Spectrum of Pneumonia in Renal Transplant Recipients: An Indian Experience.

OBJECTIVES: Respiratory tract infections are life-threatening infections in solid-organ transplant recipients that pose risk to the graft and to the patient. This study was undertaken to examine the clinical and microbiological spectrum of pneumonia in renal transplant recipients. MATERIALS AND METHODS: Of 400 consecutive renal transplant recipients, 87 recipients (21.8%) were hospitalized between November 2014 and October 2016 with pneumonia. We examined demographic profiles and clinical investigations. RESULTS: The median age of patients was 38 years (range, 19-72 y). The mean time of presentation after renal transplant was 18 months (range, 1-174 mo). Most patients (80.5%) were on maintenance immunosuppression with tacrolimus, mycophenolate mofetil, and steroids; 34% of patients had an induction agent. Chronic hepatitis C and hepatitis B infections were found in 12.6% and 2.2% of patients, respectively, and new-onset diabetes in 19.5% of patients. Fever (88%), cough (87%), shortness of breath (68%), and hypotension (33%) were common presenting symptoms. Diarrhea was the most frequent accompanying symptom, found in 9.2% of patients. Cytopenia and graft dysfunction were present in 38.7% and 80.4% of patients. Among infections, fungal infections were the most frequent (30%) followed by mixed infections (20.7%), tuberculosis (12.6%), bacterial (12.6%), and viral (3.5%) infections. Etiology could not be found in 27.6% patients. Mortality rate was 24.1%, with the highest rates for fungal infections (44%), followed by bacterial (25%) and mixed infections (18%). Presence of hypoxia and hypotension at presentation was associated with increased risk of death, whereas use of induction agents, new-onset diabetes posttransplant, diabetes mellitus, and acute kidney injury were not correlated with death or increased duration of hospital stay. CONCLUSIONS: Pneumonia carries high risk of mortality in renal transplant recipients. Fungal and bacterial infections carry high risk of mortality. Despite invasive investigations, a substantial number of patients had unidentified etiology.

A randomized trial of once daily versus twice daily dosing of oral iron in CKD.

We investigated the effect of two dosing regimens of oral iron on iron status and hematological parameters in patients with CKD. In this single center, open label, randomized, active controlled clinical trial, stable adult patients with CKD stage G3-4 with percentage transferrin saturation (%TSAT) ≤ 30% and serum ferritin ≤ 500 ng/ml were eligible. Participants were randomized to receive either 100 mg of ferrous ascorbate once daily (OD group) or 100 mg of ferrous ascorbate twice daily (BD group, total daily dose 200 mg). The primary outcome was change in %TSAT between groups over 12 weeks. The secondary outcomes were changes in other iron status and hematological parameters, serum interleukin-6 (IL-6) and hepcidin. 80 participants were enrolled out of which 76 completed the study. Change in %TSAT was not significantly different between groups (ß = - 1.43, 95% CI - 3.99 to 1.12, BD group as reference). The rise in serum ferritin was less in the OD group as compared to BD group (ß = - 0.36, 95% CI - 0.61 to - 0.10) whereas MCHC increased in the OD group as compared to decrease in the BD group (ß = 0.37, 95% CI 0.067-0.67). These observations need exploration to ascertain the impact of different oral iron dosing strategies in CKD.

Transcriptional advantage influence odorant receptor gene choice.

