooked, but treatable MKD is Fabry's disease [36]. Fabry's disease is a lysosomal storage disease with an X-linked inheritance pattern caused by deficiency of α-galactosidase A [36]. Extrarenal manifestations include affection of the nervous system, eyes, ears, skin, vascular system, heart, and gastrointestinal tract (Fig. 1) [37]. Other well-known MKD include amyloidosis, as well as cystinosis and hyperoxaluria: two diseases that can also be classified as kidney stone diseases. Details on these can be found in Table 2 (https://doi.org/10.6084/m9.figshare.25982284.v1).

MITOCHONDRIOPATHIES

Mitochondrial cytopathies are inherited disorders caused by defects in mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) affecting mitochondrial functions. With a prevalence of ∼1 in 5000, these disorders can occur at any age and are characterized by progressive clinical deterioration, often including encephalopathy and dysfunction in high metabolic rate organs [38, 39]. Kidney involvement may occur, primarily due to tubular defects resulting from the high mitochondrial density in this nephron segment. However, glomerular, tubulointerstitial, and cystic diseases can also be seen [39–41]. mtDNA exhibits a higher mutation rate than nDNA, making it more susceptible to damage, especially in tissues with a high oxidative metabolism [42, 43]. Transmission patterns vary: nDNA variants can be inherited autosomally or X-linked, while mtDNA variants are maternally inherited. Homoplasmy refers to identical mtDNA copies within a cell, whereas heteroplasmy indicates different mtDNA variants. The level of heteroplasmy influences the clinical phenotype due to a threshold effect [44]. However, the precise relationship between the expression of the clinical phenotype and the underlying molecular defects remains complex, depending on multiple influencing factors such as tissue specificity, threshold effect, heteroplasmy, and interaction with nuclear genes [45]. The complexity of this group of disorders is heightened by the mtDNA bottleneck during oogenesis, leading to varying heteroplasmy levels among offspring. Examples of kidney involvement in mitochondrial cytopathies are: (i) MT-TL1 gene variants such as m.3243A>G [associated with MELAS (mitochondrial encephalopathy, lactic acidosis, stroke-like episodes) syndrome], may manifest as focal-segmental glomerulosclerosis, sometimes misdiagnosed as Alport syndrome due to overlapping symptoms but distinct inheritance patterns and typically no hematuria in MELAS [46–50]; (ii) several mtDNA and nDNA gene variants were reported to be associated with cystic kidney disease [51–54]; (iii) cases with tubulointerstitial nephropathy linked to mtDNA variants (e.g. MT-TF and MT-ND5) and RMND1 variants present with a wide range of symptoms, including chronic kidney disease, multi-organ involvement, and distinct mitochondrial abnormalities [55, 56]; and (iv) mitochondrial variants can also cause electrolyte disturbances consistent with distal tubular dysfunction, such as hypomagnesemia and hypokalemia, and are implicated in Gitelman-like syndrome and chronic kidney disease as well as multisystem disorders [57, 58]. So far, therapeutic options are lacking but emerging therapies, e.g. coenzyme Q10 supplementation in individuals with steroid resistant nephrotic syndrome, seem to be promising [59].

COMPLEMENT MEDIATED KIDNEY DISEASES

Over the past 20 years, various associations of genetic variants of complement/coagulation proteins to kidney disease have been identified, especially in atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathies (C3G) (Table 1) [60]. For both disease entities, uncontrolled complement activation is the primary driving factor [61]. Their development can result from gain-of-function variants in complement components such as C3 and CFB and loss-of-function variants in inhibitory complement regulators such as CFH, CFI, THBD, CD46, and factor H-related proteins [62]. A disease-causing variant in one of these genes can be found in 40%–70% of aHUS and ∼25% of C3G cases [63–65]. While autosomal dominant inheritance is common, the presence of a heterozygous disease-causing variant does not necessarily lead to disease, since incomplete penetrance or very variable expressivity are the norm [60, 66]. However, identifying the genetic cause of aHUS/C3G can significantly affect a patient's therapy. For instance, those with disease-causing variants affecting the alternative complement pathway benefit from eculizumab (anti-C5 antibody) treatment [60, 67]. Extrarenal manifestations of genetic variants in genes associated with aHUS and C3G may affect the central nervous system (e.g. seizures, hemiparesis, irritability, coma; Table 2  https://doi.org/10.6084/m9.figshare.25982284.v1) and less frequently in the cardiovascular system (e.g. cardiomyopathy, myocarditis, and occlusive coronary lesions; Table 2  https://doi.org/10.6084/m9.figshare.25982284.v1), the lungs, pancreas, liver, and the gut [68]. Furthermore, genetic variants in corresponding genes might be associated with macular degeneration and anti-phospholipid-syndrome [69, 70].

