Targetable NOTCH1 rearrangements in reninoma.

Reninomas are exceedingly rare renin-secreting kidney tumours that derive from juxtaglomerular cells, specialised smooth muscle cells that reside at the vascular inlet of glomeruli. They are the central component of the juxtaglomerular apparatus which controls systemic blood pressure through the secretion of renin. We assess somatic changes in reninoma and find structural variants that generate canonical activating rearrangements of, NOTCH1 whilst removing its negative regulator, NRARP. Accordingly, in single reninoma nuclei we observe excessive renin and NOTCH1 signalling mRNAs, with a concomitant non-excess of NRARP expression. Re-analysis of previously published reninoma bulk transcriptomes further corroborates our observation of dysregulated Notch pathway signalling in reninoma. Our findings reveal NOTCH1 rearrangements in reninoma, therapeutically targetable through existing NOTCH1 inhibitors, and indicate that unscheduled Notch signalling may be a disease-defining feature of reninoma.

Tumor de células yuxtaglomerulares (reninoma) como causa de hipertensión arterial en la adolescencia. A propósito de un caso / Juxtaglomerular cell tumor (reninoma) as a cause of arterial hypertension in adolescents. A case report

La hipertensión arterial (HTA) grave en pediatría responde fundamentalmente a causas secundarias. Presentamos una paciente adolescente de 14 años con HTA grave, alcalosis metabólica e hipopotasemia, secundaria a un tumor de células yuxtaglomerulares productor de renina, diagnosticado luego de dos años de evolución de HTA.

Severe arterial hypertension (HTN) in pediatrics is mainly due to secondary causes. Here we describe the case of a 14-year-old female adolescent with severe HTN, metabolic alkalosis, and hypokalemia, secondary to a renin-secreting juxtaglomerular cell tumor diagnosed after 2 years of HTN progression.

Juxtaglomerular cell tumor (reninoma) as a cause of arterial hypertension in adolescents. A case report. / Tumor de células yuxtaglomerulares (reninoma) como causa de hipertensión arterial en la adolescencia. A propósito de un caso.

Severe arterial hypertension (HTN) in pediatrics is mainly due to secondary causes. Here we describe the case of a 14-year-old female adolescent with severe HTN, metabolic alkalosis, and hypokalemia, secondary to a renin-secreting juxtaglomerular cell tumor diagnosed after 2 years of HTN progression.

La hipertensión arterial (HTA) grave en pediatría responde fundamentalmente a causas secundarias. Presentamos una paciente adolescente de 14 años con HTA grave, alcalosis metabólica e hipopotasemia, secundaria a un tumor de células yuxtaglomerulares productor de renina, diagnosticado luego de dos años de evolución de HTA.

Immunohistochemical expression of renin and GATA3 help distinguish juxtaglomerular cell tumors from renal glomus tumors.

Juxtaglomerular cell tumors and glomus tumors both arise from perivascular mesenchymal cells. Juxtaglomerular cells are specialized renin-secreting myoendocrine cells in the afferent arterioles adjacent to glomeruli, and juxtaglomerular tumors derived from these cells are therefore unique to the kidney. In contrast, glomus tumors have been described at numerous anatomic sites and may show significant morphologic and immunophenotypic overlap with juxtaglomerular tumors when occurring in the kidney. Although ultrastructural studies and immunohistochemistry for renin may distinguish these entities, these diagnostic modalities are often unavailable in routine clinical practice. Herein, we studied the clinicopathologic features of a large series of juxtaglomerular tumors (n = 15) and glomus tumors of the kidney (n = 9) to identify features helpful in their separation, including immunohistochemistry for smooth muscle actin (SMA), CD34, collagen IV, CD117, GATA3, synaptophysin, and renin. Markers such as SMA (juxtaglomerular tumors: 12/13, 92%; glomus tumors: 9/9, 100%), CD34 (juxtaglomerular tumors: 14/14, 100%; glomus tumors: 7/9, 78%), and collagen IV (juxtaglomerular tumors: 5/6, 83%; glomus tumors: 3/3, 100%) were not helpful in separating these entities. In contrast to prior reports, all juxtaglomerular tumors were CD117 negative (0/12, 0%), as were glomus tumors (0/5, 0%). Our results show that juxtaglomerular tumors have a younger age at presentation (median age: 27 years), female predilection, and frequently exhibit diffuse positivity for renin (10/10, 100%) and GATA3 (7/9, 78%), in contrast to glomus tumors (median age: 51 years; renin: 0/6, 0%; GATA3: 0/6, 0%). These findings may be helpful in distinguishing these tumors when they exhibit significant morphologic overlap.

Spindle Cell Hemangioma and Atypically Localized Juxtaglomerular Cell Tumor in a Patient with Hereditary BRIP1 Mutation: A Case Report.

