Nephronophthisis in Young Adults Phenocopying Thrombotic Microangiopathy and Severe Nephrosclerosis

Severe hypertension revealing a CKD is a common situation in adult nephrology. Despite in-depth etiologic investigations, uncontrolled hypertension is often retained as the final cause underlying CKD. Ultimately, patients with diverse and heterogeneous clinical presentations are lumped together under the term “hypertensive nephrosclerosis” on the basis of kidney pathology examination. The recent use of whole-exome sequencing (WES) can reveal new insights in the pathogenesis of such nephropathies in adults (1).

Since September 2018, the adult nephrology department of Sorbonne University (Paris) has been able to offer WES to every patient with early-onset CKD (<45 years old) of unclear origin, including hypertensive kidney disease. We report here patients with a genetically confirmed diagnosis of nephronophthisis for which severe hypertensive disease was observed as defined by current guidelines.

From September 2018 to May 2020, of the 200 unrelated patients accessing WES, 18 received a diagnosis of ciliopathy. Among them, seven had a severe hypertensive phenotype. Six index patients were affected by the same homozygous variant in TTC21B (NM_024753.5:c.626C>T, p.Pro209Leu), and one was affected by a homozygous variation in the WDR19 gene (NM_ 025132.3:c.292G>T, p.Asp98Tyr). Very few variants are currently described for WDR19 in variant databases, impeding American College of Medical Genetics and Genomics (ACMG) upward ranking to the likely pathologic/pathologic class as opposed to TTC21B. Two cases involved siblings in a large pedigree, while the other five were sporadic cases. The 11 other molecularly proven ciliopathies did not present hypertension.

Figure 1A describes these seven pedigrees. The initial clinical features argued for severe hypertension with chronic hypertension–induced damage involving left ventricular hypertrophy and hypertensive retinopathy. Four patients underwent a kidney biopsy, all showing severe hypertensive nephrosclerosis with arteriolar thrombotic microangiopathy (TMA) (Figure 1B). The usual histologic hallmarks of nephronophthisis (kidney tubular cysts or tubular membrane disruption) were not observed. Only two patients had multiple cysts in kidney imaging. All but two patients had liver function test abnormalities with mild hepatic cholestasis or cytolysis. One patient had Caroli aspect on liver magnetic resonance imaging. Before genetic diagnosis, all of these patients were considered as having hypertensive kidney diseases. Because of the young onset of their nephropathy, causes of secondary hypertension were repeatedly but unsuccessfully sought. Complement-dependent TMA was ruled out for all patients. Indeed, two patients presented initially with the hallmark of biologic TMA, whereas histology yielded arteriolar TMA without glomerular thrombi on the kidney biopsy in three other patients.

Figure 1.

Clinical description of patients and representative pathological example. (A) Characteristics of the seven nephroangionophtisis pedigrees. (B) Histopathologic representation of severe arteriosclerosis (arrowhead) and arteriolar thrombotic microangiopathy (TMA; asterisks) on kidney biopsy (hematoxylin and eosin stain in the left panel and Masson trichrome staining in the right panel, ×200) from one patient affected by homozygous TTC21B, NM_024753.4:c.626C>T, p.Pro209Leu, class 5 variation. FSGS lesions are not observed.

Nephronophthisis is an autosomal recessive kidney disorder caused by variants in the genes that encode proteins involved in the function of primary cilia, basal bodies, and centrosomes. Textbook nephronophthisis is described as a genetic cystic kidney disease with pediatric or juvenile onset (2). Hypertension at initial presentation is thought to be absent because of salt wasting (2). Hence, our patients with “nephroangionophthisis” broaden the phenotypic spectrum of nephronophthisis. Our seven patients had an early onset of hypertension, with a mean of 23 years. In three patients, hypertension was diagnosed before any kidney dysfunction. This raised the possibility that hypertension in nephronophthisis can reflect endothelial cilium dysfunction. Regarding tubular kidney cells, endothelial cells have cilia protrusions, acting as a vascular mechanosensor, which can play a key role in BP regulation (3). TTC21B (IFT139) and WDR19 (IFT144) proteins encode for axonemal proteins both participating in the intraflagellar transport sub-complex A complex and assuring retrograde flux from the tip of the cilia to its base (2). Perturbation of intraflagellar transport sub-complex A function leads to the dysregulation of G protein-coupled receptor proteins at the tip of the cilia, and this can play a role in hypertension (4). Similarly, nine of ten pedigrees described by Huynh Cong et al. (5) presented the same P209L TTC21B variant. Patients had a “glomerulotubular” phenotype, with hypertension.

The phenotype described here includes very few of the characteristics of nephronophthisis in its canonical description. It is very unlikely that nephronophthisis would have ever been diagnosed without a broad indication of WES in nephropathy of unclear origin. In our limited monocentric experience, with 200 index patients undergoing WES sequencing, we identified seven patients with nephronophthisis misclassified as hypertensive kidney disease. It may, therefore, be posited that nephronophthisis in the adult CKD population is in fact underestimated. From the genetic perspective, it seems that the definition and clinical features of nephronophthisis need thorough reassessment in the adult population. Thus, in the context of adult nephronophthisis with CKD with severe hypertension and kidney vascular lesions, a “nephroangionophthisis” entity might emerge, especially if persistent liver function test abnormalities are observed. Likewise, critical reappraisal of the contours of so-called hypertensive kidney disease is also mandatory and, at any rate, should not deter physicians from performing WES. In fact, the poor genetic/phenotypic relationship displayed here makes a case for liberal prescription of genetic investigations alongside more established diagnostic tools such as kidney histology and magnetic resonance imaging. In addition to providing new clinical insights, genetic investigation complements other examinations by allowing for family counseling and donor selection for transplantation.

Disclosures

A. Karras reports receiving honoraria from Abbvie, Amgen, Gilead, and Roche Pharmaceuticals. Y. Luque reports serving as a scientific advisor or member of Club des Jeunes Néphrologues, Research Comission French Society of Nephrology, and Young Nephrologist French Association. C. Rafat reports receiving honoraria from M3, Qualworld, and Sermo. L. Raymond reports employment with Eurofins Biomnis Laboratory. R. Saraeva Lamri reports employment with Eurofins Biomnis Laboratory. All remaining authors have nothing to disclose.

Funding

None.