Leif Bostad

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.

Renal Biopsy Findings in Children and Adolescents With Fabry Disease and Minimal Albuminuria

BACKGROUND Information concerning renal pathological characteristics in Fabry disease in childhood is limited. Our objective is to define renal morphological abnormalities in children and adolescents with Fabry disease and minimal proteinuria. STUDY DESIGN Case series. SETTING & PARTICIPANTS 9 symptomatic patients (7 males, 2 females; age range, 7 to 18 years); 2 patients had received enzyme replacement therapy for 2 years. OUTCOMES & MEASUREMENTS Renal morphological changes assessed by using light and electron microscopy. RESULTS All patients had acroparesthesia and typical eye changes, 7 showed hypohidrosis, 7 had gastrointestinal problems, and 2 had typical angiokeratomas. Mean albumin-creatinine ratio was 38 mg/g [corrected] (range, 5.3 to 104.3 mg/g). [corrected] Measured glomerular filtration rate was normal in all patients. Light microscopy showed changes in glomerular, tubulointerstitial, or vascular compartments alone or in combination in 7 patients. Electron microscopy showed lesions in all patients. LIMITATIONS Small sample size. CONCLUSIONS Glomerular and vascular changes are present before progression to overt proteinuria and decreased glomerular filtration rate. The combination of acroparesthesia and mild albuminuria, glomerular endothelial cell deposits, and arteriopathy may constitute a clinical and morphological combination heralding a potentially progressive renal disease.

Safety and Complications of Percutaneous Kidney Biopsies in 715 Children and 8573 Adults in Norway 1988–2010

BACKGROUND AND OBJECTIVES Skepticism about performing renal biopsies is often because of uncertainty regarding risk of complications. The aim of this study was to evaluate safety and relevant complications of renal biopsies in pediatric and adult patients in a large national registry study. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Kidney biopsies reported in the Norwegian Kidney Biopsy Registry from 1988 to 2010 were included. Risk factors for major complications (blood transfusion and/or surgical or catheter intervention) were analyzed using logistic regression statistics. RESULTS Of the 9288 biopsies included, 715 were from children, and 8573 were from adults (≥18 years). Median age was 49 years (range=2 weeks to 94 years). Gross hematuria appeared after biopsy in 1.9% of the patients; 0.9% of patients needed blood transfusion, and 0.2% of patients needed surgical intervention/catheterization. The frequencies were 1.9%, 0.9%, and 0.2% in adults and 1.7%, 0.1% and 0.1% in children, respectively; 97.9% of the biopsies were without complications. In unadjusted analyses, risk factors for major complications were age>60 years, estimated GFR<60 ml/min per 1.73 m(2), systolic hypertension, acute renal failure, and smaller clinical center size (<30 biopsies/yr). Adjusted analyses (adjusted for age and/or estimated GFR) showed higher odds ratios (OR) only for smaller clinical center (OR=1.60 [1.02-2.50]) and low estimated GFR (estimated GFR=30-59 ml/min per 1.73 m(2) [OR=4.90 (1.60-14.00)] and estimated GFR<30 ml/min per 1.73 m(2) [OR 15.50 (5.60-43.00)]). CONCLUSIONS Percutaneous renal biopsy is a low-risk procedure in all ages. Reduced estimated GFR and smaller center size are associated with an increased risk of major complications.

Observation Should be Considered as an Alternative in Management of Renal Masses in Older and Comorbid Patients

BACKGROUND Renal masses diagnosed in older and comorbid patients represent a challenge with regard to treatment. OBJECTIVE To evaluate clinical outcome and tumor progression in patients with renal masses managed by observation due to age and comorbidity. DESIGN, SETTING, AND PARTICIPANTS The medical records of 63 consecutive patients with renal masses primarily managed by observation during 2002-2007 were reviewed retrospectively and analyzed. The mean age for all patients at diagnosis was 76.6 yr, and 59% were male. Mean tumor size was 4.3 cm in diameter at diagnosis. Of these, 30% had Eastern Cooperative Oncology Group performance status (PS) of 2 or 3, 78% were American Society of Anesthesiologists (ASA) class 3, and the patients had a mean of 2.8 other medical conditions. MEASUREMENTS Registration of age, ASA class, PS, comorbid conditions, computed tomography scans, primary tumor size, tumor growth rate, pathology parameters, observation time, survival time. RESULTS AND LIMITATIONS Five-year overall survival (OS) and cancer-specific survival (CSS) rates were 42.8% and 93.3%, respectively. For tumors < or =4.0 cm in size, 5-yr CSS was 100%. Nine patients received delayed radical treatment, none of whom had later progression of the disease. In 18 patients histopathologic diagnosis of the renal masses were available, and in 15 patients (83%) renal cell carcinoma (RCC) was verified. The annual growth rate was <1cm/yr in 85.4% of the cases. In tumors < or =4.0 cm, only 1 of 27 tumors (3.7%) grew faster than 1cm/yr. CONCLUSIONS Management of renal masses by observation among older and comorbid patients seems to give acceptable results with regard to OS and CSS rates after 5 yr. The risk of disease progression is significantly higher in patients with larger sized renal masses (>4 cm). Thus, selection for observation in this group has to be stricter than in a group of patients with smaller sized renal masses (< or =4.0 cm).

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.