Spindle cell hemangioma is a benign vascular tumor typically occurring in the dermis or subcutis of distal extremities as red-brown lesions that can grow in both size and number over time. They can be very painful and potentially disabling. A family history of cancer or previous history may be relevant and must be taken into consideration. Juxtaglomerular cell tumor (reninoma) is an extremely rare cause of secondary hypertension diagnosed mostly among adolescents and young adults. Excessive renin secretion results in secondary hyperaldosteronism. Subsequent hypokalemia and metabolic alkalosis, together with high blood pressure, are clues for clinical diagnosis. Histological examination of the excised tumor leads to a definitive diagnosis. Reninoma is found in subcapsular localization, in most cases as a solitary mass, in imaging studies of kidneys. Exceptionally, it can be located in another part of a kidney. Both spindle cell hemangioma and reninoma are extremely rare tumors in children and adolescents. Herein, the authors present a case report of a patient with hereditary BRCA1 interacting protein C-terminal helicase 1 (BRIP1) mutation, spindle cell hemangioma, and secondary hypertension caused by atypically localized reninoma.

Case report: a nonfunctioning juxtaglomerular cell tumor mimicking renal cell carcinoma.

INTRODUCTION: Based on existing literature, the juxtaglomerular cell tumor (JGCT) is a rare renal tumor, typically present with hypertension and hypokalemia. Nonfunctioning JGCT, without hypertension or hypokalemia, is extremely rare. PATIENT CONCERNS: Herein, we report a case of nonfunctioning JGCT mimicking renal cell carcinoma. The 29-year-old woman with an unremarkable past medical history presented with a left renal tumor without hypertension or hypokalemia. DIAGNOSIS: Both CT and 18F-FDG-PET/CT suggested a malignancy, possibly renal cell carcinoma. INTERVENTIONS: The tumor was then removed completely via robotic assistant laparoscopic partial nephrectomy; and pathology result was JGCT. Since the patient had no hypertension or hypokalemia, a nonfunctional JGCT was diagnosed. OUTCOMES: The patient recovered uneventfully, and was in good health in 6-months' follow-up period. CONCLUSION: Preoperative identification of JGCT is very difficult due to the lack of specific clinical manifestations. This case teaches us that for young patients with renal tumors whose CT enhancement is not obvious at the early phase, JGCT should be considered as a differential diagnosis. Radical nephrectomy should be avoided for JGCT in consideration of its relatively good prognosis.

Increased FDG Uptake on Juxtaglomerular Cell Tumor in the Left Kidney Mimicking Malignancy.

Juxtaglomerular cell tumor is a rare and benign tumor arising from the juxtaglomerular apparatus that overproduces renin, resulting in secondary hypertension. A 29-year-old woman was incidentally found to have a left renal mass by ultrasonography in a routine health examination. Contrast-enhanced CT results suggested renal cell carcinoma. FDG PET/CT performed for metastatic workup showed increased FDG uptake to the left renal mass and did not reveal any other abnormal FDG-avid lesions. The renal mass was surgically resected and pathological examination confirmed the juxtaglomerular cell tumor of the left kidney.

A Young Female With Refractory Hypertension.

A 29-year-old female was referred to the urology clinic because of an incidentally found left renal mass discovered during workup for secondary erythrocytosis. Since 12 years of age, she has had headaches and poorly controlled hypertension refractory to trimodal antihypertensive therapy. Laboratory workup revealed markedly elevated aldosterone and renin levels. Computed tomography demonstrated a 3 cm left renal mass. The patient was admitted for intravenous blood pressure control. After partial nephrectomy, aldosterone and renin levels normalized. The patient was weaned off of blood pressure medications. Pathology was consistent with a juxtaglomerular cell tumor secreting renin (ie, reninoma).

Juxtaglomerular Cell Tumor With Atypical Pathological Features: Report of a Case and Review of Literature.

Juxtaglomerular cell tumor (JGCT) is a rare renal tumor with a predominantly benign clinical course. It affects young adults, who often present with hypertension, hypokalemia, and hyperaldosteronism. The tumor cells are round to spindle-shaped with occasional mild to moderate atypia, but mitotic figures are usually absent. Surgical resection is the treatment of choice. Typically, the blood pressure and renin levels normalize after removal of the tumor. Rare cases of metastatic and recurrent JGCT have been reported including cases with vascular invasion. These cases typically occur in older adults and present with larger tumor size (9-15 cm). We report a case of JGCT, 5.5 cm in greatest dimension, with atypical pathological features including invasion of the renal vein, lymphovascular invasion, and significant pleomorphism with rhabdoid morphology, along with a brief review of the literature.

