ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Renal manifestations of tuberous sclerosis complex

Renal manifestations of tuberous sclerosis complex
Literature review current through: Jan 2024.
This topic last updated: Jun 14, 2022.

INTRODUCTION — Tuberous sclerosis complex (TSC) is a genetic disease with autosomal dominant inheritance. (See "Tuberous sclerosis complex: Genetics and pathogenesis", section on 'Genetics'.)

This topic will review the renal manifestations of TSC, which include angiomyolipomas (AMLs), renal cysts, renal cell carcinoma (RCC), and other, less common manifestations. Sporadic renal AMLs and renal AMLs associated with sporadic pulmonary lymphangiomyomatosis (LAM) are discussed elsewhere (see "Renal angiomyolipomas (AMLs): Management"). The clinical features, diagnosis, and management of TSC are also discussed in detail elsewhere. (See "Tuberous sclerosis complex: Clinical features" and "Tuberous sclerosis complex associated lymphangioleiomyomatosis in adults" and "Tuberous sclerosis complex: Management and prognosis".)

GENETICS — TSC is caused by mutations in either the TSC1 gene on chromosome 9 or the TSC2 gene on chromosome 16. The gene product of TSC1 is hamartin, and the gene product of TSC2 is tuberin. (See "Tuberous sclerosis complex: Genetics and pathogenesis", section on 'Genetics'.)

TSC2 mutations generally produce a more severe phenotype than TSC1 mutations [1,2]. This includes a higher frequency and severity of renal angiolipomas and renal cysts and a higher risk for the development of renal cell carcinoma (RCC). (See "Tuberous sclerosis complex: Genetics and pathogenesis", section on 'Genotype-phenotype correlations'.)

TSC2 mutations may also be associated with autosomal dominant polycystic kidney disease (PKD) since the TSC2 gene is adjacent (tail-to-tail) to the PKD1 gene. Deletions that inactivate both genes are associated with polycystic kidneys that are most often diagnosed during the first year of life or early childhood; this disorder is called the TSC2/PKD1 contiguous gene syndrome. By contrast, somatic mosaicism, which is well documented in TSC, can greatly attenuate both phenotypic manifestations and severity of the disease [3]. This condition is due to a TSC mutation acquired by one of multiple pluripotent stem cells during early embryogenesis and is increasingly recognized in TSC patients with no detectable mutations using next-generation sequencing [4]. (See 'TSC2/PKD1 contiguous gene syndrome' below and "Autosomal dominant polycystic kidney disease (ADPKD): Genetics of the disease and mechanisms of cyst growth", section on 'Genetics'.)

The prevalence of renal lesions in TSC increases with age, eventually affecting up to 80 percent of patients [2,5-8].

ANGIOMYOLIPOMAS

Epidemiology — Angiomyolipoma (AML) is the most common renal lesion observed among patients with TSC. In various series, AML have been reported in 75 to 85 percent of TSC patients with renal lesions and in 49 to 60 percent of TSC patients overall [2,5,6] (see 'Genetics' above). AMLs belong to a family of tumors collectively referred to as "neoplasms with perivascular epithelioid differentiation," which were previously called "perivascular epithelioid cell tumors" and now are referred to as "PEComas" [9]. These tumors arise by clonal proliferation of epithelioid cells distributed around blood vessels [10] and, in patients with TSC, include renal AMLs and pulmonary lymphangioleiomyomatosis (LAM). A TSC-associated AML lesion may be due to clonal expansion of pericytes in the kidney that has undergone biallelic (ie, germline plus a somatic) mutations of a TSC gene [11].

Among patients with TSC, the prevalence and size of renal AMLs increase with age [2,5,6,12-18]. Renal AMLs are more numerous and reach a larger size in women than in men, suggesting a hormonal effect on TSC development and growth, which can also occur in prepubertal girls, who have higher estradiol levels than boys [19].

In one study of 164 children with TSC who underwent serial renal ultrasonography or computed tomography (CT), there were no renal AMLs in the first year of life [15,16]. In contrast, renal AMLs were present in 37 percent of the children between one and five years of age and in 41 percent of boys and 63 percent of girls after five years of age.

Increasing prevalence with age has been described in older children with TSC. In a longitudinal study of 60 such patients, renal AMLs were present in 48 percent of boys and 60 percent of girls at a mean age of 6.9 years and in 76 percent of boys and 83 percent of girls at follow-up at a mean age of 10.5 years [5]. The overall prevalence of AMLs among patients with TSC is discussed above. (See 'Genetics' above.)

In addition to the increase in prevalence of renal AMLs, the number and size of renal AMLs also increase with age [2,5,6,17,18].

In the above series of children with TSC who had follow-up at a mean age of 10.5 years, growth of renal AMLs occurred in 10 of 18 boys (3 an increase in number and 7 an increase in size) and in 18 of 27 girls (17 an increase in number and all 18 an increase in size) [5].

In a large series from the Netherlands (351 adult TSC patients and 244 with at least one AML ≥3.5 cm) in which AML were classified according to size, number, and renal morphology, the median age of patients with no detectable AML >1 cm was 37 years, whereas the median age with stage 3 (ie, at least one AML ≥3.5 cm) was 46 years (table 1) [20].

Cautious interpretation is warranted when considering these ultrasound data, however, because ultrasound often cannot detect fat-poor angiomyolipomata, and approximately a third of patients demonstrate such fat-poor lesions.

Histology — There are two major histologic types of renal AMLs associated with TSC: classic and epithelioid (picture 1) [13,21,22]. (See "Renal angiomyolipomas (AMLs): Management".)

An epithelial component may be more common in patients with TSC than patients with sporadic AML, 27 versus 7 percent in one series [23]. Epithelioid variants may undergo malignant transformation. Although this is infrequent, the relative risk is greater in patients with TSC [23-25].

The histology of AMLs is discussed in detail separately. (See "Renal angiomyolipomas (AMLs): Management".)

Clinical presentation — Although renal involvement is common in TSC, many patients have few or no symptoms related to the kidney disease [8]. Thus, most patients with TSC-related AML come to attention on surveillance imaging. (See "Tuberous sclerosis complex: Clinical features" and "Tuberous sclerosis complex: Evaluation and diagnosis", section on 'Initial evaluation' and "Tuberous sclerosis complex: Management and prognosis", section on 'Renal disease'.)