Odorant receptors (ORs) obey mutual exclusivity and monoallelic mode of expression. Efforts are ongoing to decipher the molecular mechanism that drives the 'one-neuron-one-receptor' rule of olfaction. Recently, single-cell profiling of olfactory sensory neurons (OSNs) revealed the expression of multiple ORs in the immature neurons, suggesting that the OR gene choice mechanism is much more complex than previously described by the silence-all-and-activate-one model. These results also led to the genesis of two possible mechanistic models i.e. winner-takes-all and stochastic selection. We developed Reverse Cell Tracking (RCT), a novel computational framework that facilitates OR-guided cellular backtracking by leveraging Uniform Manifold Approximation and Projection embeddings from RNA Velocity Workflow. RCT-based trajectory backtracking, coupled with statistical analysis, revealed the OR gene choice bias for the transcriptionally advanced (highest expressed) OR during neuronal differentiation. Interestingly, the observed selection bias was uniform for all ORs across different spatial zones or their relative expression within the olfactory organ. We validated these findings on independent datasets and further confirmed that the OR gene selection may be regulated by Upf3b. Lastly, our RNA dynamics-based tracking of the differentiation cascade revealed a transition cell state that harbors mixed molecular identities of immature and mature OSNs, and their relative abundance is regulated by Upf3b.

StripeDiff: Model-based algorithm for differential analysis of chromatin stripe.

Multiple recent studies revealed stripes as an architectural feature of three-dimensional chromatin and found stripes connected to epigenetic regulation of transcription. Whereas a couple of tools are available to define stripes in a single sample, there is yet no reported method to quantitatively measure the dynamic change of each stripe between samples. Here, we developed StripeDiff, a bioinformatics tool that delivers a set of statistical methods to detect differential stripes between samples. StripeDiff showed optimal performance in both simulation data analysis and real Hi-C data analysis. Applying StripeDiff to 12 sets of Hi-C data revealed new insights into the connection between change of chromatin stripe and change of chromatin modification, transcriptional regulation, and cell differentiation. StripeDiff will be a robust tool for the community to facilitate understanding of stripes and their function in numerous biological models.

Atypical Presentation of Acute Mitral Regurgitation Secondary to Papillary Muscle Rupture.

Acute mitral regurgitation (MR) is a life-threatening condition presenting with severe decompensated heart failure due to sudden retrograde blood flow into the left atrium. The causes are broadly classified into ischemic and non-ischemic. Rapid and accurate diagnosis of acute MR and its potential causes is essential. This case uniquely highlights an atypical presentation of severe MR secondary to papillary muscle rupture without a known, identifiable cause. Therefore, suspicion of acute MR should be high if clinical symptoms are present, even without known risk factors, due to the high morbidity and mortality associated with delayed management.

Management of Lupus Nephritis: An Update.

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease, and lupus nephritis (LN) is associated with increased morbidity and mortality. Renal biopsy is essential and the gold standard to diagnose LN. Extra-glomerular involvement is seen in up to 60% of patients with LN and is associated with poor outcomes. The revised International Society of Nephrology/Renal Pathology Society classification for LN has changed the parameters for activity index scoring, redefined crescent and highlighted the significance of extra-glomerular involvement. Repeat renal biopsy is done for resistant disease or during a flare, usually when atypical features are present or when the baseline biopsy showed non-proliferative histology. Protocol repeat biopsy may prove to be valuable as a monitoring tool in patients with LN. Newer modalities of therapy like multitargeted therapy and biological agents may pave a way for better outcomes with minimal adverse effects to the patients.

Impact of anemia on the cardiovascular status in children with chronic kidney disease: A pilot study.

BACKGROUND & AIMS: Myocardial dysfunction is one of the common complications in children with chronic kidney disease which results in significant morbidity and mortality. We aimed to find the impact of anemia with cardiac changes in children with chronic kidney disease (CKD). METHODS: In this cross-sectional pilot study, 54 children (38 males) up to the age of 16 years with different stages of CKD, not on dialysis, were enrolled. Cardiovascular functions were evaluated using 2D-echocardiography using EPIC-7 (Philips) machine by an independent trained Pediatric Cardiologist. The M-mode measurements of the left ventricle were measured, indexed for body surface area and z-scores were calculated. They were divided into two groups i. e with and without anemia. RESULTS: Out of the 54 children with CKD, children with and without anemia were 34 and 20 respectively. The end-diastolic volume was significantly higher in patients with anemia when compared with those without anemia (46.43 ± 16.49 ml vs 32.51 ± 4.98 ml). The mean left ventricular mass (59.54 ± 23.99 vs 37.24 ± 7.88 g) and end-diastolic thickness of the interventricular septum (0.73 ± 0.14 vs 0.54 ± 0.05 cm) was significantly elevated in CKD children with anemia. CONCLUSIONS: Left ventricular hypertrophy along with left ventricular dimension and left ventricular diastolic dysfunction was found to be significantly correlating with the degree of anemia. CKD children with anemia should be screened for underlying cardiac dysfunction and appropriate dietary modification and nutritional rehabilitation for iron deficiency should be addressed.

