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.

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.

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.

Birth Weight Is Associated With Kidney Size in Middle-Aged Women.

INTRODUCTION: Low birth weight (LBW) is associated with increased risk of kidney disease due to lower nephron endowment leading to hyperfiltration and subsequent nephron loss. Kidney size is commonly used as a proxy for nephron number. We compared kidney volume measured by magnetic resonance imaging (MRI) with measured glomerular filtration rate (mGFR) in adults with either normal birth weight (NBW) or low birth weight (LBW). METHODS: Healthy individuals aged 42 to 52 years with LBW (1100-2300 g) and NBW (3500 -4000 g) were invited to participate. The GFR was measured using plasma clearance of iohexol. Kidney volume was measured on magnetic resonance images using axial T2 images and coronal T1 images with fat saturation without contrast enhancement; calculations were performed according to the ellipsoid formula π/6 × length × width × depth. RESULTS: We included 102 individuals (54 LBW and 48 NBW). Total kidney volume was 302 ± 51 ml for female NBW vs 258 ± 48 ml for female LBW individuals (P = 0.002). For male individuals, total kidney volume was 347 ± 51 ml vs. 340 ± 65 ml (P = 0.7). The mGFR was significantly associated with kidney volume, with r = 0.52 (P < 0.001) for women and r = 0.39 (P = 0.007) for men. A mediation analysis showed that the association between birth weight and mGFR (significant in total sample and women) was mediated by kidney volume. CONCLUSION: Healthy female individuals born with LBW have smaller kidneys than healthy females born with NBW. The previously shown associations between LBW and lower mGFR in adult women might be explained by smaller kidney volume.

Familial Contributions to the Association Between Low Birth Weight and Risk of CKD in Adult Life.

INTRODUCTION: Previous studies have revealed that individuals with low birth weight (LBW) have higher risk of chronic kidney disease (CKD) and that LBW and CKD cluster in families. This study investigates how familial factors affect the association between birth-related risk markers and risk of CKD. METHODS: The Medical Birth Registry (MBR) of Norway has registered all births in Norway since 1967. Sibling data were available through the Norwegian Population Registry. The Norwegian Patient Registry has registered diagnostic codes for all admissions and outpatient visits to Norwegian hospitals since 2008. Data from these registries were linked. Risk of CKD according to whether the individual himself or at least one of his siblings had LBW was analyzed using logistic regression statistics. RESULTS: Of 1,847,565 individuals, 3336 had been diagnosed with CKD. Compared with individuals without LBW and no siblings with LBW, individuals without LBW but who had a sibling with LBW had adjusted odds ratio (aOR) of 1.33 (1.19-1.49), those with LBW but no siblings with LBW had aOR of 1.74 (1.55-1.95), and those with LBW and a sibling with LBW had aOR of 1.77 (1.54-2.04) for CKD. Similar results were found for LBW for gestational age, but preterm birth revealed weaker associations. CONCLUSION: Individuals who have a sibling with LBW have an increased risk of CKD later in life, and individuals who themselves have LBW have an even higher risk. Our findings suggest that there are familial contributions to the nephron endowment in utero hypothesis.

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.

Blood Pressure Treatment in Kidney Transplant Recipients-Can We Improve?

