Non-nephrotic Range Proteinuria Research Articles

Determinants of non-diabetic kidney diseases in type 2 diabetic patients: Twenty years of single center experience.

Diabetic nephropathy is one of the most common complications associated with diabetes. However, non-diabetic kidney disease has been reported in patients with type 2 diabetes at varying incidence rates. The objective of our study is to investigate the occurrence, clinicopathological characteristics, and inflammatory markers linked to diabetic and non-diabetic nephropathy (NDN) in patients with type 2 diabetes mellitus (DM). Additionally, we aimed to explore the possibility of identifying non-diabetic pathology using different biopsy indications. A total of 159 patients with type 2 DM who underwent renal biopsy at a tertiary care nephrology clinic between January 2000 and January 2022 were enrolled in the study. We collected comprehensive data, including patient demographics, co-morbidities, diabetes duration, renal biopsy indications and results, serological markers, renal function, diabetic retinopathy (DRP), full blood count, blood biochemistry, urinalysis, and inflammatory markers. Patients were categorized based on their biopsy indications, and their biopsy results were classified into three groups: isolated NDN, isolated diabetic nephropathy (DN), and mixed nephropathy with concurrent NDN. We evaluated the relationship between biopsy indications and accompanying pathologies and statistically assessed the likelihood of each biopsy indication detecting non-diabetic renal pathology. Additionally, differences in other data, including demographic and laboratory results and medical histories, among the three groups were investigated. The most frequent indication of renal biopsy was atypical presentations of nephrotic syndrome or nephrotic range proteinuria (ANS/ANP) in 25.1% of patients. Other indications included unexplained renal failure (URF) in 22.6%, atypical presentations of non-nephrotic range proteinuria (ANNP) in 18.2%, acute kidney injury or rapidly progressive kidney dysfunction (AKI/RPKD) in 16.9%, microscopic hematuria in 15.7%, URF with ANNP in 11.3%, and severe nephrotic range proteinuria (SNP) in 9.4%. Renal biopsy revealed isolated NDN in 64.8%, DN in 25.1%, and mixed nephropathy in 10.1% of patients. Primary glomerular diseases were the main non-diabetic renal pathology, predominantly focal segmental glomerulosclerosis (FSGS) (36.4%) followed by MN (10.6%) and IgA nephropathy (7.5%). In comparison with the isolated DN and mixed nephropathy groups, patients in the isolated NDN group had significantly shorter diabetes duration, fewer DRP, as well as lower serum creatinine and neutrophil-to-lymphocyte ratio (NLR). Multivariate logistic regression analysis revealed that presence of hematuria (OR 4.40; 95% CI 1.34 - 14.46, p = 0.014), acute nephrotic range proteinuria (OR 11.93; 95% CI 1.56 - 90.77, p = 0.017), and AKI/APKD (OR 41.08; 95% CI 3.40 - 495.39, p = 0.003) were strong predictors of NDN. Lower NLR (OR 0.77; 95% CI 0.60 - 0.98, p = 0.035), shorter duration of diabetes (OR 0.90; 95% CI 0.84 - 0.97, p = 0.010), and absence of DRP (OR 0.35; 95% CI 0.12 - 0.98, p = 0.046) were also found to be independent indicators of NDN. Receiver operating characteristic curve (ROC) analysis revealed a cut-off value of ≤ 3.01 for NLR (sensitivity of 63.1%, specificity of 63.5%) with regards to predicting non-diabetic renal pathology (p = 0.006). Renal biopsy findings in patients with type 2 DM highlight that the prevalence of NDN may be higher than assumed, as presented mainly in the form of primary glomerular disease. The presence of AKI/RPKD, hematuria, and ANS/ANP serves as a reliable indicator of non-diabetic renal pathology. In more ambiguous situations, factors such as a shorter duration of diabetes, absence of DRP, and a lower NLR value may assist clinicians in biopsy decision.

Clinical characteristics and risk factors for kidney involvement in children with immunoglobulin A vasculitis.

Immumoglobulin A (IgA) vasculitis (IgAV), formerly known as Henoch-Schönlein purpura (HSP), is a self-limiting systemic vasculitis in children. Kidney involvement is associated with a long-term unfavorable outcome and can lead to significant morbidity. This study was conducted to describe the clinical and laboratory characteristics of childhood IgAV with kidney involvement and to identify risk factors associated with IgAV nephritis (IgAVN). This was an ambidirectional descriptive study of 77 children with IgAV. All demographic data, clinical features, and laboratory tests were collected from electronic medical records from January 2010 to December 2022. Risk factors for kidney involvement in IgAV were assessed using multivariate logistic regression. Kaplan-Meier survival analysis was used to calculate the time to commencement of kidney involvement. Twenty-five children (32.4% of the IgAV patients) developed IgAVN. The common findings in IgAV with kidney involvement were microscopic hematuria (100%), nephrotic range proteinuria (44%), and non-nephrotic range proteinuria (40%). Multivariate logistic regression showed that age greater than 10 years (adjusted hazard ratio, AHR 4.66; 95% confidence interval, CI, 1.91-11.41; p = 0.001), obesity (body mass index, BMI, z-score ≥ +2 standard deviations, SDs) (AHR 3.59; 95% CI 1.41-9.17; p = 0.007), and hypertension at onset (AHR 4.78; 95% CI 1.76-12.95; p = 0.002) were associated significantly with kidney involvement. During follow up, most IgAV patients developed nephritis within the first 9 months. Age greater than 10 years, obesity, and hypertension at presentation were predictive factors for IgAVN. Our study emphasized that IgAV patients with risk factors should be closely monitored for at least 1 year after the onset of the disease.

