Proximal Tubular Dysfunction Research Articles

Dent’s disease: case series from a single center

Background. Dent’s disease (DD) is a rare X-linked recessive tubulopathy characterized by low molecular weight proteinuria, hypercalciuria, nephrocalcinosis/nephrolithiasis and chronic kidney disease. With this manuscript, we reported three patients diagnosed as DD in our department in the last 10 years and thereby described the genetics, pathophysiology, clinical presentation, course and management of the disease. Cases. The first case was a male newborn who was consulted to our department after medullary nephrocalcinosis was detected. The second case was a 4-year-old boy who was treated with a diagnosis of urinary tract infection but was found to have proteinuria. Our last case was an 11-month-old male infant who was being followed up for recurrent urinary tract infection and who had millimetric crystalloids in the renal collecting system. Proteinuria and hypercalciuria were present in all cases. Variants were observed in the CLCN5 gene for the first two cases (c.1852G>A and c.1557+1G>T, respectively) and OCRL gene (c.952C>T) for the last case. All patients were recommended oral hydration and a low-salt diet, and hydrochlorothiazide and enalapril were started. No deterioration in kidney function was observed in any patient. Conclusion. DD is a disease that shows different phenotypes even among individuals with mutations in the same gene. Therefore, it should be considered in all patients with hypercalciuria, proteinuria, nephrolithiasis or nephrocalcinosis with/without proximal tubular dysfunction especially in the early childhood period. Classical treatments for hypercalciuria should be utilized, and a patient-based treatment plan should be drawn especially for proteinuria.

CCDC158: A novel regulator in renal proximal tubular endocytosis unveiled through exome sequencing and interactome analysis.

Renal proximal tubular reabsorption of proteins and polypeptides is tightly regulated by a concerted action of the multi-ligand receptors with subsequent processing from the clathrin-coated pits to early/recycling and late endosomes and towards lysosomes. We performed whole exome-sequencing in a male patient from a consanguineous family, who presented with low- and intermediate molecular weight proteinuria, nephrocalcinosis and oligospermia. We identified a new potential player in tubular endocytosis, coiled-coil domain containing 158 (CCDC158). The variant in CCDC158 segregated with the phenotype and was also detected in a female sibling with a similar clinical kidney phenotype. We demonstrated the expression of this protein in kidney tubules and modeled its structure in silico. We hypothesized that the protein played a role in the tubular endocytosis by interacting with other endocytosis regulators, and used mass spectrometry to identify potential interactors. The role of CCDC158 in receptor-mediated endocytosis was further confirmed by transferrin and GST-RAP trafficking analyses in patient-derived proximal tubular epithelial cells. Finally, as CCDC158 is known to be expressed in the testis, the presence of oligospermia in the male sibling further substantiated the pathogenic role of the detected missense variant in the observed phenotype. In this study, we provide data that demonstrate the potential role of CCDC158 in receptor-mediated endocytosis, most likely by interaction with other endocytosis-related proteins that strongly correlate with the proximal tubular dysfunction phenotype as observed in the patients. However, more studies are needed to fully unravel the molecular mechanism(s) in which CCDC158 is involved.

Pediatric Dent disease presenting with rickets and end-stage renal disease: case report and literature review.

Dent disease is a rare disease with proximal renal tubular dysfunction, and is characterized by low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis, and chronic kidney disease. Renal failure slowly progresses and end-stage renal disease may develop in the late decades of life. We report a case of a 15-year-old boy who was diagnosed with Dent disease 1 with a CLCN5 truncating mutation. The patient presented with arthralgia and rickets at the onset of Dent disease and he was diagnosed with end-stage renal disease at the age of 15 years. His only symptoms were arthralgia and rickets during the disease course. The findings in this case suggest that patients with arthralgia and rickets could have a rare cause such as Dent disease.

Clinical characteristics and genetic profile of children with WDR72-associated distal renal tubular acidosis: a nationwide experience.

