scholarly journals The Rationale and Evidence for SGLT2 Inhibitors as a Treatment for Nondiabetic Glomerular Disease

2021 ◽  
Vol 1 (1) ◽  
pp. 21-33
Author(s):  
Kana N. Miyata ◽  
Shao-Ling Zhang ◽  
John S.D. Chan
Keyword(s):  
Glucose Transporter ◽  
Mesangial Cells ◽  
Systemic Blood Pressure ◽  
Glomerular Disease ◽  
Renal Tubules ◽  
Protective Effects ◽  
Glomerular Diseases ◽  
Urinary Glucose ◽  
Proximal Tubular ◽  
History Of

Background: Recent studies show that sodium-glucose cotransporter 2 inhibitors (SGLT2i), originally approved for glycemic control in patients with type 2 diabetes, also exert renoprotective effects independently from effects on dysglycemia. Moreover, recent work indicates that SGLT2i treatment may be effective in patients with nondiabetic chronic kidney disease, including primary and secondary glomerular diseases. Summary: SGLT2i lower blood glucose by blocking glucose resorption in the early renal proximal tubule through the glucose transporter, SGLT2, leading to enhanced urinary glucose excretion. Recent studies indicate that SGLT2i may have pleiotropic effects on cells other than proximal tubular cells. SGLT2i reduce the glomerular workload by decreasing the intraglomerular pressure, thus ameliorating hyperfiltration, if present, and may also decrease systemic blood pressure. SGLT2i may also act directly on endothelial cells, possibly via modulating the effects of adhesion molecules and reducing inflammatory cytokines and reactive oxygen species. SGLT2i may have direct anti-inflammatory and antifibrotic effects on renal tubules. Some reports suggest direct protective effects on podocytes and mesangial cells as well. Here, we provide a review of the potential mechanisms of renoprotection, therapeutic utility, and potential side effects of SGLT2i in patients with nondiabetic glomerular diseases, based on data from studies carried out in cells, experimental animals, and humans. Key Messages: SGLT2i may be a promising addition to the glomerular disease treatment armamentarium. However, it is unclear at what point of the natural history of specific glomerular diseases (whether this is immune or nonimmune mediated) SGLT2i can be beneficial. Additionally, further studies are needed to assess the long-term efficacy and safety of SGLT2i in patients with nondiabetic glomerular diseases.

Impaired intestinal and renal glucose transport in PDK-1 hypomorphic mice

2006 ◽  
Vol 291 (5) ◽  
pp. R1533-R1538 ◽  
Author(s):  
Ferruh Artunc ◽  
Rexhep Rexhepaj ◽  
Harald Völkl ◽  
Florian Grahammer ◽  
Christine Remy ◽  
...  
Keyword(s):  
Small Intestine ◽  
Glucose Transport ◽  
Glucose Transporter ◽  
Ussing Chamber ◽  
Glucose Absorption ◽  
Renal Tubules ◽  
Glucose Transporter 1 ◽  
Glucose Reabsorption ◽  
Urinary Glucose ◽  
Proximal Tubular

The phosphoinositide-dependent kinase-1 (PDK-1) activates the serum- and glucocorticoid-inducible kinase and protein kinase B isoforms, which, in turn, are known to stimulate the renal and intestinal Na+-dependent glucose transporter 1. The present study has been performed to explore the role of PDK-1 in electrogenic glucose transport in small intestine and proximal renal tubules. To this end, mice expressing ∼20% of PDK-1 ( pdk1 hm) were compared with their wild-type littermates ( pdk1 wt). According to Ussing chamber experiments, electrogenic glucose transport was significantly smaller in the jejunum of pdk1 hm than of pdk1 wt mice. Similarly, proximal tubular electrogenic glucose transport in isolated, perfused renal tubule segments was decreased in pdk1 hm compared with pdk1 wt mice. Intraperitoneal injection of 3 g/kg body wt glucose resulted in a similar increase of plasma glucose concentration in pdk1 hm and in pdk1 wt mice but led to a higher increase of urinary glucose excretion in pdk1 hm mice. In conclusion, reduction of functional PDK-1 leads to impairment of electrogenic intestinal glucose absorption and renal glucose reabsorption. The experiments disclose a novel element of glucose transport regulation in kidney and small intestine.