Hypertension in kidney transplant (KTx) recipients is common, affecting both patient and graft survival. Annual data from the Norwegian Renal Registry reveal that <50% of adult (>18 y) KTx recipients reach target blood pressure (BP) ≤130/80 mm Hg. The aim of this study was to identify the determinants of failure to achieve BP control. METHODS: In conjunction with the 2018 annual data reporting, additional questions were added for recipients with BP >130/80 mm Hg (treating physician´s target BP for each patient, reasons for not achieving target, method of measurement). RESULTS: Annual forms were received from 98% (3407 of 3486) of KTx recipients, with 1787 (52%) reporting a BP >130/80 mm Hg ("above-target" group). These recipients were older, mostly male, with higher body mass index and serum creatinine levels (P < 0.05) compared with patients with controlled hypertension ("on-target" group). Valid survey answers were available for 84% of the "above-target" group (Survresp) with no significant demographic differences versus nonresponders (Survnonresp). Among Survresp, 32% were under antihypertensive dose titration, whereas dose-limiting side effects were reported in 7%. Target BP was confirmed to 130/80 mm Hg for 60% of Survresp. In recipients for whom the treating physician set target BP >130/80 mm Hg, 51% did not reach these individual targets. The number of antihypertensive drugs was significantly higher in the "above-target" group versus "on-target" group (mean 2.1 ± 1.2 versus 1.8 ± 1.3) and 36% versus 25% used ≥3 antihypertensive drugs (P < 0.05). Automatic attended BP measurement was utilized by 51%. CONCLUSIONS: In KTx recipients, a higher BP target achievement seems possible, potentially in the range of 75%-80%.

Measurement of renal functional response using iohexol clearance-a study of different outpatient procedures.

BACKGROUND: Glomerular filtration rate (GFR) increases after a heavy protein load; an increase termed renal functional response (RFR). Decreased RFR could be a marker of early kidney damage, but published methods are cumbersome in the outpatient setting. The present study investigates the use of iohexol clearance to measure RFR in outpatients using both one- and two-sample methods. METHODS: Fourteen healthy volunteers with a mean ± SD age of 42 ± 12 years were included (six males and eight females). GFR was measured using plasma iohexol clearance with one- and two-sample methodologies. Four measurements in each individual were performed: one baseline test and three protein loading tests containing 80 g protein (commercially available protein supplementations from Myo Nutrition and Proteinfabrikken and 350 g chicken breast). RFR was calculated as percentage increase in GFR from the baseline test. RESULTS: Mean RFR was 11.4 ± 5.4% and 12.1 ± 6.4% using one- and two-sample methods, respectively. The three different protein loads resulted in similar mean RFR but there was considerable intra-individual variability. One- and two-sample methods for measurement of RFR showed similar results with near-identical means, but there was some intra-individual variation that was similar for different protein loads. The overall 95% limit of agreement between one- and two-sample methods for calculating RFR was -8.7 to 7.3. CONCLUSIONS: RFR can be investigated using plasma iohexol clearance in an outpatient setting. Protocols using commercially available protein supplementation showed a mean RFR of about 12%. One- and two-sample methods for measuring RFR yield similar results.

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.

Intrauterine Growth Restriction and Risk of Diverse Forms of Kidney Disease during the First 50 Years of Life.

BACKGROUND AND OBJECTIVES: Previous studies have shown that individuals with low birth weight (LBW) or small for gestational age (SGA) have higher risk of kidney failure. This study investigates birth-related exposures and risk of CKD and other kidney diagnoses. DESIGN, SETTING, PARTICIPANT, & MEASUREMENTS: The Medical Birth Registry of Norway has registered extensive medical data on all births in Norway since 1967. The Norwegian Patient Registry has registered diagnostic codes for all admissions and outpatient visits to Norwegian hospitals since 2008. Data from these registries were linked, and risk of CKD and other groups of kidney disease were analyzed using logistic regression statistics. LBW (below the tenth percentile), SGA (birth weight below the tenth percentile for gestational age), and preterm birth (<37 weeks) were analyzed as exposures. RESULTS: A total of 2,663,010 individuals were included. After a mean follow-up of 26 years (maximum 50 years), 4495 had been diagnosed with CKD and 12,818 had been diagnosed with other groups of kidney disease. LBW was associated with an odds ratio (OR) for CKD of 1.72 (95% confidence interval [95% CI], 1.60 to 1.90), SGA with an OR of 1.79 (95% CI, 1.65 to 1.94), and preterm birth with an OR of 1.48 (95% CI, 1.33 to 1.66). Analyses using diagnosis of CKD at stages 3-5 as end point showed similar results. Results were similar for men and women. We analyzed adjusted ORs for other groups of kidney disease and found that LBW was associated with an adjusted OR of 1.44 (95% CI, 1.33 to 1.56) for acute kidney disease, 1.24 (95% CI, 1.14 to 1.36) for GN, 1.35 (95% CI, 1.17 to 1.56) for cystic kidney disease, and 1.15 (95% CI, 1.06 to 1.25) for kidney disease resulting from kidney or urinary tract malformations. CONCLUSIONS: LBW, SGA, and preterm birth are associated with higher risk of CKD in the first 50 years of life. Risk of other groups of kidney disease was less pronounced. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2020_08_17_CJN04080320.mp3.

