Persistent Microscopic Hematuria Research Articles

#817 Genetic analysis in a group of patients with persistent isolated microscopic hematuria

Abstract Background and Aims Autosomal dominant Alport syndrome (ADAS) is a genetic disease caused by pathogenic variants in COL4A3 and COL4A4 genes. ADAS is the main cause of isolated persistent microscopic hematuria (PMH). However, other diseases like IgA nephropathy (IgAN) can present with PMH. Establishing a precise genetic diagnosis in this type of patients would avoid invasive studies like kidney biopsies. In this study we performed a comprehensive genetic test in a cohort of patients with isolated PMH to evaluate the frequency of ADAS or other genetic abnormalities and compare the clinical characteristics of patients with or without ADAS Method Fifty-two patients with PMH were included in the study. PMH was defined by the presence of 3 or more dysmorphic red blood cells per field in at least 5 consecutive urine sediments and a time-averaged proteinuria <1 gr/day. Average proteinuria was determined for every 6 months of follow-up and time-averaged (TA) proteinuria represented an average of the mean proteinuria measurements in each 6-month period. A comprehensive genetic study using whole exome next-generation sequencing was performed. One hundred and one genes related to familial hematuria, focal segmental glomerulosclerosis and cystic kidney diseases were analyzed. Patients with known secondary causes of hematuria were excluded. The baseline clinical characteristics of patients with and without ADAS were compared. Patients with pathogenic variants in COL4A5 gene were excluded of this analysis. Results Thirty-one (60%) patients were diagnosed with ADAS (16 patients with pathogenic variants in COL4A3, 15 in COL4A4), 3 (6%) patients (2 women, 1 man) presented pathogenic variant in COL4A5 gene, and the genetic study was negative in the remaining 18 patients (variants of unknown significance in COL4A3 or COL4A4 were found in 3 of the latter). No other genetic abnormalities were detected in the panel of 101 genes. Table 1 shows the baseline clinical characteristics of patients with and without ADAS. Patients with ADAS presented a higher TA proteinuria [0.23 (0.11-0.6) vs 0.08 (0.05-0.16), p = 0.01], and a more frequent familial history of isolated microscopic hematuria (76% vs 40%, p = 0.01) chronic kidney disease (CKD) (44% vs 0%, p = 0.01) or end stage kidney disease (32% vs 0%, p = 0.02). In the multivariate analysis, only a family history of microscopic hematuria was associated with ADAS: OR 5.62 (1.25-25.49, p = 0.02). Conclusion ADAS is the most common cause of PMH. A genetic study should be the first diagnostic step in order to obtain a precise cause of the disease and avoid invasive procedures. A family history of microscopic hematuria and of CKD increases the likelihood of ADAS prior to the performance of genetic test.

Nephrology referral slows the progression of chronic kidney disease, especially among patients with anaemia, diabetes mellitus, or hypoalbuminemia: A single-centre, retrospective cohort study.

The Kidney Disease Improving Global Outcomes guidelines recommend nephrology referral for patients with chronic kidney disease (CKD) stages 4 to 5, significant proteinuria and persistent microscopic haematuria. However, the recommendations are opinion-based and which patients with CKD benefit more from nephrology referral has not been elucidated. In this retrospective cohort study, patients referred to our nephrology outpatient clinic from April 2017 to March 2019 were included. We excluded patients considered to have an acute decline in kidney function (annual decline in estimated glomerular filtration rate [eGFR] >10 mL/min/1.73 m2). The slopes of eGFR before and after nephrology referral were estimated and compared by linear mixed effects models. Interaction between time and referral status (before or after referral) was assessed and effect modifications by the presence of diabetes, proteinuria (defined by urine dipstick protein 2+ or more), urine occult blood, hypoalbuminemia (defined by albumin levels less than 3.5 g/dL) and anaemia (defined by haemoglobin levels less than 11.0 g/dL) were evaluated. The eGFR slope significantly improved from -2.05 (-2.39 to -1.72) to -0.96 (-1.36 to -0.56) mL/min/1.73 m2/year after nephrology referral (p < .001). The improvement in eGFR slope was more prominent among those with diabetes mellitus, anaemia, and hypoalbuminemia (all p-values for three-way interaction <.001 after adjustment for covariates). Further adjustments for time-dependent haemoglobin levels, the use of erythropoiesis-stimulating agents, iron supplementation, anti-hypertensives and anti-diabetic medications did not change the significance of the interactions. Nephrology referral slows CKD progression, especially among those with hypoalbuminemia, diabetes or anaemia. Patients with hypoalbuminemia, diabetes or anaemia might benefit more from specialized care and lifestyle modifications by nephrologists. The inclusion of anaemia and hypoalbuminemia in nephrology referral criteria should be considered.