Limited data, primarily from small case series, exist regarding the clinical profile, genetic variants, and outcomes of WDR72-associated distal renal tubular acidosis (WDR72-dRTA). Our study enrolled children diagnosed with WDR72-dRTA below 18years of age from 9 Indian centers and analyzed their clinical characteristics, genetic profiles, and outcomes. Potential genotype-phenotype correlations were explored. We report 22 patients (59% female) with WDR72-dRTA who were diagnosed at a median age of 5.3 (3, 8) years with polyuria (n = 17; 77.3%), poor growth (16; 72.7%), and rickets (9; 40.9%). Amelogenesis imperfecta was present in 21 (95.5%) cases. At presentation, all patients had normal anion gap metabolic acidosis; hypokalemia and nephrocalcinosis were seen in 17 (77.3%) patients each. Seven (31.8%) patients had concomitant proximal tubular dysfunction. Genetic analysis identified biallelic nonsense variants in 18 (81.8%) patients, including novel variants in 6 cases. A previously reported variant, c.88C > T, and a novel variant, c.655C > T, were the most frequent variants, accounting for 10 (45.5%) cases. Over a median follow-up of 1.3 (1, 8) years, the height velocity improved by 0.74 (0.2, 1.2) standard deviation scores, while 3 children (13.6%) progressed to chronic kidney disease (CKD) stage 2, with eGFR ranging from 67 to 76mL/min/1.73 m2, respectively, after 11.3-16years of follow-up. No specific genotype-phenotype correlation could be established. WDR72-dRTA should be considered in children with typical features of amelogenesis imperfecta and dRTA. Biallelic nonsense variants are common in Asians. While most patients respond well to treatment with improved growth and preserved eGFR, on long-term follow-up, a decline in eGFR may occur.

Ketogenic Diet and Progression of Kidney Disease in Animal Models of Nephropathic Cystinosis.

Nephropathic cystinosis is a rare inherited lysosomal storage disorder caused by mutations in the CTNS gene that encodes for cystinosin, a lysosomal cystine/H+ symporter. From the standpoint of the kidneys, patients develop early-onset renal Fanconi syndrome and progressive chronic kidney disease. Current therapy with cysteamine delays but does not prevent kidney failure, and has significant side effects that limit adherence and reduce the quality of life of patients. We have tested biochemically and histologically the effects of ketogenic diet on kidney disease of two animal models of nephropathic cystinosis. When Ctns-/- mice were fed with ketogenic diet from 3 to 12 months of age, we observed significant nearly complete prevention of Fanconi syndrome, including low molecular weight proteinuria, glycosuria and polyuria. Compared to wild-type animals, BUN at 12 months was higher in cystinotic mice fed with standard diet (P<0.001), but not with ketogenic diet. At sacrifice, kidneys of knock out mice fed with ketogenic diet appeared macroscopically similar to those of wild type animals, which was reflected microscopically by a significant reduction of interstitial cell infiltration (CD3 and CD68 positive cells, P<0.01), of interstitial fibrosis (Masson and α-SMA staining, P< 0.001), and of apoptosis (cleaved caspase 3 levels; P<0.001), and by indirect evidence of restoration of a normal autophagic flux (SQSTM1/p62 and LC3-II expression, P<0.05). Beneficial effects of ketogenic diet on tubular function were also observed after mice were fed with this ketogenic diet from the age of 6 months to the age of 15 months, after they had developed proximal tubular dysfunction. Although slightly less pronounced, these results were replicated in Ctns-/- rats fed with ketogenic diet from 2 to 8 months of life. These results indicate significant mitigation of the kidney phenotype in cystinotic animals fed with ketogenic diet.

Kidney Outcomes and Trajectories of Tubular Injury and Function in Critically Ill Patients With and Without COVID-19.

COVID-19 may injure the kidney tubules via activation of inflammatory host responses and/or direct viral infiltration. Most studies of kidney injury in COVID-19 lacked contemporaneous controls or measured kidney biomarkers at a single time point. To better understand mechanisms of acute kidney injury in COVID-19, we compared kidney outcomes and trajectories of tubular injury, viability, and function in prospectively enrolled critically ill adults with and without COVID-19. The COVID-19 Host Response and Outcomes study prospectively enrolled patients admitted to ICUs in Washington State with symptoms of lower respiratory tract infection, determining COVID-19 status by nucleic acid amplification on arrival. We evaluated major adverse kidney events (MAKE) defined as a doubling of serum creatinine, kidney replacement therapy, or death, in 330 patients after inverse probability weighting. In the 181 patients with available biosamples, we determined trajectories of urine kidney injury molecule-1 (KIM-1) and epithelial growth factor (EGF), and urine:plasma ratios of endogenous markers of tubular secretory clearance. At ICU admission, the mean age was 55 ± 16 years; 45% required mechanical ventilation; and the mean serum creatinine concentration was 1.1 mg/dL. COVID-19 was associated with a 70% greater occurrence of MAKE (relative risk 1.70; 95% CI, 1.05-2.74) and a 741% greater occurrence of KRT (relative risk 7.41; 95% CI, 1.69-32.41). The biomarker cohort had a median of three follow-up measurements. Urine EGF, secretory clearance ratios, and estimated glomerular filtration rate (eGFR) increased over time in the COVID-19 negative group but remained unchanged in the COVID-19 positive group. In contrast, urine KIM-1 concentrations did not significantly change over the course of the study in either group. Among critically ill adults, COVID-19 is associated with a more protracted course of proximal tubular dysfunction and reduced eGFR despite similar degrees of kidney injury.