Occasionally, patients with TSC present with a renal AML, either because of retroperitoneal hemorrhage, hematuria, or impingement of the AMLs on normal tissue, which can impair renal function.

Following are common clinical presentations:

Hemorrhage – The most common clinical manifestations of symptomatic renal AMLs are related to hemorrhage (hematuria, intratumoral, or retroperitoneal hemorrhage) and to their mass effect (abdominal or flank mass, flank pain and/or tenderness, hypertension, and renal insufficiency) [2,13,18,26,27]. The chances of developing symptoms among patients who have an AML is directly related to its size. As a rule, renal AMLs larger than 4 cm are more likely to grow, develop micro- and macroaneurysms, and cause symptoms [13,27]. The International Guidelines for surveillance and management of TSC have recommended that AMLs that are ≥3 cm in diameter and enlarging should be treated preemptively [28].

AMLs may cause significant and occasionally life-threatening hemorrhage. Renal AMLs are the most common cause of Wunderlich syndrome, a life-threatening, nontraumatic renal hemorrhage into the subcapsular and perirenal spaces [29].

The risk of significant hemorrhage is related to the degree of vascularity, the AML size, and the size of aneurysms within the AML. Increased vascularity [30] and/or aneurysm size (5 mm or more) [31] are associated with an increased risk of AML rupture. The risk of bleeding may rise during pregnancy, possibly due to rapid growth induced by hormonal changes and/or increased blood volume [32-35].

Chronic kidney disease (CKD) – Some patients develop significant renal impairment, including end-stage kidney disease (ESKD), due to destruction of renal tissue related to extensive bilateral renal AMLs. (See 'Chronic kidney disease' below.)

Anemia – Anemia is common. In the series from the Netherlands, anemia was present in 60 percent of patients overall and positively correlated with the size and number of AMLs [20].

Hypertension – Hypertension is often observed. Hypertension is less common in patients who only have renal AMLs compared with patients who have renal cysts with or without AMLs. Hypertension correlates with the size and number of AMLs [20].

Malignant renal epithelioid angiomyolipomas — In contrast to the uniformly benign prognosis of classic renal AMLs, epithelioid variants may undergo malignant transformation, although this is infrequent. Malignant transformation is manifested by local recurrence and/or distal metastases. The relative risk is greater in patients with TSC, but most patients with malignant transformation have sporadic renal AMLs [23-25].

Diagnosis

Radiographic diagnosis — The diagnosis of renal AMLs is usually made by imaging studies (magnetic resonance imaging [MRI], CT, or ultrasound) and relies on the demonstration of the tumor. We generally usually use MRI for the initial screen and use ultrasound alternating with MRI to monitor growth, depending on findings. It is occasionally difficult to get good-quality MRI without motion artifact unless general anesthesia is used among patients with cognitive impairment. Ultrasound should be followed up with MRI if a lesion is detected. The international guideline recommends MRI for diagnosis and imaging every one to three years [36].

The fat, if present, appears hyperechogenic on ultrasound; has a low attenuation value on CT scan (image 1); and, with MRI, appears bright on T1-weighted images, dark on T2-weighted images with fat saturation, and intermediate on T2-weighted images [6,37-40]. The early, small lesions have a characteristic radial, striated, or wedge-shaped pattern, with the base of the wedge facing the surface of the kidney. As the AMLs grow, there may be a mass effect within the renal parenchyma, or they can become exophytic (ie, grow outward).

The diagnostic accuracy often depends upon the amount of fat tissue in the tumor. A potential source of error in the interpretation of imaging studies is that small amounts of fat can be found within the borders of renal cell carcinomas (RCCs) that invade renal sinus fat (which is the major differential diagnosis to AMLs). The demonstration of fat occasionally leads to misinterpretation of an RCC as an AML. In addition, approximately 5 percent of renal AMLs contain at least components with minimal amounts of fat and are called minimal fat or fat poor. It is difficult to distinguish fat-poor AML (either classic AML [predominantly composed of smooth muscle cells] or epithelioid AML) from RCC and oncocytoma. Failure to detect fat in an AML may also be due to intratumoral hemorrhage obscuring the fat attenuation signal. (See 'Renal cell carcinoma' below.)

Specific radiographic criteria have been proposed that define fat-rich, fat-poor, and fat-invisible AML based on quantitative values observed on CT and MRI [41]. A fat-invisible AML (defined by CT attenuation greater than -10 HU and an MRI tumor-to-spleen ratio of 0.71 or greater and a signal intensity index of 16.5 percent or less) requires biopsy for diagnosis [41,42]. The approach to fat-poor AML, defined by attenuation of more than -10 HU on CT images but with an MRI tumor-to-spleen ratio less than 0.71 or a signal intensity index greater than 16.5 percent, is controversial [42]. Often, combining imaging modalities can be helpful.

Several findings on CT, MRI, and CT/positron emission tomography (PET) may help to distinguish renal AMLs with no or minimal fat from RCC. These include (image 2) [43-47]:

Adjacent fat attenuation pixels within the lesion by thin-section unenhanced CT

Homogeneously high attenuation on unenhanced CT

Homogeneous and prolonged enhancement pattern on dynamic contrast-enhanced CT

Low T2 signal intensity on MRI

Microscopic fat on in-phase and opposed-phase gradient echo MR sequences

Homogeneous signal on diffusion-weighted MRI

Other tests have also been evaluated:

Combining tumor to renal cortex signal intensity ratios on T1- and T2-weighted images, signal intensities on in- and opposed-phase gradient echo MRIs, and arterial-to-delayed enhancement ratio has been reported to differentiate AML without visible fat from RCC with 73 percent sensitivity, 99 percent specificity, and 96 percent accuracy [46].

Dual-tracer 18F-fluorodeoxyglucose (FDG) and 11C-acetate PET/CT have been reported to differentiate fat-poor AMLs from RCC with 94 percent sensitivity, 98 percent specificity, and 97 percent accuracy [47]. AMLs showed negative 18F-FDG but markedly increased 11C-acetate metabolism, significantly higher than RCC.