Scoring system for renal pathology in Fabry disease: report of the International Study Group of Fabry Nephropathy (ISGFN)

BACKGROUND In Fabry nephropathy, alpha-galactosidase deficiency leads to accumulation of glycosphingolipids in all kidney cell types, proteinuria and progressive loss of kidney function. METHODS An international working group of nephrologists from 11 Fabry centres identified adult Fabry patients, and pathologists scored histologic changes on renal biopsies. A standardized scoring system was developed with a modified Delphi technique assessing 59 Fabry nephropathy cases. Each case was scored independently of clinical information by at least three pathologists with an average final score reported. RESULTS We assessed 35 males (mean age 36.4 years) and 24 females (43.9 years) who mostly had clinically mild Fabry nephropathy. The average serum creatinine was 1.3 mg/dl (114.9 micromol/l); estimated glomerular filtration rate was 81.7 ml/min/1.73 m(2) and urine protein to creatinine ratio was 1.08 g/g (122.0 mg/mmol). Males had greater podocyte vacuolization on light microscopy (mean score) and glycosphingolipid inclusions on semi-thin sections than females. Males also had significantly more proximal tubule, peritubular capillary and vascular intimal inclusions. Arteriolar hyalinosis was similar, but females had significantly more arterial hyalinosis. Chronic kidney disease stage correlated with arterial and glomerular sclerosis scores. Significant changes, including segmental and global sclerosis, and interstitial fibrosis were seen even in patients with stage 1-2 chronic kidney disease with minimal proteinuria. CONCLUSIONS The development of a standardized scoring system of both disease-specific lesions, i.e. lipid deposition related, and general lesions of progression, i.e. fibrosis and sclerosis, showed a spectrum of histologic appearances even in early clinical stage of Fabry nephropathy. These findings support the role of kidney biopsy in the baseline evaluation of Fabry nephropathy, even with mild clinical disease. The scoring system will be useful for longitudinal assessment of prognosis and responses to therapy for Fabry nephropathy.

Adverse Perinatal Outcome and Later Kidney Biopsy in the Mother

Strong associations of adverse perinatal outcomes have been identified with later cardiovascular disease in the mother. Few studies have addressed associations with kidney disease. This study investigated whether perinatal outcomes are associated with later clinical kidney disease as diagnosed by kidney biopsy. The Medical Birth Registry of Norway contains data on all childbirths in Norway since 1967. The Norwegian Kidney Biopsy Registry contains data on all kidney biopsies in Norway since 1988. All women with a first singleton delivery from 1967 to 1998 were included. Pregnancy-related predictors of later kidney biopsy were analyzed by Cox regression analyses. A total of 756,420 women were included, and after a mean period of 15.9+/-9.4 yr, 588 had a kidney biopsy. Compared with women without preeclampsia and with offspring with birth weight of >or=2.5 kg, women with no preeclampsia and with offspring with birth weight of 1.5 to 2.5 kg had a relative risk (RR) for a later kidney biopsy of 1.7, women with no preeclampsia and with offspring with birth weight of <1.5 kg had an RR of 2.9, women with preeclampsia and with offspring with a birth weight of >or=2.5 kg had an RR of 2.5, women with preeclampsia and with offspring with a birth weight of 1.5 to 2.5 kg had an RR of 4.5, and women with preeclampsia and with offspring with a birth weight of <1.5 kg had an RR of 17. Similar results were found in adjusted analyses and after exclusion of women with diabetes, kidney disease, or rheumatic disease before pregnancy. The same risk patterns applied to any of the specific categories of kidney disease as well as specific kidney diseases investigated. Women who have preeclampsia and give birth to offspring with low birth weight and short gestation have a substantially increased risk for having a later kidney biopsy.

The Expression of Thrombospondin-1 and p53 in Clear Cell Renal Cell Carcinoma: Its Relationship to Angiogenesis, Cell Proliferation and Cancer Specific Survival

PURPOSE We evaluated possible associations among thrombospondin-1, p53 expression, microvessel density, cell proliferation index, nuclear grade, tumor stage and continuously coded tumor size in clear cell renal cell carcinoma. The value of thrombospondin-1 as a prognostic marker in clear cell renal cell carcinoma was examined. MATERIALS AND METHODS A total of 172 consecutive patients with clear cell renal cell carcinoma treated with radical nephrectomy were initially enrolled in the study. However, due to technical problems and lack of material 12 cases were excluded from analysis. A total of 68 patients (43%) died of renal cell carcinoma and 46 (29%) died of other diseases. Median followup for the surviving 42 patients (29%) was 13.8 years. The expression of thrombospondin-1, Ki-67 (proliferation index), p53 and microvessel density were analyzed without knowledge of the clinical outcome on formalin fixed, paraffin embedded tissues. RESULTS Low expression of thrombospondin-1 was significantly associated with advanced stage (p <0.001), high nuclear grade (p = 0.001), positive p53 status (p <0.001), high proliferation index (p = 0.001), high microvessel density (p = 0.036) and tumor progression (p = 0.006). On univariate analysis thrombospondin-1, microvessel density, proliferation index, p53 over expression, TNM stage, Fuhrman nuclear grade (p <0.001) and continuously coded tumor size (p = 0.002) had a significant impact on survival. Multivariate analysis revealed TNM stage, thrombospondin-1, p53, Ki-67 (proliferation index) and microvessel density were independent predictors of cancer specific survival. CONCLUSIONS Thrombospondin-1 expression is strongly associated with prognostic tumor features in clear cell renal cell carcinoma and is an independent prognostic factor for cancer specific survival. Our findings revealed a significant correlation among p53, proliferation index, microvessel density and thrombospondin-1 expression, and indicate that thrombospondin-1 may have an impact on angiogenesis, proliferation and tumor aggressiveness in clear cell renal cell carcinoma.

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

Abstract 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/m2) were compared to non-obese patients (BMI < 30 kg/m2) 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/m2. 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.

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.