Cystic phenotype and chronic kidney disease in autosomal dominant Alport syndrome.

Autosomal Dominant Alport Syndrome (ADAS), also known as Thin Basement Membrane Disease (TBMD), is caused by pathogenic variants in COL4A3 and COL4A4 genes. A cystic phenotype has been described in some patients with TBMD, but no genetic studies were performed. We conducted a genetic and radiologic investigation in a cohort of ADAS patients to analyze the prevalence of multicystic kidney disease (MKD) and its association with Chronic Kidney Disease (CKD). Retrospective single-center cohort study. Thirty-one patients showing pathogenic or likely pathogenic variants in COL4A3 or COL4A4 from a cohort of 79 patients with persistent microscopic hematuria were included. Mean follow-up was 9.4±9.6 years. The primary objective of the study was to determine the prevalence of MKD in the cohort of ADAS patients. Secondary objectives were to determine risk factors associated with an eGFR<45 ml/min/1.73m2 at the time of genetic and radiologic evaluation and to investigate the coexistence of other genetic abnormalities associated with familial hematuria and cystic kidney disease. MKD was found in 16 patients (52%). Mean number of cysts per kidney was 12.7±5.5. No genetic abnormalities were found in a panel of 101 other genes related to familial hematuria, focal segmental glomerulosclerosis and cystic kidney disease. A greater number of patients with MKD had an eGFR<45 ml/min/1.73m2 (63% vs 7%, p=0.006) and more advanced CKD than patients without MKD. The annual rate of eGFR decline was greater in patients with MKD: -1.8 vs 0.06 ml/min/1.73m2/year (p=0.009). By multivariable linear regression analysis, the main determinants of eGFR change per year were time-averaged proteinuria (p=0.002) and MKD (p=0.02). MKD is commonly found in ADAS and is associated with a worse kidney outcome. No pathogenic variants were found in genes other than COL4A3/COL4A4.

Treatment of IgA Nephropathy: A Rapidly Evolving Field.

The pivotal event in the pathophysiology of IgA nephropathy is the binding of circulating IgA-containing immune complexes to mesangial cells, with secondary glomerular and tubulointerstitial inflammation and fibrosis. The paramount difficulty in the management of IgA nephropathy is the heterogeneity in its clinical presentation and prognosis, requiring an individualized treatment approach. Goal-directed supportive care remains the bedrock of therapy for all patients, regardless of risk of progression. Sodium-glucose transporter 2 inhibitors and sparsentan should be integral to contemporary supportive care, particularly in patients with chronic kidney damage. Pending the development of reliable biomarkers, it remains a challenge to identify patients prone to progression due to active disease and most likely to derive a net benefit from immunosuppression. The use of clinical parameters, including the degree of proteinuria, the presence of persistent microscopic hematuria, and the rate of eGFR loss, combined with the mesangial hypercellularity, endocapillary hypercellularity, segmental glomerulosclerosis, tubular atrophy/interstitial fibrosis, crescents score, is currently the best approach. Systemic glucocorticoids are indicated in high-risk patients, but the beneficial effects wane after withdrawal and come at the price of substantial treatment-associated toxicity. Therapies with direct effect on disease pathogenesis are increasingly becoming available. While targeted-release budesonide has garnered the most attention, anti-B-cell strategies and selective complement inhibition will most likely prove their added value. We propose a comprehensive approach that tackles the different targets in the pathophysiology of IgA nephropathy according to their relevance in the individual patient.