Hypophosphatemic osteomalacia due to cadmium toxicity in silverware industry: A curious case of aches and pains

ABSTRACT Hypophosphatemic osteomalacia in an adult often gives clinical diagnostic challenges. Usually, they are caused by either tumor-induced osteomalacia or due to genetically mediated hypophosphatemia, particularly X-linked hypophosphatemia. However, heavy metal toxicity, leading to global proximal renal tubular dysfunction, is a rare cause, and in particular, cadmium toxicity is rarely encountered in clinical practice. The presence of bony pain and neurological deficit, along with a classical exposure history, provides the diagnostic clue. In this background, here we present a middle-aged man who had severe bony pains all over his body and lower back stiffness for five years. He underwent an initial workup as a suspected spondyloarthropathy but was later on, found to have hypophosphatemic osteomalacia and severe proximal renal tubular dysfunction. Further, the workup revealed elevated FGF-23. His occupational history revealed prolonged exposure to cadmium fumes in the silverware industry. He improved moderately with treatment; however, significant renal damage is still present. This case highlights the importance of considering cadmium toxicity in proper clinical and occupational contexts in the evaluation of hypophosphatemic osteomalacia in an adult.

#2858 Immunohistochemical study reveals increased GLUT1 expression in proximal tubules of patients with acute interstitial nephritis

Abstract Background and Aims Interstitial inflammation in acute interstitial nephritis can advance into tubular epithelial cells and produce proximal tubular dysfunction, which may be clinically expressed as renal glycosuria. Previous studies have shown that the presence of renal glycosuria in acute kidney injury is a diagnostic clue for acute interstitial nephritis (AIN) with an excellent specificity. Sodium-independent glucose transporter 1 (GLUT1) is localized in the basolateral membrane of epithelial cells along the entire length of the proximal tubule, mainly in the S3 segment, and it is involved in the transcellular glucose transport. The aim of this study was to examine renal expression of GLUT1 in the proximal tubules of patients with biopsy-proven AIN. Method We identified patients with biopsy-proven AIN. After excluding patients with diabetes mellitus and patients who had received steroid treatment previous to the kidney biopsy, we selected 10 patients with biopsy-proven AIN, and we selected 10 patients with acute tubular necrosis (ATN) matched for age, proteinuria and glomerular filtration rate as the control group. An immunohistochemical study for GLUT1 was performed on the biopsies of patients with AIN and ATN. Staining intensity was graded as 0 (negative), 1+ (weak), 2+ (moderate), and 3+ (strong). GLUT1 expression was defined as focal when &amp;lt;50% of epithelial cells stained positive, and diffuse when &amp;gt;50% of the tissue showed strong staining. Results Renal glycosuria was present in 60% of the selected patients with AIN, with a median glycosuria of 150 mg/dl (IQR 0-162 mg/dl), while only 1 patient (10%) with ATN presented glycosuria (p = 0.037). All patients with AIN showed moderate or strong cytoplasmic GLUT1 staining in the epithelial cells of proximal tubules, which was significantly more intense (2+; 20% vs 11%, 3+; 80% vs 33.3%, p = 0.008) and diffuse (80% vs 22.2%, p = 0.002) than in patients with ATN. There was a tendency for positive correlation between the concentration of glycosuria and the extension of GLUT1 staining (r = 0.316, p = 0.078). Conclusion We found higher expression of GLUT1 in the cytoplasm of proximal tubular cells in patients with AIN in comparison to ATN. These findings suggest that proximal tubular injury plays a key role in the pathogenesis of AIN, leading to renal glycosuria in some cases. We hypothesize that the localization of strong GLUT1 staining in the cytoplasm of proximal tubular cells may indicate a misallocation of GLUT1 from plasma membrane where it is functional and a reversed cell polarity which might account for the observed renal glycosuria.

