Validation of two IgA nephropathy risk-prediction tools using a cohort with a long follow-up.

BACKGROUND: Recently, two immunoglobulin A (IgA) nephropathy-prediction tools were developed that combine clinical and histopathologic parameters. The International IgAN Prediction Tool predicts the risk for 50% declines in the estimated glomerular filtration rate or end-stage kidney disease up to 80 months after diagnosis. The IgA Nephropathy Clinical Decision Support System uses artificial neural networks to estimate the risk for end-stage kidney disease. We aimed to externally validate both prediction tools using a Norwegian cohort with a long-term follow-up. METHODS: We included 306 patients with biopsy-proven primary IgA nephropathy in this study. Histopathologic samples were retrieved from the Norwegian Kidney Biopsy Registry and reclassified according to the Oxford Classification. We used discrimination and calibration as principles for externally validating the prognostic models. RESULTS: The median patient follow-up was 17.1 years. A cumulative, dynamic, time-dependent receiver operating characteristic analysis showed area under the curve values ranging from 0.90 at 5 years to 0.83 at 20 years for the International IgAN Prediction Tool, while time-naive analysis showed an area under the curve value at 0.83 for the IgA Nephropathy Clinical Decision Support System. The International IgAN Prediction Tool was well calibrated, while the IgA Nephropathy Clinical Decision Support System tends to underestimate risk for patients at higher risk and overestimates risk in the lower risk categories. CONCLUSIONS: We have externally validated two prediction tools for IgA nephropathy. The International IgAN Prediction Tool performed well, while the IgA Nephropathy Clinical Decision Support System has some limitations.

Utilizing the MEST score for prognostic staging in IgA nephropathy.

BACKGROUND: The Oxford classification/MEST score is an established histopathologic scoring system for patients with IgA nephropathy (IgAN). The objective of this study was to derive a prognostic model for IgAN based on the MEST score and histopathologic features. METHODS: A total of 306 patients with biopsy-proven primary IgAN were included. Histopathologic samples were retrieved from the Norwegian Kidney Biopsy Registry and reclassified according to the Oxford classification. The study endpoint was end-stage renal disease (ESRD). Patients were subclassified into three risk models based on histologic features (Model A), a composite score calculated from the adjusted hazard ratio values (Model B), and on quartiles (Model C). RESULTS: The mean follow-up time was 16.5 years (range 0.2-28.1). In total, 61 (20%) patients reached ESRD during the study period. Univariate analysis of M, E, S, T and C lesions demonstrated that all types were associated with an increased risk of ESRD; however, a multivariate analysis revealed that only S, T and C lesions were associated with poor outcomes. Statistical analysis of 15-year data demonstrated that Models A and B were as predictive as the MEST score, with an area-under-the-curve at 0.85. The Harrel c index values were 0.81 and 0.80 for the MEST score and Models A and B, respectively. In the present cohort, adding C lesions to the MEST score did not improve the models prognostic value. CONCLUSIONS: Patients can be divided into risk classes based on their MEST scores. Histopathologic data provide valuable prognostic information at the time of diagnosis. Model B was the most suitable for clinical practice because it was the most user-friendly.

Serum levels of the IL-6 family of cytokines predict prognosis in renal cell carcinoma (RCC).