scholarly journals A Case of Essential Thrombocythemia and IgA Nephropathy with Literature Review of the Concurrence

2019 ◽  
Vol 2019 ◽  
pp. 1-5
Author(s):  
Shoja Rahimian ◽  
Timothy Johnson ◽  
Ronald Herb
Keyword(s):  
Renal Function ◽  
Literature Review ◽  
Essential Thrombocythemia ◽  
Myeloproliferative Neoplasms ◽  
Immunoglobulin A ◽  
Glomerular Disease ◽  
Common Finding ◽  
Glomerular Diseases ◽  
Pathological Review ◽  
History Of

Myeloproliferative neoplasms such as essential thrombocythemia (ET) have been associated with glomerular disease on rare instances. A case of ET associated with immunoglobulin A nephropathy (IgAN) is described in a 57-year-old man with a history of hypertension. Progressively worsening renal function was noted in the patient along with unexplained mild thrombocytosis. Pathological review of renal biopsy identified IgAN concurrently with newly diagnosed JAK2-mutated ET. The patient was started on aspirin therapy and closely monitored for his renal function. A literature review of the association of ET and renal disease revealed nine cases of ET associated with IgAN, focal segmental glomerulosclerosis, and fibrillary glomerulonephritis. Comparison of the pathological features of the renal biopsies within the cases noted mesangial proliferation as a common finding, which has been described to be potentiated by platelet-derived growth factor (PDGF). This commonality may represent a link between ET and glomerular disease which deserves further attention in future cases. Improved management of such cases depends on the recognition of the combined occurrence of ET and glomerular diseases and uncovering the shared pathogenesis between platelets and glomeruli.

scholarly journals Transgenic overexpression of GLUT1 in mouse glomeruli produces renal disease resembling diabetic glomerulosclerosis

2010 ◽  
Vol 299 (1) ◽  
pp. F99-F111 ◽  
Author(s):  
Youli Wang ◽  
Kathleen Heilig ◽  
Thomas Saunders ◽  
Andrew Minto ◽  
Dilip K. Deb ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Transforming Growth Factor ◽  
Mesangial Cells ◽  
Glomerular Disease ◽  
Membrane Thickness ◽  
Renal Tubules ◽  
Glomerular Mesangial Cells ◽  
Diabetic Glomerulosclerosis ◽  
Basement Membrane Thickness ◽  
Intracellular Glucose

Previous work identified an important role for hyperglycemia in diabetic nephropathy (The Diabetes Control and Complications Trial Research Group. N Engl J Med 329: 977–986, 1993; UK Prospective Diabetes Study Group. Lancet 352: 837–853, 1998), and increased glomerular GLUT1 has been implicated. However, the roles of GLUT1 and intracellular glucose have not been determined. Here, we developed transgenic GLUT1-overexpressing mice (GT1S) to characterize the roles of GLUT1 and intracellular glucose in the development of glomerular disease without diabetes. GLUT1 was overexpressed in glomerular mesangial cells (MC) of C57BL6 mice, a line relatively resistant to diabetic nephropathy. Blood pressure, blood glucose, glomerular morphometry, matrix proteins, cell signaling, transcription factors, and selected growth factors were examined. Kidneys of GT1S mice overexpressed GLUT1 in glomerular MCs and small vessels, rather than renal tubules. GT1S mice were neither diabetic nor hypertensive. Glomerular GLUT1, glucose uptake, mean capillary diameter, and mean glomerular volume were all increased in the GT1S mice. Moderately severe glomerulosclerosis (GS) was established by 26 wk of age in GT1S mice, with increased glomerular type IV collagen and fibronectin. Modest increases in glomerular basement membrane thickness and albuminuria were detected with podocyte foot processes largely preserved, in the absence of podocyte GLUT1 overexpression. Activation of glomerular PKC, along with increased transforming growth factor-β1, VEGFR1, VEGFR2, and VEGF were all detected in glomeruli of GT1S mice, likely contributing to GS. The transcription factor NF-κB was also activated. Overexpression of glomerular GLUT1, mimicking the diabetic GLUT1 response, produced numerous features typical of diabetic glomerular disease, without diabetes or hypertension. This suggested GLUT1 may play an important role in the development of diabetic GS.