#2565 Urine amino acid profiles enlighten new prediction models for renal Fanconi syndrome and its association with eGFR level

Abstract Background and Aims Renal Fanconi syndrome (FS) presented dysfunctions of renal proximal tubular (PT) transport with or without excessive urine amino acids (AAs) excretion, which might contribute to the progression of eGFR decline. This study aimed to explore the clinical benefit of 21 urinary AAs excretion patterns in renal FS and eGFR decline. Method Liquid chromatography-tandem Mass spectrometry (LC-MS-MS) is currently quantitative and detects over 21 types of amino acids in 157 patients with renal proximal tubular dysfunctions. To evaluate the diagnostic values of urine AAs in renal FS, we established a machine learning algorithm to perform binary classification using Random Forest Regressor in Python (version 3.8.8) with a training set and a testing set (8:2). We used Randomized search to find out the best model hyperparameters, calculated feature importance for contribution evaluation, and Receiver Operating Characteristic (ROC) curves to evaluate the performance of classification algorithms. Results A model based on a machine learning algorithm of all urine AAs to diagnose renal FS established with sensitivity = 0.71, specificity = 0.73, and AUC = 0.83 (95% CI 0.648-0.957) (Fig. 1), with similar performance in combined six urine AAs (citrulline, asparagine, threonine, phenylalanine, ornithine, and proline) models. The urine proline level independently correlated with eGFR &amp;lt; 60 ml/min/1.73 m2 (bias regression coefficient 0.84, P = 0.001, OR = 2.31, 95% CI 1.41-3.80) when adjusted by age, etiology, gender, and blood urea nitrogen level. For the primary diseased diagnosis, the most susceptible urine AAs were citrulline (56.7%), proline (56.0%,) threonine (52.2%), and ornithine (45.9%) and the less susceptible ones were histidine (24.8%), aspartate (16.6%), and arginine (13.4%). Accordingly, the most common affected AA transporters were SLC6A19 (B0AT1) and etiology-specific urine AA atlas major in the eight urine AAs (isoleucine, glutamine, methionine, proline, alanine, ornithine, lysine, and arginine). Different from primary Sjӧgren syndrome patients (n = 26) with less susceptible, the patients with plasmacyte diseases (n = 8) showed elevations of almost all the urine AAs except glycine and aspartate. The connection between urine AAs excretion and hypouricemia showed gender differences, with 20 urine AAs significantly negatively correlating with serum uric acid levels in males but only five in females. Conclusion We first established a model based on the urine AA atlas detected by (LC-MS-MS) which contributed to differentiating the etiologies of renal tubular dysfunctions and associated well with eGFR. It shed light on the clinical practice in precision evaluation of tubule injury.

Role of Urinary Biomarkers (Transforming Growth Factor β1, Neutrophil Gelatinase-Associated Lipocalin, and Cystatin C) as a Prognostic Factor of Renal Outcome in the Posterior Urethral Valve.

The urinary biomarker response precedes the appearance of any renal structural or functional derangement. Transforming growth factor-β1 (TGF-β1), neutrophil gelatinase associated lipocalin (NGAL), and Cystatin C (CysC) can act as the early prognostic markers in posterior urethral valve (PUV) patients. To compare the urinary levels of TGF-β1, NGAL, and CysC between PUV cases and age matched controls and to correlate these with renal structural and functional parameters. This prospective study included children with PUV diagnosed using the standard investigations and an equal number of age-matched controls with nonurological problems. For the study subjects, the urinary samples were collected at three different time points (pre- and postoperatively at 3 and 6 months), whereas for controls, only single-voided samples were studied. The urinary levels of TGF-β1, NGAL, and CysC were estimated by the standardized techniques using the ELISA kits. Statistical methods were used to drive the comparisons between cases and controls. Fifteen children with a median age of 10 (5-48) months were enrolled in each of the two groups. The mean uTGF-β1 in the case group was significantly higher at all three time points (43.20 ± 6.13 pg/ml, 43.33 ± 11.89 pg/ml and 40.71 ± 9.01 pg/ml) as compared to the control group (29.12 ± 8.31 pg/ml) (P ≤ 0.001). The median uNGAL in the case group was also higher (17.78 ng/ml, 2.35 ng/ml and 2.536 ng/ml) as compared to the control group (1.31 ng/ml). However, the difference was significant only preoperatively (P = 0.02). The median uCysC in case group was similarly higher (0.347 μg/ml, 0.439 μg/ml, and 0.382 μg/ml) than the control group (0.243 μg/ml) (P > 0.05). Serum creatinine in the case group (0.49 mg/dl) showed no significant rise above that of control (0.24 mg/dl). A cutoff value of uTGF-β1 = 36.55 pg/ml (P < 0.001), uNGAL = 0.879 ng/ml (P = 0.02), and uCysC = 0.25 μg/ml (P = 0.22) was found to be associated with renal damage in PUV. A significant correlation was found between uNGAL and S. creatinine at 3 months (r = 0.43, P = 0.017) and 6 months (r = 0.47, P = 0.08). The elevated uTGF-β1, a decline in uNGAL and an increase in uCysC suggests ongoing inflammation, improvement in hydronephrosis and a prolonged proximal tubular dysfunction in PUV patients, respectively.

