Long-term outcome of biopsy-proven idiopathic tubulointersitial nephritis with or without uveitis in children—a nationwide follow-up study

Background Only a few studies reporting the long-term outcome of children with idiopathic tubulointerstitial nephritis (TIN) and uveitis syndrome (TINU) are available. We studied the long-term kidney and ocular outcome in a nationwide cohort of children with TIN or TINU. Methods All patients followed up for a minimum of 1 year by a paediatrician and an ophthalmologist were enrolled. The data on plasma creatinine (P-Cr), estimated glomerular filtration rate (eGFR), proteinuria, hypertension and uveitis were collected retrospectively. Results Fifty-two patients were studied. Median age at time of diagnosis was 13.1 (1.8–16.9) years and median follow-up time was 5.7 (1.1–21.2) years. Forty-five (87%) patients were initially treated with glucocorticoids. The median of the maximum P-Cr was 162 μmol/l (47–1,016) and that of eGFR 47 ml/min/1.73m2 (8–124). Uveitis was diagnosed in 33 patients (63%) and 21 (40%) patients developed chronic uveitis. P-Cr normalised in a median of 2 months. Eleven (21%) patients had nephritis recurrence during or after discontinuation of glucocorticoids. At the latest follow-up, 13 (25%) patients had eGFR < 90 ml/min/1.73m2 (median 83; 61–89 ml/min/1.73m2). Six patients had tubular proteinuria; all presented with TIN without uveitis. Seven (13%) patients were hypertensive. Eleven (21%) patients had uveitis. One patient developed uraemia and was later transplanted. Conclusions Our study questions the previously reported good long-term kidney and ocular outcome of patients with TIN/TINU. Decreased kidney function and/or ocular co-morbidities may persist for several years; thus, both kidney and ocular follow-up for at least 1 year is warranted. Graphical abstract A higher resolution version of the Graphical abstract is available as Supplementary information

MO523PATIENTS FROM COVID-19 MOSTLY RECOVER FROM TUBULAR PROTEINURIA AND ACUTE KIDNEY INJURY AFTER HOSPITAL DISCHARGE

Background and Aims Proteinuria, hematuria and acute kidney injury (AKI) are frequently observed in hospitalized patients with COVID-19. However, few data are available on these parameters after hospital discharge. Method This retrospective, observational and monocentric study included 153 hospitalized patients, in whom urine total proteinuria and α1-microglobulin (a marker of tubular injury) were measured. Thirty patients died. Among the 123 survivors, follow-up urine and creatinine analyses were available for 72 patients (after a median of 51 [19;93] days following hospital discharge). Results The median proteinuria at hospitalization and follow-up (n=72) was 419 [239; 748] and 79 [47; 129] mg/g, respectively (p&lt;0.0001). The median concentrations of urinary α1-microglobulin (n=66) were 50 [25; 81] and 8 [0; 19] mg/g, respectively (p&lt;0.0001). Estimating glomerular filtration rate (eGFR) was lower during the hospitalization compared to the follow-up: 81 [62; 92] versus 87 [66; 98] mL/min/1.73m² (p=0.0222). At follow-up, a decreased renal function was observed in 10/72 (14%) of patients, with 50% of them presenting decreased renal function before COVID-19 hospitalization and others developing severe AKI and/or proteinuria during hospitalization. Conclusion In most hospitalized patients with COVID-19, proteinuria and eGFR significantly improved after hospital discharge. Only patients who developed severe AKI and/or heavy proteinuria will require a specific follow-up by nephrologists.

Proteinuria in COVID-19: prevalence, characterization and prognostic role

Background Proteinuria has been commonly reported in patients with COVID-19. However, only dipstick tests have been frequently used thus far. Here, the quantification and characterization of proteinuria were investigated and their association with mortality was assessed. Methods This retrospective, observational, single center study included 153 patients, hospitalized with COVID-19 between March 28th and April 30th, 2020, in whom total proteinuria and urinary α1-microglobulin (a marker of tubular injury) were measured. Association with mortality was evaluated, with a follow-up until May 7th, 2020. Results According to the Kidney Disease Improving Global Outcomes staging, 14% (n = 21) of the patients had category 1 proteinuria (< 150 mg/g of urine creatinine), 42% (n = 64) had category 2 (between 150 and 500 mg/g) and 44% (n = 68) had category 3 proteinuria (over 500 mg/g). Urine α1-microglobulin concentration was higher than 15 mg/g in 89% of patients. After a median follow-up of 27 [14;30] days, the mortality rate reached 18%. Total proteinuria and urinary α1-microglobulin were associated with mortality in unadjusted and adjusted models. This association was stronger in subgroups of patients with normal renal function and without a urinary catheter. Conclusions Proteinuria is frequent in patients with COVID-19. Its characterization suggests a tubular origin, with increased urinary α1-microglobulin. Tubular proteinuria was associated with mortality in COVID-19 in our restropective, observational study.