Kidney disease in antiphospholipid antibody syndrome

Antiphospholipid syndrome (APS) is a rare autoimmune disease characterized by recurrent arterial and venous thromboembolic events. Renal complications occur in 3 % of patients. Renal artery stenosis is the most common, and APS-related nephropathy is the predominant microvascular complication. APS nephropathy has heterogeneous manifestations ranging from hematuria and non-nephrotic range proteinuria to hypertension and multi-organ failure caused by catastrophic antiphospholipid antibody syndrome. Anticoagulation and thromboprophylaxis are key to management. Immunosuppression has been used with some success but lacks randomized controlled trial validation for their use.

The epidemiology of primary FSGS including cluster analysis over a 20-year period

IntroductionFocal segmental glomerulosclerosis (FSGS) is one of the leading causes of nephrotic syndrome in adults. This epidemiological study describes a renal centre’s 20-year experience of primary FSGS.MethodsPatients were identified with a diagnosis of primary FSGS after exclusion of known secondary causes. In this retrospective observational study, data was collected for baseline demographics, immunosuppression and outcomes. A two-step cluster analysis was used to identify natural groupings within the dataset.ResultsThe total cohort was made up of 87 patients. Those who received immunosuppression had lower median serum albumin than those who did not- 23g/L vs 40g/L (p<0.001) and higher median urine protein creatinine ratios (uPCR)- 795mg/mmol vs 318mg/mmol (p <0.001). They were more likely to achieve complete remission (62% vs 40%, p=0.041), but relapsed more 48.6% vs 22% (p=0.027). Overall 5 year mortality was 10.3% and 5 year progression to RRT was seen in 17.2%. Complete remission was observed in 49.4%. The 2-step cluster analysis separated the cohort into 3 clusters: cluster 1 (n=26) with ‘nephrotic-range proteinuria’; cluster 2 (n=43) with ‘non-nephrotic-range proteinuria’; and cluster 3 (n=18) with nephrotic syndrome. Immunosuppression use was comparable in clusters 1 and 3, but lower in cluster 2 (77.8% and 69.2% vs 11.6%, p<0.001). Rates of complete remission were greatest in clusters 1 and 3 vs cluster 2: 57.7% and 66.7% vs 37.2%.ConclusionPeople who received immunosuppression had lower serum albumin and achieved remission more frequently, but were also prone to relapse. Our cluster analysis highlighted 3 FSGS phenotypes: a nephrotic cluster that clearly require immunosuppression; a cohort with preserved serum albumin and non-nephrotic range proteinuria who will benefit from supportive care; and lastly a cluster with heavy proteinuria but serum albumin > 30g/L. This group may still have immune mediated disease and thus could potentially benefit from immunosuppression.Trial registrationThis study protocol was reviewed and approved by the ‘Research and Innovation committee of the Northern Care Alliance NHS Group’, study approval number (Ref: ID 22HIP54).

Histopathology Findings and Outcomes of Non-Nephrotic Range Proteinuria in Adults and Children

Histopathology Findings and Outcomes of Non-Nephrotic Range Proteinuria in Adults and Children

Outcomes of minimal change disease without nephrotic range proteinuria.

Minimal change disease (MCD) is characterized by edema and nephrotic range proteinuria (NS). However, the fate of MCD without nephrotic proteinuria requires elucidation. We retrospectively reviewed 79 adults diagnosed with primary MCD at their initial renal biopsy at a tertiary hospital between May 2003 and June 2017. Clinicopathologic features were compared between patients with and without NS. The frequency of flaring to nephrotic proteinuria and renal outcomes were assessed during follow-up. There were 20 and 59 patients in the Non-NS and NS groups, respectively. The Non-NS group had a lower frequency of acute kidney injury (AKI) during the follow-up period [5.0% vs. 59.3%, p <0.001]. The response rate to steroid treatment was 100% in the Non-NS group and 92.3% in the NS group (p = 1.000). Except for one patient, the Non-NS group was treated with steroids when their proteinuria increased to a nephrotic level. There were no differences in the frequency of the first relapse or the number of relapses among patients with initial remission from nephrotic range proteinuria. At the final visit, the complete remission rate was 73.4%. The estimated glomerular filtration rate during follow-up was significantly better in the NS group than the Non-NS group, given the higher rates of AKI at renal biopsy. The rates of renal events, end-stage renal disease, and mortality did not differ between the groups. Adult MCD patients with nephrotic and non-nephrotic range proteinuria showed similar outcomes. Accordingly, this population must be carefully managed, regardless of the amount of proteinuria at renal biopsy.