PURPOSE: An improved understanding of RCC immunology should shed further light on RCC tumor biology. Our objective was to study to what extent serum levels of the IL-6 family of cytokines at diagnosis were relevant to survival. METHODS: A total of 118 consecutively patients with RCC, in which the tumor was surgically removed at Haukeland University Hospital during the period from 2007 to 2010, were included. The patients were followed-up for 10 years. The morning before surgery blood was sampled and serum frozen, with levels of IL-6, IL-27, IL-31, OSM, CNTF, IL-6Rα and gp130 determined. RESULTS: Among patients with the highest quartile of IL-6 (> 8 pg/ml) (n = 29), six of nine who had metastasis at diagnosis had such high IL-6 values. Among presumed radically treated patients, a high IL-6 and IL-27 strongly predicted recurrence. In particular, the predictions among patients with large (diameter > 7 cm) tumors were excellent regarding both IL-6 and IL-27 values. High gp130 serum levels predicted an overall survival (OS) among RCC patients with large tumors. Patients with a high IL-6 exhibited a strong expression of IL-6 in endothelial- and vascular smooth muscle cells. Moreover, the level of intra-tumoral CD3-positive cells predicted survival. CONCLUSIONS: IL-6 and IL-27 seem to play a role in RCC biology. IL-6 enables the pinpointing of metastatic condition at diagnosis, as well as together with IL-27, the predicting of survival and recurrence. Endothelial cells and vascular smooth muscle cells are both suggested as important sources of IL-6.

The levels of IL-6 and soluble IL-33R are increased in the renal vein during surgery for clear cell renal cell carcinoma.

PURPOSE: The main aim was to map serum levels of IL-1/IL-6 family cytokines and relevant receptors from serum samples taken across treatment in patients with Renal Cell Carcinoma (RCC). Additionally, we explored the possible interactions between these measurements, immunohistochemistry and intratumoral blood flow. METHODS: We included 40 patients undergoing open surgery for renal tumors. Blood samples were collected before, during (taken simultaneously from a peripheral site and the renal vein (RV) before clamping) and after surgery. Samples were analyzed for IL-6, IL-27, IL-31, OSM, TNF-α, serum (s)-gp130, s-IL-6Rα, s-IL-33R, IL-1Rα and VEGF. All 35 RCC tumors were histologically subtyped as clear cell (CCRCC), papillary or chromophobe. Immunohistochemistry for the CCRCC group included expression of IL-6/IL-6R. Intratumoral blood flow was determined by calculating intratumoral contrast enhancement on preoperative computerized tomography (CT) imaging. RESULTS: In the CCRCC patients, the intraoperative RV concentration of IL-6 was significantly higher than in both the preoperative and postoperative samples (p = 0.005 and p = 0.032, respectively). Furthermore, the intraoperative ratio showed significantly higher levels of IL-6 in the RV than in the simultaneously drawn peripheral sample. Immunohistochemistry showed general expression of IL-6 (23/24) in both tumor cells and the vasculature (20/23). Moreover, s-IL-6R was expressed in tumor cells in 23/24 studied patients. Increased blood flow in the CCRCC tumors predicted increased IL-6 levels in the RV (p < 0.001). The other cytokines and receptors showed an overall stability across the measurements. However, the intraoperative ratios of IL-33R and gp130 showed significantly higher levels in the RV. CONCLUSION: Serum levels of IL-6 increased during surgery. Intraoperative IL-6 and s-IL-33R values were higher in the RV compared to the periphery, suggesting secretion from the tumor or tumor microenvironment itself. Supportive of this is an almost general expression of IL-6/s-IL-6R in tumor cells and IL-6 in vasculature in the tumor microenvironment. Other studied cytokines/receptors were remarkably stable across all measurements.