Clinical guidelines for diagnosis of hematuria

Background: Hematuria is a common condition caused by various factors, including infections, inflammations, stone diseases, and anatomical abnormalities. While hematuria can be mistaken for other conditions, its significance should not be overlooked, as studies have shown that some patients with hematuria are diagnosed with urological cancers.Current Concepts: Experts agree on the need for specific diagnostic tests such as cystoscopy, upper urinary tract imaging, and urine cytology for visible hematuria. However, opinions differ when it comes to microscopic hematuria. Delays in diagnosing bladder cancer can significantly impact mortality rates. Therefore, objective diagnostic criteria, as well as guidelines to reduce excessive evaluations, costs, and side effects, are required. As of 2020, the American Urological Association has released new guidelines for the diagnosis and management of microscopic hematuria, that focus on assessing the risk of urological malignancies in individual patients and recommend tailored evaluations based on risk levels. This article provides an overview of these guidelines, discussing diagnostic criteria, initial evaluations, risk stratification, and recommended evaluations of the urinary tract.Discussion and Conclusion: Guidelines on hematuria aim to reduce unnecessary invasive procedures, provide appropriate follow-up strategies to patients with persistent or recurrent microscopic hematuria, and improve patient outcomes while minimizing unnecessary tests and procedures.

WCN23-1022 Persistent microscopic hematuria in IgA nephropathy and frequency of gross hematuria following SARS-CoV-2 mRNA vaccination

WCN23-1022 Persistent microscopic hematuria in IgA nephropathy and frequency of gross hematuria following SARS-CoV-2 mRNA vaccination

Managing Kidney Disease in Patients with Sickle Cell Disease: A Quality Initiative at the Cleveland Clinic

Background Sickle cell disease (SCD) when complicated by sickle cell nephropathy and chronic kidney disease (CKD) is associated with high morbidity and mortality. Early intervention with appropriate specialist care and timely evaluation for transplant are essential to improve outcomes. There is considerable variability in the screening, diagnosis and management of renal complications in SCD. Current guidelines from the NHLBI (2014), ASH (2019) and expert opinion endorse (1) annual screening for proteinuria, (2) the initiation of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARB) in patients with significant proteinuria, (3) early involvement of nephrology for declining renal function, (4) testing for alternative etiologies of kidney disease, (5) referral for renal transplant in advanced CKD with regular red cell exchange in those being considered for transplant, and (6) combination therapy with hydroxyurea and erythropoiesis-stimulating agents (ESA) for patients with worsening anemia from CKD. We sought to audit our care of SCD patients along these metrics to devise effective interventions to improve outcomes in SCD patients with comorbid kidney disease. Methods We conducted a retrospective quality review of renal disease screening, referral, and management in adults with SCD who were seen in the outpatient setting at the Cleveland Clinic in the past 3 years. Results We reviewed 258 adults with SCD who were seen between July 2019 and July 2022. Of these, 16 patients had insufficient laboratory data and were excluded from further analysis. Our final cohort of 242 patients was comprised of 169 (70%) female patients and the median age was 42 (18-90) years. The majority [213 (88%)] had appropriate screening for proteinuria. Of 46 patients with significant proteinuria, 18 (39%) were on ACEi/ARB in part reflecting challenges with tolerance (hyperkalemia, cough, hypotension). CKD was present in 43 (18%) patients; 25 (58%) had CKD stage 3a, 5 (12%) stage 3b, 6 (14%) stage 4, and 7 (16%) were on dialysis. Nephrology was involved in 27 (63%) of those with CKD. Most [31 (72%)] were evaluated for other causes of CKD, however the extent of testing was inconsistent. Referral for renal transplant evaluation was made in 7 (16%) patients with CKD and approximately half [3 (43%)] of these patients were receiving regular red cell exchange transfusions. Only 2 (5%) patients received a kidney transplant. Of the subset of 13 patients with advanced CKD stages 4 or 5, 9 (69%) were receiving ESA and 3 (23%) were on combination hydroxyurea and ESA. In our larger cohort of 242, an additional 30 (12%) patients had isolated persistent microscopic hematuria and 44 (18%) patients demonstrated a trend of chronically rising creatinine within the laboratory normal range. Additional analysis is planned to evaluate screening and management in this at-risk cohort with more subtle presentation. Discussion The management of renal disease in SCD is complex and a paucity of data to support evidence-based guidelines presents a major challenge. We found that rates of screening for proteinuria and declining renal function in SCD patients were high, however the subsequent management was inconsistent. CKD in SCD is highly morbid, and patients with SCD continue to experience low rates of transplant evaluation and eligibility with devastating consequences. A root cause analysis, patient and provider education campaigns, and additional activities are planned to improve the management of kidney disease in patients with SCD.

An evidence-based microscopic hematuria care pathway optimizes decision-making among providers.

