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Nature Reviews. Disease Primers Aug 2020Podocytopathies are kidney diseases in which direct or indirect podocyte injury drives proteinuria or nephrotic syndrome. In children and young adults, genetic variants... (Review)
Review
Podocytopathies are kidney diseases in which direct or indirect podocyte injury drives proteinuria or nephrotic syndrome. In children and young adults, genetic variants in >50 podocyte-expressed genes, syndromal non-podocyte-specific genes and phenocopies with other underlying genetic abnormalities cause podocytopathies associated with steroid-resistant nephrotic syndrome or severe proteinuria. A variety of genetic variants likely contribute to disease development. Among genes with non-Mendelian inheritance, variants in APOL1 have the largest effect size. In addition to genetic variants, environmental triggers such as immune-related, infection-related, toxic and haemodynamic factors and obesity are also important causes of podocyte injury and frequently combine to cause various degrees of proteinuria in children and adults. Typical manifestations on kidney biopsy are minimal change lesions and focal segmental glomerulosclerosis lesions. Standard treatment for primary podocytopathies manifesting with focal segmental glomerulosclerosis lesions includes glucocorticoids and other immunosuppressive drugs; individuals not responding with a resolution of proteinuria have a poor renal prognosis. Renin-angiotensin system antagonists help to control proteinuria and slow the progression of fibrosis. Symptomatic management may include the use of diuretics, statins, infection prophylaxis and anticoagulation. This Primer discusses a shift in paradigm from patient stratification based on kidney biopsy findings towards personalized management based on clinical, morphological and genetic data as well as pathophysiological understanding.
Topics: Humans; Kidney; Nephrotic Syndrome; Podocytes; Prevalence; Proteinuria
PubMed: 32792490
DOI: 10.1038/s41572-020-0196-7 -
Annales de Biologie Clinique Feb 2019The typing of proteinuria is one of the complementary examinations carried out during the exploration of proteinuria. It aims to separate and identify the different... (Review)
Review
The typing of proteinuria is one of the complementary examinations carried out during the exploration of proteinuria. It aims to separate and identify the different proteins, or fractions of proteins, that make up proteinuria. The nature and relative importance of the proteins present reflect the location of the renal involvement and help to determine the etiology. The typing of a proteinuria also allows the detection of a monoclonal component in urine and its quantification. Finally, it allows highlighting the existence of a proteinuria of overload that can occur in the absence of kidney damage. Many methods allow the typing of proteinuria, and these have benefited in recent years from technological advances. The purpose of this review is to summarize typing methods currently used, their benefits and limitations, and the help that these diagnostic tools can provide to the management of patients.
Topics: Diagnosis, Differential; Glomerular Filtration Rate; Humans; Kidney Diseases; Kidney Function Tests; Patient Selection; Proteinuria; Urinalysis
PubMed: 30799294
DOI: 10.1684/abc.2018.1401 -
Pediatrics in Review Dec 2018Pediatricians must be aware of screening indications and the evaluation and management of a child with hematuria and/or proteinuria. (Review)
Review
PRACTICE GAP
Pediatricians must be aware of screening indications and the evaluation and management of a child with hematuria and/or proteinuria.
OBJECTIVES
After completing this article, readers should be able to: 1. Understand the common causes of proteinuria and hematuria and be able to differentiate between benign and serious causes. 2. Describe screening techniques for initial evaluation of hematuria and proteinuria. 3. Recognize the criteria for diagnosis of proteinuria and hematuria. 4. Plan the appropriate initial evaluation for hematuria and proteinuria and interpret laboratory findings essential for diagnosis. 5. Recognize serious causes of hematuria and proteinuria that warrant immediate referral.
Topics: Adolescent; Child; Child, Preschool; Hematuria; Humans; Proteinuria; Urinalysis
PubMed: 30504250
DOI: 10.1542/pir.2017-0300 -
Seminars in Immunopathology Oct 2021IgA nephropathy (IgAN) is the most common type of glomerulonephritis in Asia and the Western world. In most patients, it follows an asymptomatic to oligosymptomatic... (Review)
Review
IgA nephropathy (IgAN) is the most common type of glomerulonephritis in Asia and the Western world. In most patients, it follows an asymptomatic to oligosymptomatic course and GFR loss, if any, is slow. The mainstay of therapy therefore is optimized supportive care, i.e., measures that lower blood pressure, reduce proteinuria, minimize lifestyle risk factors, and otherwise help to reduce non-specific insults to the kidneys. The value of immunosuppression has become controversial and if at all, systemic high-dose corticosteroid therapy should be considered for a few months taking into account patient characteristics that would caution against or preclude such therapy. In addition, adverse events related to corticosteroid therapy markedly increase as GFR declines. Beyond corticosteroids, there is little evidence that any additional immunosuppression is helpful, with the exception of mycophenolate mofetil in patients of Asian descent. A considerable number of clinical trials ranging from enteric coated budesonide to blockade of B-cell function to complement inhibitors are currently ongoing and will hopefully allow a more targeted therapy of high-risk patients with progressive IgAN in the future.