AGAP2-AS1 as a prognostic biomarker in low-risk clear cell renal cell carcinoma patients with progressing disease.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cancer and one of the most common cancers. While survival for localized ccRCC is good, the survival of metastatic disease is not, and thirty percent of patients with ccRCC develop metastases during follow-up. Although current scoring methods accurately identify patients at low progression risk, a small subgroup of those patients still experience metastasis. We therefore aimed to identify ccRCC progression biomarkers in "low-risk" patients who were potentially eligible for adjuvant treatments or more intensive follow-up. METHODS: We assembled a cohort of ccRCC patients (n = 443) and identified all "low-risk" patients who later developed progressing tumors (n = 8). Subsequently, we performed genome-wide expression profiling from formalin-fixed samples obtained at initial surgery from these "low-risk" patients and 16 matched patients not progressing to recurrence with metastasis. The patients were matched for Leibovich sore, creatinine, age, sex, tumor size and tumor stage. Key results were confirmed with qPCR and external data from The Cancer Genome Atlas. RESULTS: Principal component analysis indicated that systematic transcriptomic differences were already detectable at the time of initial surgery. One thousand one hundred sixty-seven genes, mainly associated with cancer and immune-related pathways, were differentially expressed between progressors and nonprogressors. A search for a classifier revealed that overexpression of AGAP2-AS1, an antisense long noncoding RNA, correctly classified 23 of 24 samples, years (4.5 years average) in advance of the discovery of metastasis and without requiring larger gene panels. Subsequently, we confirmed AGAP2-AS1 gene overexpression by qPCR in the same samples (p < 0.05). Additionally, in external data from The Cancer Genome Atlas, overexpression of AGAP2-AS1 is correlated with overall unfavorable survival outcome in ccRCC, irrespective of other prognostic predictors (p = 2.44E-7). CONCLUSION: AGAP2-AS1 may represent a novel biomarker identifying high-risk ccRCC patients currently classified as "low risk" at the time of surgery.

Predictive value of C-reactive protein in patients treated with sunitinib for metastatic clear cell renal cell carcinoma.

BACKGROUND: Sunitinib has become mainstay first line treatment for patients with metastatic renal clear cell carcinoma (mRCC). Still, useful predictive markers of response are lacking and urgently needed for clinical decision making. METHODS: In the present study we investigated the predictive value of standard serum markers as well as clinical markers, including C-reactive protein (CRP), Neutrophil to Lymphocyte ratio (NLR) and early hypertension (eHTN) in an unselected prospective patient population treated with sunitinib for mRCC. Forty-six patients were enrolled in a prospective single-arm study of predictive markers for sunitinib response. Response rates according to RECIST 1.1 were used as primary end-point. Secondary objectives were to evaluate prognostic value of the candidate markers with regard to progression free survival (PFS) and overall survival (OS). In addition, toxicity rates and quality of life was recorded. RESULTS: Median PFS and OS was 9.1 months and 15.0 months, respectively. Of 38 patients evaluable for response, 1 patient had complete response (CR), 7 had partial response (PR), 18 had stable disease (SD) and 12 had progressive disease (PD). Normal CRP at baseline was significantly associated with objective response (CR + PR) (p = 0.01). Normal CRP was also significantly associated with improved PFS and OS (Log rank, p = 0.05 and <0.01, respectively). Early hypertension, NLR and IMDC risk score were not significantly associated with response rates or survival. CONCLUSION: Baseline CRP was a significant predictive factor of sunitinib response and a prognostic factor of survival. Baseline CRP might be a useful biomarker in the treatment planning of mRCC. Due to the relatively small sample size, our results need to be confirmed in larger studies.

A prospective risk-stratified follow-up programme for radically treated renal cell carcinoma patients: evaluation after eight years of clinical use.

PURPOSE: In mid-2007, we introduced a new risk-stratified follow-up programme (FUP) for surgically treated localized renal cell carcinoma. After inclusion, the patients have been followed prospectively. In this study, we present the results in regard to stratification, completeness of the FUP and recurrences. METHODS: The FUP consists of three risk groups: low risk (LR), intermediate risk (IR) and high risk (HR), based on the risk stratification model introduced by Leibovich et al. (Cancer 97(7):1663-1671, 2003). In all risk groups, the patients are scheduled for ten follow-up visits (FUV) over 5 years, but seven, five and three FUVs, respectively, are outsourced to the patient's general practitioner (GP). Chest X-ray and abdomen CT are the imaging modalities used in the FUP. RESULTS: Of 312 included patients, 195 (62.5 %) had a complete FUP. However, in 86 patients the scheduled FUP had to be reduced, leaving 86.3 % of the remaining patients with a complete FUP. By including GPs, the number of FUVs at the hospital was reduced by ~60 %. The 5-year probability for freedom of recurrence is 0.98, 0.84 and 0.52 for the LR, IR and HR groups, respectively. Of 31 recurrences, 20 patients (65 %) were diagnosed within the FUP. Eleven patients (35 %) were diagnosed due to symptoms, and five of these had recurrences in locations not covered by standard imaging. Patients diagnosed within the FUP showed a better prognosis for survival and could in greater part receive tumour-directed treatment. CONCLUSIONS: After 8 years of clinical use, the outcome measures of the FUP seem to be within acceptable ranges.

