Glomerular proteomic profiling reveals early differences between preexisting and de novo type 2 diabetes in human renal allografts.

BACKGROUND: Diabetes mellitus (DM), either preexisting or developing after transplantation, remains a crucial clinical problem in kidney transplantation. To obtain insights into the molecular mechanisms underlying PTDM development and early glomerular damage before the development of histologically visible diabetic kidney disease, we comparatively analysed the proteome of histologically normal glomeruli from patients with PTDM and normoglycaemic (NG) transplant recipients. Moreover, to assess specificities inherent in PTDM, we also comparatively evaluated glomerular proteomes from transplant recipients with preexisting type 2 DM (T2DM). METHODS: Protocol biopsies were obtained from adult NG, PTDM and T2DM patients one year after kidney transplantation. Biopsies were formalin-fixed and embedded in paraffin, and glomerular cross-sections were microdissected. A total of 4 NG, 7 PTDM and 6 T2DM kidney biopsies were used for the analysis. The proteome was determined by liquid chromatography-tandem mass spectrometry. Relative differences in protein abundance and significantly dysregulated pathways were analysed. RESULTS: Proteins involved in cell adhesion, immune response, leukocyte transendothelial filtration, and cell localization and organization were less abundant in glomeruli from PTDM patients than in those from NG patients, and proteins associated with supramolecular fibre organization and protein-containing complex binding were more abundant in PTDM patients. Overall, proteins related to adherens and tight junctions and those related to the immune system, including leukocyte transendothelial migration, were more abundant in NG patients than in transplanted patients with DM, irrespective of the timing of its development. However, proteins included in cell‒cell junctions and adhesion, insulin resistance, and vesicle-mediated transport were all less abundant in PTDM patients than in T2DM patients. CONCLUSIONS: The glomerular proteome profile differentiates PTDM from NG and T2DM, suggesting specific pathogenetic mechanisms. Further studies are warranted to validate these results, potentially leading to an improved understanding of PTDM kidney transplant pathophysiology and to the identification of novel biomarkers.

Proteomic signature of tubulointerstitial tissue predicts prognosis in IgAN.

BACKGROUND: IgA nephropathy (IgAN) is associated with a significant risk of progression to kidney failure. Tubular atrophy is an established important risk factor for progressive disease, but few studies have investigated tubulointerstitial molecular markers and mechanisms of progression in IgAN. METHODS: Based on data from the Norwegian Renal Registry, two groups were included: IgAN patients with (n = 9) or without (n = 18) progression to kidney failure during 10 years of follow-up. Tubulointerstitial tissue without discernible interstitial expansion or pronounced tubular alterations was microdissected, proteome was analysed using tandem mass spectrometry and relative protein abundances were compared between groups. RESULTS: Proteome analyses quantified 2562 proteins with at least 2 unique peptides. Of these, 150 proteins had significantly different abundance between progressive and non-progressive IgAN patients, 67 were more abundant and 83 less abundant. Periostin was the protein with the highest fold change between progressive and non-progressive IgAN (fold change 8.75, p < 0.05) and periostin staining was also stronger in patients with progressive vs non-progressive IgAN. Reactome pathway analyses showed that proteins related to inflammation were more abundant and proteins involved in mitochondrial translation were significantly less abundant in progressive vs non-progressive patients. CONCLUSIONS: Microdissection of tubulointerstitial tissue with only mild damage allowed for identification of proteome markers of early progressive IgAN. Periostin abundance showed promise as a novel and important risk marker of progression.

Low birthweight is associated with lower glomerular filtration rate in middle-aged mainly healthy women.