The diagnostic approach to renal masses, including surveillance, is discussed at length elsewhere. (See "Diagnostic approach, differential diagnosis, and management of a small renal mass".)

Biopsy — When the diagnosis of renal AMLs cannot be reliably established by imaging techniques, biopsy is required to make a diagnosis. Image-guided percutaneous needle biopsy using a sheath technique should be considered as an alternative to surgical exploration [48]. The risk of bleeding following needle biopsy of a minimal-fat AML does not appear to be higher than that of a biopsy for other renal tumors, particularly when fine needles are used.

The differentiation of renal AML from RCC has become more reliable with the aid of immunocytochemical analysis. Melanocytic markers such as HMB-45 and melan A are expressed in classic and epithelioid renal AMLs but not in typical RCC, while epithelial cell-associated markers such as cytokeratin and EMA are present in RCC but not in renal AMLs [21,49-51].

An exception to this distinction occurs in rare RCCs characterized by t(6;11)(p21;q12), a chromosome translocation involving the gene for transcription factor EB [52-54]. These carcinomas consistently express HMB-45 and melan A, are often negative or only focally positive for cytokeratin, and are more common in children and young adults in the general population but would be exceedingly rare in the TSC population given the frequencies of the diseases.

Differential diagnosis — The differential diagnoses of AML include other renal masses detected by imaging, including RCC and oncocytoma, and metastatic lesions from primary tumors elsewhere. (See 'Renal cell carcinoma' below and 'Oncocytoma' below.)

These entities are usually distinguished from each other by characteristic radiographic features (see 'Radiographic diagnosis' above). However, as noted above, the diagnosis may be challenging among patients with minimal-fat AMLs; such patients may require biopsy with analysis of tissue using specific immunohistochemical techniques. (See 'Biopsy' above.)

The rate of growth of the lesion may help to differentiate a slowly growing, benign AML from a more rapidly growing RCC. However, data are limited. In a study of 185 solid masses, 133 were typical AMLs, and 52 were indeterminate on CT [17]. On follow-up testing with repeat CT or MRI plus interval renal ultrasonography, only three indeterminate masses showed rapid growth, defined as >0.5 cm per year: One was an RCC, and two were minimal-fat AMLs. (See 'Surveillance for small, stable lesions' below and "Diagnostic approach, differential diagnosis, and management of a small renal mass".)

Management

Surveillance for small, stable lesions — Because of the potential for renal AML growth throughout life, international guidelines recommend renal surveillance with MRI at the time of diagnosis and at least yearly in patients with known AMLs [36,55]. The frequency of monitoring may be reduced to every two to three years for small lesions (ie, ≤1 cm) if stable for at least three years (ie, no growth of preexisting lesions and no new lesions).

We avoid group I gadolinium contrast agents in these patients. (See "Nephrogenic systemic fibrosis/nephrogenic fibrosing dermopathy in advanced kidney disease".)

In patients with known renal lesions, the serum creatinine and blood pressure should be measured at least once per year.

Potential issues in women — Several clinical observations suggest that female sex hormones promote the growth of renal AMLs. These include reported increased frequency and size of renal AMLs in women, hemorrhagic complications during pregnancy, and reports of renal AML growth during pregnancy [32-35] or after treatment with exogenous hormone therapy [56].

Thus, women with known renal AMLs should be cautioned about the potential risks of pregnancy and estrogen administration, and the frequency of imaging surveillance should be increased. For women starting estrogen therapy, we suggest imaging every six months or yearly once stability has been established. If the lesions are typical fat-containing lesions, ultrasounds can be used in between the MRI scans.

For renal AMLs that are growing and large (>4 cm) or have features suggesting malignant transformation (eg, intratumoral necrosis or calcifications), a surgical consultation should be obtained. If a decision for observation is made, repeat imaging should be performed at intervals not longer than six months. Surgery should be considered if the renal AMLs continue to grow. There are no data to define a growth rate that indicates the need for surgery. The decision should take into account the clinical context, patient age, and comorbidities.

Treatment — Treatment is required in a minority of patients with renal lesions and TSC [2]. Our approach, including nephron-sparing interventions and administration of mammalian target of rapamycin (mTOR) inhibitors, depends on the clinical presentation and is discussed elsewhere. (See "Renal angiomyolipomas (AMLs): Management".)

RENAL CYSTS — Renal cystic disease is the second most common renal manifestation of TSC after angiomyolipomas (AMLs) and has been reported in 17 to 45 percent of TSC patients with renal lesions and 14 to 47 percent of TSC patients overall, depending on the imaging used [2,5,6]. The three most common of renal cystic disease associated with TSC are single or multiple renal cysts, TSC2/PKD1 contiguous gene syndrome, and glomerulocystic kidney disease [57].

Single or multiple renal cysts — In most patients with TSC, the number of renal cysts is limited, their size is small, and they cause no symptoms. The prevalence of renal cysts increases with age and may be more common in males than females (figure 1) [5,15,16]. Cysts do not require regular surveillance imaging. However, TSC patients require routine surveillance imaging for AML since most will develop AML as they age. (See 'Surveillance for small, stable lesions' above.)

TSC2/PKD1 contiguous gene syndrome — The TSC2 gene and the autosomal dominant polycystic kidney disease type 1 (PKD1) gene lie adjacent to each other in a tail-to-tail orientation on chromosome 16 at 16p13.3. (See "Autosomal dominant polycystic kidney disease (ADPKD): Genetics of the disease and mechanisms of cyst growth", section on 'Genetics' and "Tuberous sclerosis complex: Genetics and pathogenesis", section on 'Genetics'.)

Deletions inactivating both genes are associated with polycystic kidneys, a disorder that is called the TSC2/PKD1 contiguous gene syndrome [3,58,59]. Affected patients are usually diagnosed during the first year of life or early childhood, but rarely patients are not diagnosed until adulthood, with hypertension and renal insufficiency being the major manifestations.

These general features were illustrated in a study of 17 patients, in which the following findings were noted [3]:

Fourteen were diagnosed in the first year of life, two at two years, and one at 10 years.