KIDNEY CANCER

The lifetime risk of developing kidney cancer is ∼2%, and 5%–8% of kidney cancers diagnosed may be attributed to hereditary kidney cancer [71]. Many hereditary kidney cancer syndromes are known including von Hippel–Lindau (VHL), hereditary papillary renal cell carcinoma, Birt–Hogg–Dubè (BHD), hereditary leiomyomatosis and renal cell carcinoma (HLRCC), succinate dehydrogenase kidney cancer, tuberous sclerosis complex, Cowden syndrome, and microphthalmia-associated transcription factor (Table 1). These syndromes are associated with germline variants, e.g. in the genes VHL, MET, FLCN, FH, SDHB/C/D, TSC1/2, PTEN, or MITF [72]. Extrarenal manifestations in people suffering from kidney cancer can be indicative of a certain kidney cancer syndrome, such as in cerebellar hemangioblastoma (VHL), cutaneous fibrofolliculomas (BHD), or leiomyomas (HLRCC; Table 2  https://doi.org/10.6084/m9.figshare.25982284.v1) [73–75]. Other hereditary kidney cancers may, however, have a more subtle clinical presentation and their diagnosis depends on other factors. These signs may be a positive family history, specific tumor histologies (e.g. oncocytic renal cell carcinoma in BHD), bilateral/multifocal tumors, and age of onset [76]. The age of onset for hereditary kidney cancer and kidney cancer syndromes (46 years) is much younger than observed in the general population (64 years) and is therefore a general important criterion when considering the presence of hereditary kidney cancer [76]. A comprehensive overview of all extrarenal manifestations in kidney cancer syndromes can be found in Table 2 (https://doi.org/10.6084/m9.figshare.25982284.v1).

CONCLUSION

IKD manifestations often extend beyond the kidney and/or urinary tract. Individuals present with extrarenal affections based on the genetically disrupted pathways, even if not directly recognizable. To optimize the treatment of these patients, it is paramount to examine them regularly for possible extrarenal involvement by an interdisciplinary team of health care professionals. Initiating referrals for individuals with suspected IKD is imperative for ensuring a prompt diagnosis and effective management of extrarenal manifestations. For this purpose, a structured plan for regular clinical examination of these individuals needs to be developed to detect extrarenal involvement at an early stage and to treat it accordingly. Early detection of possible extrarenal manifestations and complications optimizes the quality of treatment for these individuals. Systematic collection of extrarenal manifestations especially of newly detected genes causing IKD seems indispensable as well as the creation of compendia for clinicians. To achieve this international data pooling is essential through international nephrogenetic consortia and/or registries (e.g. ERKReg and associated registries The European Rare Kidney Disease Reference Network, https://www.erknet.org; UKKA UK Kidney Association RaDaR National Registry of Rare Kidney Diseases, https://ukkidney.org; and European Network of Cancer Registries, https://www.encr.eu).

FUNDING

The work of U.T.S. was supported by the German Federal Ministry of Education and Research (BMBF) within the framework of the Med research and funding concept (grant 01ZX1912B). This work was also supported by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) and the Technical University of Munich (TUM) in the framework of the Open Access Publishing Program. J.H. received funding from the DFG (HO 2583/8-3). T.H. acknowledges support from the DFG (HE 7456/4-1, HE 7456/7-1, and project ID 431984000–SFB 1453). The work of M.W. was supported by German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) Project ID 431984000, SFB 1453.

AUTHORS’ CONTRIBUTIONS

Research idea and study design: J.H., J.E., T.H., M.W., and U.T.S.; data acquisition: J.H., J.E., T.H., M.W., and U.T.S.; data analysis/interpretation: J.H., M.W., and U.T.S.; supervision or mentorship: J.H. and U.T.S.

Each author contributed important intellectual content during manuscript drafting or revision, and agrees to be personally accountable for the individual's own contributions and to ensure that questions pertaining to the accuracy or integrity of any portion of the work, even one in which the author was not directly involved, are appropriately investigated and resolved, including with documentation in the literature if appropriate.

DATA AVAILABILITY STATEMENT

All used data are publicly available.

CONFLICT OF INTEREST STATEMENT

U.T.S. is working for Synlab MVZ Humangenetik GmbH Freiburg. All other authors have nothing to disclose.

REFERENCES