Renal manifestations in adult-onset Still's disease: a systematic review.

We aimed to review the literature on the clinical presentation, renal pathology, treatment, and outcome of renal manifestations in adult-onset Still's disease (AOSD). We used PRISMA guidelines for our systematic review and included all English-language original articles from inception till September 15, 2023, on AOSD and kidney involvement in any form. Data on patient demographics, diagnostic criteria, clinical presentation, renal pathology, treatment employed including dialysis, outcome, cause of death were collected and analyzed. The median age at the diagnosis of renal issues was 37, with a higher prevalence among females (58.1%). Among the cases, 28 experienced renal problems after being diagnosed with AOSD, 12 had simultaneous diagnoses of renal issues and AOSD, and in 4 cases, renal problems appeared before AOSD diagnosis. Out of the 44 cases, 36 underwent renal biopsy, revealing various pathology findings including AA amyloidosis (25%), collapsing glomerulopathy (11.4%), thrombotic microangiopathy (TMA) (11.4%), IgA nephropathy (9.1%), minimal change disease (6.8%), and others. Some cases were clinically diagnosed with TMA, proximal tubular dysfunction, or macrophage activation syndrome-related acute kidney injury. Treatment approaches varied, but glucocorticoids were commonly used. Renal involvement was associated with increased mortality and morbidity, with 6 out of 44 patients passing away, 4 progressing to end-stage renal disease (ESRD), and data on 2 cases' outcomes not available. Renal manifestations in AOSD are diverse but rarely studied owing to the rarity of the disease. Studies with larger data would be essential to study further on the pathogenesis and implications.

Prospective Multicenter Study on Early Proximal Tubular Injury in COVID-19–Related Acute Respiratory Distress Syndrome

IntroductionDuring COVID-19, renal impairment is the most frequent after lung impairment and is associated with poor prognosis particularly in intensive care unit (ICU). We aimed to assess the existence and incidence of early renal dysfunction and its prognostic value in patients with COVID-19-related acute respiratory distress syndrome (ARDS). MethodsIn this prospective multicenter study, patients aged over 18 years with invasive mechanical ventilation for ARDS were enrolled in 3 ICUs. Precise evaluation of renal dysfunction markers including urinary proteins electrophoresis (UPE) and quantification, was performed within 24 hours after mechanical ventilation onset. ResultsFrom March 2020 to December 2021, 135 patients were enrolled: 100 COVID-19 ARDS and 35 non-COVID-19 ARDS. UPE found more tubular dysfunction in COVID-19 patients (68% vs. 21.4%, p<0.0001) and more normal profiles in non-COVID-19 patients (65.0% vs. 11.2%, p=0.0003). COVID-19 patients significantly displayed early urinary leakage of tubular proteins like beta-2-microglobulin and free-light chains, tended to display more frequently acute kidney injury (AKI) (51.0% vs 34.3%, p=0.088), had longer mechanical ventilation (20 vs. 9 days, p<0.0001) and longer ICU stay (26 vs. 15 days, p<0.0001). In COVID-19 ARDS, leakage of free lambda light chain was associated with the onset of KDIGO ≥2 AKI (OR: 1.014, 95%CI [1.003-1.025], p=0.011). ConclusionsPatients with COVID-19-related ARDS display a proximal tubular dysfunction, prior to the onset of AKI, which predicts AKI. Proximal tubular damage seems an important mechanism of COVID-19-induced nephropathy. Analysis of urinary proteins is a reliable non-invasive tool to assess proximal tubular dysfunction in the ICU.