All of the patients had enlarged cystic kidneys, with radiographic findings that resembled advanced autosomal dominant PKD. (See "Autosomal dominant polycystic kidney disease (ADPKD) in adults: Epidemiology, clinical presentation, and diagnosis".)

Five of the patients presented with cystic kidneys before the onset of other features of TSC, initially leading to an incorrect diagnosis of early-onset autosomal dominant PKD or autosomal recessive PKD.

Two patients developed small echogenic areas consistent with renal AMLs, which typically develop after the first year of life in these patients.

Hypertension requiring antihypertensive drugs occurred in 12 patients.

The glomerular filtration rate (GFR) was normal or only slightly reduced in the first 10 years of life but was markedly reduced in older patients. The three oldest patients reached end-stage kidney disease (ESKD) at ages 19, 20, and 29 years. The age of progression to ESKD is consistent with other studies and is much lower than in autosomal dominant PKD alone. (See "Autosomal dominant polycystic kidney disease (ADPKD): Treatment".)

In summary, the TSC2/PKD1 contiguous gene syndrome should be considered in the differential diagnosis of renal cysts in children with no family history of autosomal dominant or autosomal recessive PKD, particularly in children less than two years of age. The additional finding of renal AMLs in this setting is virtually pathognomonic of TSC.

Patients with TSC2/PKD1 continuous gene syndrome are at risk for angiomyolipomata, and perhaps renal cell carcinoma (RCC), and require regular screening every one to three years.

Glomerulocystic kidney disease — Glomerulocystic kidney disease (ie, glomerular cysts) is a rare finding that is usually diagnosed during the neonatal period [60,61]. Seven of the eight reported cases were unilateral, and four cases had segmental lesions, with normal kidney tissue on the affected side [60]. Affected kidneys were typically enlarged and had renal cysts on imaging studies and glomerular cysts on histologic examination.

RENAL CELL CARCINOMA — Patients with TSC may be at increased risk for the development of renal cell carcinoma (RCC) [2,62-64]. It has been suggested that the increased risk may be related at least in part to the presence of hyperplasia and atypia in the cells lining renal cysts [14] (see 'Renal cysts' above). A "TSC-associated papillary RCC" (PRCC) has been described with a distinct morphologic, immunologic, and molecular profile. This profile includes prominent papillary architecture and uniformly deficient succinate dehydrogenase subunit B (SDHB) expression [65,66]. Other morphologic variants include a hybrid oncocytic chromophobe tumor and a granular eosinophilic macrocystic RCC. All are melanosome-associated protein (HMB-45) negative [66].

The magnitude of risk of RCC has not been well defined [2,62,63]. In a report of 167 patients with TSC cited above, four of these patients (4 percent) had RCC, and six (6 percent) had lesions on imaging in which RCC and minimal-fat renal angiomyolipomas (AMLs) could not be distinguished. (See 'Differential diagnosis' above.)

RCC in patients with TSC is often multifocal and bilateral. These cancers develop at an early age compared with RCCs in the general population, and there are numerous reports of RCC occurring in children [2,67-72]. The risk seems to be higher in patients with TSC2 than TSC1 mutations, and patients with the contiguous gene syndrome may have the greatest risk. (See 'TSC2/PKD1 contiguous gene syndrome' above.)

A diagnosis of RCC should be considered in patients with enlarging lesions and no demonstrable fatty tissue. If a diagnosis cannot be established by imaging, a fine-needle aspiration biopsy should be performed with both histologic examination and, to distinguish RCC from a malignant renal AML, immunohistochemical analysis. (See 'Malignant renal epithelioid angiomyolipomas' above.)

The diagnostic uncertainty in some patients is in part due to the lack of distinction in many reports between HMB-45- and melan A-positive, cytokeratin-negative epithelioid AMLs and cytokeratin-positive, HMB-45- and melan A-negative RCCs. As an example, an early study published before this distinction was fully appreciated described six patients with TSC and RCC [64]. Four of these patients had HMB-45-positive tumors, suggesting that they had a malignant AML, not RCC.

Because of the frequent bilaterality of renal lesions in TSC, ablative therapies (radiofrequency or cryotherapy) or nephron-sparing surgery should be performed whenever possible [73]. (See "Renal angiomyolipomas (AMLs): Management".)

LESS COMMON RENAL MANIFESTATIONS

Oncocytoma — Renal oncocytomas are benign tumors composed of polygonal cells with abundant, finely granular, eosinophilic cytoplasm and densely packed mitochondria. In patients with TSC, they are usually discovered during surveillance ultrasonography and evaluation for flank pain and hematuria. (See "Epidemiology, pathology, and pathogenesis of renal cell carcinoma", section on 'Oncocytomas'.)

Renal oncocytomas are a more common cause of renal cell neoplasms in patients with TSC than in the general population. In a study of 36 patients with concurrent renal angiomyolipomas (AMLs) and renal cell malignancy, oncocytomas accounted for a higher proportion of renal cell malignancies in the 11 patients with TSC than in the remaining patients with sporadic renal AMLs (27 versus 8 percent) [62].

Renal oncocytomas are usually unilateral and single in the general population but may be multiple and bilateral in patients with TSC [74].

The diagnosis of renal oncocytoma should be confirmed by immunohistochemistry since epithelioid AMLs can be confused with oncocytomas.

Nephron-sparing surgery is the treatment of choice since the diagnosis cannot be definitively made with noninvasive testing. Cryoablation or radiofrequency ablation is an alternative in some centers. (See "Renal angiomyolipomas (AMLs): Management".)

Other renal lesions — A variety of other renal lesions have been infrequently described in patients with TSC. These include:

Parapelvic or perirenal lymphatic cysts in patients with extrapulmonary lymphangioleiomyomatosis (LAM) [75,76].

Medium-sized and large vessels, including the renal arteries, are rarely involved, and a few cases of renal artery stenosis and aortic coarctation have been reported [77-81].

Other abnormalities described in TSC, such as horseshoe kidney, are probably coincidental [82-84].

