Cellular and Molecular Mechanisms of Kidney Injury in 2,8-Dihydroxyadenine Nephropathy.

BACKGROUND: Hereditary deficiency of adenine phosphoribosyltransferase causes 2,8-dihydroxyadenine (2,8-DHA) nephropathy, a rare condition characterized by formation of 2,8-DHA crystals within renal tubules. Clinical relevance of rodent models of 2,8-DHA crystal nephropathy induced by excessive adenine intake is unknown. METHODS: Using animal models and patient kidney biopsies, we assessed the pathogenic sequelae of 2,8-DHA crystal-induced kidney damage. We also used knockout mice to investigate the role of TNF receptors 1 and 2 (TNFR1 and TNFR2), CD44, or alpha2-HS glycoprotein (AHSG), all of which are involved in the pathogenesis of other types of crystal-induced nephropathies. RESULTS: Adenine-enriched diet in mice induced 2,8-DHA nephropathy, leading to progressive kidney disease, characterized by crystal deposits, tubular injury, inflammation, and fibrosis. Kidney injury depended on crystal size. The smallest crystals were endocytosed by tubular epithelial cells. Crystals of variable size were excreted in urine. Large crystals obstructed whole tubules. Medium-sized crystals induced a particular reparative process that we term extratubulation. In this process, tubular cells, in coordination with macrophages, overgrew and translocated crystals into the interstitium, restoring the tubular luminal patency; this was followed by degradation of interstitial crystals by granulomatous inflammation. Patients with adenine phosphoribosyltransferase deficiency showed similar histopathological findings regarding crystal morphology, crystal clearance, and renal injury. In mice, deletion of Tnfr1 significantly reduced tubular CD44 and annexin two expression, as well as inflammation, thereby ameliorating the disease course. In contrast, genetic deletion of Tnfr2, Cd44, or Ahsg had no effect on the manifestations of 2,8-DHA nephropathy. CONCLUSIONS: Rodent models of the cellular and molecular mechanisms of 2,8-DHA nephropathy and crystal clearance have clinical relevance and offer insight into potential future targets for therapeutic interventions.

[Inflammatory fibroid polyp in the jejunum - a case report].

Inflammatory fibroid polyps (IFP) are rare type of benign tumours found in the gastrointestinal tract. IFP´s are in most cases small in size and without symptoms but can cause intussuception and haemorrhage. We present a case of a 25 year old female who presented with abdominal pain and symptoms and signs of anemia, hemoglobin was 36 g/L upon arrival. Further workup revealed a large tumor in the small intestine. The patient underwent a partial resection of the proximal jejunum. Pathology of the specimen showed inflammatory fibroid polyp.

The impact of tumour size on the probability of synchronous metastasis and survival in renal cell carcinoma patients: a population-based study.

BACKGROUND: The observed low metastatic potential and favorable survival of small incidentally detected renal cell carcinomas (RCCs) have been a part of the rationale for recommending partial nephrectomy as a first treatment option and active surveillance in selected patients. We examined the relationship between tumor size and the odds of synchronous metastases (SMs) (primary outcome) and disease specific survival (secondary outcome) in a nationwide RCC registry. METHODS: Retrospective study of the 794 RCC patients diagnosed in Iceland between 1971 and 2005. Histological material and TNM staging were reviewed centrally. The presence of SM and survival were recorded. Cubic spline analysis was used to assess relationship between tumor size and probability of SM. Univariate and multivariate statistics were used to estimate prognostic factors for SM and survival. RESULTS: The probability of SM increased in a non-linear fashion with increasing tumor size (11, 25, 35, and 50%) for patients with tumors of ≤4, 4.1-7.0, 7.1-10.0, and >10 cm, respectively. On multivariate analysis, tumor size was an independent prognostic factor for disease-specific survival (HR = 1.05, 95% CI 1.02-1.09, p < 0.001), but not for SM. CONCLUSION: Tumor size affected the probability of disease-specific mortality but not SM, after correcting for TNM staging in multivariate analysis. This confirms the prognostic ability of the 2010 TNM staging system for renal cell cancer in the Icelandic population.

Incidental detection of renal cell carcinoma is an independent prognostic marker: results of a long-term, whole population study.