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.

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.

Prevalence and prognostic ability of the GOLD 2017 classification compared to the GOLD 2011 classification in a Norwegian COPD cohort.

Rationale: The Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017 is based on an ABCD assessment tool of symptoms and exacerbation history and grade 1-4 of airflow limitation severity, facilitating classification either into 4 groups (ABCD) or 16 groups (1A-4D). We aimed to compare the GOLD 2011, GOLD 2017 ABCD, and GOLD 2017 1A-4D classifications in terms of their distribution and prediction of mortality and hospitalizations. Methods: In the GenKOLS study, 912 COPD patients with FEV1 less than 80% of the predicted answered questionnaires and performed lung function testing in 2003-2005. The patients were recruited from a hospital patient registry (n=662) and from the general population (n=250), followed up until 2011 with respect to all-cause and respiratory mortality, and all-cause and respiratory hospitalizations. We performed logistic regression and receiver operating curve (ROC) analyses for the different classifications with estimations of area under the curve (AUC) for comparisons. Results: Mean age at baseline was 60 years (SD 11), 55% were male. Mean duration of follow-up was 91 months. By GOLD 2011, 21% were classified as group A, 29% group B, 6% group C, and 43% as group D, corresponding percentages for GOLD 2017 were: 25%, 52%, 3%, and 20%. The GOLD 2011 classification had higher AUC values than the GOLD 2017 group ABCD classification for respiratory mortality and hospitalization, but after inclusion of airflow limitation severity in GOLD 2017 groups 2A-4D, AUC values were significantly higher with GOLD 2017. Conclusion: In a clinically relevant sample of COPD patients, the GOLD 2017 classification doubles the prevalence of group B and halves the prevalence of groups C and D as compared to the GOLD 2011 classification. The prediction of respiratory mortality and respiratory hospitalization was better for GOLD 2017 2A-4D taking airflow limitation severity into account, as compared to GOLD 2017 ABCD and GOLD 2011.

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.

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.

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.

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.

Exposure to Mycophenolate and Fatherhood.

BACKGROUND: Mycophenolic acid (MPA) is the active immunosuppressive substance in both mycophenolate mofetil and mycophenolate sodium, and it is widely used after organ transplantation. In women, taking MPA is teratogenic and may also influence spermatogenesis. There is a lack of knowledge regarding outcome of pregnancies fathered by men exposed to MPA. METHODS: We compared outcomes in pregnancies fathered by renal transplant men per whether they had been exposed to MPA or not at time of conception. A nationwide population-based retrospective cohort study was performed. Data from the Norwegian Renal Registry with all renal transplanted men alive between January 1, 1995 and December 31, 2015 were included, and relevant outcome data were extracted from the Medical Birth Registry of Norway. RESULTS: During the given time, 230 immunosuppressed renal transplanted men fathered 350 children (155 on MPA/195 not on MPA). There were no significant increased risks of malformation (3.9% vs. 2.6%, P = 0.49) in MPA exposed versus unexposed cohorts of children. The average dose (±SD) of mycophenolate was 1.42 ± 0.3 g/day and the individual median MPA trough concentration in the time period of anticipated conception and pregnancy was 2.8 ± 1.6 mg/L. Birth weight was similar in exposed and unexposed cohorts of children; 3381 ± 681 g vs. 3429 ± 714 g (P = 0.53). CONCLUSIONS: Paternal exposure to MPA did not increase the risk of adverse birth outcomes in children fathered by male kidney transplanted patients. These results are reassuring and support the continuation of paternal MPA treatment before, during, and after conception.