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2.
Intern Med J ; 45(3): 319-29, 2015 Mar.
Article in English | MEDLINE | ID: mdl-25581282

ABSTRACT

BACKGROUND: Aminoglycoside clearance depends on kidney function, but the Australian Therapeutic Guidelines for antibiotics (version 14, 2010) recommend initial dosing based on weight without consideration of kidney function. Other guidelines that modify dosing based on kidney function estimates often use the Cockroft-Gault equation, but the role of the estimated glomerular filtration rate equations for this purpose is unclear. AIM: To determine the performance of current guideline dosing in achieving target area-under-the-curve and examine the relative precision of the estimated glomerular filtration rate equations compared with traditional Cockroft-Gault creatinine clearance in predicting aminoglycoside clearance. METHODS: We analysed 496 aminoglycoside treatment episodes involving 1377 infusions in adult patients. Conformity with antibiotic guideline dosing was achieved if the discrepancy between prescribed and recommended dose was less than 15%. Aminoglycoside clearance was determined from linear regression using a one compartment model with the Aminoglycoside Levels and Daily Dose Indicator programme. We assessed the precision of the Cockroft-Gault, Modification of Diet in renal Disease Study and Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equations in predicting aminoglycoside clearance by correlation and linear regression. RESULTS: Conformity with guideline dosing was not associated with achieving target area-under-the-curve. The CKD-EPI estimated glomerular filtration rate adjusted for body surface area showed the highest correlation (gentamicin, r = 0.66; tobramycin, r = 0.82) and best predictive model for aminoglycoside clearance. CONCLUSION: Current guideline dosing may be suboptimal for achieving target area-under-the-curve. The CKD-EPI equation adjusted for patient body surface area best predicts aminoglycoside clearance, and could be evaluated as a covariate in determining initial aminoglycoside dosing.


Subject(s)
Aminoglycosides/administration & dosage , Area Under Curve , Gentamicins/administration & dosage , Glomerular Filtration Rate/drug effects , Metabolic Clearance Rate/drug effects , Tobramycin/administration & dosage , Adolescent , Adult , Aged , Aminoglycosides/metabolism , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/metabolism , Dose-Response Relationship, Drug , Female , Gentamicins/metabolism , Glomerular Filtration Rate/physiology , Humans , Infusions, Intravenous , Male , Metabolic Clearance Rate/physiology , Middle Aged , Renal Insufficiency, Chronic/drug therapy , Renal Insufficiency, Chronic/metabolism , Tobramycin/metabolism , Young Adult
3.
Intern Med J ; 43(12): 1330-4, 2013 Dec.
Article in English | MEDLINE | ID: mdl-24330363

ABSTRACT

Renal tubular acidosis is a common cause of normal anion gap metabolic acidosis but these disorders can be easily missed or misdiagnosed. We highlight the approach to assessing renal tubular acidosis by discussing a case study with a temporal data set collected over more than 5 weeks. We highlight the principles and the necessary information required for a diagnosis of classic distal renal tubular acidosis. We also briefly review several aspects of type 1 renal tubular acidosis related to autoimmune disease, drugs and thyroid disorders.


Subject(s)
Acidosis, Renal Tubular/complications , Acidosis, Renal Tubular/diagnosis , Sjogren's Syndrome/complications , Sjogren's Syndrome/diagnosis , Acidosis, Renal Tubular/metabolism , Aged , Biomarkers/blood , Biomarkers/urine , Female , Humans , Sjogren's Syndrome/metabolism
4.
Am J Physiol Renal Physiol ; 300(2): F301-10, 2011 Feb.
Article in English | MEDLINE | ID: mdl-21147843