Ultrasound placental image texture analysis using artificial intelligence to predict hypertension in pregnancy.

BACKGROUND: The placental pathological changes in hypertensive disorders of pregnancy (HDP) starts early in pregnancy, the deep convolutional neural networks (CNN) can identify these changes before its clinical manifestation. OBJECTIVE: To compare the placental quantitative ultrasound image texture of women with HDP to those with the normal outcome. METHODS: The cases were enrolled in the first trimester of pregnancy, good quality images of the placenta were taken serially in the first, second, and third trimester of pregnancy. The women were followed till delivery, those with normal outcomes were controls, and those with HDP were cases. The images were processed and classified using validated deep learning tools. RESULTS: Total of 429 cases were fully followed till delivery, 58 of them had HDP (13.5%). In the first trimester, there was a significant difference in the placental length (p = .033), uterine artery PI (p = .019), biomarkers PAPP-A (p = .001) PlGF (p = .013) and placental image texture (p = .001) between the cases and controls. In the second trimester the uterine artery PI, serum PAPP-A (p = .010) and PlGF (p = .005) levels were significantly low among women who developed hypertension later on pregnancy. The image texture disparity between the two groups was highly significant (p < .001). The model "resnext 101_32x8d" had Cohen kappa score of 0.413 (moderate) and the accuracy score of 0.710 (good). In the first trimester the best sensitivity and specificity was observed for abnormal placental image texture (70.6% and 76.6%, respectively) followed by PlGF (64% and 50%, respectively), in the second trimester the abnormal image texture had the highest sensitivity and specificity (60.4% and 73.3%, respectively) followed by uterine artery PI (58.6% and 54.7%, respectively). Similarly in the third trimester, uterine artery PI had sensitivity and specificity of 60.3% and specificity of 50.7%, whereas the abnormal image texture had sensitivity and specificity of 83.5%. CONCLUSION: Ultrasound placental analysis using artificial intelligence (UPAAI) is a promising technique, would open avenues for more research in this field.

Intermittent Online Postdilution Hemodiafiltration versus High-Flux Hemodialysis in Non-critical Acute Kidney Injury: A Pilot Randomized Controlled Trial.

The preferential use of convective modes of hemodialysis (HD) for targeting hyper-cytokinemia state in sepsis-related acute kidney injury (AKI) has been questioned for its efficacy. Several studies have used predilution hemodiafiltration (HDF) in critically ill AKI patients with mixed results. In this study, we compared intermittent online postdilution HDF with the standard high-flux (HF) intermittent HD in non-critically ill patients with community-acquired (CA) AKI. In this pilot study, stable patients with CA AKI and systemic inflammatory response syndrome were included and given either postdilution online-HDF (OL-HDF) or standard HF HD outside intensive care units. The primary objectives were to assess the feasibility of conducting the study at a larger scale and to detect the differential impact of convective clearance on the rates of independence from dialysis at discharge or after 30 days. Plasma cytokine clearance was assessed as a secondary objective. Eighty consecutive AKI patients were randomized to receive dialysis in one of the treatment arms after fulfilling the eligibility criteria. The baseline parameters of clinical severity, etiology, and indications of dialysis, plus the baseline plasma cytokine profiles, were comparable. Moreover, 83% in the control arm and 71.1% in the intervention arm became independent from dialysis at discharge or at 30 days (P = 0.189). No survival advantage of postdilution OL-HDF was observed (P >0.05). Similar plasma cytokine clearance levels were noted in both arms. The current study confirms the feasibility; however, it does not support the preferential use of postdilution OL-HDF over HF-HD in non-critical patients.