#3269 EPIDEMIOLOGY OF PRIMARY FSGS INCLUDING CLUSTER ANALYSIS OVER A 20-YEAR PERIOD

Abstract Background and Aims Focal segmental glomerulosclerosis (FSGS) is one of the leading causes of nephrotic syndrome (NS) in adults. This epidemiological study describes a renal centre's 20 year ‘real world' experience of patients with primary FSGS including cluster analysis. Method This retrospective analysis was conducted on patients diagnosed with primary FSGS at a tertiary renal centre with a catchment population of 1.55 million, over 2 decades. Data collection included baseline demographics, laboratory results, immunosuppression (IS) and outcomes: Complete &amp; partial remission, relapse, progression to renal replacement therapy (RRT) and mortality. A two-step cluster analysis was used to reveal groupings to aid prognostication and treatment decisions. Pre-specified cluster variables were: Serum albumin (sAlb), urine protein: creatinine ratio (uPCR) &amp; estimated glomerular filtration rate (eGFR). Results 87 patients were identified with primary FSGS after exclusion of secondary causes. Mean age was 49.3 years, 60.9% male, 86.2% white with median eGFR 46 ml/min, uPCR 573 mg/mmol, sAlb 33g/l (Table 1). Rates of partial and complete remission were 23% &amp; 49.4% respectively. Progression to RRT occurred in 27.4%, death in 27.4%. Comparing those receiving IS vs not: sAlb was lower 23 g/L vs 40 g/L (p&amp;lt;0.001), uPCR was higher 795 mg/mmol vs 318 mg/mmol (p &amp;lt;0.001). The IS group was more likely to achieve complete remission (62% vs 40%, p = 0.041), but relapsed more 48.6% vs 22% (p&amp;lt;0.027). There were no statistically significant differences between mortality or RRT. The 2-step cluster analysis separated the cohort into 3 clusters, see Fig. 1: Cluster 1 (n = 26) with ‘nephrotic range proteinuria’ mean sAlb 30 g/L, uPCR 778 mg/mmol and eGFR 72 ml/min; Cluster 2 (n = 43) with ‘non-nephrotic range proteinuria’, mean sAlb 39 g/L, uPCR 284 mg/mmol and eGFR 46 ml/min; Cluster 3 (n = 18) ‘NS’ sAlb 20 g/L, uPCR 1117 mg/mmol and eGFR 25 ml/min. IS use was comparable in the NS (cluster 3) and nephrotic range proteinuria (cluster 1) cohorts, but lower in cluster 2 (non-nephrotic range proteinuria) 77.8% &amp; 69.2% vs 11.6% p &amp;lt;0.001. Rates of complete remission were greatest in clusters 1 &amp; 3 vs cluster 2: 57.7% &amp;66.7% vs 37.2% though this did not achieve statistical significance (p 0.067). Conclusion Although there have been several recent US &amp; Asian reviews of primary FSGS, this study provides a review of the epidemiology of FSGS over a 20-year period in a predominantly white cohort in the UK. In general, the patients who received IS had lower sAlb and achieved remission more frequently. Although the aetiology of primary FSGS is unknown, it is hypothesised that it is due to an undiscovered circulating permeability factor. After the exclusion of secondary causes, KDIGO suggests only making the diagnosis in the presence of NS. Despite this the average sAlb in most epidemiological studies of primary FSGS have been above 30g/l. This is likely because of the inclusion of undiagnosed genetic or adaptive FSGS, but it may also be true that NS phenotype alone is too insensitive to diagnose primary ‘antibody driven’ FSGS. Our cluster analysis highlighted 3 potential FSGS phenotypes: A nephrotic cluster that clearly require IS; a cohort with preserved sAlb and non-nephrotic range proteinuria who will benefit from supportive care; lastly a cluster with heavy proteinuria but a sAlb &amp;gt; 30g/l. This group may still have antibody driven disease and thus benefit from immunosuppression and potentially genetic testing. The study received grant support from CSL Vifor

#6543 TUBULOINTERSTITIAL NEPHRITIS AND UVEITIS (TINU) SYNDROME: A REPORT OF 6 CASES WITH RENAL BIOPSY AND ELECTRON MICROSCOPY EVALUATION.

Abstract Background and Aims Tubulointerstitial nephritis with uveitis (TINU) syndrome is a rare, but probably under-diagnosed, immune-mediated clinical entity, characterized by simultaneous renal and ocular manifestations Diagnosis requires exclusion of all other causes of tubulointerstitial nephritis (TIN). We present six patients with clinical, laboratory and renal biopsy findings consistent with TINU syndrome Method Medical records review. All patients underwent renal biopsy. Histochemical (pas, masson, silver, Congo-red) and immunohistochemical stains for immune cell populations (CD3, CD20, CD4, CD8, PGM1, CD138) and for the assessment of β2-microglobulin were conducted. Electron microscopy (ΕΜ) was also performed. Results All our patients experienced ocular and renal manifestations, defined by bilateral uveitis, photosensitivity, and decline of renal function. In some patients, increased serum creatinine was accompanied by non-nephrotic range proteinuria, glucosuria or “full blown” Fanconi syndrome. The rest of the laboratory evaluation was normal apart from the presence of elevated erythrocyte sedimentation rate and urine β2-microglobulin. Follow-up, ranged from 18 months to 10 years. Histological evaluation revealed interstitial inflammatory infiltration consisting of lymphocytes, with a T-cell predominance, along with several macrophages. Inflammation severity varied, with some showing scarce foci of immune cell clusters, while others demonstrated a dense, diffuse interstitial infiltration. Interestingly, in two cases, non-necrotic, ill-defined granulomas were detected. Tubulitis was also encountered in some patients. A divergence was noted regarding chronicity index, with different levels of tubular atrophy, interstitial fibrosis and global glomerulosclerosis among different cases. β2-Microglobulin immunohistochemical evaluation revealed diminution of cytoplasmic staining in tubular epithelial cells compared to control kidneys. A notable finding derived from ΕΜ was the presence, in one patient, of scattered granular electron-dense-deposits along tubular basement membranes. First-line treatment included steroids, supplemented in some cases by additional immunosuppressive agents. Three patients experienced partial or complete response. Progressive renal damage was observed in a case with severe chronic lesions and persistence of inflammation-triggering factor (illicit substance). Conclusion Our cases seem to represent progressive stages within the continuum of disease evolution. Patients with more prominent inflammation might represent a more initial state, while those with more severe chronicity index, probably depict more advanced stages. While the predominance of T-cells predicates a cell-mediated autoimmune mechanism, as the driving force of the disease occurrence, the presence of immune-complexes in more advanced stages might indicate the involvement of humoral immunity as a late event during disease course.