PURPOSE: The true effect of incidental detection on the survival of patients with renal cell carcinoma has been debated. We used centralized databases in Iceland to study prognostic factors of survival, focusing on the effect of incidental detection. MATERIALS AND METHODS: This retrospective study included all living patients diagnosed with renal cell carcinoma in Iceland from 1971 to 2005. Hospital charts and histology were reviewed. Incidentally diagnosed renal cell carcinomas were compared to symptomatic tumors and prognostic factors were evaluated using Cox multivariate analysis. RESULTS: Of the 910 patients 254 (27.9%) were diagnosed incidentally, most often by abdominal ultrasound (29.5%) or computerized tomography (28.3%). The incidental detection rate increased from 11.1% in 1971 through 1975 to 39.2% in 2001 through 2005 (p <0.001). During the same period the incidence increased significantly in males but in females only during the last 5 study years. Mortality remained unchanged for each gender. Incidentally detected tumors were an average of 2.6 cm smaller and diagnosed at lower stage and lower grade than symptomatic tumors. Age and histology were similar in each group. TNM stage was by far the strongest independent prognostic factor of survival but age, calendar year of diagnosis and ESR were also significant. After correcting for confounders patients with symptomatic renal cell carcinoma had worse survival than those diagnosed incidentally. CONCLUSIONS: With increased incidence and unchanged mortality the survival of patients with renal cell carcinoma has improved. This is mainly related to a steep increase in incidental detection. Incidental detection affects survival favorably and to a greater extent than can be explained by lower stage compared to the survival of patients diagnosed with symptoms.

Chromophobe renal cell carcinoma in Iceland: an epidemiological and clinicopathological study.

OBJECTIVE: Numerous studies have suggested that the rare chromophobe renal cell carcinoma (CRCC) has a more favourable prognosis than the other more common subtypes of RCC, clear cell RCC (CCRCC) and papillary RCC (PRCC). These studies have, however, usually involved selected patient cohorts and not whole populations. This study compared CRCC patients with patients with the other two major histological subtypes and established a population-based age-standardized incidence rate (ASR). MATERIAL AND METHODS: Of 828 histopathologically confirmed RCCs diagnosed between 1971 and 2005 in Iceland, 15 CRCC cases were identified. Histological material was reviewed, the TNM system was used for staging and cancer-specific survival was estimated. Univariate and multivariate analysis was used to compare CRCC to both CCRCC (n = 740) and PRCC (n = 66). Mean follow-up was 6.7 years. RESULTS: CRCC accounted for 1.8% of RCCs, the ASR being 0.17/100,000 per year. Compared to other subtypes, CRCC was detected incidentally less often (7% vs 29%, p = 0.02), but was more often diagnosed at lower stages (73% vs 45% at stage I + II, p < 0.001). One patient had synchronous metastasis and another developed recurrent CRCC; both died of CRCC. Five-year survival for CRCC, CCRCC and PRCC was 86%, 59% and 50%, respectively (p = 0.004). After correcting for TNM stage (odds ratio 1.98), multivariate analysis did not indicate that CRCC subtype was an independent predictive factor for survival. CONCLUSION: CRCC is a rare neoplasm with an ASR of 0.17/100,000 per year. These tumours often present with symptoms despite being at lower stages than the other RCC subtypes. The more favourable survival of the CRCC subtype appears to be explained by these tumours being diagnosed at low stages. These findings may suggest that CRCC has a different biological behaviour.

Sveinsson chorioretinal atrophy/helicoid peripapillary chorioretinal degeneration: first histopathology report.

PURPOSE: To report the histopathologic features in an eye with Sveinsson chorioretinal atrophy (SCRA), also termed helicoid peripapillary chorioretinal degeneration, for the first time. PARTICIPANT: An 82-year-old woman clinically and genetically confirmed to have SCRA. DESIGN: Examination of an eye obtained after death. METHOD: Light microscopic examination of an eye of an 82-year-old woman documented to have SCRA since the age of 10 years. MAIN OUTCOME MEASURE: The findings in ocular tissues were determined by light microscopy. RESULTS: In the most advanced areas of chorioretinal atrophy, the sensory retina, retinal pigment epithelium (RPE), choriocapillaris, and choroid were absent. In the transition between affected and unaffected areas, the RPE and the outer segments of the photoreceptors only were affected. The optic nerve was smaller than normal, but well myelinated. Other ocular tissues retained a relatively normal appearance for a patient who had died at this age. CONCLUSIONS: The mildest and presumably earliest morphologic changes involved the photoreceptor outer segments, the RPE, and choriocapillaris in this progressive degenerative disease of the retina and choroid.