Long-Term Follow-Up of Cyclical Cyclophosphamide and Steroids Versus Tacrolimus and Steroids in Primary Membranous Nephropathy.

INTRODUCTION: Kidney Disease: Improving Global Outcomes (KDIGO) 2012 recommends cyclical cyclophosphamide plus glucocorticoids (GC) (modified Ponticelli regimen) or calcineurin inhibitors (CNIs) such as tacrolimus (TAC) or cyclosporine as the first-line agents for the management of primary membranous nephropathy (PMN) that is resistant to antiproteinuric therapy with renin-angiotensin system blockers. However, the long-term outcome of patients treated with CNIs is not known. METHODS: We report the outcomes of 70 patients randomized 1:1 to receive modified Ponticelli regimen or TAC/GC for renin-angiotensin system-resistant PMN who were prospectively followed for 6 years. Patients were followed monthly for 12 months, then quarterly for 12 months, and then every 6 months through the end of 6 years. RESULTS: At the end of 6 years, 21 (61.76%) and 9 (28.12%) patients maintained relapse-free remission in modified Ponticelli regimen and TAC/GC groups, respectively (relative risk [RR]: 2.19, 95% confidence interval [CI]: 1.23 to 4.15), and 30 (88.23%) and 17 (53.12%) patients were in remission (including relapses) in modified Ponticelli regimen and TAC/GC groups (RR: 1.66; 95% CI: 1.21 to 2.45), respectively. There was no significant difference in the proportion of patients who had a 40% decline in the estimated glomerular filtration rate (eGFR), death, or end-stage kidney disease between the groups. None of the patients treated with modified Ponticelli regimen reported a solid organ or hematological malignancy. CONCLUSIONS: To conclude, in the long-term, modified Ponticelli regimen is superior to TAC/GC as first-line therapy for the management of antiproteinuric-resistant PMN.

Cardiac Abnormalities in Children with Pre-Dialysis Chronic Kidney Disease in a Resource-Limited Setting: A Cross-Sectional Observational Study.

BACKGROUND: Cardiovascular disease is the leading cause of morbidity and mortality in children with chronic kidney disease (CKD). We aim to estimate the prevalence of cardiac abnormalities in children up to age 16 years with CKD and their association with various risk factors. METHODS: This cross-sectional observational study was conducted on 107 CKD children. We assessed the systolic and diastolic function using 2D echocardiographic evaluation and M-mode measurements of the left ventricle (LV) indexed for BSA and z-scores were calculated. Results were compared with age, sex, stage of CKD, anaemia, estimated glomerular filtration rate (eGFR) and various laboratory parameters. RESULTS: LV diastolic dysfunction was seen in 88%, followed by increased LV dimensions in 33.6%, LV systolic dysfunction in 16%, right ventricle systolic dysfunction in 11.2% while increased pulmonary artery (PA) systolic pressure was seen in 9.3% of cases. LV dimensions correlated directly with parathormone levels and inversely with eGFR, serum calcium and haemoglobin levels. Left ventricular hypertrophy correlated directly with parathormone while inversely with eGFR, serum calcium and haemoglobin. Ejection fraction directly correlated to eGFR and serum calcium while inversely related to parathormone. Left PA pressure directly correlated with age and inversely with eGFR. Right ventricular systolic function assessed by tricuspid annular plane systolic excursion correlated inversely with haemoglobin. CONCLUSION: LV diastolic dysfunction and increased LV dimensions were the most common cardiac abnormality in children with CKD. LV dimensions correlated directly with parathormone levels and inversely with eGFR, serum calcium and haemoglobin. Diastolic dysfunction positively correlated with serum creatinine and parathormone levels.

Quantification of Age-Related Decline in Transcriptional Homeostasis.