Development of a disease-specific health-related quality of life (HRQoL) questionnaire intended to be used in conjunction with the general European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) in renal cell carcinoma patients.

BACKGROUND: Studying health-related quality of life (HRQoL) following cancer treatment has become part of a growing number of standardized treatment protocols. The European Organization for Research and Treatment of Cancer (EORTC) has developed HRQoL questionnaires aimed at cancer patients. A disease-specific part is not available for renal cell carcinoma (RCC) patients, and the present aim was to develop an EORTC-compatible RCC-specific HRQoL questionnaire. MATERIAL AND METHODS: In total 413 RCC patients were treated with radical or partial nephrectomies in Western Norway during the period from 1997 to 2010. Three hundred and nine patients with histologically proven cancer were still alive at the inclusion time point and 185 RCC patients (71% response rate) returned the questionnaires. We determined HRQoL by the EORTC-QLQ C30 questionnaire. We also asked 13 candidates questions aimed at constituting a disease-specific part. Furthermore, we tested parts of personality by the Eysenck Personality Inventory and coping by the COPE questionnaire. Given tumor treatment, TNM stage, alcohol consumption level and smoking levels were also determined from the hospital records. RESULTS: A factor analysis showed that five factors were formed: one general symptomatic, one general functional, one with disease-specific questions (flank pain, blood in the urine, flank edema, urinary tract infection), one about sexuality and one about weight loss or gain. Ten RCC-specific HRQoL questions were derived from a factor analysis, including four questions related particularly to pain, mobility and social functioning, also representing a short version of the EORTC C30. The psychometric properties and the relation to other psychological and clinical variables were further determined to be satisfactory. CONCLUSIONS: The suggested disease-specific EORTC-QLQ-style RCC10 version adds important information about the HRQoL of RCC patients, providing additional apparent value to the general questionnaire and personality variables, as well as being psychometrically satisfactory. The questionnaire has a potential as a "stand alone" HRQoL questionnaire among RCC patients.

Agalsidase benefits renal histology in young patients with Fabry disease.

The effect of early-onset enzyme replacement therapy on renal morphologic features in Fabry disease is largely unknown. Here, we evaluated the effect of 5 years of treatment with agalsidase alfa or agalsidase beta in 12 consecutive patients age 7-33 years (median age, 16.5 years). We performed renal biopsies at baseline and after 5 years of enzyme replacement therapy; 7 patients had additional biopsies after 1 and 3 years. After a median of 65 months, biopsy findings from all patients showed total clearance of glomerular endothelial and mesangial cell inclusions, and findings from 2 patients showed complete clearance of inclusions from epithelial cells of the distal tubule. The 4 patients who received the highest dose of agalsidase exhibited substantial clearance of podocyte inclusions, and the youngest patient had nearly complete clearance of these inclusions. Linear regression analysis showed a highly significant correlation between podocyte globotriaocylceramide clearance and cumulative agalsidase dose (r=0.804; P=0.002). Microalbuminuria normalized in five patients. In summary, long-term enzyme replacement therapy in young patients can result in complete globotriaocylceramide clearance of mesangial and glomerular endothelial cells across all dosage regimens, and clearance of podocyte inclusions is dose-dependent.