Clinical, genetic profile and therapy evaluation of 11 Chinese pediatric patients with Fanconi-Bickel syndrome

BackgroundFanconi-Bickel syndrome (FBS) is a rare autosomal recessive disorder characterized by impaired glucose and galactose utilization as well as proximal renal tubular dysfunction.MethodsClinical, biochemical, genetic, treatment, and follow-up data for 11 pediatric patients with FBS were retrospectively analysed.ResultsHepatomegaly (10/11), short stature (10/11) and hypophosphataemic rickets (7/11) were the most common initial symptoms. At diagnosis, all patients had decreased fasting blood glucose (FBG), plasma bicarbonate (HCO3−) and serum phosphorus, as well as elevated liver transaminases, alkaline phosphatase (AKP) and proximal renal tubular dysfunction. Two infant patients were misdiagnosed with transient neonatal diabetes mellitus. After therapy with uncooked cornstarch and conventional rickets treatment, remission of hepatomegaly was observed in all patients, with significant improvements in pre-prandial blood glucose, liver transaminases, triglyceride, plasma HCO3− and AKP (p < 0.05). At the last follow-up, 5/7 patients with elevated AKP had nephrocalcinosis. The mean height standard deviation score (Ht SDS) of eight patients with regular treatment increased from − 4.1 to -3.5 (p = 0.02). Recombinant human growth hormone (rhGH) was administered to 4/9 patients, but their Ht SDS did not improve significantly (p = 0.13). Fourteen variants of the SLC2A2 gene were identified, with six being novel, among which one was recurrent: c.1217T > G (p.L406R) (allele frequency: 4/22, 18%). Patients with biallelic missense variants showed milder metabolic acidosis than those with null variants. Two of five patients from nonconsanguineous families with rare homozygous variations showed 5.3 Mb and 36.6 Mb of homozygosity surrounding the variants, respectively; a region of homozygosity (ROH) involving the entire chromosome 3 covering the SLC2A2 gene, suggesting uniparental disomy 3, was detected in one patient.ConclusionsEarly diagnosis of FBS is difficult due to the heterogeneity of initial symptoms. Although short stature is a major issue of treatment for FBS, rhGH is not recommended in FBS patients who have normal GH stimulation tests. Patients with biallelic null variants may require alkali supplementation since urine bicarbonate loss is genetically related. ROH is a mechanism for rare homozygous variants of FBS in nonconsanguineous families.

Effects of Prolonged Administration of Tenofovir Disoproxil Fumarate-Containing Antiviral Regimen on Renal Function in Low-Risk of Kidney Injury HIV Patients.

This study intended to investigate the impact of long-termtenofovir fumarate (TDF) antiviral regimen on renal function in human immunodeficiency virus (HIV)-infected patients with low-risk of kidney injury. The observational study involving 100 HIV-infected patients without underlying diseases who achieved virological suppression and immunological recovery after sustained antiviral regimen of TDF+ lamivudine+ efavirenz (TLE) for 3.19 years. Renal function, including estimated glomerular filtration rate (eGFR), blood and urine β2 microglobulin, and other parameters, was assessed every 3 months over a period of 2.5 years. The eGFR showed a slight increasement from 116.0 at month 0 to 119.7 at month 30. Blood β2 microglobulin increased from 2.02 mg/L at month 0 to 2.77 mg/L at month 30. Compared to month 0, the difference in blood β2 microglobulin was statistically significant at month 6 and months 12-30 (P<.05). The incidence of proximal renal tubular dysfunction fluctuated from 2% at month 0 to 2.5% at month 30. The urine β2 microglobulin fluctuated from 0.5 (0.3-1.1) to 0.8 (0.5-1.35) mg/L at months 18-30, which was higher than 0.41 (0.18-1.1) mg/L at month 0 (P<.05). The abnormal concentration proportion of urine β2 microglobulin fluctuated from 72.7% to 81.3% at months 18-30, which was higher than the proportion of 57.0% at month 0. The abnormal proportion of blood β2 microglobulin, urine β2 microglobulin, and proximal renal tubular dysfunction were not correlated with eGFR (r1 = 0.119, r2 = -0.008, r3 = -0.165, P>.05). Long-term TDF antiviral regimen in low-risk of kidney injury HIV-infected patients may lead to damage in the proximal renal tubules and glomeruli. Blood and urine β2 microglobulin levels may be helpful in screening for renal dysfunction.

Inherited Fanconi renotubular syndromes: unveiling the intricacies of hypophosphatemic rickets/osteomalacia.