Defective immunoglobulin A (IgA) glycosylation and IgA deposits in patients with IgA nephropathy.

Defective glycosylation and immune complex (IC) formation may be of primary importance in immunoglobulin A nephropathy (IgAN) pathogenesis. The aim of this study was to determine whether defective IgA1 glycosylation might support renal deposition of IgA and disease activity. IgA was isolated from the serum of 44 IgAN patients and 46 controls and glycosylation analysed by ELISA using glycan-specific lectins. IgA was measured by immunodiffusion and immune complexes by ELISA. IgA subclasses in IC deposits in kidney glomeruli were identified by immunohistochemical methods. A significant increase in N-acetylgalactosamine (GalNAc) in terminal position (p = 0.02) observed in some of the IgAN patients, became more pronounced when sialic acid was removed from IgA1, indicating enhanced expression of α-2,6-sialyltransferase in patients compared with controls (p < 0.0001). Patients with defective galactosylation had lower serum IgA than other IgAN patients (p = 0.003). IgAN patients with both IgA1 and IgA2 glomerular deposits (21.7%) had increased GalNAc in terminal position (p = 0.003). Taken together, our results show that increased IgA glycosylation in IgAN associates with low levels of IgA, concomitant IgA1 and IgA2 glomerular deposits and poor clinical outcome.

A common variant at 8q24.21 is associated with renal cell cancer.

Renal cell carcinoma (RCC) represents between 80 and 90% of kidney cancers. Previous genome-wide association studies of RCC have identified five variants conferring risk of the disease. Here we report the results from a discovery RCC genome-wide association study and replication analysis, including a total of 2,411 patients and 71,497 controls. One variant, rs35252396[CG] located at 8q24.21, is significantly associated with RCC after combining discovery and replication results (OR=1.27, P(combined)=5.4 × 10(-11)) and has an average risk allele frequency in controls of 46%. rs35252396[CG] does not have any strongly correlated variants in the genome and is located within a region predicted to have regulatory functions in several cell lines, including six originating from the kidney. This is the first RCC variant reported at 8q24.21 and it is largely independent (r(2)≤0.02) of the numerous previously reported cancer risk variants at this locus.

[Small renal cell carcinomas and synchronous metastases]. / Litil nyrnafrumukrabbamein og fjarmeinvorp.

OBJECTIVE: The incidence of renal cell carcinoma (RCC) is rising in part due to small tumors (≤4cm) detected incidentally with abdominal imaging. Survival for small RCCs has been regarded as favorable and guidelines recommend partial rather than total nephrecteomy. We studied the frequency of synchronous metastasis in patients with small RCCs in Iceland. MATERIALS AND METHODS: A retrospective study on 257 patients with RCC ≤4cm out of 1102 RCC patients diagnosed in Iceland 1971-2010. Patients with metastasis were compared to those with localized disease. Hospital charts were reviewed and histology, TNM-stage and disease-specific survival compared between groups. RESULTS: The proportion of small tumors increased from 9% in 1971-1980 to 33% in 2001-2010 (p<0,001) and incidental detection increased from 14% to 39% during the same period. Out of the 257 patients with small RCCs, 25 (10%) had synchronous metastases, most frequently in lungs or bones. Patients with metastases were on average 1.9 years older, their tumors were 0.2 cm larger and more often located in the right kidney, their hemoglobin was lower and nuclear grade and T-stage higher. Histology was similar in both groups. Five-year survival of patients with and without metastases was 7 vs. 94%, respectively (p<0.001). CONCLUSIONS: One out of ten patients with small RCC has synchronous metastases at diagnosis. This is higher than in most previous reports that usually include surgical patients only. Patients with metastases are significantly older, more often symptomatic, their tumor are larger and their prognosis worse. Our results indicate that small RCC is a potentially systemic disease at diagnosis that has to be taken seriously.

[Acute flank pain syndrome: a common presentation of acute renal failure in young men in Iceland]. / Brátt síðuheilkenni: algeng birtingarmynd bráðrar nýrnabilunar hjá ungum mönnum á Íslandi.