BACKGROUND: Low birthweight (LBW) has been shown to increase the risk of severe kidney disease. Studies have also shown associations between LBW and lower estimated glomerular filtration rate (GFR) in young adults. In this study we investigated whether LBW associates with measured GFR (mGFR) in middle-aged mainly healthy adults. METHODS: We invited individuals with LBW (1100-2300 g) and individuals with normal BW (NBW; 3500-4000 g) ages 41-52 years. GFR was measured using plasma clearance of iohexol. BW and BW for gestational age (BWGA) were obtained from the Medical Birth Registry of Norway and tested as main predictors. GFR was the main outcome. RESULTS: We included 105 individuals (57 LBW and 48 NBW). The mean GFR was 95 ± 14 mL/min/1.73 m2 in the LBW group and 100 ± 13 mL/min/1.73 m2 in the NBW group (P = 0.04). There was a significant sex difference: in women the mean GFR was 90 ± 12 versus 101 ± 14 mL/min/1.73 m2 in the LBW and NBW groups, respectively (P = 0.006), whereas corresponding values for men were 101 ± 15 versus 100 ± 11 mL/min/1.73 m2 (P = 0.7). Using linear regression, we found the GFR was 4.5 mL/min/1.73 m2 higher per 1 kg higher BW for women (P = 0.02), with a non-significant 1.2 mL/min/1.73 m2 lower GFR for men (P = 0.6). In analyses of BWGA, there was also a significant association for women, but not for men. CONCLUSIONS: Middle-aged mainly healthy women with LBW had lower mGFR as compared with women with NBW. No such difference was found for men.

A woman in her fifties with abdominal pain and severe lactic acidosis. / En kvinne i 50-årene med magesmerter og alvorlig laktacidose.

BACKGROUND: Pheochromocytoma is referred to as 'the great mimic' with a broad spectrum of presenting symptoms. In the following case, the diagnosis had an unusual presentation as a medical emergency - pheochromocytoma crisis. CASE PRESENTATION: A previously healthy woman in her fifties was admitted due to abdominal pain and dyspnoea. At admission she was haemodynamically stable, with stable respiration, but arterial blood gas showed serious lactic acidosis with pH 6.8 (7.35-7.45), HCO3 3 mmol/l (22-26) and lactate 28 mmol/L (0.4-1.8). Her haemoglobin level was 12 g/dl (11,7-17,0). Further examination with CT and gastroscopy confirmed a duodenal bleeding. The lactic acidosis was corrected quickly, but the patient developed acute kidney injury, rhabdomyolysis and increased liver enzymes. The complex composition of organ manifestations could not be explained by the duodenal bleeding alone. An adrenal mass with high density was identified through re-evaluation of the CT scans. In the following case, a duodenal bleeding provoked catecholamine-induced haemodynamic instability and end-organ damage in a patient with an undiagnosed pheochromocytoma. INTERPRETATION: Endocrine emergencies are important differential diagnoses in critically ill patients. Pheochromocytoma crisis most commonly presents as hypertensive crisis or catecholamine cardiomyopathy but can also lead to lactic acidosis and multi-organ failure.

Intrauterine growth restriction, preterm birth and risk of end-stage renal disease during the first 50 years of life.

BACKGROUND: Low birth weight (LBW) is associated with a higher risk of end-stage renal disease (ESRD). The relative impacts of absolute birth weight, birth weight in relation to gestational age and preterm birth are, however, uncertain. METHODS: The Medical Birth Registry of Norway has since 1967 recorded data on all births. All patients with ESRD since 1980 have been registered in the Norwegian Renal Registry. Data from these registries were linked. All individuals registered in the Medical Birth Registry were included and the development of ESRD was used as endpoint in Cox regression statistics. LBW and LBW for gestational age [small for gestational age (SGA)] according to the 10th percentiles were used as the main predictor variables. RESULTS: Of the 2 679 967 included subjects, 1181 developed ESRD. Compared with subjects without LBW, subjects with LBW had an adjusted hazard ratio (aHR) for ESRD of 1.61 (1.38-1.98). SGA had an aHR of 1.44 (1.22- 1.70). Further analyses showed that as compared with subjects who had none of the risk factors LBW, SGA and preterm birth, subjects with one risk factor had an aHR of 1.05 (0.84-1.31), subjects with two risk factors had an aHR of 1.67 (1.40-1.98) and subjects with three risk factors had an aHR of 2.96 (1.84-4.76). CONCLUSIONS: We conclude that LBW was associated with increased risk for ESRD during the first 50 years. Our analyses add to previous knowledge showing that only subjects with at least two of the risk factors LBW, SGA or preterm birth have increased risk.