IgA Nephropathy: Are We Doing Enough?

Immunoglobulin A nephropathy (IgAN) was first identified and described as a disease by Berger and Hinglais in 1968. It is the most common primary glomerulopathy worldwide [1], most prevalent in East Asians and Caucasians and rare in black individuals. There are four key elements that contribute to IgAN, which determine the severity, course, and prognosis of the disease: circulating IgA immunocomplexes that favor mesangial deposition, the efficiency of the reticuloendothelial system, mesangial cell affinity and reaction to mesangial accumulation of poorly glycosylated IgA1, and the renal tendency to glomerulosclerosis and interstitial fibrosis. Clinical manifestations among patients with IgAN include hematuria, approximately 40% to 50% of cases present with one or more episodes of hematuria, usually preceded by upper respiratory tract infections. Between 30% and 40% present with hematuria and non-nephrotic range proteinuria that may be associated with arterial hypertension and impaired renal function. The TESTING study reveal a significant decrease in outcomes such as the risk of a 40% decrease in glomerular filtration rate or the need for renal replacement therapy in the group treated with steroids. The decrease in renal function compared to the group treated in the previously mentioned STOP-IgAN trial was 4 times less than in the TESTING study. Are we doing enough? Obviously, more trials are required with the use of adequate nephroprotection measures. We present 3 patients with a diagnosis of IgA nephropathy who attend the follow-up consultation and voluntarily decide to take part in the review.

Clinical and genetic characterization of children with cubilin variants.

Cubilin is one of the receptor proteins responsible for reabsorption of albumin in proximal tubules and is encoded by the CUBN gene. We aimed to evaluate clinical and genetic characterization of six patients with proteinuria who had CUBN mutations. Patients' characteristics, serum creatinine, albumin, vitamin B12 levels, urine analysis, spot urine protein/creatinine, microalbumin/creatinine, beta-2 microglobulin/creatinine ratios, estimated glomerular filtration rates (eGFR), treatments, kidney biopsies, and genetic analyses were evaluated. Six patients (2 female, 4 male) with an incidental finding of proteinuria were evaluated. Mean admission age and follow-up time were 7.3 ± 2.9 and 6.5 ± 5.6years, respectively. Serum albumin, creatinine, and eGFR were normal; urine analysis revealed no hematuria, and C3, C4, ANA, and anti-DNA were negative; kidney ultrasonography was normal for all patients. Urine protein/creatinine was 0.9 ± 0.3mg/mg, and microalbumin was high in all patients. Serum vitamin B12 was low in two patients and normal in four. Kidney biopsy was performed in four patients, three demonstrated normal light microscopy, and there was one focal segmental glomerulosclerosis (FSGS). Genetic tests revealed four homozygous and two compound heterozygous mutations in the C-terminal part of cubilin. All patients had normal eGFR and still had non-nephrotic range proteinuria at last visit. CUBN gene mutations should be considered in patients with isolated non-nephrotic range proteinuria and normal kidney function. Diagnosing these patients, who are thought to have a better prognosis, is important in terms of avoiding unnecessary treatment and predicting prognosis. CUBN gene mutations may also present as FSGS which extends the spectrum of renal manifestation of these patients. A higher resolution version of the Graphical abstract is available as Supplementary information.

Effect of FN1 mutation on outcomes of fibronectin glomerulopathy in a systematic review and meta-analysis