Developments in the Immunotherapy of Glomerular Disease

2002 ◽  
Vol 15 (6) ◽  
pp. 472-489
Author(s):  
Patrick H. Nachman ◽  
Jeffrey Martin
Keyword(s):  
Alkylating Agents ◽  
Clinical Manifestations ◽  
Calcineurin Inhibitors ◽  
Immunosuppressive Drugs ◽  
Glomerular Disease ◽  
Drug Induced ◽  
Glomerular Diseases ◽  
Care Givers ◽  
Clinical Syndromes ◽  
History Of

Glomerular diseases span a broad spectrum of clinical syndromes, with varied clinical manifestations, underlying etiologies, and pathogenic mechanisms. They can be secondary to underlying infectious, toxic, environmental, or drug exposures, or present as “primary entities.” In the latter case, most glomerular diseases are thought to be due to autoimmune dysregulation, and their treatment is primarily immunosuppressive. The armamentarium for immunomodulation includes corticosteroids, alkylating agents, anti-metabolites, calcineurin inhibitors, and new biological agents designed to block specific inflammatory pathways. The choice of therapy for an individual patient must be based on the specific character of the glomerular disease and its acuity and severity, as well as the patient’s comorbidities, history of prior exposure to immunosuppressive drugs, and risk factors for developing complications of the disease or its treatment. The complexities of such therapy can best be addressed by an experienced team of care givers in which the clinical pharmacist can help minimize, if not eliminate, potential sources of drug induced toxicities and adverse effects. This article will describe the major agents and modalities used in the management of the most common glomerular diseases.

scholarly journals A longitudinal study of suicide and suicide attempt in northwest of Iran: incidence, predictors, and socioeconomic status and the role of sociocultural status

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Ali Fakhari ◽  
Mostafa Farahbakhsh ◽  
Elham Davtalab Esmaeili ◽  
Hosein Azizi
Keyword(s):  
Socioeconomic Status ◽  
Longitudinal Study ◽  
Religious Commitment ◽  
Incidence Rates ◽  
Demographic Characteristics ◽  
Protective Effects ◽  
Wide Range ◽  
Multiple Variable ◽  
History Of

Abstract Background A detailed community-level understanding of socioeconomic status (SES) and sociocultural status (SCS) of suicides and suicide attempters (SAs) in a prospective design could have significant implications for policymakers at the local prevention and treatment levels. The effect of SCS and SES on SAs is poorly understood and investigated in Iran. The present study aimed to investigate the incidence, trend, and role of SES and SCS on suicide and SAs. Methods A longitudinal study was conducted based on the registry for SAs in Malekan County, Iran, from 2015 to 2018. Demographic characteristics, SES, SCS, incidence rates, and predictors of suicidal behaviors were measured via structured instruments. Simple and multiple logistic regressions were used to estimate crude and adjusted odds ratios (ORs) and 95% confidence intervals (CIs). Results A total of 853 SAs (32 suicides and 821 attempts) were identified during the study. Trend analysis revealed that the suicide rate significantly decreased from 2014 (10.28) to 2018 (1.75) per 100,000. In the final multiple variable models, age (26–40), male sex, unemployment, antisocial activities, history of SA, hanging method, and season (spring) increased the suicide risk while religious commitment had protective effects on suicide. Conclusions Our findings indicated that demographic characteristics, low SES, and SCS are associated with suicide. In this county, trend of suicide and SA were decreased from 2014 to 2018. This study findings highlight the need to consider a wide range of contextual variables, socio-demographic, SES, and SCS in suicide prevention strategies. Improving inter-sectoral collaborations and policymakers’ attitudes are imperative for SA reduction.