Transcriptome-proteome integration of archival human renal cell carcinoma biopsies enables identification of molecular mechanisms.

Renal cell cancer is among the most common forms of cancer in humans, with around 35,000 deaths attributed to kidney carcinoma in the European Union in 2012 alone. Clear cell renal cell carcinoma (ccRCC) represents the most common form of kidney cancer and the most lethal of all genitourinary cancers. Here, we apply omics technologies to archival core biopsies to investigate the biology underlying ccRCC. Knowledge of these underlying processes should be useful for the discovery and/or confirmation of novel therapeutic approaches and ccRCC biomarker development. From partial or full nephrectomies of 11 patients, paired core biopsies of ccRCC-affected tissue and adjacent ("peritumorous") nontumor tissue were both sampled and subjected to proteomics analyses. We combined proteomics results with our published mRNA sequencing data from the same patients and with published miRNA sequencing data from an overlapping patient cohort from our institution. Statistical analysis and pathway analysis were performed with JMP Genomics and Ingenuity Pathway Analysis (IPA), respectively. Proteomics analysis confirmed the involvement of metabolism and oxidative stress-related pathways in ccRCC, whereas the most affected pathways in the mRNA sequencing data were related to the immune system. Unlike proteomics or mRNA sequencing alone, a combinatorial cross-omics pathway analysis approach captured a broad spectrum of biological processes underlying ccRCC, such as mitochondrial damage, repression of apoptosis, and immune system pathways. Sirtuins, immunoproteasome genes, and CD74 are proposed as potential targets for the treatment of ccRCC.

Characterization of glomerular extracellular matrix in IgA nephropathy by proteomic analysis of laser-captured microdissected glomeruli.

BACKGROUND: IgA nephropathy (IgAN) involves mesangial matrix expansion, but the proteomic composition of this matrix is unknown. The present study aimed to characterize changes in extracellular matrix in IgAN. METHODS: In the present study we used mass spectrometry-based proteomics in order to quantitatively compare protein abundance between glomeruli of patients with IgAN (n = 25) and controls with normal biopsy findings (n = 15). RESULTS: Using a previously published paper by Lennon et al. and cross-referencing with the Matrisome database we identified 179 extracellular matrix proteins. In the comparison between IgAN and controls, IgAN glomeruli showed significantly higher abundance of extracellular matrix structural proteins (e.g periostin, vitronectin, and extracellular matrix protein 1) and extracellular matrix associated proteins (e.g. azurocidin, myeloperoxidase, neutrophil elastase, matrix metalloproteinase-9 and matrix metalloproteinase 2). Periostin (fold change 3.3) and azurocidin (3.0) had the strongest fold change between IgAN and controls; periostin was also higher in IgAN patients who progressed to ESRD as compared to patients who did not. CONCLUSION: IgAN is associated with widespread changes of the glomerular extracellular matrix proteome. Proteins important in glomerular sclerosis or inflammation seem to be most strongly increased and periostin might be an important marker of glomerular damage in IgAN.

Low birth weight associates with glomerular area in young male IgA nephropathy patients.

BACKGROUND: In a recent study we demonstrated that low birth weight (LBW) was associated with increased risk of progressive IgA nephropathy (IgAN). In the present study we investigate whether this could be explained by differences in glomerular morphological parameters. METHODS: The Medical Birth Registry of Norway has registered all births since 1967 and the Norwegian Kidney Biopsy Registry has registered all kidney biopsies since 1988. Patients diagnosed with IgAN, registered birth weight and estimated glomerular filtration rate above 60 ml/min/1.73m2 at time of diagnosis were eligible for inclusion. Patients were included in a case-control manner based on whether or not they had LBW or were small for gestational age (SGA). Glomerular area, volume and density were measured using high resolution digital images and differences were compared between groups. RESULTS: We included 51 IgAN patients with a mean age of 23.6 years, 47.1% male. Compared to IgAN patients without LBW or SGA, IgAN patients with LBW and/or SGA had larger glomerular area (16,235 ± 3744 vs 14,036 ± 3502 µm2, p-value 0.04). This was significant for total cohort and male but not female. On separate analysis by gender, glomerular area was significantly larger only in males (17,636 ± 3285 vs 13,346 ± 2835 µm2, p-value 0.004). Glomerular density was not different between groups. In adjusted linear regression analysis, glomerular area was negatively associated with birth weight. CONCLUSION: Among young adult IgAN patients, low birth weight is associated with having larger glomerular area, especially in males. Larger glomeruli may be a sign of congenital nephron deficit that may explain the increased risk of progressive IgAN.