Microscopic hematuria (MH) has many etiologies in women and requires specific gynecologic evaluation. We created a standardized MH pathway to serve as an evidence-based decision aid for providers in our practice. Using a modified Delphi process, a multidisciplinary team reviewed existing guidelines for MH diagnosis and treatment to reach consensus on care pathway components. Entry into the care pathway by an advanced practice provider is determined by the finding of ≥3 red blood cells per high-power field (RBC/HPF) on microscopic urinalysis. Initial evaluation includes history and physical exam. If there are signs of a gynecologic cause of MH, the conditions are treated and repeat urinalysis is performed in 6 months. If repeat urinalysis shows persistent MH or there are no other apparent causes for MH, we proceed with risk stratification. Through shared decision-making, low-risk patients may undergo repeat urinalysis in 6 months or cystoscopy with urinary tract ultrasound. For intermediate-risk patients, cystoscopy and urinary tract ultrasound are recommended. For high-risk patients, cystoscopy and axial upper urinary tract imaging are recommended. If evaluation is positive, urology referral is provided. If evaluation is negative, low-risk patients are released from care, but intermediate-risk or high-risk patients undergo repeat urinalysis in 12 months. If repeat urinalysis is positive, shared decision-making is used to determine a plan. We developed an MH care pathway to standardize care of women with MH across a multidisciplinary group. This pathway serves as a component of value-based care and supports evidence-based care by providers.

An Unusual Etiology of Proteinuria and Hematuria in a Case with IgA Vasculitis Nephropathy: Nutcracker Syndrome

IgA vasculitis is the most frequent type of vasculitis in children and progresses with the involvement of skin, gastrointestinal system, joints and glomerulonephritis. The most frequent findings of IgAV nephritis are microscopic hematuria and proteinuria ranging from trace amounts to nephrotic levels. The nutcracker syndrome (NCS) is a phenomenon that refers to compression of the left renal vein between the abdominal aorta and superior mesenteric artery. The presenting manifestations are hematuria, orthostatic proteinuria, abdominal pain or left flank pain. Herein we reported a case diagnosed with NCS with regard to persistent microscopic hematuria, intermittent macroscopic hematuria and a fluctuating proteinuria in non-nephrotic levels during the follow up of IgA vasculitis nephritis. A 4,5 year-old boy with rashes extending from the dorsal foot to the sacral regions, arthritis of the ankles and abdominal pain had been admitted to hospital and diagnosed with IgA vasculitis. The total urine analysis revealed +3 proteinuria, and +2 erythrocyte. Nephrotic range of proteinuria was detected in 24-hour urine analysis. The renal biopsy was in accordance with grade II IgA vasculitis nephritis according to the ISKDC classification. The patient was started on an ACE inhibitor and fish oil. In further follow-up, intermittent microscopic hematuria and non-nephrotic range of proteinuria reappeared. The amount of proteinuria was measured in the urine collected during the daytime and the nighttime urine and it was observed that the proteinuria was orthostatic. The patient was re-evaluated regarding etiologies for proteinuria and hematuria. Renal Doppler ultrasonography revealed that the angle between the abdominal aorta and SMA was 14 degrees. Abdominal computed tomography angiography demonstrated that the left renal vein was trapped between aorta and SMA, so the case was diagnosed with NCS. In conclusion, non-glomerular etiologies should be kept in mind in the differential diagnosis of patients with hematuria and/or proteinuria although they are being followed for glomerular pathologies.

Persistent Asymptomatic Isolated Microscopic Hematuria in Adolescents is not Associated With an Increased Risk for Early Onset Urinary Tract Cancer

ObjectiveTo elucidate the association between adolescent microscopic hematuria and early onset urothelial carcinoma and renal cell carcinoma. MethodsNationwide, population-based, retrospective cohort study using medical data of 970,366 adolescents aged 16 through 19 years (58.6% male) examined for fitness for military service between 1980 and 1997. Diagnoses of persistent isolated microscopic hematuria were given after thorough work up process excluding any other renal abnormalities. Incident cases of urothelial carcinoma and renal cell carcinoma diagnosed during the years of 1982-2012 were retrieved from the Israeli National Cancer Registry. Cox proportional hazards models were used to estimate the hazard ratio (HR) separately for urothelial carcinoma and renal cell carcinoma. ResultsDuring a cumulative follow-up of 22,115,629 person-years (median follow-up, 22.8), persistent isolated microscopic hematuria was diagnosed among 5509 (0.6%) adolescents. Urothelial carcinoma and renal cell carcinoma developed in 332 (3 among those with persistent isolated microscopic hematuria) and 292 (2) individuals, respectively. The adjusted HR for incident urothelial carcinoma among adolescents with isolated microscopic hematuria was 1.17 (95% CI, 0.38-3.66) and the adjusted HR for renal cell carcinoma was 1.02 (95% CI, 0.25-4.12). ConclusionPersistent asymptomatic isolated microscopic hematuria at adolescence was not associated with increased risk for urothelial carcinoma nor renal cell carcinoma.