Proteinuria in COVID-19: prevalence, characterization and prognostic role

Background: Proteinuria has been commonly reported in patients with COVID-19, suggesting a renal involvement in this infection. However, only dipstick tests have been used thus far. Here, the quantification and characterization of proteinuria and hematuria are investigated. Their potential association with mortality was assessed. Methods: This retrospective, observational and monocentric study includes 153 patients hospitalized with COVID-19 between March 28th and April 30th 2020, in whom total proteinuria and urine α1-microglobulin (a marker of tubular injury) have been measured. Association with mortality was evaluated with a follow-up until May 7th 2020. Results: According to the Kidney Disease Improving Global Outcomes staging, 14% (n=21) had stage 1 proteinuria (<150 mg/g of urine creatinine), 42% (n=64) had stage 2 (between 150 and 500 mg/g) and 44% (n=68) had stage 3 (over 500 mg/g). Urine α1-microglobulin concentration was higher than 10 or 15 mg/g in 94% and 89% of patients, respectively. After a median follow-up of 27 [14;30] days, the mortality rate reached 18%. Total proteinuria and urine α1-microglobulin (as continuous and/or categorical variables) were associated with mortality in unadjusted and adjusted models. This association was even stronger in subgroups of patients with normal renal function or without urinary catheter. Conclusions: Proteinuria is frequent in patients with COVID-19. Its characterization suggests a tubular origin with increased urine α1-microglobulin. Tubular proteinuria seems associated with mortality in COVID-19.

Making a Dent in Dent Disease

Dent disease (DD) is a rare kidney disorder caused by mutations in the Cl−/H+ exchanger ClC-5. Extensive physiologic characterization of the transporter has begun to illuminate its role in endosomal ion homeostasis. Nevertheless, we have yet to understand how loss of ClC-5 function in the kidney proximal tubule impairs membrane traffic of megalin and cubilin receptors to cause the low molecular weight proteinuria characteristic of DD. This review identifies open questions that remain to be answered, evaluates the current literature addressing these questions, and suggests new testable models that may link loss of ClC-5 function to tubular proteinuria in DD.

3329 Hemoglobin selectively inhibits renal proximal tubular uptake of proteins: Implications for vitamin D deficiency and kidney disease in sickle cell disease

OBJECTIVES/SPECIFIC AIMS: While Hb-induced toxicity has been assumed to cause PT dysfunction, the development of tubular proteinuria from this dysfunction in SCD patients is not well understood. We previously found that free Hb, at concentrations predicted to be present chronically and during hemolytic crisis in the tubular filtrate of SCD patients, impairs uptake of albumin by PT cells via direct competition for binding to megalin and cubilin receptors. The purpose of this study is to further evaluate the consequences of increased filtered Hb concentrations on vitamin D reabsorption and activation. METHODS/STUDY POPULATION: We have developed a PT cell culture model that closely mimics in vivo PT cell structure, morphology, and endocytic capacity. Using this model, we treated cells with physiologic levels of cell-free Hb estimated in SCD and measured protein endocytosis and toxicity/oxidative stress. Endocytosis of fluorescently-tagged DBP and RBP were evaluated and quantified by confocal imaging and spectrofluorometry. Cellular toxicity and oxidative stress were assessed by measuring aconitase activity and accumulation of mitochondrial reactive oxygen species. RESULTS/ANTICIPATED RESULTS: PT cell uptake of DBP was significantly inhibited by both concentrations of Hb estimated to be filtered into the tubule lumen under chronic conditions (0.6μM Hb; 39% inhibition) and hemolytic crisis (≤20μM Hb; up to 92% inhibition) in SCD patients. ****p<0.0001 by one-way ANOVA, Dunnett’s multiple comparisons test. PT cell uptake of RBP was minimally affected by the same concentrations of Hb that profoundly inhibited internalization of DBP. RBP uptake was not significantly inhibited by all concentrations of Hb tested except the estimated hemolytic crisis maximum concentration (20μM; 27% inhibition). RBP uptake inhibition at 20μM Hb treatment was dramatically less than DBP uptake inhibition under the same treatment condition (27% RBP inhibition vs 92% DBP inhibition). *p<0.05 by one-way ANOVA, Dunnett’s multiple comparisons test. Mitochondrial oxidative stress, measured as a decrease in aconitase activity, was significantly increased in cells exposed to Hb (~43% aconitase activity reduction after 72h 20μM Hb treatment, and ~11% aconitase activity reduction after 72h 1μM Hb treatment). *p<0.05, **p<0.01 by one-sample t-test of the differences between treatment and untreated control conditions. We are currently assessing changes in PT cell vitamin D hydroxylase expression levels and vitamin D metabolism after exposure to chronic and hemolytic concentrations of Hb. Because oxidative stress has been previously reported to affect hydroxylase expression and activity, we expect to find a decrease in vitamin D hydroxylase expression and/or activity, resulting in decreased vitamin D activation. DISCUSSION/SIGNIFICANCE OF IMPACT: Our results suggest that competition for megalin/cubilin binding between Hb and normally-filtered proteins, including DBP, may be the primary cause of tubular proteinuria in SCD patients. This inhibition appears to be selective for proteins that are largely α-helical in structure, such as albumin and DBP. Understanding the structural basis for Hb competition with filtered proteins for PT uptake could identify biomarkers to detect tubular proteinuria in SCD patients prior to the onset of kidney disease. This may also help develop therapeutic compounds that would selectively inhibit Hb binding to megalin/cubilin receptors. We have developed a highly sensitive fluorescence-based assay to test for such compounds. Inhibition of DBP uptake and vitamin D metabolism in the PT could lead or contribute to vitamin D deficiency. To our knowledge, our study is the first to suggest a mechanism for vitamin D deficiency commonly observed in SCD patients. Ongoing studies focus on measuring vitamin D metabolism in both cell and mouse models of SCD.