Glomerular abundance of complement proteins characterized by proteomic analysis of laser-captured microdissected glomeruli associates with progressive disease in IgA nephropathy.

BACKGROUND: The clinical course of IgA nephropathy (IgAN) is variable and complement activation may predict prognosis. The present study investigated whether glomerular abundance of complement proteins associates with progression to end-stage renal disease (ESRD) in patients for whom prognosis could not be predicted based on clinical variables. METHODS: Based on data from the Norwegian Kidney Biopsy Registry and the Norwegian Renal Registry, three groups were included: IgAN patients with (n = 9) or without (n = 16) progression to ESRD during 10 years, and controls (n = 15) with a normal kidney biopsy. IgAN patients had eGFR > 45 ml/min/1.73 m2 and non-nephrotic proteinuria at time of biopsy. Using stored formalin-fixed paraffin embedded kidney biopsy tissue, about 100 glomerular cross sections were microdissected for each patient. Samples were analyzed by liquid chromatography-tandem mass spectrometry and relative abundances of complement proteins were compared between groups. RESULTS: Proteomic analyses quantified 2018 proteins, of which 28 proteins belong to the complement system. As compared to IgAN patients without progressive disease, glomeruli from patients with progressive IgAN had significantly higher abundance of components of the classical and the terminal complement pathways, and inhibitory factors such as Factor H and factor H related proteins. Abundance of complement proteins classified progressors from non-progressors with an area under ROC curve of 0.91 (p = 0.001). Clinical and morphological data were similar between the two patient groups and could not predict progressive IgAN. CONCLUSIONS: In conclusion, higher glomerular abundance of complement proteins was associated with a progressive clinical course in IgAN and are candidate biomarkers to predict prognosis.

Long-term outcome in 145 patients with assumed benign immunoglobulin A nephropathy.

BACKGROUND: Patients with immunoglobulin A nephropathy (IgAN) who present with mild to moderate proteinuria and normal renal function are assumed to have excellent short-term renal prognosis, but the long-term prognosis is uncertain. METHODS: Patients were selected from the Norwegian Kidney Biopsy Registry based on the following criteria: diagnostic renal biopsy performed in the period 1988-99, with estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 and proteinuria <1 g/24 h at the time of biopsy. Patients were invited for a nephrological examination with a review of medical history and investigation of blood pressure, urinary findings and eGFR. RESULTS: A total of 145 patients attended the examination, performed by the first author, after a median of 22 (interquartile range 19-25) years after diagnosis. At the examination, 27 patients (18.6%) had a ≥50% decrease in GFR, of whom 4 (2.8%) had developed end-stage renal disease (ESRD). The mean duration from renal biopsy to ≥ 50% decrease in GFR was 17.3 ± 5.1 years in our cohort. Clinical remission was observed in 42 (29.0%) patients. Renal biopsies were re-examined utilizing the Oxford classification criteria. Mesangial hypercellularity was found in 12.3%, endocapillary proliferation was detected in 10.7% and segmental glomerulosclerosis was observed in 23.8%. All biopsies were scored as T0 (tubular atrophy in < 25% of the cortical area). None of the clinical or histopathological variables recorded at the time of biopsy could identify patients with progressive disease. Cumulative risks of ≥50% decrease in eGFR were 2.1% after 10 years, 4.1% after 15 years, 13.9% after 20 years and 24.7% after 25 years. CONCLUSIONS: We have shown that 18.6% of patients with assumed benign IgAN had progressive disease after a median duration of 22 years and that these patients could not be predicted at the time of biopsy. Our study demonstrates that an extended follow-up period is needed when assessing prognosis in this group of patients.

Familial Factors, Low Birth Weight, and Development of ESRD: A Nationwide Registry Study.