CHRONIC KIDNEY DISEASE — Some patients with TSC develop chronic kidney disease (CKD) with subnephrotic proteinuria that can progress to end-stage kidney disease (ESKD) in the absence of large renal angiomyolipomas (AMLs) or extensive renal macrocystic disease [15,16,85-88]. The kidneys are typically small and echogenic on ultrasonography.

Kidney biopsy often reveals focal segmental glomerulosclerosis (FSGS), with chronic interstitial disease that is thought to be a secondary disorder induced by nephron loss [85]. The proteinuria and renal insufficiency in secondary FSGS develop slowly. This is in contrast to the course in primary FSGS, which is typically characterized by the acute or subacute onset of nephrotic syndrome. These issues are discussed in detail elsewhere. (See "Focal segmental glomerulosclerosis: Pathogenesis", section on 'Pathogenesis of secondary FSGS' and "Focal segmental glomerulosclerosis: Clinical features and diagnosis", section on 'Classification and clinical features'.)

Some patients with TSC have a different type of chronic interstitial disease, in which there is a diffuse, hyperplastic appearance of the interstitial stroma, with areas of spindle, smooth muscle, and fibroblastic cells [15,77]. The pathogenesis of this disorder has not been defined. It may be mediated at least in part by the genetic deficiency in tuberin in TSC since tuberin regulates the expression and promoter activity of the cell fibrosis protein alpha-smooth muscle cell actin [89]. (See "Tuberous sclerosis complex: Genetics and pathogenesis", section on 'Role of mTOR'.)

The typical presenting findings in this disorder include an elevated serum creatinine concentration, a benign urine sediment, normal or mildly reduced kidney size, hyperechoic kidneys on ultrasonography, and skin features of TSC that have often been overlooked by both the patient and clinicians. When performed, brain imaging reveals pathognomonic features of TSC, such as multiple calcified subependymal nodules and tubers. There is no known therapy. (See "Tuberous sclerosis complex: Clinical features", section on 'Brain lesions' and "Tuberous sclerosis complex: Clinical features", section on 'Dermatologic manifestations' and "Tuberous sclerosis complex: Evaluation and diagnosis".)

General principles of therapy — CKD of any cause can be associated with a variety of complications including volume overload, electrolyte disorders such as metabolic acidosis and hyperkalemia, hyperphosphatemia, renal osteodystrophy, and hypertension. (See "Overview of the management of chronic kidney disease in adults".)

In addition to protecting against cardiovascular disease, the rate of progression of CKD can be reduced by lowering the blood pressure to the suggested goal and, in patients with proteinuria, by lowering protein excretion to less than 1000 mg/day via the use of an angiotensin inhibitor and, if necessary, certain other antihypertensive drugs. These issues are discussed in detail elsewhere. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults".)

End-stage kidney disease — Causes of ESKD include polycystic kidneys, destruction of the renal parenchyma by multiple renal AMLs, and nephrectomies to treat life-threatening hemorrhage. Patients with CKD due to secondary FSGS can also progress to ESKD (see 'Chronic kidney disease' above). Kidney disease is also an important cause of death in patients with TSC. (See 'Effect of kidney disease on patient prognosis' below.)

Management — As the treatment of the neurologic manifestations and life expectancy improve in patients with TSC, progression of CKD to ESKD will become a more important complication.

Both dialysis and kidney transplantation provide adequate means of survival in patients who develop ESKD, but the risks of renal hemorrhage and malignant transformation in TSC pose special problems. Thus, native kidney imaging should continue, and bilateral nephrectomy could be considered when a patient with TSC and ESKD enters a dialysis or kidney transplantation program [90-92].

Because of the beneficial effect of mammalian (mechanistic) target of rapamycin (mTOR) inhibitors on the cutaneous, central nervous system, and pulmonary manifestations of TSC, immunosuppressive regimens including everolimus or sirolimus are the treatment of choice following transplantation in patients with TSC [92,93].

EFFECT OF KIDNEY DISEASE ON PATIENT PROGNOSIS — Kidney disease is the second leading cause of death in patients with TSC, after neurologic disease, and is the most common cause of death in affected adults [16,94]. Renal causes of death include end-stage kidney disease (ESKD), retroperitoneal hemorrhage, and metastatic disease. (See "Tuberous sclerosis complex: Management and prognosis", section on 'Mortality'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic kidney disease in adults" and "Society guideline links: Tuberous sclerosis".)

SUMMARY AND RECOMMENDATIONS

Angiomyolipoma (AML) is the most common renal lesion observed among patients with tuberous sclerosis complex (TSC) and occurs in 49 to 60 percent of TSC patients overall. Other common lesions include renal cysts and possibly renal cell carcinoma (RCC). (See 'Angiomyolipomas' above and 'Renal cysts' above and 'Renal cell carcinoma' above.)

The majority of patients with AML have few or no symptoms related to the kidney disease, and lesions are detected on surveillance imaging. However, some patients may present with severe hemorrhage, chronic kidney disease (CKD), anemia, or hypertension. AMLs may cause significant and occasionally life-threatening hemorrhage. (See 'Clinical presentation' above.)

The diagnosis of renal AMLs is usually made by magnetic resonance imaging (MRI) studies and relies on the demonstration of fat in the tumor. Lesions that are fat poor are difficult to distinguish from RCC. When the diagnosis of renal AMLs cannot be reliably established by imaging techniques, biopsy is required to make a diagnosis. (See 'Diagnosis' above.)

We recommend renal surveillance with MRI at the time of diagnosis and at least yearly in patients with known AMLs. Women may require more frequent imaging if they are pregnant or starting estrogen therapy. In patients with known renal lesions, the serum creatinine should be measured at least once per year. (See 'Surveillance for small, stable lesions' above and 'Potential issues in women' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges William M Bennett, MD, who contributed to earlier versions of this topic review.

