Bilateral Glomerulocystic Kidney Disease With Extensive Embryonal Hyperplasia in a Setting of HNF1B Mutation

Introduction

The term “glomerulocystic kidney,” was first proposed in 1976 to describe the morphologic finding of renal cystic disease involving Bowman’s capsule. ¹ In 1993, Bernstein more precisely defined the term and categorized glomerulocystic kidney (GCK) as a dilatation of Bowman’s space 2 to 3 times normal. ² Additionally, glomerular tufts were required to be present in at least 5% of cysts, with or without tubular cysts. More recently, 5 categories were proposed for classifying glomerulocystic kidneys: (i) GCK in polycystic kidney disease (PKD); (ii) GCKD, synonymous with heritable/familial GCK; (iii) syndromic GCK; (iv) obstructive GCK; and (v) sporadic GCK. The term “GCKD” should be reserved for inherited subtypes, including GCK resulting from mutated hepatocyte nuclear factor-1β (HNF1B). ³

Though mutations in HNF1B were first reported as a rare cause of maturity-onset diabetes type 5 (MODY5), it is now known that HNF1B mutations are responsible for many renal diseases. ⁴ The most common clinical manifestation in HNF1B mutation-associated disease is renal cysts. Renal cysts are often identified on antenatal ultrasound, which commonly shows bilateral hyperechogenic kidneys. Renal hyperechogenicity may be secondary to multiple microscopic cysts, renal dysplasia, or tubular dilation. ⁵ Many patients with HNF1B-associated renal cysts experience early-onset diabetes mellitus, resulting in a diagnosis of renal cysts and diabetes (RCAD) syndrome.^6,7

Morphologic findings in a setting of HNF1B mutation may include glomerulocystic kidneys, multicystic renal dysplasia, solitary functioning kidney, horseshoe kidney, and oligomeganephronia.^5,8,9 Progression to end-stage kidney disease in childhood is rare, with 1% to 8% of HNF1B mutation carriers progressing to CKD stage 5.^5,10,11

Glomerulocystic kidney disease (GCKD) with embryonal hyperplasia has very rarely been reported, but none have been genetically characterized.^1,12,13 We report a case of bilateral GCKD with extensive embryonal hyperplasia of uncertain clinical significance in a setting of a de novo germline HNF1B mutation.

Case Report

A 2-year-old male presented for renal transplant due to bilateral polycystic kidney disease (PKD) with progressive renal failure. He was born at 36.5 weeks following induction of labor for known fetal anomalies diagnosed on routine prenatal ultrasound studies, including PKD and severe oligohydramnios. At birth, appropriate APGARs were recorded following resuscitation (8, 8). His liver and pulmonary function were normal, and he produced significant volumes of urine despite impaired renal clearance (CKD stage 5). Serum creatinine increased for the first few days of life until stabilizing at 4.5 to 4.8 mg/dL. He had severe metabolic acidosis and hyperkalemia which improved with enteral base supplementation. His labs remained relatively stable with an elevated serum creatinine and mildly elevated BUN.

A renal ultrasound at 20 days showed enlarged kidneys, measuring 5.6 cm in length, with a generalized increase in echodensity and numerous small anechoic cysts. There was no significant collecting system dilatation. He was started on an erythropoietin stimulating agent and a gastrostomy tube was placed to assist in management of feeding intolerance. Although his eGFR was poor at ~5 ml/min/1.73 m², he did not require dialysis during his initial hospitalization, and discharge occurred at 27 days.

Peritoneal dialysis was initiated around 4 months of age because of worsening symptoms of uremia and growth arrest. Whole genome sequencing demonstrated a homozygous germline mutation in HNF1B (NM_000458.4:c.241G>T; p.Glu81Ter), consistent with renal cysts and diabetes syndrome (RCAD). Parental testing confirmed it to be de novo. A renal transplant with explant of the native kidneys was performed at 26 months of age.