The Prognostic Value of Human Papillomavirus Status in Penile Cancer: Outcomes From a Norwegian Cohort Study.

INTRODUCTION: Penile squamous cell carcinoma (PSCC) can develop from human papillomavirus (HPV) infection. This study investigates if the prognostic value of the TNM stage groups or the components tumor stage (pT), grade of differentiation (Grade), lymphovascular invasion (LVI), and nodular stage (pN) depend on HPV status. Also, whether the value of tumor parameters (pT, Grade, and LVI) for predicting node-positive disease depends on HPV status was investigated. PATIENTS AND METHODS: Stored tumor tissue from 226 patients treated for PSCC in Western Norway between 1973 and 2023 was investigated for HPV DNA. Histopathological variables were reevaluated according to the current TNM classification. Disease course was registered from hospital records. Inclusion of an interaction term between HPV and TNM stage groups in Cox regression enabled analysis of whether cancer-specific survival (CSS) of the stage groups depended on HPV status. This was also done separately for pT, Grade, LVI, and pN. Logistic regression with interaction terms between HPV and the tumor parameters were used to investigate if their predictive value depended on HPV status. RESULTS: HPV DNA was detected in 43% of the tumors. Stratified by HPV status, there was no significant interaction term in the Cox regression between HPV status and TNM stage groups (P = .74). Similar results were found for pT (P = .94), Grade (P = .08), LVI (P = .91) and pN (P = .77). Moreover, there were no significant interaction terms in the logistic regression between HPV status and the tumor parameters pT, Grade, and LVI (all P > .2). CONCLUSIONS: This study found that prognosis of the TNM stage groups and the components pT, Grade, LVI, and pN were not modified by HPV in PSCC. The value of pT, Grade, and LVI for predicting lymph node-positive disease was not affected by HPV status.

Long-term follow-up of IgA nephropathy: clinicopathological features and predictors of outcomes.

Background: The establishment of the Oxford classification and newly developed prediction models have improved the prognostic information for immunoglobulin A nephropathy (IgAN). Considering new treatment options, optimizing prognostic information and improving existing prediction models are favorable. Methods: We used random forest survival analysis to select possible predictors of end-stage kidney disease among 37 candidate variables in a cohort of 232 patients with biopsy-proven IgAN retrieved from the Norwegian Kidney Biopsy Registry. The predictive value of variables with relative importance >5% was assessed using concordance statistics and the Akaike information criterion. Pearson's correlation coefficient was used to identify correlations between the selected variables. Results: The median follow-up period was 13.7 years. An isolated analysis of histological variables identified six variables with relative importance >5%: T %, segmental glomerular sclerosis without characteristics associated with other subtypes (not otherwise specified, NOS), normal glomeruli, global sclerotic glomeruli, segmental adherence and perihilar glomerular sclerosis. When histopathological and clinical variables were combined, estimated glomerular filtration rate (eGFR), proteinuria and serum albumin were added to the list. T % showed a better prognostic value than tubular atrophy/interstitial fibrosis (T) lesions with C-indices at 0.74 and 0.67 and was highly correlated with eGFR. Analysis of the subtypes of segmental glomerulosclerosis (S) lesions revealed that NOS and perihilar glomerular sclerosis were associated with adverse outcomes. Conclusions: Reporting T lesions as a continuous variable, normal glomeruli and subtypes of S lesions could provide clinicians with additional prognostic information and contribute to the improved performance of the Oxford classification and prognostic tools.

Penile Cancers Attributed to Human Papillomavirus Are Associated with Improved Survival for Node-positive Patients. Findings from a Norwegian Cohort Study Spanning 50 Years.