  1. Dabora SL, Jozwiak S, Franz DN, et al. Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs. Am J Hum Genet 2001; 68:64.
  2. Rakowski SK, Winterkorn EB, Paul E, et al. Renal manifestations of tuberous sclerosis complex: Incidence, prognosis, and predictive factors. Kidney Int 2006; 70:1777.
  3. Sampson JR, Maheshwar MM, Aspinwall R, et al. Renal cystic disease in tuberous sclerosis: role of the polycystic kidney disease 1 gene. Am J Hum Genet 1997; 61:843.
  4. Tyburczy ME, Dies KA, Glass J, et al. Mosaic and Intronic Mutations in TSC1/TSC2 Explain the Majority of TSC Patients with No Mutation Identified by Conventional Testing. PLoS Genet 2015; 11:e1005637.
  5. Ewalt DH, Sheffield E, Sparagana SP, et al. Renal lesion growth in children with tuberous sclerosis complex. J Urol 1998; 160:141.
  6. Casper KA, Donnelly LF, Chen B, Bissler JJ. Tuberous sclerosis complex: renal imaging findings. Radiology 2002; 225:451.
  7. Stillwell TJ, Gomez MR, Kelalis PP. Renal lesions in tuberous sclerosis. J Urol 1987; 138:477.
  8. O'Callaghan FJ, Noakes MJ, Martyn CN, Osborne JP. An epidemiological study of renal pathology in tuberous sclerosis complex. BJU Int 2004; 94:853.
  9. Hornick JL, Pan C-C. PEComa. In: World Health Organization classification of tumours of soft tissue and bone, 4th, Fletcher CDM, Brodge JA, Hogendoorn PCW, Mertens F (Eds), IARC, Lyon 2013. p.230.
  10. Martignoni G, Pea M, Reghellin D, et al. PEComas: the past, the present and the future. Virchows Arch 2008; 452:119.
  11. Siroky BJ, Yin H, Dixon BP, et al. Evidence for pericyte origin of TSC-associated renal angiomyolipomas and implications for angiotensin receptor inhibition therapy. Am J Physiol Renal Physiol 2014; 307:F560.
  12. Bissler JJ, Kingswood JC. Renal angiomyolipomata. Kidney Int 2004; 66:924.
  13. Nelson CP, Sanda MG. Contemporary diagnosis and management of renal angiomyolipoma. J Urol 2002; 168:1315.
  14. Bernstein J, Robbins TO. Renal involvement in tuberous sclerosis. Ann N Y Acad Sci 1991; 615:36.
  15. Torres VE, King BF, Holley KE, et al. The kidney in the tuberous sclerosis complex. Adv Nephrol Necker Hosp 1994; 23:43.
  16. Torres VE, King BF, McKusick MA, et al. Update on tuberous sclerosis complex. Contrib Nephrol 2001; :33.
  17. Patel U, Simpson E, Kingswood JC, Saggar-Malik AK. Tuberose sclerosis complex: analysis of growth rates aids differentiation of renal cell carcinoma from atypical or minimal-fat-containing angiomyolipoma. Clin Radiol 2005; 60:665.
  18. Seyam RM, Bissada NK, Kattan SA, et al. Changing trends in presentation, diagnosis and management of renal angiomyolipoma: comparison of sporadic and tuberous sclerosis complex-associated forms. Urology 2008; 72:1077.
  19. Klein KO, Baron J, Colli MJ, et al. Estrogen levels in childhood determined by an ultrasensitive recombinant cell bioassay. J Clin Invest 1994; 94:2475.
  20. Eijkemans MJ, van der Wal W, Reijnders LJ, et al. Long-term Follow-up Assessing Renal Angiomyolipoma Treatment Patterns, Morbidity, and Mortality: An Observational Study in Tuberous Sclerosis Complex Patients in the Netherlands. Am J Kidney Dis 2015; 66:638.
  21. Martignoni G, Pea M, Rocca PC, Bonetti F. Renal pathology in the tuberous sclerosis complex. Pathology 2003; 35:505.
  22. Lane BR, Aydin H, Danforth TL, et al. Clinical correlates of renal angiomyolipoma subtypes in 209 patients: classic, fat poor, tuberous sclerosis associated and epithelioid. J Urol 2008; 180:836.
  23. Aydin H, Magi-Galluzzi C, Lane BR, et al. Renal angiomyolipoma: clinicopathologic study of 194 cases with emphasis on the epithelioid histology and tuberous sclerosis association. Am J Surg Pathol 2009; 33:289.
  24. Nese N, Martignoni G, Fletcher CD, et al. Pure epithelioid PEComas (so-called epithelioid angiomyolipoma) of the kidney: A clinicopathologic study of 41 cases: detailed assessment of morphology and risk stratification. Am J Surg Pathol 2011; 35:161.
  25. Brimo F, Robinson B, Guo C, et al. Renal epithelioid angiomyolipoma with atypia: a series of 40 cases with emphasis on clinicopathologic prognostic indicators of malignancy. Am J Surg Pathol 2010; 34:715.
  26. Dixon BP, Hulbert JC, Bissler JJ. Tuberous sclerosis complex renal disease. Nephron Exp Nephrol 2011; 118:e15.
  27. Oesterling JE, Fishman EK, Goldman SM, Marshall FF. The management of renal angiomyolipoma. J Urol 1986; 135:1121.
  28. Kingswood JC, Bissler JJ, Budde K, et al. Review of the Tuberous Sclerosis Renal Guidelines from the 2012 Consensus Conference: Current Data and Future Study. Nephron 2016; 134:51.
  29. Albi G, del Campo L, Tagarro D. Wünderlich's syndrome: causes, diagnosis and radiological management. Clin Radiol 2002; 57:840.
  30. Rimon U, Duvdevani M, Garniek A, et al. Large renal angiomyolipomas: digital subtraction angiographic grading and presentation with bleeding. Clin Radiol 2006; 61:520.
  31. Yamakado K, Tanaka N, Nakagawa T, et al. Renal angiomyolipoma: relationships between tumor size, aneurysm formation, and rupture. Radiology 2002; 225:78.
  32. Lewis EL, Palmer JM. Renal angiomyolipoma and massive retroperitoneal hemorrhage during pregnancy. West J Med 1985; 143:675.