Bilateral kidneys were received (57 g left, 48 g right) with total replacement of renal parenchyma by innumerable, smooth-walled cysts containing serous fluid and ranging in size from 0.1 to 0.7 cm (Figure 1). Microscopy showed cysts lined by single layers of bland cuboidal cells, with many containing glomerular tufts. In both kidneys, the cyst size increased from cortex to medulla. Normal medullary tissue was not present, though there were scattered small tubular structures near the interface with the renal sinus. Diminutive renal papillae were present with a few papillary ducts. Numerous nodular to diffuse epithelial proliferations composed of tubular to glomeruloid structures were identified throughout the intervening stroma of both kidneys (Figures 2–4). The epithelial cells were small and ovoid with minute nucleoli and no significant mitotic activity. These appeared to represent well-differentiated nephrogenic structures and were positive for CAM5.2 and WT1 (nuclear) and negative for EMA and BRAF V600E by immunohistochemistry. The differential diagnosis based on the morphology included nephrogenic rests, embryonal hyperplasia, and metanephric adenoma. These structures were not localized to the subcapsular region, as is seen in perilobar nephrogenic rests. Furthermore, they were not clearly associated with Bowman’s capsule hyperplasia but were located adjacent to the glomeruli and within the interstitium. No dominant or overtly neoplastic nodules were seen, as would be expected for metanephric adenoma. These proliferations are best described as embryonal hyperplasia.

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Figure 1.

Right and left kidneys showing spongy appearing parenchyma with scattered larger cysts.

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Figure 2.

(A) Embryonal hyperplasia and increasing cyst volume from cortex toward medulla (top-bottom). (B) Medulla and renal sinus showing extension of cysts and embryonal hyperplasia to the interface with the renal sinus. A diminutive renal papilla is seen in the center. (H&E, 2×).

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Figure 3.

High power image of a focus of embryonal hyperplasia showing glomeruloid nephrogenic structures with ovoid nuclei without significant mitotic activity (H&E, 40×).

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Figure 4.

Immunohistochemical staining shows (A) CAM5.2 staining of the embryonal hyperplasia, with focal staining of Bowman’s capsule, (B) EMA is negative in both the embryonal hyperplasia and Bowman’s capsule, (C) WT-1 staining of both the embryonal hyperplasia and Bowman’s capsule, and (D) BRAF V600E is negative in all areas.

Discussion

GCKD with the additional findings of extensive embryonal hyperplasia has been described in rare case reports. Roos reported a case in 1941 of a 5-month-old female with failure to gain weight, hepatosplenomegaly, and 2 bilateral abdominal masses. Following a 3-month hospitalization, death occurred due to bronchopneumonia. Autopsy showed pale, symmetrically enlarged polycystic kidneys (each kidney 100 g, 9.1 × 3.6 × 3.4 cm), and the entire cortex was occupied by honeycombed tissue with fluid-filled, pinhead-sized cysts; the medulla was completely uninvolved. Microscopic examination showed glomerulocystic kidneys with cysts lined by a monolayer of “flat cells” and containing capillary tufts. Near the poles of many cysts, areas of epithelial hyperplasia were reported; however, communication with definitive tubular structures was not identified. ¹² While the described findings are consistent with our case, the images provided are difficult to evaluate.

Similar to Roos, Taxy and Filmer reported a case in 1976 of a 9-week-old female with abdominal distention and constipation.^1,12 An intravenous pyelogram was performed; however, death occurred following an anaphylactic reaction to the contrast medium. Autopsy showed enlarged kidneys. The kidney cortices were entirely occupied by small cysts, 1 to 3 mm in diameter. Microscopic examination showed numerous thin-walled cystic spaces lined by cuboidal and primitive columnar cells resting on a thin basement membrane. Many cysts showed papillary proliferations described as abortive glomeruli. The cysts were continuous with adjacent small proliferations of primitive columnar cells, again similar to those seen in our case, but smaller.

The most strikingly similar case from a histologic perspective was reported as an online teaching case by the Renal and Transplantation Pathology group (Patología Renal y de Trasplantes [PYRT]) at the University of Antioquia in Medellín, Colombia. The patient was a 3-year-old male with a diagnosis of multicystic renal dysplasia via imaging. While undergoing transplant, a unilateral nephrectomy was performed. The kidney was enlarged and showed multiple cysts consistent with GCKD with diffusely interspersed proliferations described as nephroblastomatosis. ¹⁴ The proliferations were nearly identical to our case, but less extensive.