Topics: Glomerulonephritis, IGA; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney; Proteinuria
PubMed: 34495361
DOI: 10.1007/s00281-021-00888-3 -
Journal of the American Society of... Sep 2022The complement system is highly activated in primary membranous nephropathy (MN). Identifying the complement components that damage podocytes has important therapeutic...
BACKGROUND
The complement system is highly activated in primary membranous nephropathy (MN). Identifying the complement components that damage podocytes has important therapeutic implications. This study investigated the role of C3a and the C3a receptor (C3aR) in the pathogenesis of MN.
METHODS
C3aR expression in kidneys and circulating levels of C3a of MN patients were examined. Human podocyte damage was assessed after exposure to MN plasma +/- C3aR blockade (SB290157, JR14a). C3aR antagonists were administered to rats with Heymann nephritis on day 0 or after proteinuria. Clinical and pathologic parameters, specific IgG and complement activation, and podocyte injuries were then assessed.
RESULTS
In the glomeruli, C3aR staining merged well with podocin. Overexpression of C3aR correlated positively with proteinuria, serum creatinine, and no response to treatments. Human podocytes exposed to MN plasma showed increased expression of PLA2R, C3aR, and Wnt3/-catenin, reduced expression of synaptopodin and migration function, downregulated Bcl-2, and decreased cell viability. C3aR antagonists could block these effects. In Heymann nephritis rats, C3aR blockade attenuated proteinuria, electron-dense deposition, foot process width, and glomerular basement membrane thickening in glomeruli. The increased plasma C3a levels and overexpression of C3aR were also alleviated. Specific, but not total, IgG levels decreased, with less deposition of rat IgG in glomeruli and subsequent reduction of C1q, factor B, and C5b-9.
CONCLUSION
C3a anaphylatoxin is a crucial effector of complement-mediated podocyte damage in MN. The C3aR antagonist may be a potentially viable treatment for this disease.
Topics: Rats; Humans; Animals; Glomerulonephritis, Membranous; Complement C3a; Podocytes; Proteinuria; Immunoglobulin G; Complement Activation
PubMed: 35777783
DOI: 10.1681/ASN.2021101384 -
Journal of Reproductive Immunology Sep 2019Early-onset preeclampsia has been linked to poor placentation and fetal growth restriction, whereas late-onset preeclampsia was suggested to result from maternal... (Review)
Review
Early-onset preeclampsia has been linked to poor placentation and fetal growth restriction, whereas late-onset preeclampsia was suggested to result from maternal factors. We have proposed an alternative model, suggesting that both early- and late-onset preeclampsia result from placental syncytiotrophoblast stress. This stress represents a common endpoint of several Stage 1 processes, promoting the clinical stage 2 of preeclampsia (new-onset hypertension and proteinuria or other signs of end-organ dysfunction), but the causes and timing of placental malperfusion differ. We have suggested that late-onset preeclampsia, without evidence of poor spiral artery remodelling, may be secondary to intraplacental (intervillous) malperfusion due to mechanical restrictions. As the growing placenta reaches its size limit, malperfusion and hypoxia occurs. This latter pathway reflects what is observed in postmature or multiple pregnancies. Our revised two-stage model accommodates most risk factors for preeclampsia including primiparity, chronic pre-pregnancy disease (e.g. obesity, diabetic-, chronic hypertensive-, and some autoimmune diseases), and pregnancy risk factors (e.g. multiple or molar pregnancies, gestational diabetes or hypertension, and low circulating Placental Growth Factor). These factors may increase the risk of progressing to the second stage of preeclampsia (both early- and late-onset) by affecting one of or both pathways leading to Stage 1, as well as potentially accelerating the steps towards Stage 2, including priming the maternal cardiovascular susceptibility to inflammatory factors shed by the placenta. This paper reviews previous preeclampsia findings and concepts, which fit with the revised two-stage model, and argues that "maternal" preeclampsia does not exist, as all preeclampsia requires a placenta.
Topics: Female; Humans; Models, Biological; Pre-Eclampsia; Pregnancy; Proteinuria; Trophoblasts
PubMed: 31301487
DOI: 10.1016/j.jri.2019.07.004 -
JAMA Network Open Feb 2023The role of mycophenolate mofetil (MMF) in management of immunoglobulin A nephropathy (IgAN) remains highly controversial. (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
The role of mycophenolate mofetil (MMF) in management of immunoglobulin A nephropathy (IgAN) remains highly controversial.