How condom use, number of receptive anal intercourse partners and history of external genital warts predict risk for external anal warts

2005 ◽  
Vol 16 (3) ◽  
pp. 203-211 ◽  
Author(s):  
D J Wiley ◽  
Diane M Harper ◽  
David Elashoff ◽  
Michael J Silverberg ◽  
Christine Kaestle ◽  
...  
Keyword(s):  
Condom Use ◽  
Anal Intercourse ◽  
Consistent Condom ◽  
Prior History ◽  
Receptive Anal Intercourse ◽  
Protective Effects ◽  
Lifetime Number ◽  
History Of ◽  
Anal Warts ◽  
External Genital Warts

Few analytic opportunities have allowed us to evaluate the role that specific sexual acts and male latex condoms play in the acquisition of external anal warts (EAW) using longitudinal data. The acquisition of EAWs occurs from epithelial contact with other HPV-infected surfaces, and hence is dependent upon sexual behaviour. Our objectives were to classify the relative importance of condom use, receptive anal intercourse (RAI) and prior history of EGWs on acquisition of EAWs. The observational Multicenter AIDS Cohort Study followed 2925 men over nine semiannual study visits for behavioural and physical examinations with laboratory testing. The main outcome measure was the occurrence of examiner-diagnosed EAWs in a homosexual population. EAWs were diagnosed among 10% of men studied across 22,157 visits reviewed for this study. Men with history of EGWs were more likely than those previously unaffected to have developed EAWs (cOR = 2.4 (2.0, 2.9)), as were men who reported multiple anoreceptive intercourse partners (e.g., compared with men who reported no RAI partners, men with 1, 2–5, ≥6 RAI partners had crude risk ratios 1.0 (0.8, 1.3), 1.6 (1.2, 2.1), 3.9 (2.7, 5.8), respectively). These relations persisted after other demographic and sexual risk factors were controlled for in the analyses. Consistent condom usage showed no protective effect for EAWs in our crude or adjusted analyses. Patient education messages should be tailored to reflect our uncertainty about the protective nature of condoms for the development of anal warts, but to continue to assert the protective effects of a limited lifetime number of sexual partners and the heightened risk for wart recurrence once infected.

CONGENITAL PITRESSIN RESISTANT DIABETES INSIPIDUS OF RENAL ORIGIN

PEDIATRICS ◽  
1955 ◽  
Vol 15 (3) ◽  
pp. 298-372
Author(s):  
William B. Macdonald
Keyword(s):  
Diabetes Insipidus ◽  
Extracellular Fluid ◽  
Male Infant ◽  
Renal Tubules ◽  
Post Mortem ◽  
Water Metabolism ◽  
History Of ◽  
Renal Clearances ◽  
Renal Function Tests ◽  
Renal Origin

1) The history of a male infant who presented soon after birth with features of failure to gain weight, dehydration and pyrexia of obscure origin, has been described. A diagnosis of pitressin resistant diabetes insipidus was made. 2) Renal function tests and post-mortem examination, including microdissection of the kidney, indicates that the basic defect in water metabolism was a functional inability of the distal renal tubules to respond to antidiuretic hormone. 3) Consequent dehydration was insufficient to cause circulatory collapse, but affected renal clearances. 4) There was evidence of increased catabolism and poor protein utilisation. 5) Hyperosmolarity of the extracellular fluid was accompanied by a rise in body temperature, probably due to a depression of sweat gland activity. 6) Post-mortem evidence suggests that infants with pitressin resistant diabetes insipidus should be investigated for cystine storage disease.