ABSTRACT

The db/db mouse is the most widely used animal model of type 2 diabetic nephropathy. Recent studies have utilized genetic backcrossing with transgenic mouse strains to create novel db/db strains that either lack or overexpress specific genes. These novel strains [ICAM-1-/-, CCL2-/-, MKK3-/-, osteopontin-/-, plasminogen activator inhibitor-1 (PAI-1)-/-, endothelial nitric oxide synthase-/-, SOD-Tg, rCAT-Tg] have provided valuable insights into the molecular mechanisms which promote diabetic renal injury. In addition, surgical removal of one kidney has been shown to accelerate injury in the remaining kidney of diabetic db/db mice. A number of novel therapeutic agents have also been tested in db/db mice, including inhibitors of inflammation (chemokine receptor antagonists, anti-CCL2 RNA aptamer, anti-c-fms antibody); oxidative stress (oxykine, biliverdin); the renin-angiotensin-aldosterone system (aliskiren, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, eplerenone); advanced glycation end products (AGE; pyridoxamine, alagebrium, soluble AGE receptor); angiogenesis (NM-3, anti-CXCL12 RNA aptamer, soluble Flt-1); lipid accumulation (statins, farnesoid X receptor agonists, Omacor); intracellular signaling pathways (PKC-ß or JNK inhibitors); and fibrosis [transforming growth factor (TGF)-ß antibody, TGF-ßR kinase inhibitor, soluble betaglycan, SMP-534, CTGF-antisense oligonucleotide, mutant PAI-1, pirfenidone], which have identified potential therapeutic targets for clinical translation. This review summarizes the advances in knowledge gained from studies in genetically modified db/db mice and treatment of db/db mice with novel therapeutic agents.


Subject(s)
Diabetes Mellitus, Type 2/complications , Diabetic Nephropathies/genetics , Disease Models, Animal , Animals , Chemokine CCL2/genetics , Diabetic Nephropathies/drug therapy , Diabetic Nephropathies/enzymology , Diabetic Nephropathies/surgery , Female , Inflammation/drug therapy , Inflammation/genetics , Intercellular Adhesion Molecule-1/genetics , MAP Kinase Kinase 3/genetics , Male , Mice , Mice, Inbred C57BL , Nitric Oxide Synthase Type III/genetics , Osteopontin/genetics , Plasminogen Activator Inhibitor 1/genetics , Renin-Angiotensin System/drug effects , Renin-Angiotensin System/genetics
5.
Diabetologia ; 53(8): 1772-82, 2010 Aug.
Article in English | MEDLINE | ID: mdl-20422398

ABSTRACT

AIMS/HYPOTHESIS: Diabetic nephropathy is an inflammatory disease with prominent leucocyte infiltration of the kidneys. While the importance of macrophages in diabetic renal injury has been clearly demonstrated, the role of lymphocytes is still unknown. We therefore examined the development of diabetic renal injury in lymphocyte-deficient mice. METHODS: Streptozotocin was used to induce diabetes in Rag1(-/-) mice, which lack mature T and B lymphocytes, and in wild-type (Rag1(+/+) ) controls. The development of renal injury was examined over 20 weeks of diabetes. RESULTS: Both groups developed equivalent diabetes, however only Rag1(+/+) mice had kidney infiltration with CD4, CD8, CD22 and forkhead box P3-positive cells, as well as glomerular immunoglobulin deposition. At 20 weeks, Rag1(+/+) mice exhibited renal hypertrophy, increased mesangial and interstitial matrix, kidney macrophage accumulation, tubular injury, progressive albuminuria and a decline in renal function. In comparison, diabetic Rag1(-/-) mice showed similar histological damage, matrix expansion, macrophage accrual and loss of renal function, but were protected from increasing albuminuria. This protection was associated with protection against loss of podocytes and glomerular podocin production, and with reduced glomerular macrophage activation. CONCLUSIONS/INTERPRETATION: These results show that lymphocytes contribute to the development of diabetic albuminuria, which may partly arise from increasing glomerular macrophage activation and podocyte damage. In contrast, lymphocytes do not appear to promote tubular injury, increased matrix deposition or decline in renal function in a mouse model of type 1 diabetes. Our findings suggest that innate immunity rather than adaptive immune responses are the major inflammatory contributor to the progression of diabetic renal injury.