Fanconi renotubular syndromes (FRTS) are a rare group of inherited phosphaturic disorders with limited Indian as well as global data on this condition. Here, we describe the experience of a single Endocrinology center from Western India on FRTS. Comprehensive clinical, biochemical, radiological, management, and genetic details of FRTS patients managed between 2010 and 2023 were collected and analyzed. FRTS probands had mutations (eight novel) in six genes [CLCN5(n = 4), SLC2A2(n = 2), GATM, EHHADH, HNF4A,andOCRL(1 each)].Among 15 FRTS patients (11 families), rickets/osteomalaciawas the most common (n = 14) presentation with wide inter- and intra-familial phenotypic variability. Delayed diagnosis (median: 8.8years), initial misdiagnosis (8/11 probands), and syndrome-specific discriminatory features (8/11 probands) were commonly seen. Hypophosphatemia, elevated alkaline phosphatase, normal parathyroid hormone (median: 36 pg/ml), high-normal/elevated 1,25(OH)2D (median: 152 pg/ml), hypercalciuria (median spot urinary calcium to creatinine ratio: 0.32), and variable proximal tubular dysfunction(s) were observed. Elevated C-terminal fibroblast growth factor 23 in two probands was misleading, till the genetic diagnosis was reached. Novel observations in our FRTS cohort were preserved renal function (till sixth decade) and enthesopathy in FRTS1 and FRTS3 families, respectively. Our findings underscore frequent under- and misdiagnosis of FRTS; hence, a high index of suspicion for FRTS in phosphopenic rickets/osteomalacia, with early consideration of genetic testing is essential to ensure timely diagnosis of FRTS. The novel variants and phenotypic manifestations described here expand the disease spectrum of FRTS.

Rare renal proximal tubular dysfunctions in primary biliary cholangitis

Introduction Renal involvement of primary biliary cholangitis (PBC) usually presents as distal renal tubular acidosis. Proximal tubular (PT) dysfunctions in PBC were rarely reported with unclear clinicopathological characteristics and renal prognosis. Methods We identified 11 cases of PBC with PT dysfunctions (PBC-PT). Their medical document, kidney pathology, and follow-up data were retrospectively reviewed and analyzed. Results The 11 PBC-PT patients were mainly middle-aged (57.8 ± 5.2 years) females (81.8%). Most of them were asymptomatic PBC (7, 63.6%) with a high prevalence of elevated serum immunoglobulin M (IgM, 81.8%) and G (IgG, 54.5%) levels. In the kidney, they had a mean estimated glomerular filtration rate (eGFR) level of 46.54 ± 23.03 ml/min/1.73m2, and 81.8% of them had eGFR below 60 ml/min/1.73m2. They showed different degrees of PT dysfunctions, including hyperuricosuria, hypouricemia, normoglycemic glycosuria, generalized aminoaciduria, hyperphosphaturia, and hypophosphatemia. Their kidney pathology showed tubulointerstitial nephritis with lymphoplasmacytic infiltrates, brush border defects, and proximal tubulitis. After glucocorticoids treatment, the PT dysfunctions manifesting as hypophosphatemia, hypouricemia, and renal glycosuria all recovered, and the eGFR levels were improved from 43.24 ± 19.60 ml/min/1.73m2 to 55.02 ± 21.14 ml/min/1.73m2 (p = 0.028), accompanied by significant improvements of serum IgM levels (from 5.97 ± 4.55 g/L to 2.09 ± 1.48 g/L, p = 0.019). Conclusions The PT dysfunctions were rare in PBC patients, and glucocorticoids treatment could benefit the improvements of eGFR and tubular functions.

Mediation analysis of chronic kidney disease risk factors using kidney biomarkers in women living with HIV.

Novel urinary biomarkers reflecting kidney tubule health are associated with chronic kidney disease (CKD) risk in persons living with HIV. However, it is unknown whether these biomarkers provide mechanistic insight into the associations between clinical risk factors for CKD and subsequent CKD risk. Among 636 women living with HIV in the Women's Interagency HIV Study with estimated glomerular filtration rate (eGFR) >60 ml/min/1.73 m 2 , we used a counterfactual approach to causal mediation analysis to evaluate the extent to which systolic blood pressure (SBP), diastolic blood pressure (DBP), hemoglobin a1c (Hba1c) and serum albumin associations with incident CKD were mediated by eight urine proteins. These biomarkers reflect proximal tubular reabsorptive dysfunction (α1-microglobulin [a1m], β2-microglobulin, trefoil factor 3); tubular injury (interleukin 18 [IL-18], kidney injury molecule 1 [KIM-1]); kidney repair (epidermal growth factor); tubular reserve (uromodulin); and glomerular injury (urinary albumin). Incident CKD was defined as eGFR <60 ml/min/1.73 m 2 measured at two consecutive 6-month visits with an average annual eGFR decline ≥3% per year. During a median follow-up of 7 years, 11% developed CKD. Urinary albumin and KIM-1 mediated 32% (95% CI: 13.4%, 76.6%) and 23% (6.9%, 60.7%) of the association between SBP and incident CKD, respectively; and 19% (5.1%, 42.3%) and 22% (8.1%, 45.7%) of the association between DBP and incident CKD, respectively. Urinary albumin, α1m, and IL-18 were significant mediators of the association between Hba1c and incident CKD. None of the eight biomarkers mediated the association between serum albumin and incident CKD. Among women living with HIV, several urinary biomarkers reflecting distinct dimensions of kidney health may partially explain the associations between SBP, DBP, and Hba1c and subsequent CKD risk.