BACKGROUND: Previous studies have demonstrated that low birth weight (LBW) is associated with higher risk for end-stage renal disease (ESRD). However, both LBW and ESRD cluster in families. The present study investigates whether familial factors explain the association between LBW and ESRD. STUDY DESIGN: Retrospective registry-based cohort study. SETTING & PARTICIPANTS: Since 1967, the Medical Birth Registry of Norway has recorded medical data for all births in the country. Sibling data are available through the Norwegian Population Registry. Since 1980, all patients with ESRD in Norway have been registered in the Norwegian Renal Registry. Individuals registered in the Medical Birth Registry with at least 1 registered sibling were included. PREDICTOR: LBW in the participant and/or LBW in at least 1 sibling. OUTCOME: ESRD. RESULTS: Of 1,852,080 included individuals, 527 developed ESRD. Compared with individuals without LBW and with no siblings with LBW, individuals without LBW but with a sibling with LBW had an HR for ESRD of 1.20 (95% CI, 0.91-1.59), individuals with LBW but no siblings with LBW had an HR of 1.59 (95% CI, 1.18-2.14), and individuals with LBW and a sibling with LBW had an HR of 1.78 (95% CI, 1.26-2.53). Similar results were observed for individuals who were small for gestational age (SGA). Separate analyses for the association of age 18 to 42 years and noncongenital ESRD showed stronger associations for SGA than for LBW, and the associations were not statistically significant for age 18 to 42 years for LBW. LIMITATIONS: Follow-up only until 42 years of age. CONCLUSIONS: LBW and SGA are associated with higher risk for ESRD during the first 40 years of life, and the associations were not explained by familial factors. Our results support the hypothesis that impaired intrauterine nephron development may be a causal risk factor for progressive kidney disease.

Addition of eGFR and Age Improves the Prognostic Absolute Renal Risk-Model in 1,134 Norwegian Patients with IgA Nephropathy.

BACKGROUND: Predicting outcome in individual patients with IgA nephropathy (IgAN) is difficult but important. For this purpose, the absolute renal risk (ARR) model has been developed in a French cohort to calculate the risk of end-stage renal disease (ESRD) and death. ARR (0-3) is scored in individual IgAN patients based on the presence of proteinuria ≥1 g/24 h, hypertension, and severe histopathological lesions (1 point per risk factor). We have validated the ARR model in a Norwegian cohort of IgAN patients and tested whether adding data on initial estimated glomerular filtration rate (eGFR) and age improved prediction. METHODS: IgAN patients diagnosed between 1988 and 2012 were identified in the Norwegian Kidney Biopsy Registry, and endpoints were identified by record linkage with the Norwegian Renal Registry (ESRD) and the Population Registry (deaths). RESULTS: We identified 1,134 IgAN patients. The mean duration of follow-up was 10.2 years (range 0.0 to 25.7 years). Two hundred and fifty one patients developed ESRD and there were 69 pre-ESRD deaths. The ARR model significantly stratified the IgAN cohort according to risk of ESRD/death. The inclusion of eGFR and age significantly improved the ARR prognostic model; in the receiver operator characteristics (ROC) analysis, area under the curve (AUC) at 10-years of follow-up increased from 0.79 to 0.89, p < 0.001. CONCLUSIONS: ARR is a suitable prognostic model for stratifying IgAN patients according to the risk of ESRD or death. Including initial eGFR and age in the model substantially improved its accuracy in our nationwide cohort.

Proteomic analysis of formalin-fixed paraffin-embedded glomeruli suggests depletion of glomerular filtration barrier proteins in two-kidney, one-clip hypertensive rats.