Age-dependent dysregulation of transcription regulatory machinery triggers modulations in the gene expression levels leading to the decline in cellular fitness. Tracking of these transcripts along the temporal axis in multiple species revealed a spectrum of evolutionarily conserved pathways, such as electron transport chain, translation regulation, DNA repair, etc. Recent shreds of evidence suggest that aging deteriorates the transcription machinery itself, indicating the hidden complexity of the aging transcriptomes. This reinforces the need for devising novel computational methods to view aging through the lens of transcriptomics. Here, we present Homeostatic Divergence Score (HDS) to quantify the extent of messenger RNA (mRNA) homeostasis by assessing the balance between spliced and unspliced mRNA repertoire in single cells. We validated its utility in two independent aging datasets, and identified sets of genes undergoing age-related breakdown of transcriptional homeostasis. Moreover, testing of our method on a subpopulation of human embryonic stem cells revealed a set of differentially processed transcripts segregating these subpopulations. Our preliminary analyses in this direction suggest that mRNA processing level information offered by single-cell RNA sequencing (scRNA-seq) data is a superior determinant of chronological age as compared to transcriptional noise.

OdoriFy: A conglomerate of artificial intelligence-driven prediction engines for olfactory decoding.

The molecular mechanisms of olfaction, or the sense of smell, are relatively underexplored compared with other sensory systems, primarily because of its underlying molecular complexity and the limited availability of dedicated predictive computational tools. Odorant receptors (ORs) allow the detection and discrimination of a myriad of odorant molecules and therefore mediate the first step of the olfactory signaling cascade. To date, odorant (or agonist) information for the majority of these receptors is still unknown, limiting our understanding of their functional relevance in odor-induced behavioral responses. In this study, we introduce OdoriFy, a Web server featuring powerful deep neural network-based prediction engines. OdoriFy enables (1) identification of odorant molecules for wildtype or mutant human ORs (Odor Finder); (2) classification of user-provided chemicals as odorants/nonodorants (Odorant Predictor); (3) identification of responsive ORs for a query odorant (OR Finder); and (4) interaction validation using Odorant-OR Pair Analysis. In addition, OdoriFy provides the rationale behind every prediction it makes by leveraging explainable artificial intelligence. This module highlights the basis of the prediction of odorants/nonodorants at atomic resolution and for the ORs at amino acid levels. A key distinguishing feature of OdoriFy is that it is built on a comprehensive repertoire of manually curated information of human ORs with their known agonists and nonagonists, making it a highly interactive and resource-enriched Web server. Moreover, comparative analysis of OdoriFy predictions with an alternative structure-based ligand interaction method revealed comparable results. OdoriFy is available freely as a web service at https://odorify.ahujalab.iiitd.edu.in/olfy/.

EcTracker: Tracking and elucidating ectopic expression leveraging large-scale scRNA-seq studies.

Dramatic genomic alterations, either inducible or in a pathological state, dismantle the core regulatory networks, leading to the activation of normally silent genes. Despite possessing immense therapeutic potential, accurate detection of these transcripts is an ever-challenging task, as it requires prior knowledge of the physiological gene expression levels. Here, we introduce EcTracker, an R-/Shiny-based single-cell data analysis web server that bestows a plethora of functionalities that collectively enable the quantitative and qualitative assessments of bona fide cell types or tissue-specific transcripts and, conversely, the ectopically expressed genes in the single-cell ribonucleic acid sequencing datasets. Moreover, it also allows regulon analysis to identify the key transcriptional factors regulating the user-selected gene signatures. To demonstrate the EcTracker functionality, we reanalyzed the CRISPR interference (CRISPRi) dataset of the human embryonic stem cells differentiated into endoderm lineage and identified the prominent enrichment of a specific gene signature in the SMAD2 knockout cells whose identity was ambiguous in the original study. The key distinguishing features of EcTracker lie within its processing speed, availability of multiple add-on modules, interactive graphical user interface and comprehensiveness. In summary, EcTracker provides an easy-to-perform, integrative and end-to-end single-cell data analysis platform that allows decoding of cellular identities, identification of ectopically expressed genes and their regulatory networks, and therefore, collectively imparts a novel dimension for analyzing single-cell datasets.