Efficacy and Safety of a Dispersible Tablet of GPO-Deferasirox Monotherapy among Children with Transfusion-Dependent Thalassemia and Iron Overload

The study aimed to determine efficacy and safety of generic deferasirox monotherapy. Deferasirox was administered in transfusion-induced iron overloaded thalassemia. Efficacy was defined as responders and nonresponders by ≤ 15 reduced serum ferritin from baseline. Adverse events were also monitored. Fifty-two patients with mainly Hb E/β-thalassemia at the mean (SD) age of 8.7 (4.1) years, were enrolled. The mean (SD) daily transfusion iron load was 0.47 (0.1) mg/kg and maximum daily deferasirox was 35.0 (6.2) mg/kg. Altogether, 52, 40 and 18 patients completed the first, second and third years of study, respectively. The median baseline serum ferritin 2,383 ng/mL decreased to 1,478, 1,038 and 1,268 ng/mL at the end of first, second and third years, respectively, with overall response rate at 73.1% (38/52). Patients with baseline serum ferritin >2,500 ng/mL showed a change in serum ferritin higher than those ≤2,500 ng/mL starting from the 9th month of chelation. Adverse events were found in 5 of 52 patients (9.6%) including transaminitis (n = 2), one each of proteinuria, rash and proximal tubular dysfunction which resolved after transient stopping or decreasing the chelation dose. Generic deferasirox was effective and safe among pediatric patients with transfusion-induced iron overloaded thalassemia.

Proximal tubular dysfunction as a predictor of AKI in Hospitalized COVID-19 patients.

High concentration of Angiotensin converting enzyme receptors in the proximal tubules make kidneys an early target in COVID-19. Proximal tubular dysfunction (PTD) may act as an early predictor of acute kidney injury (AKI) and more severe disease. This prospective observational study was conducted in the COVID unit, Bangabandhu Sheikh Mujib Medical University. 87 COVID-19 patients without known kidney disease were screened for 6 markers of PTD on admission-hyperuricosuria, normoglycemic glycosuria, proteinuria, renal phosphate leak, sodium leak and potassium leak. Positivity of 2 of the first 4 markers was considered as PTD. 35 patients with PTD and 35 without PTD were followed up throughout their hospital stay. 52.9% had PTD on admission. The most prevalent markers were renal sodium leak (67%), followed by proteinuria (66.7%), hyperuricosuria (42.5%), potassium leak (32.2%), phosphate leak (28.7%) and normoglycemic glycosuria (20.7%). Mean age was 55.7 years. 32.9% patients developed AKI. PTD group had higher odds of developing AKI (odds ratio 17.5 for stage 1, 24.8 for stage 2 and 25.5 for stage 3; p<0.0001). The mean duration of hospital stay was 9 days higher in the PTD group (p<0.001). PTD group also had higher odds of transferring to ICU (OR = 9.4, p = 0.002), need for mechanical ventilation (OR = 10.1, p = 0.002) and death (OR = 10.3, p = 0.001). 32.6% had complete PTD recovery during follow-up. Proximal tubular dysfunction is highly prevalent in COVID-19 patients very early in the disease and may act as a predictor of AKI, ICU transfer, need for mechanical ventilation and death.

“A Complex Conundrum”- Fanconi-Bickel Syndrome

Fanconi-Bickel Syndrome (FBS) is a rare form of Glycogen Storage Disease (GSD) type 11 characterised by massive hepatomegaly due to the buildup of glycogen and severe hypophosphatemic rickets due to a proximal renal tubular dysfunction. Since 1940, it has been initially known as hepatorenal glycogenesis with proximal renal tubular dysfunction. It is due to a pathogenic mutation of the GLUT-2 (glucose transporter) gene. Herein, present case report a young toddler who is the firstborn of 3rd-degree consanguinity, presented with rickets, recurrent respiratory tract infections, and hepatomegaly, and was subsequently diagnosed with FBS with the help of genetic studies, showing a mutation in the GLUT-2 gene. With less than 200 cases reported so far, this child represents a unique case with recurrent respiratory infections and developmental delay as presentations along with rachitic features.