A child with genetic FN1 mutation in the absence of classic glomerulopathy with fibronectin deposits(GFND) findings on biopsy

BackgroundGlomerulopathy with fibronectin deposits (GFND) is a rare autosomal dominant genetic disorder, and proteinuria and hematuria are the most common clinical manifestations. The pathogenesis of this disease is primarily related to mutation of the fibronectin 1 gene. Unfortunately, without specific treatment, the prognosis remains poor. Here we present a case report that investigates the clinical characteristics, renal pathology, and gene testing of childhood GFND.Case presentationA two-year-old child was brought to our hospital for “persistent hematuria for 1 year and 10 months.” The disease onset was at the age of 4 months, with persistent microscopic hematuria accompanied by intermittent gross hematuria, occasionally with proteinuria, and without hypertension or renal failure. The chief complaint was intermittent gross hematuria, without massive proteinuria, hypertension, or renal failure. Family history: The child’s mother had microscopic hematuria, his maternal aunt had nephrotic syndrome due to focal segmental glomerulosclerosis, and his maternal grandmother had end-stage renal disease. No significant pathological changes were found in the renal pathological biopsy of the child under a light microscope. Under the electron microscope, the basement membrane was found to be of uneven thickness, ranging from 150 to 400 nm. The stratum compactum of the basement membrane was thickened, with a small part showing tear-like and cobweb-like morphology. No electron-dense deposits were found. The renal tubular epithelial cells were vacuolated, and there were no unique pathological changes in the renal interstitium. Immunofluorescence showed that IgG, IgM, IgA, C3, and C1q were all negative. Alport syndrome was preliminarily considered. However, exome sequencing revealed a mutated site in the fibronectin 1 gene. The child’s mother was the carrier of the pathogenic gene and the final diagnosis was GFND.ConclusionsFibronectin deposition is a typical pathological change in GFND, and the disease progresses slowly to end-stage renal disease. There is no specific treatment so far, and the prognosis is poor. The early onset of childhood patients may not show typical renal pathological changes, but only changes in the thickness of basement membrane, etc. Genome sequencing technology may helpful for the early diagnosis of GFND.

Bladder Xanthoma

A 35-year-old male presented with multiple interrupted episodes of frank hematuria and persistent micro-scopic hematuria. CT urogram demonstrated a nonspecific lesion in the bladder. Cystoscopy showed a lesion in the bladder wall that was biopsied, and histopathology confirmed a xanthoma, a rare diagnosis in the bladder. This case report performs a review of current literature and examines necessary investigations,differential diagnoses, and management required for bladder xanthoma.

MO944: Persistent Microscopic Hematuria At Kidney Donor Screening and Long-Term Post-Donation Kidney Outcomes

Abstract BACKGROUND AND AIMS According to current guidelines, a kidney biopsy is indicated in prospective living kidney donors with persistent microscopic hematuria and negative urological work-up. We investigated whether persistent microscopic hematuria at donor screening is associated with changes in post-donation eGFR, proteinuria, or blood pressure. METHOD We included 701 living kidney donors who underwent two urinalyses before donation and had annual evaluation of estimated glomerular filtration rate (eGFR), protein:creatinine ratio (PCR) and systolic blood pressure (SBP). The association between pre-donation persistent microscopic hematuria (≥ 1 red blood cell per high power field or ≥3 red blood cell per µL) and outcomes was assessed using generalized linear mixed models. RESULTS Mean age was 52 ± 11 years, median [interquartile range] follow-up time was 5 [2–8] years. Pre-donation persistent microscopic hematuria was present in 88 donors (80% female, versus 45% in non-hematuria group, P &amp;lt; 0.001). There were no significant associations between persistent microscopic hematuria at screening and course of eGFR [0.44 mL/min/1.73 m2 increase/year for hematuria donors versus 0.34 mL/min/1.73 m2 increase/year for non-hematuria donors (P = 0.65)], PCR (0.02 versus 0.04 mg/mmol increase/year, P = 0.38), or SBP (1.42 versus 0.92 mmHg increase/year, P = 0.17) post-donation, even after adjusting for pre-donation age, sex, body mass index, eGFR, PCR, SBP and ACE inhibitor/angiotensin receptor blocker use. Sensitivity analyses in subgroups with risk-factor(s) of kidney disease and subgroups with poorer post-donation courses of the outcomes yielded similar results. CONCLUSION Donors with persistent microscopic hematuria at donor screening had no increased risk of progressive eGFR decline, proteinuria, or hypertension. Despite the limitation of potential selection bias, it seems safe to allow donors with persistent microscopic hematuria without other risk factors to donate without prior kidney biopsy. However, these results warrant validation on the longer term after donation.