Subject(s)
Albuminuria/etiology , Diabetic Nephropathies/etiology , Kidney/pathology , Lymphocytes/immunology , Albuminuria/pathology , Analysis of Variance , Animals , Blood Glucose , Diabetes Mellitus, Experimental/immunology , Diabetes Mellitus, Experimental/pathology , Diabetic Nephropathies/immunology , Diabetic Nephropathies/pathology , Enzyme-Linked Immunosorbent Assay , Immunity, Innate/immunology , Immunohistochemistry , Kidney/immunology , Lymphocytes/pathology , Mice , Mice, Knockout , Reverse Transcriptase Polymerase Chain Reaction
6.
Diabetologia ; 52(8): 1669-79, 2009 Aug.
Article in English | MEDLINE | ID: mdl-19466391

ABSTRACT

AIMS/HYPOTHESIS: Macrophage-mediated renal injury plays an important role in the development of diabetic nephropathy. Colony-stimulating factor (CSF)-1 is a cytokine that is produced in diabetic kidneys and promotes macrophage accumulation, activation and survival. CSF-1 acts exclusively through the c-fms receptor, which is only expressed on cells of the monocyte-macrophage lineage. Therefore, we used c-fms blockade as a strategy to selectively target macrophage-mediated injury during the progression of diabetic nephropathy. METHODS: Obese, type 2 diabetic db/db BL/KS mice with established albuminuria were treated with a neutralising anti-c-fms monoclonal antibody (AFS98) or isotype matched control IgG from 12 to 18 weeks of age and examined for renal injury. RESULTS: Treatment with AFS98 did not affect obesity, hyperglycaemia, circulating monocyte levels or established albuminuria in db/db mice. However, AFS98 did prevent glomerular hyperfiltration and suppressed variables of inflammation in the diabetic kidney, including kidney macrophages (accumulation, activation and proliferation), chemokine CC motif ligand 2 levels (mRNA and urine protein), kidney activation of proinflammatory pathways (c-Jun amino-terminal kinase and activating transcription factor 2) and Tnf-alpha (also known as Tnf) mRNA levels. In addition, AFS98 decreased the tissue damage caused by macrophages including tubular injury (apoptosis and hypertrophy), interstitial damage (cell proliferation and myofibroblast accrual) and renal fibrosis (Tgf-beta1 [also known as Tgfb1] and Col4a1 mRNA). CONCLUSIONS/INTERPRETATION: Blockade of c-fms can suppress the progression of established diabetic nephropathy in db/db mice by targeting macrophage-mediated injury.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Diabetic Nephropathies/physiopathology , Inflammation/prevention & control , Receptor, Macrophage Colony-Stimulating Factor/immunology , Animals , Cell Division/immunology , Diabetic Nephropathies/complications , Diabetic Nephropathies/pathology , Genotype , Kidney Tubules/immunology , Kidney Tubules/pathology , Leptin/genetics , Mice , Mice, Inbred C57BL , Mice, Obese , Obesity/complications , Obesity/pathology , Obesity/physiopathology , Polymerase Chain Reaction , Receptor, Macrophage Colony-Stimulating Factor/antagonists & inhibitors
7.
Diabetologia ; 52(2): 347-58, 2009 Feb.
Article in English | MEDLINE | ID: mdl-19066844