Usefulness of Magnetic Resonance Imaging in the Diagnosis of Juxtaglomerular Cell Tumors: A Report of 10 Cases and Review of the Literature.

Juxtaglomerular cell tumors (JCTs), a rare but potentially curable cause of hypertension, are difficult to diagnose because they may be missed or misidentified as a cyst by computed tomography (CT). Their magnetic resonance imaging (MRI) pattern has not been well described. We report the clinical, biological, and radiologic features of 10 patients with JCTs. Eight were women, and median age was 24.5 years. All had severe hypokalemic hypertension related to marked secondary hyperaldosteronism. Median plasma renin and aldosterone concentrations were 392 (minimum-maximum [min-max], 70.5-4,800) mIU/L and 1,490 (min-max, 671-2,492) pmol/L, respectively. Plasma prorenin concentration was 835.5 (min-max, 133-6,546) mIU/L. Median tumor size was 17.5mm. On CT, JCTs were spontaneously isodense, with little enhancement after contrast media injection. On MRI, JCTs were iso- (7/10) or hypointense (3/10) on T1-weighted images (WIs). On T2-WIs, JCTs were hypointense (2/10), isointense (4/10), or heterogeneously hyperintense (4/10). A thin peripheral "pseudo-capsule" (hypointense on T2-WIs) was observed in 6 of 10 cases. Contrast enhancement was low, slightly heterogeneous, and delayed. On diffusion-WIs, tumors were hyperintense with a restricted apparent diffusion coefficient. When hypertension with secondary hyperaldosteronism remains unexplained after CT, MRI of the kidney should be considered, especially for young women.

Phenotypic dissection of the mouse Ren1d knockout by complementation with human renin.

Normal renin synthesis and secretion is important for the maintenance of juxtaglomerular apparatus architecture. Mice lacking a functional Ren1d gene are devoid of renal juxtaglomerular cell granules and exhibit an altered macula densa morphology. Due to the species-specificity of renin activity, transgenic mice are ideal models for experimentally investigating and manipulating expression patterns of the human renin gene in a native cellular environment without confounding renin-angiotensin system interactions. A 55-kb transgene encompassing the human renin locus was crossed onto the mouse Ren1d-null background, restoring granulation in juxtaglomerular cells. Correct processing of human renin in dense core granules was confirmed by immunogold labeling. After stimulation of the renin-angiotensin system, juxtaglomerular cells contained rhomboid protogranules with paracrystalline contents, dilated rough endoplasmic reticulum, and electron-lucent granular structures. However, complementation of Ren1d-/- mice with human renin was unable to rescue the abnormality seen in macula densa structure. The juxtaglomerular apparatus was still able to respond to tubuloglomerular feedback in isolated perfused juxtaglomerular apparatus preparations, although minor differences in glomerular tuft contractility and macula densa cell calcium handling were observed. This study reveals that the human renin protein is able to complement the mouse Ren1d-/- non-granulated defect and suggests that granulopoiesis requires a structural motif that is conserved between the mouse Ren1d and human renin proteins. It also suggests that the altered macula densa phenotype is related to the activity of the renin-1d enzyme in a local juxtaglomerular renin-angiotensin system.

Juxtaglomerular cell tumor: Clinical and immunohistochemical features.

Juxtaglomerular cell tumor (JGCT) is a rare tumor, with approximately 100 cases reported in the literature. The authors respectively studied the clinical data of 11 patients diagnosed with JGCT in Peking Union Medical College Hospital from 2004 to 2014, and investigated the immunohistochemical profiles in 10 tumors. Nine of the 11 patients were diagnosed before the age of 40 years. Hypertension was present in all patients, while hypokalemia occurred in seven of 11 patients. Computed tomography detected JGCTs with a sensitivity of 100%. Immunoreactivities for CD34 and vascular endothelial growth factor were observed in most tumor specimens, suggesting that JGCTs express a variety of vessel-related immunohistochemical markers, although JGCTs are considered a tumor without abundant blood supply. Nuclear accumulation of cyclin D1 was common in JGCTs. Results from immunohistochemistry were negative for BRAF, HER2, and TFE3, suggesting that BRAF, HER2, and TFE3 genes might not play a part in tumorigenesis in JGCTs.

Preoperative Diagnosis of Juxtaglomerular Cell Tumors in Eight Patients.