BACKGROUND: It is well known that hypertension may cause glomerular damage, but the molecular mechanisms involved are still incompletely understood. METHODS: In the present study, we used formalin-fixed paraffin-embedded (FFPE) tissue to investigate changes in the glomerular proteome in the non-clipped kidney of two-kidney one-clip (2K1C) hypertensive rats, with special emphasis on the glomerular filtration barrier. 2K1C hypertension was induced in 6-week-old Wistar Hannover rats (n = 6) that were sacrificed 23 weeks later and compared with age-matched sham-operated controls (n = 6). Tissue was stored in FFPE tissue blocks and later prepared on tissue slides for laser microdissection. Glomeruli without severe morphological damage were isolated, and the proteomes were analysed using liquid chromatography-tandem mass spectrometry. RESULTS: 2K1C glomeruli showed reduced abundance of proteins important for slit diaphragm complex, such as nephrin, podocin and neph1. The podocyte foot process had a pattern of reduced abundance of transmembrane proteins but unchanged abundances of the podocyte cytoskeletal proteins synaptopodin and α-actinin-4. Lower abundance of important glomerular basement membrane proteins was seen. Possible glomerular markers of damage with increased abundance in 2K1C were transgelin, desmin and acyl-coenzyme A thioesterase 1. CONCLUSIONS: Microdissection and tandem mass spectrometry could be used to investigate the proteome of isolated glomeruli from FFPE tissue. Glomerular filtration barrier proteins had reduced abundance in the non-clipped kidney of 2K1C hypertensive rats.

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.

Mortality in patients with IgA nephropathy.

BACKGROUND: Immunoglobulin A nephropathy (IgAN) is the most common glomerulonephritis globally. Few studies have investigated mortality in patients with IgAN compared with the age- and sex-adjusted general population. STUDY DESIGN: Cohort study with record linkage between the Norwegian Kidney Biopsy Registry, Norwegian Cause of Death Registry, and Norwegian Renal Registry. SETTING & PARTICIPANTS: 633 patients diagnosed with IgAN in 1988-2004. PREDICTOR: Estimated glomerular filtration rate (eGFR), age, and sex. OUTCOMES: Deaths and causes of death before and after the onset of end-stage renal disease through 2008. RESULTS: Mean follow-up was 11.8 (range, 0-20.8) years. During the observation period, the observed number of deaths was 80 and the expected number was 42.1, resulting in a standardized mortality ratio (SMR) of 1.9 (95% CI, 1.5-2.4). Risk stratification based on initial eGFR showed that SMR was 1.0 (95% CI, 0.6-1.6) if eGFR was ≥60 mL/min/1.73 m(2), 1.9 (95% CI, 1.3-2.8) if eGFR was 30-60 mL/min/1.73 m(2), and 3.6 (95% CI, 2.6-5.0) in patients with eGFR <30 mL/min/1.73 m(2). Renal replacement therapy (RRT) was initiated in 146 patients and 35 of the 80 deaths occurred after the start of RRT. The age- and sex-adjusted SMR was not increased significantly in the pre-RRT period (1.3; 95% CI, 1.0-1.7), but was increased after initiation of RRT (4.9; 95% CI, 3.5-7.0). The most common cause of death was cardiovascular disease, accounting for 45% of all deaths. LIMITATIONS: Treatment during follow-up is not known. CONCLUSIONS: Mortality in patients with IgAN was twice the expected rate, but not significantly increased before RRT. The risk of end-stage renal disease was substantially higher than risk of death.

Preeclampsia in healthy women and endothelial dysfunction 10 years later.

OBJECTIVE: Recent studies have shown that women with a history of preeclampsia have an increased risk of cardiovascular disease. The present study investigated cardiovascular risk factors 10 years after preeclampsia in previously healthy women. STUDY DESIGN: Based on data from the Medical Birth Registry in Norway, we selected 182 women with and 180 women without preeclampsia in their first pregnancy 9-11 years earlier, excluding women with cardiovascular or renal disease before pregnancy. Flow-mediated dilation of the brachial artery (FMD) and intima-media thickness (IMT) of the carotid artery were measured and blood samples were drawn. Blood samples were analyzed for cardiovascular risk markers and for circulating markers of endothelial function. RESULTS: A total of 89 women with previous preeclampsia and 69 women without preeclampsia participated, an overall attendance rate of 44%. FMD and IMT were similar between groups. Women with previous preeclampsia more often had urate and soluble fms-like tyrosine kinase values above the 75th percentile (odds ratio [OR], 2.4; P = .03, and OR, 2.4; P = .04, respectively) and high-density lipoprotein cholesterol values below the 25th percentile (OR, 2.3; P = .04). Women with preeclampsia with low birthweight offspring were associated with asymmetric dimethylarginine, L-arginine, and homoarginine above the 75th percentile, whereas the women with preeclampsia with normal-weight offspring were associated with urate and soluble fms-like tyrosine kinase above the 75th percentile. CONCLUSION: Preeclampsia was not associated with impaired FMD or increased IMT 10 years after pregnancy in previously healthy women, but preeclampsia was associated with changes in circulating markers that might represent early endothelial dysfunction.