  33. Petrikovsky BM, Vintzileos AM, Cassidy SB, Egan JF. Tuberous sclerosis in pregnancy. Am J Perinatol 1990; 7:133.
  34. Raft J, Lalot JM, Meistelman C, Longrois D. [Renal angiomyolipoma rupture during pregnancy]. Gynecol Obstet Fertil 2006; 34:917.
  35. Zapardiel I, Delafuente-Valero J, Bajo-Arenas JM. Renal angiomyolipoma during pregnancy: review of the literature. Gynecol Obstet Invest 2011; 72:217.
  36. Krueger DA, Northrup H, International Tuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol 2013; 49:255.
  37. Bosniak MA, Megibow AJ, Hulnick DH, et al. CT diagnosis of renal angiomyolipoma: the importance of detecting small amounts of fat. AJR Am J Roentgenol 1988; 151:497.
  38. Siegel CL, Middleton WD, Teefey SA, McClennan BL. Angiomyolipoma and renal cell carcinoma: US differentiation. Radiology 1996; 198:789.
  39. Halpenny D, Snow A, McNeill G, Torreggiani WC. The radiological diagnosis and treatment of renal angiomyolipoma-current status. Clin Radiol 2010; 65:99.
  40. Hindman N, Ngo L, Genega EM, et al. Angiomyolipoma with minimal fat: can it be differentiated from clear cell renal cell carcinoma by using standard MR techniques? Radiology 2012; 265:468.
  41. Song S, Park BK, Park JJ. New radiologic classification of renal angiomyolipomas. Eur J Radiol 2016; 85:1835.
  42. Park BK. Renal Angiomyolipoma: Radiologic Classification and Imaging Features According to the Amount of Fat. AJR Am J Roentgenol 2017; 209:826.
  43. Davenport MS, Neville AM, Ellis JH, et al. Diagnosis of renal angiomyolipoma with hounsfield unit thresholds: effect of size of region of interest and nephrographic phase imaging. Radiology 2011; 260:158.
  44. Tanaka H, Yoshida S, Fujii Y, et al. Diffusion-weighted magnetic resonance imaging in the differentiation of angiomyolipoma with minimal fat from clear cell renal cell carcinoma. Int J Urol 2011; 18:727.
  45. Chaudhry HS, Davenport MS, Nieman CM, et al. Histogram analysis of small solid renal masses: differentiating minimal fat angiomyolipoma from renal cell carcinoma. AJR Am J Roentgenol 2012; 198:377.
  46. Sasiwimonphan K, Takahashi N, Leibovich BC, et al. Small (<4 cm) renal mass: differentiation of angiomyolipoma without visible fat from renal cell carcinoma utilizing MR imaging. Radiology 2012; 263:160.
  47. Ho CL, Chen S, Ho KM, et al. Dual-tracer PET/CT in renal angiomyolipoma and subtypes of renal cell carcinoma. Clin Nucl Med 2012; 37:1075.
  48. Silverman SG, Gan YU, Mortele KJ, et al. Renal masses in the adult patient: the role of percutaneous biopsy. Radiology 2006; 240:6.
  49. Bonzanini M, Pea M, Martignoni G, et al. Preoperative diagnosis of renal angiomyolipoma: fine needle aspiration cytology and immunocytochemical characterization. Pathology 1994; 26:170.
  50. Pea M, Bonetti F, Martignoni G, et al. Apparent renal cell carcinomas in tuberous sclerosis are heterogeneous: the identification of malignant epithelioid angiomyolipoma. Am J Surg Pathol 1998; 22:180.
  51. Schreiner A, Daneshmand S, Bayne A, et al. Distinctive morphology of renal cell carcinomas in tuberous sclerosis. Int J Surg Pathol 2010; 18:409.
  52. Argani P, Yonescu R, Morsberger L, et al. Molecular confirmation of t(6;11)(p21;q12) renal cell carcinoma in archival paraffin-embedded material using a break-apart TFEB FISH assay expands its clinicopathologic spectrum. Am J Surg Pathol 2012; 36:1516.
  53. Pecciarini L, Cangi MG, Lo Cunsolo C, et al. Characterization of t(6;11)(p21;q12) in a renal-cell carcinoma of an adult patient. Genes Chromosomes Cancer 2007; 46:419.
  54. Rao Q, Liu B, Cheng L, et al. Renal cell carcinomas with t(6;11)(p21;q12): A clinicopathologic study emphasizing unusual morphology, novel alpha-TFEB gene fusion point, immunobiomarkers, and ultrastructural features, as well as detection of the gene fusion by fluorescence in situ hybridization. Am J Surg Pathol 2012; 36:1327.
  55. Roach ES, DiMario FJ, Kandt RS, Northrup H. Tuberous Sclerosis Consensus Conference: recommendations for diagnostic evaluation. National Tuberous Sclerosis Association. J Child Neurol 1999; 14:401.
  56. Gould Rothberg BE, Grooms MC, Dharnidharka VR. Rapid growth of a kidney angiomyolipoma after initiation of oral contraceptive therapy. Obstet Gynecol 2006; 108:734.
  57. Polycystic Kidney Disease: Translating Mechanisms Into Therapy, Bissler JJ, Cowley Jr BD (Eds), Springer-Verlag, New York 2018.
  58. Brook-Carter PT, Peral B, Ward CJ, et al. Deletion of the TSC2 and PKD1 genes associated with severe infantile polycystic kidney disease--a contiguous gene syndrome. Nat Genet 1994; 8:328.
  59. Consugar MB, Wong WC, Lundquist PA, et al. Characterization of large rearrangements in autosomal dominant polycystic kidney disease and the PKD1/TSC2 contiguous gene syndrome. Kidney Int 2008; 74:1468.
  60. Murakami A, Gomi K, Tanaka M, et al. Unilateral glomerulocystic kidney disease associated with tuberous sclerosis complex in a neonate. Pathol Int 2012; 62:209.
  61. Bernstein J. Glomerulocystic kidney disease--nosological considerations. Pediatr Nephrol 1993; 7:464.
  62. Jimenez RE, Eble JN, Reuter VE, et al. Concurrent angiomyolipoma and renal cell neoplasia: a study of 36 cases. Mod Pathol 2001; 14:157.