BACKGROUND: Human papillomavirus (HPV) infection is a risk factor for the development of penile squamous cell carcinoma (PSCC). It remains inconclusive whether HPV-related PSCC has a different prognosis from non-HPV-related PSCC. OBJECTIVE: To investigate the relationship between HPV status and survival as well as temporal changes in the proportion of HPV-related PSCC. DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort of 277 patients treated in Norway between 1973 and 2022 was investigated for HPV DNA in tumor tissue. Clinicopathological variables and disease course were registered. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Kaplan-Meier curves and Cox regression were used to investigate the determinants of cancer-specific survival (CSS). The chi-square test for trend in proportions enabled investigation of temporal changes in the HPV-related proportion of PSCC patients treated in Western Norway (n = 211). RESULTS AND LIMITATIONS: HPV DNA was detected in tumor tissue from 131 (47%) patients. Stratified by HPV status, 5-yr CSS did not differ between groups (p = 0.37). When investigating only node-positive patients, however, presence of HPV DNA was an independent predictor of better survival in multivariable Cox regression after adjustment for age, nodal stage, and adjuvant therapy (hazard ratio 0.54, 95% confidence interval: [0.30-0.99], p = 0.04). In cases from Western Norway, an increasing proportion of HPV-related cases over time was found (p = 0.01). The main limitation is the retrospective study design. CONCLUSIONS: HPV DNA in tumor tissue was associated with significantly better CSS for node-positive patients. The proportion of HPV DNA-positive PSCC has increased significantly in Western Norway over the past 50 yr. PATIENT SUMMARY: We investigated the impact of human papillomavirus (HPV) on the survival of penile cancer patients treated over a 50-yr period in Norway. We found that for patients with lymph node metastasis, survival was better for HPV-related cases. We also found that the proportion of cases due to HPV has increased in Western Norway.

Long-term risk of ESRD in IgAN; validation of Japanese prognostic model in a Norwegian cohort.

BACKGROUND: Recently, a Japanese model used to predict 10-year risk of end-stage renal disease (ESRD) in IgA nephropathy (IgAN) patients was published. We tested the applicability of the Japanese model in predicting 10- to 20-year risk of ESRD and all-cause mortality in a cohort of Norwegian IgAN patients. METHODS: A cohort of IgAN patients (1988-2004) were identified in the Norwegian Kidney Biopsy Registry (NKBR) and ESRD or death during follow-up through 2008 was identified through record linkage with the Norwegian Renal Registry (ESRD) and the Norwegian Population Registry (deaths). Data from the NKBR were used to classify patients into nine different prognostic groups (0-1, 1-5, 5-10, 10-20, 20-30, 30-50, 50-70, 70-90 and >90% risk of ESRD) according to the Japanese prognostic model. The predicted risk was compared to the measured risk of ESRD in the different prognostic groups. RESULTS: In eight of the nine risk groups, representing 597/633 (94%) of the patients in our cohort, the observed 10-year risk was within or close to the expected 10-year risk of ESRD. ESRD occurring after >10 years of observation was most frequent in the groups with 5-30% expected risk at 10 years of follow-up. A close association between risk of ESRD and risk of death prior to ESRD was observed. CONCLUSIONS: The Japanese prognostic model is applicable to predict 10-year risk of ESRD in Norwegian IgAN patients. A new finding in the present study is that the model can also be used to predict which patients have the highest risk of developing ESRD after 10-20 years of follow-up as well as all-cause mortality risk.

Obesity is associated with an improved cancer-specific survival, but an increased rate of postoperative complications after surgery for renal cell carcinoma.