Background. Fibronectin glomerulopathy is an inherited kidney disease that is characterized with extensive depositions of fibronectin in mesangium and subendothelial space. The aim of study is to assess effect of fibronectin gene on decreased renal function and likeliness of recurrence of the disease after kidney transplantation. Materials and methods. In retrospective descriptive studies, fifty-seven patients with fibronectin glomerulopathy were enrolled in this research. Relative risk and Odds ratio for assessing effect measures of risk factor on outcomes of disease were used. Results. Of fifty-seven patients with fibronectin glomerulopathy, thirty-six patients (36/57, 63.1 %) were male and twenty-one patients were female (21/57, 36.8 %). Relative risk and Odds ratio of end-stage kidney disease (ESKD) in nephrotic-range proteinuria versus non-nephrotic range proteinuria were assessed 1.33 and 1.39, respectively. Relative risk and Odds ratio of end-stage kidney disease with kidney replacement therapy (KRT) in patients with positive FN1 gene (as risk or contributing factor) versus patients with negative FN1 gene was assessed 0.66 and 0.50, respectively. Risk of recurrence after kidney transplant with nephrotic-range proteinuria was assessed 0.83 (95% confidence interval of 0.1213 to 5.7244) and odds ratio of recurrence after kidney transplant with nephrotic proteinuria versus non-nephrotic range proteinuria was assessed 0.75 (95% confidence interval of 0.03757 to 14.9733) in the current research. Conclusions. Relative risk and odds ratio of end-stage kidney disease in nephrotic-range proteinuria versus non-nephrotic range proteinuria were assessed 1.33 and 1.39, respectively. Therefore, it appears risk of fibronectin gene 1 on end-stage kidney disease with kidney replacement therapy be low.

MO372: Concordance Between 24-H Proteinuria and Spot Urine Protein-Creatinine Ratio in the Evaluation of Patients With Glomerular Diseases

Abstract BACKGROUND AND AIMS It has been postulated that the protein-creatinine ratio in spot urine sample (uPCR) could be an adequate alternative to measurement of proteinuria in 24-h urine samples (24-h proteinuria), which despite being the gold standard for the diagnosis and follow-up of patients with kidney disease, its accuracy is frequently influenced by incorrect sample collection. Several studies have shown a correlation between uPCR in spot urine samples and 24-h proteinuria. However, in daily clinical practice we often find significant differences between both measurements. Therefore, we set out to conduct this study to analyze the concordance between uPCR in first morning spot urine samples and 24-h proteinuria in patients with biopsy-proven glomerular diseases. METHOD We identified patients with biopsy-proven glomerular diseases who were evaluated during their disease course at our center between January 1, 2005 and December 31, 2021, and included patients with paired 24-h protein excretion measurement and spot urine samples that measured protein and creatinine concentration, simultaneously collected at the same day. We excluded patients with interstitial or vascular causes for kidney disease. We performed correlation analyses of uPCR and 24-h proteinuria globally and analyzed the influence of demographic data as well as eGFR and type of glomerular disease in this relationship. The concordance between both measurements was compared using intra-class correlation coefficients (ICC) and Bland–Altman plots. RESULTS About 351 patients with simultaneous uPCR and 24-h proteinuria measured at the same day were included in the study, 67.2% were male and the mean age was 53.9 ± 17.9. Median serum creatinine was 1.28 mg/dl (IQR 0.95–1.86) and mean eGFR measured by CKD-EPI was 60.1 ± 30.6 mL/mi/1.73 m2. Median 24-h proteinuria was 1.70 g/day (IQR: 0.62–3.45) and median uPCR was 1.09 g/g (IQR: 0.35–2.70). Wilcoxon rank test showed a systematic underestimation of uPCR compared with 24-h proteinuria (Z = −8.22, P &amp;lt; 0.001). Mean ICC for both measurements was 0.82 (CI 95%: 0.77–0.85, P &amp;lt; 0.001). There was a significant agreement between both measurements after stratifying according to eGFR, with a mean ICC in patients with GFR &amp;gt;60 mL/min of 0.79 (CI 95%: 0.71–0.85, P &amp;lt; 0.001), mean ICC in patients with GFR between 30 and 60 mL/min of 0.80 (CI 95%: 0.72–0.86) and a mean ICC of 0.85 (CI 95%: 0.74–0.91, P &amp;lt; 0.001) in patients with GFR &amp;lt; 60 mL/min. Agreement between Upcr and 24-h proteinuria did not vary according to age, sex or type of glomerular disease. After dividing the cohort into three categories of proteinuria (&amp;lt;1, 1–3, &amp;gt;3 g/day for 24-h proteinuria, and &amp;lt; 1, 1–3, &amp;gt;3 g/g for uPCR), we performed Cohen's κ test to determine agreement, finding moderate agreement between measurements (κ = 0.46, P &amp;lt; 0.001). Passing-Bablok Regression and Bland-Altman plots indicated high concordance between the two methods when proteinuria &amp;lt;3.5 g/day, while outliers in the data suggested greater variability between measurements for patients with proteinuria over 3.5 g/day (Figure 2). CONCLUSION The level of concordance between proteinuria from 24-h urine samples and protein–creatinine ratio from spot urine samples is high regardless of eGFR, age, sex and type of glomerular disease. However, the level of agreement decreases in nephrotic-range proteinuria. Therefore, we suggest that uPCR could be an appropriate measure to assess and follow-up patients with glomerular diseases and non-nephrotic range proteinuria, while the degree of proteinuria should still be monitored with 24-h urine specimens in patients with proteinuria &amp;gt;3.5 g/day.

Chronic Kidney Disease from Polyvinylpyrrolidone Deposition in Persons with Intravenous Drug Use.