OBJECTIVES: The purpose of the study was to calculate the incidence of the acute flank pain syndrome in Iceland and to describe the case series. MATERIAL AND METHODS: The hospital records of those who fulfilled the following criteria were studied: age 18-41 years, acute renal failure, and a visit to Landspitali University Hospital in 1998-2007. The acute flank pain syndrome was defined as severe flank pain in combination with acute renal failure, unexplained except for the possible consumption of NSAIDs, ethanol or both. Information was collected about the sales of NSAIDs. RESULTS: One hundred and six patients had acute renal failure. Of those, 21 had the acute flank pain syndrome (20%). The annual incidence of the acute flank pain syndrome increased threefold during the study period. The average incidence was 3.2/100.000/year (relative to the population of the Reykjavik area) and 2.0/100.000/year (relative to the population of Iceland). 18 patients were male and the median age was 26 (19-35) years. The symptoms regressed spontaneously during a few days or weeks. There was history of NSAID intake in 15, ethanol consumption in 15, either in 20, and both in nine patients. The sales figures of NSAIDs were high and they increased during the study period, especially those of the over-the-counter sales of ibuprofen. CONCLUSIONS: The incidence of the acute flank pain syndrome was high. The paper describes the largest case series that has been published since the withdrawal of suprofen in 1987. Young people should be warned about consuming NSAIDs during or directly after binge drinking.

Incidence and outcome of acute phosphate nephropathy in Iceland.

BACKGROUND: Oral sodium phosphate solutions (OSPS) are widely used for bowel cleansing prior to colonoscopy and other procedures. Cases of renal failure due to acute phosphate nephropathy following OSPS ingestion have been documented in recent years, questioning the safety of OSPS. However, the magnitude of the problem remains unknown. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a population based, retrospective analysis of medical records and biopsies of all cases of acute phosphate nephropathy that were diagnosed in our country in the period from January 2005 to October 2008. Utilizing the complete official sales figures of OSPS, we calculated the incidence of acute phosphate nephropathy in our country. Fifteen cases of acute phosphate nephropathy were diagnosed per 17,651 sold doses of OSPS (0.085%). Nine (60%) were women and mean age 69 years (range 56-75 years). Thirteen patients had a history of hypertension (87%) all of whom were treated with either ACE-I or ARB and/or diuretics. One patient had underlying DM type I and an active colitis and one patient had no risk factor for the development of acute phosphate nephropathy. Average baseline creatinine was 81.7 µmol/L and 180.1 at the discovery of acute renal failure, mean 4.2 months after OSPS ingestion. No patient had a full recovery of renal function, and at the end of follow-up, 26.6 months after the OSPS ingestion, the average creatinine was 184.2 µmol/L. The average eGFR declined from 73.5 ml/min/1.73 m(2) at baseline to 37.3 ml/min/1.73 m(2) at the end of follow-up. One patient reached end-stage renal disease and one patient died with progressive renal failure. CONCLUSION/SIGNIFICANCE: Acute phosphate nephropathy developed in almost one out of thousand sold doses of OSPS. The consequences for kidney function were detrimental. This information can be used in other populations to estimate the impact of OSPS. Our data suggest that acute phosphate nephropathy may be greatly underreported worldwide.

[Renal cell carcinoma diagnosed at autopsy in Iceland 1971-2005]. / Nýrnafrumukrabbamein greind vid krufningu á Islandi 1971-2005: Samanburdur vid aexli greind í sjúklingum á lífi.