OBJECTIVE
To evaluate the efficacy and safety of MMF in patients with IgAN at high risk of kidney function loss.
DESIGN, SETTING, AND PARTICIPANTS
This randomized clinical trial with open-label, blinded end-point design was conducted among adults with IgAN, proteinuria greater than 1.0 g/d, and estimated glomerular filtration rate (eGFR) greater than 30 and less than 60 mL/min/1.73m2 or with persistent hypertension from September 2013 to December 2015. During a 3-month run-in period, 238 patients received optimized supportive care (SC), including losartan. Patients with a urinary protein excretion rate of 0.75 g/d or greater despite of 3 months optimized SC were enrolled into the trial for 3 years. Survivors of the trial who did not receive dialysis or transplant were followed up after the trial for a median (IQR) of 60 (47-76) months. Data were analyzed from March through June 2022.
INTERVENTIONS
A total of 170 participants were randomized in a 1:1 ratio to receive MMF (initially, 1.5 g/d for 12 months, maintained at 0.75-1.0 g for at least 6 months) plus SC or SC alone.
MAIN OUTCOMES AND MEASURES
The primary outcomes were (1) a composite of doubling of serum creatinine, end-stage kidney disease (dialysis, transplant, or kidney failure without receiving kidney replacement therapy), or death due to kidney or cardiovascular cause and (2) progression of chronic kidney disease.
RESULTS
Among 170 randomized patients (mean [SD] age 36.6 [9.4] years; 94 [55.3%] male patients), 85 patients received MMF with SC and 85 patients received SC alone. The mean (SD) eGFR was 50.1 (17.9) mL/min/1.73m2 and mean (SD) proteinuria level was 1.9 (1.7) g/d; 168 patients (98.8%) completed the trial, and 157 participants (92.4%) survived and did not receive dialysis or transplant. Primary composite outcome events occurred in 6 patients (7.1%) in the MMF group and 18 patients (21.2%) in the SC group (adjusted hazard ratio [aHR], 0.23; 95% CI, 0.09-0.63). Progression of chronic kidney disease occurred in 7 participants (8.2%) in the MMF group and 23 participants (27.1%) in the SC group (aHR, 0.23; 95% CI, 0.10-0.57). The effect of MMF treatment on primary outcomes was consistent across prespecified subgroups, with no significant interaction per subgroup. During posttrial follow-up, annual loss of eGFR accelerated after discontinuation of MMF; mean (SD) annual eGFR loss during the study period was 2.9 (1.0) mL/min/1.73m2 in the MMF group and 6.1 (1.2) mL/min/1.73m2 among 66 patients in the MMF group who discontinued MMF after the trial. Serious adverse events were not more frequent with MMF vs SC alone.
CONCLUSIONS AND RELEVANCE
This study found that addition of MMF to SC compared with SC alone significantly reduced risk of disease progression among patients with progressive IgAN.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT01854814.
Topics: Adult; Female; Humans; Male; Glomerulonephritis, IGA; Immunosuppressive Agents; Kidney Failure, Chronic; Mycophenolic Acid; Proteinuria; Renal Dialysis; Middle Aged
PubMed: 36745456
DOI: 10.1001/jamanetworkopen.2022.54054 -
European Review For Medical and... Oct 2014Cardiovascular disease (CVD), the leading cause of death, is mostly precipitated by cardiometabolic risk and chronic kidney disease (CKD). CVD and kidney disease are... (Review)
Review
Cardiovascular disease (CVD), the leading cause of death, is mostly precipitated by cardiometabolic risk and chronic kidney disease (CKD). CVD and kidney disease are closely interrelated and disease of one organ cause dysfunction of the other, ultimately leading to the failure of both organs. Patients with end-stage renal disease (ESRD) are at much higher risk of mortality due to CVD. Traditional CVD risk factors viz., hypertension, hyperlipidemia, and diabetes do not account for the high cardiovascular risk in CKD patients and also standard clinical interventions for managing CVD that are successful in the general population, are ineffective to lower the death rate in CKD patients. Nontraditional factors, related to disturbed mineral and vitamin D metabolism were able to provide some explanation in terms of vascular calcification, for the increased risk of CVD in CKD. Fibroblast Growth Factor 23, a bone-derived hormone that regulates vitamin D synthesis in renal proximal tubules and renal phosphate reabsorption, has been suggested to be the missing link between CKD and CVD. Acute Kidney Injury (AKI) is strongly related to the progress of CVD and its early diagnosis and treatment has significant positive effect on the outcomes of CVD in the affected patients. Besides this, non-dialysable protein-bound uraemic toxins such as indoxyl sulfate and p-cresyl sulfate, produced by colonic microbes from dietary amino acids, appear to cause renal dysfunction. Thus, therapeutic approaches targeting colonic microbiota, have led to new prospects in early intervention for CKD patients. Intervention targets for preventing CVD events in CKD patients ideally should include control of blood pressure and dyslipidemia, diabetes mellitus, lowering proteinuria, correction of anemia, management of mineral metabolism abnormalities and life style changes including smoking cessation, decreased consumption of salt, and achievement of normal body mass index. Use of β-blockers, renin-angiotensin blockers, diuretics, statins, and aspirin are helpful in the early stages of CKD. In this review, we will address the biological, pathological and clinical relationship between CVD and CKD and their therapeutic management.
Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aspirin; Blood Pressure; Cardiovascular Diseases; Diuretics; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension; Proteinuria; Renal Insufficiency, Chronic; Risk Factors; Risk Reduction Behavior
PubMed: 25339487
DOI: No ID Found -
Clinical Journal of the American... Mar 2019IgA nephropathy (IgAN) is an important cause of ESKD for which there are no approved therapies. A challenge for evaluating treatments for IgAN is the usual long time...
IgA nephropathy (IgAN) is an important cause of ESKD for which there are no approved therapies. A challenge for evaluating treatments for IgAN is the usual long time course for progression to ESKD. The aim of this Kidney Health Initiative project was to identify surrogate end points that could serve as reliable predictors of a treatment's effect on long-term kidney outcomes in IgAN and be used as a basis for approval. Proteinuria was identified as the most widely recognized and well studied risk factor for progression to ESKD in IgAN. The workgroup performed a critical review of the data on proteinuria reduction as a surrogate end point for a treatment's effect on progression to ESKD in IgAN. Epidemiologic data indicate a strong and consistent relationship between the level and duration of proteinuria and loss of kidney function. Trial-level analyses of data from 13 controlled trials also show an association between treatment effects on percent reduction of proteinuria and treatment effects on a composite of time to doubling of serum creatinine, ESKD, or death. We conclude that data support the use of proteinuria reduction as a reasonably likely surrogate end point for a treatment's effect on progression to ESKD in IgAN. In the United States, reasonably likely surrogate end points can be used as a basis for accelerated approval of therapies intended to treat serious or life-threatening conditions, such as IgAN. The clinical benefit of products approved under this program would need to be verified in a postmarketing confirmatory trial.
Topics: Controlled Clinical Trials as Topic; Disease Progression; Endpoint Determination; Glomerulonephritis, IGA; Humans; Kidney Failure, Chronic; Proteinuria; Research Design; Risk Factors; Time Factors; Treatment Outcome
PubMed: 30635299
DOI: 10.2215/CJN.08600718 -
Talanta Feb 2021Extensive medical research showed that patients, with high protein concentration in urine, have various kinds of kidney diseases, referred to as proteinuria. Urinary... (Review)
Review
Extensive medical research showed that patients, with high protein concentration in urine, have various kinds of kidney diseases, referred to as proteinuria. Urinary protein biomarkers are useful for diagnosis of many health conditions - kidney and cardio vascular diseases, cancers, diabetes, infections. This review focuses on the instrumental quantification (electrophoresis, chromatography, immunoassays, mass spectrometry, fluorescence spectroscopy, the infrared spectroscopy, and Raman spectroscopy) of proteins (the most of all albumin) in human urine matrix. Different techniques provide unique information on what constituents of the urine are. Due to complex nature of urine, a separation step by electrophoresis or chromatography are often used for proteomics study of urine. Mass spectrometry is a powerful tool for the discovery and the analysis of biomarkers in urine, however, costs of the analysis are high, especially for quantitative analysis. Immunoassays, which often come with fluorescence detection, are major qualitative and quantitative tools in clinical analysis. While Infrared and Raman spectroscopies do not give extensive information about urine, they could become important tools for the routine clinical diagnostics of kidney problems, due to rapidness and low-cost. Thus, it is important to review all the applicable techniques and methods related to urine analysis. In this review, a brief overview of each technique's principle is introduced. Where applicable, research papers about protein determination in urine are summarized with the main figures of merits, such as the limit of detection, the detectable range, recovery and accuracy, when available.
Topics: Biomarkers; Humans; Mass Spectrometry; Proteins; Proteinuria; Proteomics; Urinalysis
PubMed: 33303164
DOI: 10.1016/j.talanta.2020.121718