Persons with intravenous drug use have a higher risk of developing CKD compared with the general population. In Norway, deposits of polyvinylpyrrolidone have been observed in kidney biopsies taken from persons with opioid addiction and intravenous drug use since 2009. Polyvinylpyrrolidone is an excipient commonly used in pharmaceuticals, and the polyvinylpyrrolidone deposits observed in these patients were caused by intravenous injection of a specific oral methadone syrup containing very high molecular weight polyvinylpyrrolidone. Here, we present the clinicopathologic findings from 28 patients with CKD associated with polyvinylpyrrolidone deposition in the kidney. The 28 patients and their kidney biopsies were included when polyvinylpyrrolidone deposition was recognized, either retrospectively or at the time of diagnostic evaluation. Biopsies were taken between 2009 and 2016. We collected laboratory parameters and clinical data from digital patient charts. For each kidney biopsy, the glomerular volume, extent of polyvinylpyrrolidone deposition, and tubulointerstitial area with tubular atrophy were assessed quantitatively. All patients (mean age: 37 years) had CKD (mean eGFR: 33 ml/min per 1.73 m2) and normal urine protein or non-nephrotic-range proteinuria. Biopsies showed moderate to severe tubular atrophy (mean extent: 65%) and interstitial infiltrates of vacuolated macrophages containing polyvinylpyrrolidone (mean share of biopsy area: 1.5%). Underperfused and ischemic glomeruli were common findings. In 22 samples, ultrastructural investigation revealed polyvinylpyrrolidone-containing vacuoles in the mesangial or endothelial cells of glomeruli. At the last follow-up, most patients had stable or improved eGFR. Two patients had developed kidney failure and underwent hemodialysis. Intravenous injection of a specific oral methadone syrup caused polyvinylpyrrolidone deposition in the kidney in persons with opioid addiction and intravenous drug use. Kidney biopsy findings suggested an association between polyvinylpyrrolidone deposition and tubular atrophy.

Tale of two nephropathies; co-occurring Alport syndrome and IgA nephropathy, a case report

BackgroundAlport Syndrome and IgA Nephropathy (IgAN) are both disorders that can cause hematuria. Alport syndrome is most commonly an X-linked disease, caused by COL4A5 mutation. Mutations of COL4A3 and COL4A4 on chromosome two are also common causes of Alport syndrome. IgAN is the most common glomerulonephritis worldwide. Though IgAN is usually sporadic, an estimated 15% of cases have an inheritable component. These cases of Familal IgA Nephropathy (FIgAN) can have mutations on genes which are known to cause Alport Syndrome.Case presentationWe report a case of a 27-year-old man with strong family history of renal disease, who presented with hematuria and new non-nephrotic range proteinuria. Physical exam showed no abnormalities. His creatinine remained persistently elevated, and renal ultrasound exhibited bilaterally increased echogenicity consistent with Chronic Kidney Disease. Twenty-four-hour urinary collection revealed non-nephrotic range proteinuria of 1.4 g, with otherwise negative workup. On biopsy, he had IgA positive immunofluorescent staining as well as moderate interstitial fibrosis and tubular atrophy. Electron microscopy showed a basket-weave pattern of thickening and splitting of the lamina densa-consistent with Alport Syndrome, as well as mesangial expansion with electron-dense deposits -consistent with IgAN.ConclusionsMutations of COL4A5 on the X chromosome, as well as mutations of COL4A3 and COL4A4 on chromosome 2, can cause both Alport Syndrome and FIgAN. Genome wide association studies identified certain Angiotensin Converting Enzyme gene polymorphisms as independent risk factors for progression of IgAN. Our Presentation with this co-occurring pathology suggests a new paradigm where Alport Syndrome and FIgAN may represent manifestations of a single disease spectrum rather than two disparate pathologies. Appreciating hematuria through this framework has implications for treatments and genetic counseling. Further genome wide association studies will likely increase our understanding of Alport Syndrome, FIgAN, and other causes of hematuria.

