The spatiotemporal expression of distinctive sets of transcription factors is essential for proper programming of multi-potent cells, such as SIX1+/CITED1+ positive nephron progenitor cells (NPC), as well as for their descendants, e.g., LHX1+/EMX2+/HNF1B+ cells in pretubular aggregates and renal vesicles (Fig. 2) [9]. Deleterious variants in many of the genes encoding for these kidney developmental transcription factors lead to CAKUT in mice and humans (Supplemental Table 1).
Probably the most recognized example for monogenic CAKUT in human patients among clinicians is HNF1B nephro-uro-pathy. Deleterious heterozygous variants in HNF1B, such as the frequently reported whole gene deletion (about 50% of cases), lead to heterogeneous malformations of the kidney and/or the urinary tract and/or diabetes mellitus. Commonly, affected patients exhibit ultrasonographic small and bright kidneys with multiple small cysts and different degrees of kidney function impairment. HNF1B is expressed in epithelial cells in the liver, pancreas, and in the kidney, more specifically in UB cells, nephron precursor cells, and in kidney tubules. In developing kidney tubules, HNF1B promotes SOCS3 expression, which plays an important role in tubulogenesis [11]. Tubular dysgenesis in patients with deleterious variants in HNF1B is appreciated by the clinical term “HNF1B associated Autosomal dominant Tubular Kidney Disease” (HNF1B-ADTKD), which is characterized by chronic kidney disease including hyperuricemia with or without gout, hypokalemia, hypomagnesemia, and polyuria [12]. In a German multicenter childhood registry study for HNF1B nephropathy, 87% of probands (54/62) had bilateral kidney dysplasia, whereas the other mentioned symptoms were less frequently observed [13]. The broad expression of HNF1B in UB, liver, and pancreas explains additional extrarenal features, such as “Maturity Onset Diabetes of the Young Type 5” (MODY5) and defects of the urinary collecting system.
Variants in PAX2 are another well-established example of monogenic CAKUT. Mutations in PAX2 may cause syndromic CAKUT with ocular anomalies, such as optic nerve coloboma (OMIM # 120330) [14]. PAX2 is expressed in multiple embryonic tissues including the optical disk and the cap mesenchyme (see expression data on www.gudmap.org). In mesenchymal-epithelial transition, PAX2 promotes expression of the podocyte transcription factor WT1. Failure to promote WT1 expression seems to result in kidney dysplasia through impairment of nephron differentiation. Interestingly, patients carrying a deleterious variant in PAX2 may also present with steroid resistant nephrotic syndrome (SRNS) and focal segmental glomerulosclerosis (FSGS), similar to patients with a deleterious variant in WT1 [15]. To this notion, patients with PAX2-CAKUT may have early albuminuria, exceeding the level of albuminuria that is expected solely on the basis of chronic kidney disease. Hence, physician should carefully search for eye involvement and consider genetic testing for PAX2 mutations in patients with CAKUT and early albuminuria.
Other recent examples for transcription factors implicated in CAKUT are TBX18 and NRIP1. TBX18 is essential for differentiation of MM cells into ureter smooth muscle cells. Heterozygous deleterious mutations in TBX18 prevent smooth muscle differentiation in the ureteral wall. The absence of peristaltic contraction ability causes ureteropelvic junction obstruction (UPJO) and congenital hydronephrosis. This has been discovered and studied in a Tbx18+/− mouse model and was later found to also be a rare cause of UPJO and hydronephrosis in human patients [16, 17].
NRIP1 is a co-transcription factor of the retinoic acid receptor RARα. A heterozygous truncating variant in NRIP1 recently has been identified in a large kindred with different forms of CAKUT (kidney cysts, kidney dysplasia, dilatation of the ureter, and VUR) [18]. A causative role of this variant is supported by knock-down of Nrip1 in X. laevis larvae that causes a similar CAKUT phenotype (hydroureter, hydronephrosis, and ureterocele). Interestingly, this discovery is in line with the historic observation that alternations in maternal vitamin A supply during pregnancy increase the risk for CAKUT and thereby provides insight into a possible interplay of genetic and environmental factors [19].