OBJECTIVE: This study aimed to assess the impact of preoperative body mass index (BMI) on postoperative complications, cancer-specific survival (CSS) and overall survival (OS) in patients operated for renal cell carcinoma (RCC). MATERIAL AND METHODS: The study included 397 patients with BMI values, who underwent surgery for RCC between 1 January 1997 and 31 December 2010. Obese patients (BMI > 30 kg/m(2)) were compared to non-obese patients (BMI < 30 kg/m(2)) in regard to CSS and OS. A Cox proportional hazard model was used for the multivariate survival analyses. The mean age of the patients was 62.1 years. There were 259 males (65%) and 325 patients (82%) were non-obese. Mean BMI was 26 kg/m(2). RESULTS: In the total material, CSS was 94.7% for obese patients and 74.8% for non-obese patients (p = 0.06). The obese group had significantly better CSS in univariate analysis for presumed radically treated disease (pT1-3N0M0). Obesity was a significant protective prognostic factor in multivariate analysis. An accelerating protective effect for CSS was found with increasing levels of BMI. In regard to OS, no difference was found between the two groups. Obese patients had a significantly lower age, and a higher rate of diabetes mellitus, hypertension and incidental detection. Obese patients had a significantly higher total incidence of postoperative complications, but not surgery-related complications. CONCLUSIONS: In this material, increasing BMI was associated with improved CSS for presumed radically treated patients. However, obese patients had a higher total rate of postoperative complications.

A multiomics disease progression signature of low-risk ccRCC.

Clear cell renal cell carcinoma (ccRCC) is the most common renal cancer. Identification of ccRCC likely to progress, despite an apparent low risk at the time of surgery, represents a key clinical issue. From a cohort of adult ccRCC patients (n = 443), we selected low-risk tumors progressing within a 5-years average follow-up (progressors: P, n = 8) and non-progressing (NP) tumors (n = 16). Transcriptome sequencing, miRNA sequencing and proteomics were performed on tissues obtained at surgery. We identified 151 proteins, 1167 mRNAs and 63 miRNAs differentially expressed in P compared to NP low-risk tumors. Pathway analysis demonstrated overrepresentation of proteins related to "LXR/RXR and FXR/RXR Activation", "Acute Phase Response Signaling" in NP compared to P samples. Integrating mRNA, miRNA and proteomic data, we developed a 10-component classifier including two proteins, three genes and five miRNAs, effectively differentiating P and NP ccRCC and capturing underlying biological differences, potentially useful to identify "low-risk" patients requiring closer surveillance and treatment adjustments. Key results were validated by immunohistochemistry, qPCR and data from publicly available databases. Our work suggests that LXR, FXR and macrophage activation pathways could be critically involved in the inhibition of the progression of low-risk ccRCC. Furthermore, a 10-component classifier could support an early identification of apparently low-risk ccRCC patients.

Progressive podocyte injury and globotriaosylceramide (GL-3) accumulation in young patients with Fabry disease.

Progressive renal failure often complicates Fabry disease, the pathogenesis of which is not well understood. To further explore this we applied unbiased stereological quantitative methods to electron microscopic changes of Fabry nephropathy and the relationship between parameters of glomerular structure and renal function in 14 young Fabry patients (median age 12 years). Renal biopsies were obtained shortly before enzyme replacement therapy from these patients and from nine normal living kidney donors as controls. Podocyte globotriaosylceramide (GL-3) inclusion volume density increased progressively with age; however, there were no significant relationships between age and endothelial or mesangial inclusion volume densities. Foot process width, greater in male Fabry patients, also progressively increased with age compared with the controls, and correlated directly with proteinuria. In comparison to the biopsies of the controls, endothelial fenestration was reduced in Fabry patients. Thus, our study found relationships between quantitative parameters of glomerular structure in Fabry nephropathy and age, as well as urinary protein excretion. Hence, podocyte injury may play a pivotal role in the development and progression of Fabry nephropathy.

Pre-transplant course and risk of kidney transplant failure in IgA nephropathy patients.