Persistent asymptomatic microscopic hematuria in childhood: A single-centered experience

Persistent asymptomatic microscopic hematuria in childhood: A single-centered experience

ANCA status and renal parameters at month 12 post-diagnosis can help predict subsequent relapses in patients with granulomatosis with polyangiitis

ObjectiveTo determine the predictive value of disease characteristics at 12-month follow-up after the diagnosis of GPA for subsequent relapses in a cohort of patients followed at a tertiary vasculitis clinic. MethodsDemographic, clinical, and biological data at diagnosis and during follow-up from patients with GPA followed for at least 24 months at the Mount Sinai Hospital Vasculitis Clinic in Toronto, Canada were extracted from the Canadian Vasculitis Research Network (CanVasc) database and analyzed. The association between ANCA status and type (PR3- or MPO-ANCA), presence of microscopic hematuria, or serum creatinine level at follow-up month 12 ± 3 (M12) and relapses after M12 were assessed using Cox proportional hazard models. ResultsA total of 113 GPA patients were included in this study (50 ANCA positive, 63 ANCA negative at M12). Patient demographics and disease characteristics were similar at diagnosis, including the treatments used for induction and at M12. The global 5-year relapse rate was 55.8%, without any difference in the relapse rates after M12 between those ANCA-positive or negative at M12. However, in multivariate analyses, MPO-ANCA positivity at M12 was predictive of increased relapses after M12 (hazard ratio [HR] 3.54, P=0.01), as was the presence of microhematuria at M12 (HR 1.91, P=0.04). In contrast, higher serum creatinine levels at M12 were associated with a decreased risk of subsequent relapse (HR 0.99, P=0.04). ConclusionIn this cohort of patients with GPA, MPO-ANCA positivity and persistent microscopic hematuria at M12 were associated with increased risk of subsequent relapse, and could thus have value to predict disease outcome during follow-up.

Co-existence of Alport syndrome and C3 glomerulonephritis in a proband with family history

BackgroundAlport syndrome and C3 glomerulonephritis (C3GN) are rare kidney diseases, frequently responsible for familial haematuria, proteinuria, and renal impairment. With the rapid development of molecular genetic testing, Alport syndrome causes have been restricted mostly to variants in the COL4A5 or COL4A3/COL4A4 genes. Moreover, a broad range of genetic contributors in the complement and complement-regulating proteins are definitely implicated in the pathogenesis of C3GN.MethodsWe sought a family with persistent microscopic haematuria associated with renal failure. Clinicopathologic and follow-up data were obtained, and molecular genetic testing was used to screen for pathogenic variants.ResultsWe describe a three-generation family with Alport syndrome showing a dominant maternal inheritance. Notably, renal biopsy showed the concurrent histological evidence of C3GN in the proband harbouring an uncommon heterozygous variation in CFHR5, c.508G > A. The alteration leads to replacement of a highly conserved residue at position 170 of the β-strand subunit of CFHR5 (p.Val170Met). In silico analysis showed that the variation was predicted to deregulate complement activation by altering the structural properties and enhancing C3b binding capacity to compete with Complement Factor H (CFH), which was in line with experimental data previously published.ConclusionsThe comorbidity findings between Alport syndrome and C3GN indicate an underlying overlap and require further study.