ABSTRACT

AIMS/HYPOTHESIS: Obesity and diabetes are associated with increased intracellular p38 mitogen-activated protein kinase (MAPK) signalling, which may promote tissue inflammation and injury. Activation of p38 MAPK can be induced by either of the immediate upstream kinases, MAP kinase kinase (MKK)3 or MKK6, and recent evidence suggests that MKK3 has non-redundant roles in the pathology attributed to p38 MAPK activation. Therefore, this study examined whether MKK3 signalling influences the development of obesity, type 2 diabetes and diabetic nephropathy. METHODS: Wild-type and Mkk3 (also known as Map2k3) gene-deficient db/db mice were assessed for the development of obesity, type 2 diabetes and renal injury from 8 to 32 weeks of age. RESULTS: Mkk3 (+/+) db/db and Mkk3 (-/-) db/db mice developed comparable obesity and were similar in terms of incidence and severity of type 2 diabetes. At 32 weeks, diabetic Mkk3 (+/+) db/db mice had increased kidney levels of phospho-p38 and MKK3 protein. In comparison, kidney levels of phospho-p38 in diabetic Mkk3 ( -/- ) db/db mice remained normal, despite a fourfold compensatory increase in MKK6 protein levels. The reduced levels of p38 MAPK signalling in the diabetic kidneys of Mkk3 ( -/- ) db/db mice was associated with protection against the following: declining renal function, increasing albuminuria, renal hypertrophy, podocyte loss, mesangial cell activation and glomerular fibrosis. Diabetic Mkk3 ( -/- ) db/db mice were also significantly protected from tubular injury and interstitial fibrosis, which was associated with reduced Ccl2 mRNA expression and interstitial macrophage accumulation. CONCLUSIONS/INTERPRETATION: MKK3-p38 MAPK signalling is not required for the development of obesity or type 2 diabetes, but plays a distinct pathogenic role in the progression of diabetic nephropathy in db/db mice.


Subject(s)
Diabetes Mellitus, Type 2/physiopathology , Kidney/physiopathology , MAP Kinase Kinase 3/deficiency , p38 Mitogen-Activated Protein Kinases/metabolism , Aging/genetics , Aging/physiology , Animals , DNA Probes , Diabetes Mellitus, Type 2/enzymology , Diabetes Mellitus, Type 2/epidemiology , Diabetic Nephropathies/enzymology , Diabetic Nephropathies/genetics , Diabetic Nephropathies/pathology , Hypertrophy , Kidney/injuries , Kidney/pathology , MAP Kinase Kinase 3/genetics , MAP Kinase Kinase 3/metabolism , Mice , Mice, Inbred Strains , Mice, Knockout , Mice, Obese , Receptors, Leptin/genetics , Tumor Necrosis Factor-alpha/genetics
8.
Cochrane Database Syst Rev ; (2): CD005282, 2007 Apr 18.
Article in English | MEDLINE | ID: mdl-17443580

ABSTRACT

BACKGROUND: Calcineurin inhibitors used in kidney transplantation for immunosuppression have adverse effects that may contribute to nephrotoxicity and increased cardiovascular risk profile. Fish oils are rich in very long chain omega-3 fatty acids, which may reduce nephrotoxicity by improving endothelial function and reduce rejection rates through their immuno-modulatory effects. They may also modify the cardiovascular risk profile. Hence, fish oils may potentially prolong graft survival and reduce cardiovascular mortality. OBJECTIVES: To assess the benefits and harms of fish oil supplementation on kidney transplant recipients on a calcineurin inhibitor-based immunosuppressive regimen. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL in The Cochrane Library, issue 2 2005), MEDLINE (1966-April 2005) and EMBASE (1980-April 2005). SELECTION CRITERIA: All randomised controlled trials (RCTs) and quasi-RCTs of fish oils in kidney transplant recipients on a calcineurin inhibitor-based immunosuppressive regimen. RCTs of fish oil versus statins were included. DATA COLLECTION AND ANALYSIS: Data was extracted and the quality of studies assessed by two authors, with differences resolved by discussion with a third independent author. Dichotomous outcomes were reported as relative risk (RR) and continuous outcome measures were reported as the mean difference (MD) with 95% confidence intervals using the random effects model. Heterogeneity was assessed using a Chi(2) test on n-1 degrees of freedom and the I(2) statistic. Data not suitable for pooling were tabulated and described. MAIN RESULTS: Sixteen studies (733 patients) were suitable for analysis. Fish oil did not significantly affect patient or graft survival, acute rejection rates, calcineurin inhibitor toxicity or renal function, when compared to placebo. Fish oil treatment was associated with a lower diastolic blood pressure (MD 4.5 mmHg; P = 0.004) compared to placebo. Patients receiving fish oil for more than six months had a modest increase in HDL (MD 0.12 mmol/L; P = 0.01) compared to placebo. Fish oil effects on lipids were not significantly different from low-dose statins. There was insufficient data to analyse cardiovascular outcomes. Fishy aftertaste and gastrointestinal upset were common but did not result in significant patient drop-out. AUTHORS' CONCLUSIONS: There is insufficient evidence from currently available RCTs to recommend fish oil therapy to improve renal function, rejection rates, patient survival or graft survival. The improvements in HDL cholesterol and diastolic blood pressure were too modest to recommend routine use. To determine a benefit in clinical outcomes, future RCTs will need to be adequately powered with these outcomes in mind.