  63. Henske EP. The genetic basis of kidney cancer: why is tuberous sclerosis complex often overlooked? Curr Mol Med 2004; 4:825.
  64. Bjornsson J, Short MP, Kwiatkowski DJ, Henske EP. Tuberous sclerosis-associated renal cell carcinoma. Clinical, pathological, and genetic features. Am J Pathol 1996; 149:1201.
  65. Yang P, Cornejo KM, Sadow PM, et al. Renal cell carcinoma in tuberous sclerosis complex. Am J Surg Pathol 2014; 38:895.
  66. Henske EP, Cornejo KM, Wu CL. Renal Cell Carcinoma in Tuberous Sclerosis Complex. Genes (Basel) 2021; 12.
  67. Al-Saleem T, Wessner LL, Scheithauer BW, et al. Malignant tumors of the kidney, brain, and soft tissues in children and young adults with the tuberous sclerosis complex. Cancer 1998; 83:2208.
  68. Breysem L, Nijs E, Proesmans W, Smet MH. Tuberous sclerosis with cystic renal disease and multifocal renal cell carcinoma in a baby girl. Pediatr Radiol 2002; 32:677.
  69. Lendvay TS, Broecker B, Smith EA. Renal cell carcinoma in a 2-year-old child with tuberous sclerosis. J Urol 2002; 168:1131.
  70. Selle B, Furtwängler R, Graf N, et al. Population-based study of renal cell carcinoma in children in Germany, 1980-2005: more frequently localized tumors and underlying disorders compared with adult counterparts. Cancer 2006; 107:2906.
  71. Kubo M, Iwashita K, Oyachi N, et al. Two different types of infantile renal cell carcinomas associated with tuberous sclerosis. J Pediatr Surg 2011; 46:E37.
  72. Paul E, Thiele EA, Shailam R, et al. Case records of the Massachusetts General Hospital. Case 26-2011. A 7-year-old boy with a complex cyst in the kidney. N Engl J Med 2011; 365:743.
  73. Shapiro RA, Skinner DG, Stanley P, Edelbrock HH. Renal tumors associated with tuberous sclerosis: the case for aggressive surgical management. J Urol 1984; 132:1170.
  74. Elsamaloty H, Abdullah A, Elzawawi M. Multiple bilateral renal oncocytoms in a known case of tuberous sclerosis: a case report. Abdom Imaging 2010; 35:115.
  75. Torres VE, Björnsson J, King BF, et al. Extrapulmonary lymphangioleiomyomatosis and lymphangiomatous cysts in tuberous sclerosis complex. Mayo Clin Proc 1995; 70:641.
  76. Matsui K, Tatsuguchi A, Valencia J, et al. Extrapulmonary lymphangioleiomyomatosis (LAM): clinicopathologic features in 22 cases. Hum Pathol 2000; 31:1242.
  77. Rolfes DB, Towbin R, Bove KE. Vascular dysplasia in a child with tuberous sclerosis. Pediatr Pathol 1985; 3:359.
  78. Flynn PM, Robinson MB, Stapleton FB, et al. Coarctation of the aorta and renal artery stenosis in tuberous sclerosis. Pediatr Radiol 1984; 14:337.
  79. Patzer L, Basche S, Misselwitz J. Renal artery stenosis and aneurysmatic dilatation of arteria carotis interna in tuberous sclerosis complex. Pediatr Nephrol 2002; 17:193.
  80. Wong H, Hadi M, Khoury T, et al. Management of severe hypertension in a child with tuberous sclerosis-related major vascular abnormalities. J Hypertens 2006; 24:597.
  81. Salerno AE, Marsenic O, Meyers KE, et al. Vascular involvement in tuberous sclerosis. Pediatr Nephrol 2010; 25:1555.
  82. Kyo M, Kohda N, Fujimoto N, Nagano S. [A case of angiomyolipoma originating from polycystic kidney with horseshoe kidney]. Hinyokika Kiyo 1987; 33:1416.
  83. Ortiz Cabría R, Blanco Parra M, Rodríguez de la Rua Román J. [Tuberous sclerosis. Multiple kidney pathology. Presentation of a case]. Actas Urol Esp 1990; 14:310.
  84. Niemi AK, Northrup H, Hudgins L, Bernstein JA. Horseshoe kidney and a rare TSC2 variant in two unrelated individuals with tuberous sclerosis complex. Am J Med Genet A 2011; 155A:2534.
  85. Schillinger F, Montagnac R. [Renal lesions in tuberous sclerosis]. Nephrol Ther 2006; 2 Suppl 2:S123.
  86. Rosenberg JC, Bernstein J, Rosenberg B. Renal cystic disease associated with tuberous sclerosis complex: renal failure treated by cadaveric kidney transplantation. Clin Nephrol 1975; 4:109.
  87. Meyrier A, Rainfray M, Roland J, Merlier J. [Tuberous sclerosis with chronic renal failure treated by hemodialysis and transplantation (author's transl)]. Nephrologie 1980; 1:85.
  88. Clarke A, Hancock E, Kingswood C, Osborne JP. End-stage renal failure in adults with the tuberous sclerosis complex. Nephrol Dial Transplant 1999; 14:988.
  89. Liang S, Cuevas G, Tizani S, et al. Novel mechanism of regulation of fibrosis in kidney tumor with tuberous sclerosis. Mol Cancer 2013; 12:49.
  90. Schillinger F, Montagnac R. [Renal transplantation in Bourneville tuberous sclerosis]. Nephrologie 1994; 15:339.
  91. Sarraf M, Masoumi A, Castro-Silva FJ, et al. A case of tuberous sclerosis complex that progressed to end-stage renal disease. Nat Clin Pract Nephrol 2009; 5:172.
  92. Tarasewicz A, Debska-Slizień A, Konopa J, et al. Rapamycin as a therapy of choice after renal transplantation in a patient with tuberous sclerosis complex. Transplant Proc 2009; 41:3677.
  93. Haidinger M, Werzowa J, Weichhart T, Säemann MD. Targeting the dysregulated mammalian target of rapamycin pathway in organ transplantation: killing 2 birds with 1 stone. Transplant Rev (Orlando) 2011; 25:145.
  94. Shepherd CW, Gomez MR, Lie JT, Crowson CS. Causes of death in patients with tuberous sclerosis. Mayo Clin Proc 1991; 66:792.
Topic 1684 Version 49.0

References

آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