BACKGROUND: There is lack of knowledge to what degree clinical/morphological presentation and course of IgA nephropathy (IgAN) prior to end-stage renal disease are risk factors for graft loss after kidney transplantation. MATERIAL AND METHODS: Patients with IgAN between 1988 and 2006 (registered in the Norwegian Kidney Biopsy Registry) who later received a kidney transplant (registered in the Norwegian Renal Registry) were included. The cohort was followed up regarding death-censored graft loss throughout 2008. Graft survival with a rapid progressive (RP) vs. a slow progressive (SP) course of pre-Tx IgAN (annual GFR > or <30 mL/min/1.73 m(2) ) was studied. RESULTS: Among 106 included patients, there were 14 graft losses giving a graft loss rate of 1.9/100 patient years. Follow-up until the first kidney transplant was 6.9 ± 4.4 (range 0.1-19) yr. Patients with pre-Tx RP had a higher graft loss rate compared with SP patients (6.3 vs.1.3/100 patient years, p < 0.001). Graft loss rate with living-related donor (LRD) was similar to unrelated donor (UD) grafts. Most RP patients had received LRD grafts, and in SP patients, graft survival with LRD grafts was better than UD grafts (0.3 vs.2.1/100 patient years, p = 0.055). CONCLUSIONS: A rapid pre-transplant course is a strong risk factor for transplant failure in patients with IgAN.

The RB (pRb2/p16) and p53 (p14/p53/p21) tumor-suppressor pathways in endemic Burkitt lymphoma.

Burkitt lymphoma accounts for approximately 50% of pediatric cancers in equatorial Africa and a majority of NHL in Uganda. The aim of the study was to examine the expression profile of the RB (pRb2 or p16) and p53 (p53, p14, or p21) pathways in biopsies of endemic BL, and compare it to the pattern found in reactive lymphoid hyperplasia (RLH). A total of 51 BL and 10 RLH biopsy specimens were included in the study. p16 expression was found in 8 (16.3%) BL and 2 (20%) RLH cases. p27 was revealed in 29 (65.9%)BL and 9(90%) RLH cases, whereas 29(59.2%) BL and only 1 RLH expressed p53. Positivity for pRb2 was found in 42 (84.0%) of the BL and 8(80%)of the RLH cases. p21 and p14 were negative in all BL and RLH cases. In conclusion, our data indicate that heterogeneous RB (pRb2 or p16) and p53 (p53, p14, or p21) pathway alterations occur frequently in BL. Except for a much higher frequency of p53 protein expression in BL, close similarities were found between BL and RLH.

Previous preeclampsia and risk for progression of biopsy-verified kidney disease to end-stage renal disease.

BACKGROUND: A recent study has shown that preeclampsia is an important risk marker for end-stage renal disease (ESRD), but the underlying mechanisms are unclear. The present study investigated whether previous preeclampsia was associated with progression of established kidney disease. Material and methods. Data from the Norwegian Kidney Biopsy Registry and the Medical Birth Registry of Norway were linked. We included women who, after their last pregnancy, had had a representative kidney biopsy in 1988-2005. Women were followed up for the development of ESRD using data from the Norwegian Renal Registry. Baseline was set at the time of biopsy and Cox regression statistics were performed. RESULTS: Of the 582 included women, 76 developed ESRD 3.9 ± 3.4 years (range, 0.08-16 years) after diagnosis. Mean age at first birth was 24.0 ± 4.8 years and at the time of diagnosis 41.3 ± 9.7 years. Women with clinically diagnosed preeclampsia in their first pregnancy had a relative risk of ESRD of 1.2 (95% CI, 0.63-2.4) and women with preterm birth had a relative risk of 2.1 (95% CI, 1.2-3.9). After extensive adjustments for clinical and histopathological variables at the time of diagnosis, the relative risks were 1.1 (95% CI, 0.50-2.6) and 2.4 (95% CI, 1.2-4.6), respectively. Compared to women with a first term birth without preeclampsia, women with term preeclampsia were diagnosed at a younger age (36 vs 42 years) and women with preterm birth without preeclampsia had a lower estimated glomerular filtration rate at diagnosis (48 vs 64 ml/min/1.73 m(2)). CONCLUSION: In women with kidney disease diagnosed at kidney biopsy, previous preeclampsia does not seem to be a risk marker for progression to ESRD.