Decision-making around Commencing Dialysis.

The decision regarding dialysis initiation is complex. Awareness that renal replacement therapy should not be regarded as default therapy for every patient with advanced renal failure is necessary. Decision to initiate dialysis and modality should be individualized in a shared decision-making process involving the treating nephrologist and the patient. Patients should receive predialysis education early in the course of chronic kidney disease so as to help prepare them well in advance for this eventuality. Withholding dialysis may be a reasonable option in a certain subset of patients, especially elderly patient with multiple co-morbid illnesses. Comprehensive conservation care should be offered in all patients where the decision to not dialyze is taken.

Modeling expression ranks for noise-tolerant differential expression analysis of scRNA-seq data.

Systematic delineation of complex biological systems is an ever-challenging and resource-intensive process. Single-cell transcriptomics allows us to study cell-to-cell variability in complex tissues at an unprecedented resolution. Accurate modeling of gene expression plays a critical role in the statistical determination of tissue-specific gene expression patterns. In the past few years, considerable efforts have been made to identify appropriate parametric models for single-cell expression data. The zero-inflated version of Poisson/negative binomial and log-normal distributions have emerged as the most popular alternatives owing to their ability to accommodate high dropout rates, as commonly observed in single-cell data. Although the majority of the parametric approaches directly model expression estimates, we explore the potential of modeling expression ranks, as robust surrogates for transcript abundance. Here we examined the performance of the discrete generalized beta distribution (DGBD) on real data and devised a Wald-type test for comparing gene expression across two phenotypically divergent groups of single cells. We performed a comprehensive assessment of the proposed method to understand its advantages compared with some of the existing best-practice approaches. We concluded that besides striking a reasonable balance between Type I and Type II errors, ROSeq, the proposed differential expression test, is exceptionally robust to expression noise and scales rapidly with increasing sample size. For wider dissemination and adoption of the method, we created an R package called ROSeq and made it available on the Bioconductor platform.

Poor allograft outcome in Indian patients with post-transplant C3 glomerulopathy.

BACKGROUND: Complement 3 glomerulopathy (C3G) results from dysfunction of the alternative complement pathway (ACP). No data are available on post-transplant C3G in South Asia. METHODS: In this study, renal allograft biopsies of C3G patients performed from 2012 to 2017 were analysed for ACP functional assay (APFA), serum complement levels, complement factor H (CFH), complement factor B (CFB) and autoantibodies to CFH and CFB. Limited genetic screening for CFH/CFHR5 genes was carried out. All study patients were also followed up. RESULTS: A total of 21 cases of C3G were included, of which 11 had native C3G disease (that is, recurrent C3G). Of these 11 recurrent cases, 7 presented with allograft dysfunction and 4 with proteinuria and renal dysfunction. Early post-transplant recurrence (<1 month) was noted in six patients, whereas recurrence in five patients occurred within 8-17 months of transplant. Biopsies showed mild focal mesangial expansion with or without endocapillary proliferation and thrombotic microangiopathy. Rejection was also noted in six patients. APFA/C3 levels were low in all cases. Serum CFH levels were low [dense deposit disease (DDD), 44%; C3 glomerulonephritis (C3GN), 25%], whereas CFB levels were normal. Autoantibodies to CFH, CFB and C3 nephritic factor were present in 11, 0 and 44% of DDD cases, respectively, and in 17, 17 and 33% of C3GN cases, respectively. Genetic analysis revealed only non-pathogenic CFH gene variants (93%). No novel mutation was found. At follow-up (140 months), stable graft was noted in 28% of cases, progressive renal failure in 19%, graft loss in 34%, and 19% of patients died. CONCLUSION: Post-transplant C3G can present with graft dysfunction and/or proteinuria. Subtle histological findings demand careful interpretation of immunofluorescence results. Autoantibodies to complement pathway regulatory proteins are common, and no novel mutation has been found from limited genetic workup. Clinical outcome is poor.