ANASARCA AND MALIGNANT PLEURAL EFFUSION

TOPIC: Lung Cancer TYPE: Medical Student/Resident Case Reports INTRODUCTION: Anasarca is commonly caused by proteinuria, gastroenteral protein loss, low-synthesis states, or low intake. Etiologies of anasarca include nephrotic syndrome, cirrhosis, protein-losing enteropathy, and malnutrition [1]. Our case describes diffuse edema secondary to protein loss from recurrent malignant pleural effusion, an etiology not previously reported in the literature. CASE PRESENTATION: A 59-year-old male with stage IV non-small cell lung cancer presented with complaint of increased bilateral lower extremity edema. In the preceding month he had experienced recurrent right-sided pleural effusions requiring multiple thoracenteses and placement of a right indwelling pleural catheter. He reported draining up to 800 cc daily, with volumes of 500 cc every other day at the time of admission. The patient's lower extremity edema evolved over a span of one month and had significantly increased just prior to admission, precluding his ability to don footwear. The patient's exam was significant for diffuse edema most prominent at the feet and ankles and diminished breath sounds with dullness to percussion at the right lung base. Workup showed non-nephrotic range proteinuria, no evidence of cirrhosis, and normal ejection fraction on transthoracic echocardiogram. His total serum protein was 5.3 g/dL and serum albumin was 2.6 g/dL. He continued to drain pleural fluid from his pleural catheter at an average of 150-250cc/day. Pleural fluid protein was as high as 2.2 g/dL. Average daily pleural drainage was 200 cc, resulting in a daily protein loss of approximately 4g/day. This degree of protein loss was surmised to be the likely cause of the patient's anasarca. Over the course of his admission, the patient underwent multiple dialysis sessions resulting in a total net weight loss of 15kg. He demonstrated improvement in edema about his abdomen and legs but his ankles and feet continued to have pitting edema to a depth of 4-5 mm. DISCUSSION: This is an unusual case of protein loss via recurrent pleural effusion leading to anasarca. Diffuse edema resulting from recurrent/persistent malignant has not been previously described and thus, there is no clear guidance regarding potential complications nor management options. Other more common causes of anasarca may give some insight regarding potential problems and possible therapies. In low-protein states, diuresis has been a standard of care. Data from the treatment of nephrotic syndrome has demonstrated the loss of clotting factors resulting in coagulopathy. Additionally, patients are at increased cardiac risk due to increased lipid levels from upregulated liver synthesis [2]. Furthermore, loss of antibodies and other proteins theoretically increases the risk for infection [3]. CONCLUSIONS: The prevalence of malignant effusions leading to anasarca is unclear. This case highlights a cause of anasarca that should be considered in similar patient populations. REFERENCE #1: Blankfield RP, Finkelhor RS, Alexander JJ, Flocke SA, Maiocco J, Goodwin M, Zyzanski SJ. Etiology and diagnosis of bilateral leg edema in primary care. Am J Med. 1998;105(3):192. REFERENCE #2: Crew RJ, Radhakrishnan J, Appel G. Complications of the nephrotic syndrome and their treatment. Clin Nephrol. 2004;62(4):245. REFERENCE #3: Umar SB, DiBaise JK. Protein-losing enteropathy: case illustrations and clinical review. Am J Gastroenterol. 2010;105(1):43. Epub 2009 Sep 29. DISCLOSURES: No relevant relationships by Jaime Stull, source=Web Response

SLE strikes the heart! A rare presentation of SLE myocarditis presenting as cardiogenic shock

BackgroundAlthough systemic lupus erythematosus (SLE) can affect the cardiovascular system in many ways with diverse presentations, a severe cardiogenic shock secondary to SLE myocarditis is infrequently described in the medical literature. Variable presenting features of SLE myocarditis can also make the diagnosis challenging. This case report will allow learners to consider SLE myocarditis in the differential and appreciate the diagnostic uncertainty.Case presentationA 20-year-old Filipino male presented with acute dyspnea, pleuritic chest pain, fevers, and diffuse rash after being diagnosed with SLE six months ago and treated with hydroxychloroquine. Labs were notable for leukopenia, non-nephrotic range proteinuria, elevated cardiac biomarkers, inflammatory markers, low complements, and serologies suggestive of active SLE. Broad-spectrum IV antibiotics and corticosteroids were initiated for sepsis and SLE activity. Blood cultures were positive for MSSA with likely skin source. An electrocardiogram showed diffuse ST-segment elevations without ischemic changes. CT chest demonstrated bilateral pleural and pericardial effusions with dense consolidations. Transthoracic and transesophageal echocardiogram demonstrated reduced left ventricular ejection fraction (LVEF) 45% with no valvular pathology suggestive of endocarditis. Although MSSA bacteremia resolved, the patient rapidly developed cardiopulmonary decline with a repeat echocardiogram demonstrating LVEF < 10%. A Cardiac MRI was a nondiagnostic study to elucidate an etiology of decompensation given inability to perform late gadolinium enhancement. Later, cardiac catheterization revealed normal cardiac output with non-obstructive coronary artery disease. As there was no clear etiology explaining his dramatic heart failure, endomyocardial biopsy was obtained demonstrating diffuse myofiber degeneration and inflammation. These pathological findings, in addition to skin biopsy demonstrating lichenoid dermatitis with a granular “full house” pattern was most consistent with SLE myocarditis. Furthermore, aggressive SLE-directed therapy demonstrated near full recovery of his heart failure.ConclusionAlthough myocarditis during SLE flare is a well-described cardiac manifestation, progression to cardiogenic shock is infrequent and fatal. As such, SLE myocarditis should be promptly considered. Given the heterogenous presentation of SLE, combination of serologic evaluation, advanced imaging, and myocardial biopsies can be helpful when diagnostic uncertainty exists. Our case highlights diagnostic methods and clinical course of a de novo presentation of cardiogenic shock from SLE myocarditis, then rapid improvement.

A patient with a homozygous diacylglycerol kinase epsilon (DGKE) gene mutation with atypical haemolytic uraemic syndrome and low C3 responded well to eculizumab: a case report