Electrophoretic patterns of proteinuria in feline spontaneous chronic kidney disease

Objectives The purpose of this study was to describe the electrophoretic patterns of proteinuria in cats at risk of and cats with chronic kidney disease (CKD), and to investigate whether the presence of high-molecular-weight (HMW) and low-molecular-weight (LMW) proteins were associated with CKD, proteinuria and/or disease progression. Methods Healthy cats at risk of developing renal disease (n = 17) and cats affected with CKD at different stages (n = 22) were prospectively enrolled and sampled over time. Seventy urine samples were included and assayed with a commercially available sodium dodecyl sulfate–agarose gel electrophoresis (SDS-AGE) method. Each sample (gel lane) was inspected to identify albumin, HMW and LMW proteins, and an electrophoretic pattern (albuminuria, glomerular, tubular, mixed or negative) was assigned accordingly. Fisher’s exact test was used to assess the distribution of HMW and LMW proteins in cats grouped according to International Renal Interest Society stage and to the magnitude of proteinuria, and to assess if HMW and LMW proteins at the time of inclusion were associated with the development and progression of CKD. Results In samples of cats at risk, the most common pattern was glomerular (84.6%); glomerular pattern was also common in cats with CKD (54.2%), although mixed proteinuria and tubular proteinuria were also present (29.5% and 11.4%, respectively). The presence of LMW proteins was associated with CKD ( P <0.0001) and to a urine protein:creatinine ratio >0.2 ( P = 0.025). Both HMW and LMW proteins were not associated with progression of CKD within 6 months (n = 14). Conclusions and relevance Our results showed that HMW proteinuria is common in healthy cats at risk of developing CKD, although the pathological significance needs to be confirmed. The detection of LMW proteins in urine of cats suspected to be affected by CKD, especially in non-azotaemic, non-proteinuric or borderline proteinuric cats, suggests the presence of kidney damage.

Balkan endemic nephropathy

Balkan endemic nephropathy (BEN) is a chronic, slowly progressive tubulointerstitial nephritis, with familial clustering, occurring in several endemic rural regions in countries of the Balkan Peninsula. BEN is characterized by anaemia, tubular proteinuria, renal shrinkage, and slowly declining glomerular filtration rate (GFR). Up to one-third of patients may also develop upper urothelial tumours. The aetiology of BEN is unclear; chronic exposure to aristolochic acid and a polygenic predisposition are the most likely contributing factors. The major pathological characteristics of BEN are symmetrically shrunken, smooth-shaped kidneys, with interstitial fibrosis, mild interstitial inflammation, and tubular atrophy. Diagnosis is usually based upon positive family history of BEN, past or current residence in endemic regions, tubular proteinuria, tubular dysfunctions (such as urine acidification defects, salt wasting, and impaired excretion of ammonia, uric acid, and phosphate), scant urinary sediment, bilateral and symmetrically reduced kidney size, accompanied by severe anaemia, disproportionate to the degree of GFR reduction. There is no specific therapy for BEN; patients should therefore be treated as all patients with chronic kidney disease, in general. The use of distant water supplies or moving to another residence area should be advised to affected families. Careful evaluation for urothelial cancers is mandatory in patients with haematuria.