INTRODUCTION: The incidence of renal cell carcinoma (RCC) is rising in Iceland. This has been attributed to increased diagnostic activity, such as abdominal imaging of unrelated diseases, rather than changes in the behavior of the disease. The aim of this study was to compare RCCs diagnosed in living patients and at autopsy, but also to investigate the relationship between the incidence of RCC and autopsy findings. MATERIAL AND METHODS: RCC found incidentally in individuals at autopsy was compared to patients diagnosed alive over three decades in Iceland (1971-2005). Stage at diagnosis and tumor histology was reviewed. RESULTS: 110 tumors were diagnosed at autopsy with a rate of 7.1/1000 autopsies. When compared to patients diagnosed alive (n = 913) the mean age at diagnosis was higher in the autopsy group (74.4 vs. 65 yrs.) while male to female ratio and laterality was similar. Tumors found at autopsy were smaller (3.7 vs. 7.3 cm), at lower stage (88% at stage I+II vs. 42%) and at lower tumor grade (85% at grade I+II vs. 56%). A difference, although smaller, is present when the autopsy detected cases are compared to only incidentally detected RCCs in living patients. Furthermore the autopsy detected tumors were more frequently of papillary cell type (21% vs. 8%). After correcting for declining autospy rate (>50%), a slight trend for a reduced rate of autopsy dectected RCC cases was seen during the last 10 years of the period but the difference was not significant. CONCLUSION: RCCs diagnosed at autopsy are at a lower stage and tumor grade than in patients diagnosed alive. The autopsy-rate is declining in Iceland with fewer RCCs found per autopsy. After correcting for the decline in autopsy rate, the rate of RCC detected at autopsy is relatively unchanged. The increase in incidence of RCC is therefore not explained by findings at autopsy.

Resolution of proteinuria in a patient with X-linked Alport syndrome treated with cyclosporine.

We report a 9-year-old Icelandic male with Alport syndrome and nephrotic-range proteinuria who responded well to cyclosporine therapy. He presented at the age of 2 years with gross hematuria and proteinuria during an episode of upper respiratory tract infection. Three years later he had developed persistent proteinuria; kidney function was normal. A renal biopsy revealed marked irregularities in the glomerular basement membrane consistent with Alport syndrome. Mutation analysis revealed a single base insertion in COL4A5 which was predicted to cause a major structural defect in the collagen IV alpha5 chain. Despite angiotensin-converting enzyme inhibitor therapy his proteinuria progressed to the nephrotic range associated with edema. At the age of 7 years, cyclosporine therapy was instituted, which promptly resulted in almost complete resolution of proteinuria. Three years later his urinary protein excretion was close to the normal range and serum creatinine remained within normal limits. We conclude that closely monitored cyclosporine therapy may be a safe and effective treatment in patients with severe proteinuria and Alport syndrome.

Effect of incidental detection for survival of patients with renal cell carcinoma: results of population-based study of 701 patients.

OBJECTIVES: To conduct a population-based study to evaluate the effect of incidental detection of renal cell carcinoma (RCC) on survival. Incidental detection of RCC has increased significantly in recent years because of widespread use of abdominal imaging. The patients with incidentally diagnosed RCC have better survival; however, because of possible "lead time" bias and stage migration, the real implications of incidental detection on survival have been a matter of debate. METHODS: All living patients diagnosed with RCC in Iceland between 1971 and 2000 were included (n = 701). The histologic findings were verified, the stage (extent) of the disease was determined, and the incidence, mortality, and survival were evaluated. RESULTS: The strongest predictors of mortality were stage and nuclear grade. After correcting for these factors in the multivariate analysis, incidental diagnosis, histologic subtype, and gender lost their significance as independent prognostic factors of death. However, the incidentally diagnosed tumors were 2.3 cm smaller on average and at a lower stage and grade than symptomatic tumors, with significantly better patient survival than those with symptomatic tumors on univariate analysis (76% versus 44% 5-year disease-specific survival). An increased incidence of RCC was only seen in men, but incidental detection increased threefold during the study period in both sexes, with significant improvement in survival for the whole group as a result. CONCLUSIONS: The increased frequency of incidental detection has improved the survival of patients with RCC in Iceland. Incidental detection was not an independent prognostic factor of death, indicating that these tumors are of a similar biologic nature as symptomatic RCCs, only diagnosed earlier.

Histological subtyping and nuclear grading of renal cell carcinoma and their implications for survival: a retrospective nation-wide study of 629 patients.