MO427SAFE USE OF ALLOPURINOL TO TREAT ACUTE URIC ACID NEPHROPATHY IN PREGNANCY: A CASE REPORT

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Fahd Khan ◽  
Aizaz Ali ◽  
Jamie Willows ◽  
Didem Tez
Keyword(s):  
Uric Acid ◽  
Case Report ◽  
Serum Creatinine ◽  
Serum Uric Acid ◽  
Renal Tubules ◽  
Normal Range ◽  
History Of ◽  
Uric Acid Nephropathy ◽  
Acute Uric Acid Nephropathy ◽  
In Pregnancy

Abstract Introduction Acute uric acid nephropathy (UAN) is characterized by acute kidney injury (AKI) due to uric acid crystal precipitation within the distal tubules and collecting ducts. We present a young woman, with a history of hyperuricaemia, who was treated with allopurinol for acute UAN during her first pregnancy. She also continued allopurinol treatment during her second pregnancy for prevention of further acute UAN. To the author’s knowledge, this is the first case report of biopsy-confirmed acute UAN during pregnancy. Case report A 20 year old woman, who was 13 weeks pregnant, was admitted with AKI. Past medical history included chronic kidney disease (CKD) and gout since the age of 17. She had an extensive family history of CKD and gout (without diagnosis, despite genetic testing). She had been on daily allopurinol 300mg, but this was stopped 8 weeks prior by her rheumatology team due to concerns about teratogenicity. At that time serum creatinine was at her baseline of 100 μmol/L (normal range 50-120 μmol/L) and serum uric acid had been 740 μmol/L (normal range 140-360 μmol/L). On admission, she felt well and was euvolemic. Serum creatinine was now 352 μmol/L and her serum uric acid level was 1720 μmol/L, with an elevated urine uric acid to creatinine ratio of 1.1. She underwent renal biopsy, which showed significant deposition of uric acid crystals in the renal tubules, confirming a diagnosis of acute UAN. She was given intravenous fluids. The uncertainties of allopurinol use in pregnancy were discussed with her, and she was restarted on allopurinol 200 mg daily. Over the next 3 weeks, serum uric acid decreased to 470 μmol/L and serum creatinine to 116 μmol/L. She was maintained on allopurinol during her pregnancy and delivered a healthy baby girl. She was advised against further pregnancies due to increased risk of maternal and fetal complications. However, three years later she presented at 15 weeks’ gestation. After a discussion regarding the potential teratogenic effects of allopurinol versus the risk of recurrent severe AKI due to acute UAN if it was again discontinued, she chose to continue allopurinol. The pregnancy proceeded without complication. Her daughters are now 8 and 5 years old. They do not have any congenital malformations, though both have mild to moderate learning difficulties. Discussion Allopurinol is approved for the treatment of hyperuricaemia outside of pregnancy, but given it interrupts purine synthesis there is a biologically plausible concern regarding teratogenicity. However, in our patient with long-standing hyperuricaemia it was the discontinuation of allopurinol that precipitated AKI due to the resultant crystal formation when serum uric acid reached very high levels. Biopsy confirmation of acute UAN was vital in this case, given the possibility of missing an alternative diagnosis and the risks of giving empirical allopurinol therapy. Once the diagnosis for her severe AKI was confirmed, it was clear our patient would benefit from uric acid lowering therapy. Our patient had two healthy girls despite using allopurinol from week 16 in her first pregnancy and throughout her second pregnancy. Unfortunately, both girls have mild to moderate learning needs, though it is unprovable whether allopurinol was causative as no study has followed up long term outcomes after foetal exposure during pregnancy.