Renal Functional Response-Association With Birth Weight and Kidney Volume.

Introduction: Renal functional response (RFR) is the acute increase in glomerular filtration rate (GFR) after a protein load. Low RFR is a marker of single nephron hyperfiltration. Low birth weight (LBW) is associated with reduced number of nephrons, lower kidney function, and smaller kidneys in adults. In the present study, we investigate the associations among LBW, kidney volume, and RFR. Methods: We studied adults aged 41 to 52 years born with either LBW (≤2300 g) or normal birth weight (NBW; 3500-4000 g). GFR was measured using plasma clearance of iohexol. A stimulated GFR (sGFR) was measured on a separate day after a protein load of 100 g using a commercially available protein powder, and RFR was calculated as delta GFR. Kidney volume was estimated from magnetic resonance imaging (MRI) images using the ellipsoid formula. Results: A total of 57 women and 48 men participated. The baseline mean ± SD GFR was 118 ± 17 ml/min for men and 98 ± 19 ml/min for women. The overall mean RFR was 8.2 ± 7.4 ml/min, with mean RFR of 8.3 ± 8.0 ml/min and 8.1 ± 6.9 ml/min in men and women, respectively (P = 0.5). No birth-related variables were associated with RFR. Larger kidney volume was associated with higher RFR, 1.9 ml/min per SD higher kidney volume (P = 0.009). Higher GFR per kidney volume was associated with a lower RFR, -3.3ml/min per SD (P < 0.001). Conclusion: Larger kidney size and lower GFR per kidney volume were associated with higher RFR. Birth weight was not shown to associate with RFR in mainly healthy middle-aged men and women.

Network-Based Assessment of Minimal Change Disease Identifies Glomerular Response to IL-7 and IL-12 Pathways Activation as Innovative Treatment Target.

Background: Minimal change disease (MCD), a major cause of nephrotic syndrome, is usually treated by corticosteroid administration. MCD unresponsiveness to therapy and recurrences are nonetheless frequently observed, particularly in adults. To explore MCD-related pathogenetic mechanisms and to identify novel drug targets ultimately contributing to novel therapeutic avenues with a certain specificity for MCD, we compared glomerular transcriptomes from MCD with membranous nephropathy (MN) patients and healthy controls. Methods: Renal biopsies from adult patients with MCD (n = 14) or MN (n = 12), and non-diseased controls (n = 8) were selected from the Norwegian Kidney Biopsy Registry. RNA for 75 base-pair paired-end RNASeq were obtained from laser capture micro-dissected (LCM) glomeruli from FFPE sections. Transcriptional landscapes were computed by combining pathway-centered analyses and network science methodologies that integrate multiple bioinformatics resources. Results: Compared to normal glomeruli, cells from MCD displayed an inflammatory signature apparently governed by the IL1 and IL7 systems. While enrichment of IL1 production and secretion was a shared feature of MCD and MN compared to normal tissue, responses involving IL7 pathway activation were unique to MCD. Indeed, IL7R expressed by glomeruli was the most upregulated gene of the interleukin family in MCD versus normal controls. IL7 pathway activation was paralleled by significant enrichment in adaptive immune system processes and transcriptional regulation and depletion in pathways related to energy metabolism and transcription. Downregulation of these organ function-related themes again occurred predominately in MCD and was significantly less pronounced in MN. Immunofluorescence and immunohistochemistry, respectively, confirmed the expression of phosphorylated IL-7 receptor alpha (IL7RA, CD127) and IL12 receptor beta 1 (IL12RB1) proteins. Conclusions: Gene expression profiling of archival FFPE-biopsies identifies MCD-specific signatures with IL7RA and IL12RB1 as novel targets for MCD treatment.

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.