Another patient was briefly described with glomerulocystic kidneys and combined nephroblastomatosis who also had hemihypertrophy, which may be associated with nephrogenic rests and alterations on 11p15. ¹³ Simple cortical cysts and medullary cysts have been reported in cases of Beckwith-Wiedemann syndrome, though GCKD has not been otherwise associated with overgrowth syndromes or Beckwith-Wiedemann syndrome. ¹⁵ Molecular testing for 11p15 or other abnormalities was not documented in this or any of the cases with similar findings.

In historical case reports, the terminology used to describe these lesions has varied from descriptive to classifying them as nephrogenic rests, though that distinction is based more on similarity in appearance than an established pathobiologic link. Additionally, more recent reports of embryonal hyperplasia of Bowman’s capsular epithelium (EHBCE) have shown a similar pattern of abnormalities. EHBCE is a proliferation of poorly differentiated cells, usually surrounding sclerosed glomeruli, though rare cases show more interstitial proliferations, as in our case. These clusters of embryonal-type epithelium are thought to arise from the visceral epithelium of Bowman’s capsule and are thought to be associated with poorly differentiated glomerular epithelium.^16,17 EHBCE is most often found in patients with renal insufficiency, with most receiving long-term dialysis. ¹⁸ Further, EHBCE has been associated with WT1 mutations, metanephric adenoma, and some malignancies.^17,19-21 It is hypothesized that the association with WT1 is related to the underlying disease and not just the concurrent dialysis due to the very short duration of dialysis in at least 1 patient. ¹⁷ Keshani de Silva et al reported focal, patchy CAM5.2 and EMA staining in EHBCE, consistent with the visceral and parietal epithelium observed in early developing kidneys; however, Fukuwaza et al noted that CAM5.2 and EMA were negative in EHBCE in 2 patients with constitutional WT1 missense mutations associated with metanephric adenoma.^17,20 In our case, the strong, diffuse staining for CAM5.2 and WT1 with negative EMA and BRAF V600E supports early embryonal hyperplasia over metanephric adenoma.^17,20

Our case represents a novel combination of morphologic and genetic findings in GCKD. It lacks some of the structural abnormalities that have been reported, like renal hypoplasia, horseshoe kidney, and duplex kidney.^6,22,23 An array of histologic findings have been reported including, hypoplastic glomerulocystic kidney disease, oligomeganephronia, cystic renal dysplasia, interstitial fibrosis, enlarged glomeruli, and/or nephrons and glomerular cysts.^{7-10,22,24,25} The cysts in this case are smallest in the subcapsular region and increase in size in the deeper cortex, more similar to those seen in ciliopathies than in reports of HNF1B-associated GCKD.^26,27 Embryonal hyperplasia is not included in most descriptions of GCKD or other cystic kidney diseases. While rare cases with glomerulocystic changes have previously been reported with embryonal hyperplasia, none have been genetically characterized.^1,12,13 It is unclear whether the embryonal hyperplasia in this case is associated with dialysis, GCKD in general, or HNF1B mutations specifically. The lack of sclerotic glomeruli in this and other GCKD cases with embryonal hyperplasia argues against an association with dialysis. Given the similarities in appearance to nephrogenic rests and reported associations with germline WT1 mutations and metanephric adenoma, the question of whether these lesions have neoplastic potential has been raised, but there have been no reports of malignant transformation.

Interestingly, the authors have encountered another recent case of cystic kidney disease associated with Joubert syndrome that also showed embryonal hyperplasia, though to a lesser degree. Although much of the literature on embryonal hyperplasia in cystic kidney diseases predates current disease classifications and genetic testing, this morphologic pattern may be underrecognized. It appears to be non-specific with respect to final molecular diagnosis and clinical prognosis, but merits awareness among pediatric pathologists to help avoid potential misinterpretation.