Erratum: Iyer, A., et al. Integrative Analysis and Machine Learning Based Characterization of Single Circulating Tumor Cells. J. Clin. Med. 2020, 9, 1206.

In the published manuscript [...].

Machine-OlF-Action: a unified framework for developing and interpreting machine-learning models for chemosensory research.

SUMMARY: Machine Learning-based techniques are emerging as state-of-the-art methods in chemoinformatics to selectively, effectively and speedily identify biologically relevant molecules from large databases. So far, a multitude of such techniques have been proposed, but unfortunately due to their sparse availability, and the dependency on high-end computational literacy, their wider adaptation faces challenges, at least in the context of G-Protein Coupled Receptors (GPCRs)-associated chemosensory research. Here, we report Machine-OlF-Action (MOA), a user-friendly, open-source computational framework, that utilizes user-supplied SMILES (simplified molecular input line entry system) of the chemicals, along with their activation status, to synthesize classification models. MOA integrates a number of popular chemical databases collectively harboring approximately 103 million chemical moieties. MOA also facilitates customized screening of user-supplied chemical datasets. A key feature of MOA is its ability to embed molecules based on the similarity of their local neighborhood, by utilizing a state-of-the-art model interpretability framework LIME. We demonstrate the utility of MOA in identifying previously unreported agonists for human and mouse olfactory receptors OR1A1 and MOR174-9 by leveraging the chemical features of their known agonists and non-agonists. In summary, here we develop an ML-powered software playground for performing supervisory learning tasks involving chemical compounds. AVAILABILITY AND IMPLEMENTATION: MOA is available for Windows, Mac and Linux operating systems. It's accessible at (https://ahuja-lab.in/). Source code, user manual, step-by-step guide and support is available at GitHub (https://github.com/the-ahuja-lab/Machine-Olf-Action). For results, reproducibility and hyperparameters, refer to Supplementary Notes. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Proteinuria in Severe Hypothyroidism: A Prospective Study.

CONTEXT: Hypothyroidism is associated with reversible decline in kidney function as measured by estimated glomerular filtration rate (eGFR). eGFR and proteinuria are the most important markers for clinical assessment of kidney function. Though hypothyroidism is associated with proteinuria in cross-sectional data, the impact of treatment on proteinuria is unknown. OBJECTIVE: This study explores the effect of thyroid hormone replacement therapy on eGFR and 24-hour urine protein excretion in patients with severe primary hypothyroidism. DESIGN AND PARTICIPANTS: This study was a prospective, observational cohort study in adults with severe primary hypothyroidism (serum thyrotropin [TSH] > 50 µIU/mL). Individuals with preexisting or past kidney disease, kidney or urinary tract abnormalities, calculi or surgery, diabetes mellitus, or hypertension were excluded. The participants received thyroid hormone replacement therapy. Thyroid functions, eGFR, 24-hour urine protein excretion, and biochemical parameters were measured at baseline and 3 months. SETTING: This study took place at a single center, a tertiary care referral and teaching hospital. RESULTS: Of 44 enrolled participants, 43 completed 3 months of follow-up. At 3 months, serum TSH levels decreased and thyroxine levels increased (P < .001 for both). Significant increases in eGFR (mean difference, 18.25 ± 19.49 mL/min/1.73 m2; 95% CI, 12.25 to 24.25, P < .001) and declines in 24-hour urine protein excretion (mean difference, -68.39 ± 125.89 mg/day; 95% CI, -107.14 to -29.65, P = .001) were observed. Serum cholesterol and low-density lipoprotein levels also significantly decreased (P < .001). CONCLUSIONS: Thyroid hormone replacement therapy in patients with severe primary hypothyroidism improves eGFR and decreases 24-hour urine protein excretion, thereby suggesting reversible alterations.