The aim of this study was to improve the diagnostic efficiency for juxtaglomerular cell tumors (JCTs) and to determine whether clinical and magnetic resonance imaging features can help to differentiate JCTs from clear cell renal cell carcinoma (ccRCC). The clinical features of eight patients with JCTs and 27 patients with ccRCCs were analyzed. A flow diagram for young people with hypertension was applied to facilitate the diagnosis. Clinical presentations were analyzed, including age, hypertension, and hypokalemia. The results of our study produced a flow diagram that narrowed the scope of diagnosis. The statistical results demonstrated that patients with a renal mass aged 14 to 30 years, had grade 3 hypertension, or had moderate hypokalemia had a greater possibility of having a JCT than a ccRCC (P<.0000, P<.01, P<.0005, respectively). In addition, the flow diagram and magnetic resonance imaging features were useful to distinguish JCTs from other renal tumors.

A Case of Juxtaglomerular Cell Tumor, or Reninoma, of the Kidney Treated by Retroperitoneoscopy-Assisted Nephron-Sparing Partial Nephrectomy Through a Small Pararectal Incision.

A 15-year-old girl was found to be hypertensive (230-270/140-170 mm Hg) without any subjective symptoms. Magnetic resonance imaging confirmed the presence of a well-defined 22 mm hypodense lesion in the lower pole of the left kidney, located close to the renal hilum. Plasma rennin activity was elevated (75 ng/mL/h), and reninoma was diagnosed. Retroperitoneoscopy-assisted nephron-sparing surgery was planned. The retroperitoneum was accessed through a 4 cm left pararectal upper abdominal incision. Following blunt dissection, the abdominal wall was elevated with a lifting bar and lifting retractor, inserted below the 12th rib in the anterior axillary line to create sufficient working space in the retroperitoneal cavity without the need for pneumoperitoneum. Three 5 mm trocars were introduced above the superior iliac crest for the camera and the assistant. Gerota's fascia was opened and the kidney exposed. The surgeon dissected the left kidney through the minilaparotomy incision under both direct vision and using the magnified view on the monitor, which was particularly effective for the lateral and posterior sides of the kidney. The posterior peritoneum was incised intentionally next to the diaphragm to allow further mobilization of the kidney. Diathermy was used to remove the tumor and a layer of surrounding normal parenchymal tissue at least 0.5 cm thick. The histopathologic diagnosis was reninoma. Ischemia time was 14 minutes. Postoperatively, both plasma rennin activity and blood pressure were normal (1.9 ng/mL/h and 90-110/70-80 mm Hg, respectively). After follow-up of 12 months, there is no evidence of recurrence.

Sequential activation of the intrarenal renin-angiotensin system in the progression of hypertensive nephropathy in Goldblatt rats.

The intrarenal renin-angiotensin system (RAS) has an important role in generating and maintaining hypertension in two-kidney, one-clip (2K1C) rats. This study evaluated how various intrarenal RAS components contributed to hypertension not only in the maintenance period (5w; 5 wk after operation) but also earlier (2w; 2 wk after operation). We inserted a 2.5-mm clip into the left renal artery of Sprague-Dawley rats and euthanized them at 2w and 5w following the operation. Systolic blood pressure increased within 1 wk after the operation, and left ventricular hypertrophy occurred in 2K1C rats. At 2w, juxtaglomerular apparatus (JGA) and collecting duct (CD) renin increased in clipped kidney (CK) of 2K1C rats. The tubular angiotensin I-converting enzyme (ACE) was not changed, but peritubular ACE2 decreased in nonclipped kidney (NCK) and CK of 2K1C rats. At 5w, ACE and CD renin were enhanced, and ACE2 was still lessened in both kidneys of 2K1C rats. However, plasma renin activity (PRA) was not different from that in sham rats. In proximal tubules of CK, the ANG II type 1 receptor (AT1R) was not suppressed, but the Mas receptor (MasR) was reduced; thus the AT1R/MasR ratio was elevated. Although hypoxic change in CK could not be excluded, the JGA renin of CK and CD renin in both kidneys was highly expressed independent of time. Peritubular ACE2 changed in the earlier period, and uninhibited AT1R in proximal tubules of CK was presented in the maintenance period. In 2K1C rats, attenuated ACE2 seems to contribute to initiating hypertension while upregulated ACE in combination with unsuppressed AT1R may have a key role in maintaining hypertension.

Adult Pleomorphic Juxtaglomerular Cell Tumor.

A 40-year-old male with chronic hypertension since his teens presented to the emergency department following a motor vehicle collision. Computed tomography scan demonstrated an incidental 1.8-cm renal mass. Partial nephrectomy revealed a vascular tumor with predominantly monomorphic epithelioid cells arranged in sheets and trabeculae with foci of nuclear pleomorphism. Tumor cells were positive for vimentin, CD34, and c-KIT. Juxtaglomerular cell tumor is a rare, benign neoplasm typically found in young adults. Pleomorphism is uncommon and, in combination with older age at diagnosis, can lead to an inaccurate malignant diagnosis. Immunohistochemistry and clinical history helps in correctly diagnosing this benign entity.