C3 Glomerulonephritis associated with Anti-complement Factor H Autoantibodies in an Adolescent Male: A Case Report

C3 glomerulonephritis (C3GN), a rare condition associated with dysregulation of the alternative pathway of the complement system, is histopathologically characterized by isolated or dominant C3 deposition in the renal glomeruli. We report a case of C3GN associated with anti-complement factor H (CFH) autoantibodies and CHF-related protein deficiency in an adolescent male. A 16-year-old adolescent male was admitted to a hospital with a 1-month history of generalized edema prior to presentation. Persistent microscopic hematuria and low serum C3 levels were incidentally detected at 7 and 10 years of age, respectively. Laboratory test results revealed hypoalbuminemia, nephrotic-range proteinuria, microscopic hematuria, and normal serum creatinine levels. The serum C3 and C4 levels were 17 mg/dL (normal 80–150 mg/dL) and 22 mg/mL (17–40 mg/mL), respectively. Renal biopsy showed typical features of C3GN. Further investigations revealed positive results on plasma anti-CFH autoantibody testing and a homozygous deletion of CFHR1 and CFHR3, which encode CFH-related proteins 1 and 3, respectively. Proteinuria persisted despite treatment with intravenous methylprednisolone, mycophenolate mofetil, and angiotensin-receptor blocker; however, his renal function remained stable. In conclusion, anti-CFH autoantibodies serve as important contributors to C3GN. This is the first case report that describes C3GN in an adolescent Korean male with anti-CFH autoantibodies and homozygous CFHR1 and CFHR3 deletion. Key words: C3 glomerulonephritis, Hypocomplementemia, Anti-complement factor H autoantibodies, Complement factor H related proteins

Hematuria at dipstick on first versus second morning voiding: A screening for patients with persistent isolated hematuria?

BackgroundIn our clinical practice we observed that –differently from patients with defined glomerulopathies– children with persistent isolated microscopic hematuria (PImH) usually shows at dipstick on first compared with second morning voiding lower degree of hematuria. We hypothesized that comparison of hematuria degree between first and second morning voiding (dipstick comparison test) could help in selection of patients needing of specific investigations. In this study, we aimed preliminarily validating our hypothesis. MethodsTo define the risk of active glomerulopathies we used patients with defined glomerulopathies as cases. We prospectively enrolled 103 children during a one-year period. Sixty-nine of them had PImH, 16 microscopic/macroscopic hematuria (mMH), and 18 defined glomerulopathies.Inclusion criteria were: 1) persistent microscopic hematuria (≥1+ at dipstick) with or without defined glomerulopathy and/or previous episodes of macroscopic hematuria; 2) for the patients without defined glomerulopathy, having made regular biannual follow-up visits for at least 2 years in our department; 3) normal renal function and blood pressure at enrollment visit.We compared hematuria degree between first and second morning voiding. Possible findings were absence (NH), less degree (LH), similar degree (SH), and higher degree (HH) of hematuria in the first compared with second voiding. ResultsAt dipstick comparison test, 27.2% of patients presented NH, 44.7% LH, 28.1% SH, and none HH. NH showed specificity and PPV of 100% and significant area under receiver operating characteristic curve (AUROC = 0.66; 95%CI:0.55–0.78; p = 0.03) for absence of defined glomerulopathies. LH showed better sensitivity (76.9% Vs 33%) and NPV (78.9% Vs 24%) and lower specificity (88.2% Vs 100%) and PPV (87.0% Vs 100%) than NH for absence of defined glomerulopathies. Moreover, the LH showed a non-significant AUROC curve for presence of defined glomerulopathies. SH showed specificity of 80%, NPV of 91.9% and significant AUROC curve for presence of defined glomerulopathies (0.67; 95%CI:0.55–0.80; p = 0.009).The ROC curve analysis examining the delta of hematuria degree comparing first with second morning urine voiding showed a significant AUROC curve (AUROC = 0.78; 95%CI,0.68–0.89; p = 0.0002) with delta ≤ 1 showing the best sensitivity (80%) and specificity (66.7%) for defined glomerulopathies.None of the patients with defined glomerulopathies presented NH. Having SH presented relative risk for defined glomerulopathy of 5.1 (95%CI:1.9–13.6; p = 0.0007). Conversely, taken together NH and LH the RR was 0.2 (95%CI 0.1–0.5; p = 0.0007). InterpretationsThe dipstick on the first urine voiding underestimates the hematuria in about 70% of patients. The dipstick comparison test might easily screen patients with PImH and mMH needing of further investigations and treatment.

IgA nephropathy in children and in adults: two separate entities or the same disease?