OBJECTS: The aim of this study was to evaluate the prognostic significance of the current WHO histological subtyping and Fuhrman nuclear grading on the survival of patients with renal cell carcinoma (RCC). MATERIALS AND METHODS: A retrospective population-based study was carried out on all patients with a histopathologically confirmed diagnosis of RCC in Iceland between 1971 and 2000. Fuhrman grade, TNM stage, and survival were evaluated and multivariate analysis applied in order to determine prognostic factors. RESULTS: Out of 629 patients (387 males, 242 females, mean age 64 years), 558 (88.7%) had clear cell, 53 (8.4%) papillary, and 13 (2.1%) chromophobe RCC. Patient demographics were comparable for the two major subtypes, but chromophobe RCCs were larger in size and were diagnosed at a younger age. Clear cell RCCs were more often of higher grades (G3+G4, 48.4%) and at advanced TNM stages (III+IV, 59.3%) than papillary RCCs (22.6% and 34% respectively, p<0.001). Linear regression analysis showed a strong correlation between grade, tumor size, and stage (p<0.001). Chromophobe RCCs had a better survival in univariate analysis than both papillary and clear cell RCCs (84.6% vs. 66.5% and 54.9% 5-year disease specific survival, p<0.001). However, in the multivariate analysis, only the patient's age, calendar year of diagnosis, TNM stage, and nuclear grade were independent prognostic factors of survival. CONCLUSION: In this complete nation-wide series nuclear grading is important in predicting survival of patients with RCC. It is strongly related to both tumor size and stage, with stage being by far the strongest prognostic factor. Different histological subtypes confer different survival. However, in spite of the distinctive cytogenetic and molecular characteristics of the subtypes, the survival difference is to a large extent due to differences in grade and particularly stage.

Renal oncocytoma: a clinicopathological analysis of 45 consecutive cases.

OBJECTIVE: To evaluate the clinical behaviour and pathology of renal oncocytoma in a well-defined population over a 30-year period. PATIENTS AND METHODS: In a retrospective population-based study we assessed relevant clinical and pathological factors in 45 patients (31 men and 14 women) diagnosed with renal oncocytoma in Iceland between 1971 and 2000. Clinical presentation, pathology, survival and causes of death were evaluated. RESULTS: The age-standardized incidence was 0.3 per 100,000 per year for both men and women, the incidence of oncocytomas being 5.5% of renal cell carcinomas (RCCs) diagnosed during the same period in Iceland. Fourteen patients were diagnosed at autopsy for an unrelated disease. Of 31 living patients (mean age 70.5 years), seven were diagnosed incidentally (23%), and the others had presented with haematuria (32%), abdominal pain (29%), and weight loss (10%). All the patients had a radical nephrectomy, except for one with bilateral oncocytoma who had a partial nephrectomy. The mean (range) tumour size was 5.7 (0.9-12) cm. Eighteen patients (58%) were diagnosed at Tumour-Node-Metastasis stage I, 10 at stage II (32%) and three at stage III (10%), all of those at stage III having renal capsular penetration or tumour invasion into perirenal fat tissue (T3aN0M0). No patients were diagnosed with lymph node or distant metastasis. Two cases of coexisting RCC were detected. After a median follow-up of 8.3 years there were no recurrences or deaths from oncocytoma (100% disease-specific survival). The overall 5-year survival was 63%, with most patients dying from cardiovascular diseases or nonrenal cancers. CONCLUSIONS: In most cases renal oncocytoma behaves like a benign tumour; the long-term prognosis is excellent. Thus, in the present patients, radical nephrectomy could be regarded as an over-treatment and nephron-sparing surgery as more appropriate, especially in patients with small tumours. However, both coexisting RCC and perirenal fat invasion, a hallmark of malignant behaviour, might indicate that more radical surgery is warranted in some of these patients.

A population-based familial aggregation analysis indicates genetic contribution in a majority of renal cell carcinomas.

The etiology of RCC is incompletely understood and the inherited genetic contribution uncertain. Although there are rare mendelian forms of RCC stemming from inherited mutations, most cases are thought to be sporadic. We sought to determine the extent of familial aggregation among Icelandic RCC patients in general. Medical and pathologic records for all patients diagnosed with RCC in Iceland between 1955 and 1999 were reviewed. This included a total of 1,078 RCC cases, 660 males and 418 females. With the use of an extensive computerized database containing genealogic information on 630,000 people in Iceland during the past 11 centuries, several analyses were conducted to determine whether the patients were more related to each other than members drawn at random from the population. Patients with RCC were significantly more related to each other than were subjects in matched groups of controls. This relatedness extended beyond the nuclear family. RRs were significantly greater than 1.0 for siblings, parents and cousins of probands. RRs were 2-3 for first-degree relatives and 1.6 for third-degree relatives. The risk of RCC is significantly higher for members of the extended family of an affected individual, as well as the nuclear family. Our results indicate that germline mutations are significantly involved in what has been defined as sporadic RCC.