BackgroundAtypical haemolytic uraemic syndrome (aHUS) is a rare systemic syndrome characterized by non-immune haemolytic anaemia, thrombocytopenia, and kidney injury. In most cases, alternative complement pathway dysregulation is the identifying cause. Recently, other genetic causes have been identified, including a mutation in the diacylglycerol kinase epsilon (DGKE) gene, which theoretically affect the coagulation pathway and does not affect the complement pathway. Data about the management of these patients are limited. Ideal management and definitive treatment protocols have not yet been established.Case presentationA three-year-old boy presented with features of atypical haemolytic uraemic syndrome (aHUS) and low complement C3. He was presumed to have complement-mediated aHUS and was managed empirically with eculizumab. Two weeks after starting eculizumab, his haemoglobin levels, platelet count, and complement C3 level normalized but he continued to have non-nephrotic range proteinuria. His genetic testing revealed a homozygous DGKE mutation, with no other mutation detected. Six months after presentation, the patient was still in remission with no features of aHUS, a trial of weaning eculizumab by increasing dose interval was followed by nephrotic range proteinuria and severe oedema. His proteinuria improved and his oedema resolved after resuming his recommended eculizumab dose.ConclusionsDGKE gene mutation can lead to aHUS with theoretically no complement dysregulation. However, some patients with this mutation show alternative complement pathway activation. This case report describes a patient with aHUS due to a DGKE gene mutation and low C3 levels who responded to eculizumab, adding to the previously reported cases of patients with DGKE gene mutations who had complete remission with no relapse with C5 blockers and/or plasma exchange. A randomized controlled study on patients with DGKE mutations might be beneficial in understanding the disease and generating a management protocol.

Risk factors for renal involvement in Henoch–Schönlein purpura

ObjectiveHenoch–Schönlein purpura is a systemic vasculitis that mainly occurs in children. Renal impairment is a major complication of Henoch–Schönlein purpura, but there is no established predictive marker for renal involvement. Thus, in this study, we investigated the risk factors for renal involvement in children with Henoch–Schönlein purpura. MethodThe medical records of children newly diagnosed as having Henoch–Schönlein purpura between 2005 and 2020 were reviewed retrospectively. Selected laboratory data were recorded before treatment initiation. The date and the age at diagnosis; sex; and the presence of arthralgia, gastrointestinal and renal involvement were obtained retrospectively. ResultsThis study included a total of 186 patients with Henoch–Schönlein purpura. Among them, 36.0% had renal involvement; 28.4% had only microscopic hematuria, 53.7% had non-nephrotic range proteinuria, and 17.9% had nephrotic-range proteinuria during follow-up. The mean age was higher (p = 0.016) and female sex was predominant (p = 0.001) in patients with renal involvement than in those without renal involvement. Blood neutrophil/lymphocyte ratio (p = 0.002) and platelet/lymphocyte ratio (p = 0.002) were significantly higher than that of the patients without renal involvement. No statistically significant differences were observed in the hemoglobin concentration, platelet count, presence of arthralgia, and gastrointestinal involvement between patients with and without renal involvement. Logistic regression analysis revealed female sex (odd ratio = 3.213) and neutrophil/lymphocyte ratio (odd ratio = 1.329) as risk factors for renal involvement. ConclusionsFemale sex and high neutrophil/lymphocyte ratio were risk factors for renal involvement in Henoch–Schönlein purpura.

A child with Imerslund-Gr\xe4sbeck syndrome concealed by co\u2010existing \u03b1-thalassaemia presenting with subacute combined degeneration of the spinal cord: a case report

BackgroundImerslund-Gräsbeck syndrome is a rare genetic disease characterised by vitamin B12 deficiency and proteinuria.Case presentationA 4-year old Sri Lankan boy presented with gradually worsening difficulty in walking for two weeks duration. He was previously diagnosed and managed as having non-transfusion-dependent α-thalassaemia based on the presence of hypochromic microcytic anaemia, haemoglobin H inclusion bodies in the blood film and compound heterozygous α-thalassaemia genotype with a gene deletion. However, his transfusion requirement increased over the past three months and he gradually lost his motor developmental milestones during two weeks before admission. The neurological examination revealed generalised hypotonia, exaggerated knee jerks and extensor plantar response. His complete blood count showed pancytopenia, and bone marrow biopsy revealed megaloblastic changes. Serum vitamin B12 and red blood cell folate levels were low. MRI revealed sub-acute combined degeneration of the spinal cord with characteristic ‘inverted V sign’. Urine analysis showed non-nephrotic range proteinuria. The diagnosis of Imerslund-Gräsbeck syndrome was made due to the presence of non-nutritional vitamin B12 deficiency and asymptomatic proteinuria. He showed a rapid haematological and neurological improvement to intramuscular hydroxocobalamin.ConclusionsThis case report presents a rare occurrence of severe vitamin B12 deficiency due to Imerslund-Gräsbeck syndrome masked by co-existent α-thalassaemia, resulting in serious consequences. It highlights the need for a high index of suspicion in evaluating children with severe anaemia, especially in the presence of mixed pathologies.

A case of dasatinib-induced focal segmental glomerulosclerosis in a patient with Philadelphia chromosome positive chronic myeloid leukemia

Focal segmental glomerulosclerosis is a common glomerular histological lesion, which is usually characterised by non-nephrotic range proteinuria or nephrotic syndrome. It may be idiopathic or occurs secondarily to drugs, diabetes, obesity or HIV nephropathy and other infections. Dasatinib, a tyrosine kinase inhibitor that has been used for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia, has a few renal adverse effects. Exceptional cases with non-nephrotic range proteinuria have been reported in relation with dasatinib. In this case, we report a patient with symptoms of nephrotic syndrome and nephrotic range proteinuria, who was diagnosed as focal segmental glomerulosclerosis by kidney biopsy after treated with dasatinib.