IgA nephropathy (IgAN) is observed in subjects of any age, however perspective and management of this disease are different between adult and pediatrician Nephrologists. Most children with IgAN present with gross hematuria rapidly vanishing or persistent mild microscopic hematuria, which rarely progresses to end stage renal disease (ESRD) over the pediatric observation. The perspective of IgAN in adults is of a slowly progressive glomerular disease with 30-40% probabilities to reach ESRD. However, mild cases of IgAN in children might be missed with manifestation of irreversible damage only decades after the true onset, as 50% of subjects with IgAN enter renal replacement treatment before the age of 50years. In both adults and children the assessment of risk profile is crucial to avoid overtreatment in benign cases or institute a prompt and valid therapy in potentially progressive cases. In case of common risk factors, new therapeutic opportunities tested in adults might be applied to children with the expectation of similar results. If IgAN is the same disease in spite of different clinical profiles in children and adults, an early intervention may be the correct way to prevent progression decades later. On the contrary, if we are dealing with different clinical entities, the treatment in pediatric and in adult settings must be kept apart. This review addresses to report similarities and differences of IgAN across the life periods in order to reason on the application of newly offered treatments over the entire spectrum of this disease or in focused age indications.

SUN-460 RECURRENT ACUTE KIDNEY INJURY AND GROSS HEMATURIA IN A CHILD WITH DENSE DEPOSIT DISEASE (DDD) AND PRESERVED KIDNEY FUNCTIONS ON LONG TERM FOLLOW-UP

Glomerulonephritis (GN) in children are in most cases post infectious GN (PIGN), characterized by complement activation with reduction of serum C3 levels that usually normalizes within four to eight weeks. When serum C3 levels are persistently low, other GN needs to be ruled out such as membranoproliferative GN (MPGN). Cases with MPGN and reduction of C3 levels in the absence of Ig on biopsy are now classified as “C3 GN” a member of “C3 glomerulopathies” (C3Gs); this also includes dense deposit disease (DDD). DDD is a rare disorder that most commonly affects children. The rarity of DDD, which afflicts 2 - 3 only two to three individuals per million populations, has impeded studies into its clinical course and optimal treatment. Its natural history is variable, but approximately 50% of patients progress to ESRD within 8 to 10 year. Case Report A previously healthy 11-year-old child was admitted at age of 8 years with history of fever, vomiting and red color urine since 4 days before admission. He had history of Upper Respiratory Tract Infection (URTI) 2 weeks before presentation without any history of skin rash or bleeding tendency or trauma or any drug ingestion. Family history was negative for any renal disease or bleeding tendency. At the presentation, he had oliguria, mild generalized body edema with acceptable blood pressure readings. Urinalysis showed proteinuria (2+) and dysmorphic erythrocytes in the urinary sediment. Laboratory tests showed picture of acute kidney injury(AKI) serum creatinine was 463 umol/l, hypocomplementemia C3 (0.51 mg/dL; normal rang value 0.9-1.8 g/l), high C-reactive protein (113 mg/l ; normal range <3 mg/l), High microalbuminuria (1088.4 mg/l ;, normal range 4-25 mg/l) & Microalbumine/creatinine ratio of 194 mg/mmol( N.R:0-2.5 mg/mmol) with low serum albumin of 29 g/l. The other immunological workup was normal. The initial diagnosis was acute post-streptococcal GN. Three days later, his urine output was improving with trending down of renal profile on conservative management till normalization on follow up. However, due to persistent hypocomplementemia C3 (0.6 mg/dl) after twelve weeks of onset. His Complement analysis revealed alternate pathway activation, persistent low levels of C3, low CH50 but normal levels of C5b-C9 and negative C3 nephritic factor (C3Nef) auto-antibodies. To exclude secondary G.N, a renal biopsy was performed and the result was consistent with C3glomuralopathy-DDD. Subsequently, genetic evaluation was performed for complement genes which were negative. On follow up, he was doing well with persistent microscopic hematuria and low C3. Then, he developed another episode of AKI with gross hematuria which was 2 years from the first presentation and resolved spontaneously. We repeated renal biopsy to determine disease activity and exclude other causes of GN. Again, the biopsy result was consistent with DDD. During his long term follow-up (over 36 months), he was doing well with persistent low C3, microscopic hematuria and non-significant proteinuria (24hr urine for protein was 0.1g/l) with preserved renal functions (creatinine 59 0-60 umol/l).View Large Image Figure ViewerDownload Hi-res image Download (PPT)View Large Image Figure ViewerDownload Hi-res image Download (PPT) We report a unique case of DDD in a child with preserved renal functions who had persistent microscopic hematuria and with hypocomplementemia (C3) on long term follow-up.