Subject(s)
Calcineurin Inhibitors , Fish Oils/therapeutic use , Graft Rejection/prevention & control , Graft Survival/drug effects , Kidney Transplantation , Blood Pressure/drug effects , Blood Pressure/physiology , Humans , Kidney/drug effects , Kidney/physiology , Kidney Transplantation/mortality , Kidney Transplantation/physiology , Lipids/blood , Randomized Controlled Trials as Topic
9.
Intern Med J ; 37(1): 55-9, 2007 Jan.
Article in English | MEDLINE | ID: mdl-17199845

ABSTRACT

Severe autoimmune myasthenia gravis is difficult to manage and may require immunosuppression with cyclosporine. However, cyclosporine dependency is associated with the risk of nephrotoxicity. Mycophenolate mofetil is a non-nephrotoxic alternative which should be considered to rescue cyclosporine-dependent, severe myasthenia gravis sufferers with renal impairment from progression to end-stage renal failure. However, the evidence is limited and studies have not assessed the outcome of a direct substitution in these cyclosporine-dependent patients. We study three such patients who successfully converted to mycophenolate mofetil, and briefly examine the evidence behind this option. We believe that total cyclosporine withdrawal is feasible, but strongly recommend overlapping mycophenolate mofetil treatment with cyclosporine.


Subject(s)
Cyclosporine/adverse effects , Immunosuppressive Agents/therapeutic use , Kidney Diseases/chemically induced , Myasthenia Gravis/drug therapy , Mycophenolic Acid/analogs & derivatives , Adult , Cyclosporine/therapeutic use , Diabetic Nephropathies/chemically induced , Diabetic Nephropathies/complications , Drug Evaluation , Female , Humans , Hypertension, Renal/chemically induced , Immunosuppressive Agents/adverse effects , Kidney Diseases/blood , Kidney Diseases/complications , Kidney Failure, Chronic/etiology , Male , Middle Aged , Myasthenia Gravis/surgery , Myasthenia Gravis/therapy , Mycophenolic Acid/therapeutic use , Plasma Exchange , Prednisolone/adverse effects , Prednisolone/therapeutic use , Recurrence , Thymectomy
10.
Intern Med J ; 36(7): 465-7, 2006 Jul.
Article in English | MEDLINE | ID: mdl-16780456

ABSTRACT

This report describes a case of quinine-induced acute renal failure as a result of a combination of haemolytic uraemic syndrome and rhabdomyolysis with disseminated intravascular coagulation. The abrupt onset of symptoms occurred after ingestion of 300 mg of quinine along with atorvastatin. The patient recovered with supportive management, suggesting that plasma exchange may not be necessary in this situation. The possibility of a drug interaction contributing to rhabdomyolysis is raised. The proposed mechanism is through quinine inhibition of the cytochrome P450 isoenzyme 3A4, which may increase systemic levels of atorvastatin by reducing its first-pass metabolism.


Subject(s)
Acute Kidney Injury/etiology , Anticholesteremic Agents/adverse effects , Heptanoic Acids/adverse effects , Muscle Relaxants, Central/adverse effects , Pyrroles/adverse effects , Quinine/adverse effects , Acute Kidney Injury/chemically induced , Atorvastatin , Disseminated Intravascular Coagulation/chemically induced , Drug Synergism , Female , Hemolytic-Uremic Syndrome/chemically induced , Humans , Middle Aged , Rhabdomyolysis/chemically induced , Sleep-Wake Transition Disorders/drug therapy
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