Extracellular ATP causes apoptosis and necrosis of cultured mesangial cells via P2Z/P2X7receptors

1998 ◽  
Vol 275 (6) ◽  
pp. F962-F971 ◽  
Author(s):  
Eckhard Schulze-Lohoff ◽  
Christian Hugo ◽  
Sylvia Rost ◽  
Susanne Arnold ◽  
Angela Gruber ◽  
...  
Keyword(s):  
Cell Death ◽  
Dna Fragmentation ◽  
Mesangial Cells ◽  
Lucifer Yellow ◽  
Fold Increase ◽  
Extracellular Atp ◽  
Glomerular Disease ◽  
Terminal Deoxynucleotidyl Transferase ◽  
P53 Expression ◽  
Apoptosis And Necrosis

Mesangial cells undergo cell death both by apoptosis and necrosis during glomerular disease. Since nucleotides are released from injured and destroyed cells in the glomerulus, we examined whether extracellular ATP and its receptors may regulate cell death of cultured mesangial cells. Addition of extracellular ATP (300 μM to 5 mM) to cultured rat mesangial cells for 90 min caused a 5.8-fold increase in DNA fragmentation (terminal deoxynucleotidyl transferase assay) and a 4.2-fold increase in protein levels of the tumor suppressor p53, which is thought to regulate apoptosis. Apoptotic DNA fragmentation was confirmed by the diphenylamine assay and by staining with the DNA-specific fluorochrome Hoechst 33258. The necrotic markers, release of lactate dehydrogenase and uptake of trypan blue, were not positive before 3 h of ATP addition. The effects of ATP on DNA fragmentation and p53 expression were reproduced by the purinergic P2Z/P2X7 receptor agonist, 3′- O-(4-benzoylbenzoyl)-ATP, and inhibited by the P2Z/P2X7 receptor blocker, oxidized ATP. Transcripts encoding the P2Z/P2X7 receptor were expressed by cultured mesangial cells as determined by Northern blot analysis. P2Z/P2X7 receptor-associated pore formation in the plasma membrane was demonstrated by the Lucifer yellow assay. We conclude that activation of P2Z/P2X7 receptors by extracellular ATP causes apoptosis and necrosis of cultured mesangial cells. Activation of purinergic P2Z/P2X7 receptors may play a role in causing death of mesangial cells during glomerular disease.

scholarly journals Porcine Babesiosis Caused by Babesia sp. Suis in a Pot-Bellied Pig in South Africa

2021 ◽  
Vol 7 ◽  
Author(s):  
Alida Avenant ◽  
Janice Y. Park ◽  
Ilse Vorster ◽  
Emily P. Mitchell ◽  
Angela M. Arenas-Gamboa
Keyword(s):  
South Africa ◽  
Blood Smear ◽  
Clinical Manifestations ◽  
Small Ruminants ◽  
Renal Tubules ◽  
Dipstick Test ◽  
Uncommon Disease ◽  
Urine Dipstick Test ◽  
History Of ◽  
Tick Borne Disease

Babesiosis is a worldwide, tick-borne disease of economic importance in livestock caused by Babesia spp., which are hemoparasitic piroplasms that target the host erythrocytes. Cattle, dogs, small ruminants, and wild ruminants are the species most commonly affected, while in cats, horses, and pigs, it is less frequently reported. Although babesiosis has been observed worldwide, porcine babesiosis remains an uncommon disease with a very limited number of cases reported. Here, we describe a case in a 12-year old pot-bellied pig from South Africa that died after a history of anorexia and reluctance to rise for 2 days. A complete necropsy, blood smear cytology, reverse line blot (RLB) hybridization and 18S rRNA sequencing were performed. Numerous Babesia spp. hemoparasites and a moderate regenerative anemia were identified on blood smear, and a urine dipstick test yielded 4+ heme. Diffuse icterus and splenomegaly were observed upon gross examination. Histopathology revealed hemoglobin casts within renal tubules and collecting ducts, pulmonary edema, splenic congestion, and intrahepatic cholestasis. BLASTN homology of the 18SrRNA sequence revealed a 100% identity to the published sequence of Babesia sp. Suis isolated from pigs in Italy. This case of babesiosis in a pig highlights the clinical manifestations and gross and pathological findings of porcine babesiosis.

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