The relationship of systemic markers of renal function and vascular function with retinal blood vessel responses

Purpose: To test the hypothesis of a significant relationship between systemic markers of renal and vascular function (processes linked to cardiovascular disease and its development) and retinal microvascular function in diabetes and/or cardiovascular disease.Methods: Ocular microcirculatory function was measured in 116 patients with diabetes and/or cardiovascular disease using static and continuous retinal vessel responses to three cycles of flickering light. Endothelial function was evaluated by von Willebrand factor (vWf), endothelial microparticles and soluble E selectin, renal function by serum creatinine, creatinine clearance and estimated glomerular filtration rate (eGFR). HbA1c was used as a control index.Results: Central retinal vein equivalence and venous maximum dilation to flicker were linked to HbA1c (both p<0.05). Arterial reaction time was linked to serum creatinine (p=0.036) and eGFR (p=0.039), venous reaction time was linked to creatinine clearance (p=0.018). Creatinine clearance and eGFR were linked to arterial maximum dilatation (p<0.001 and p=0.003 respectively) and the dilatation amplitude (p=0.038 and p=0.048 respectively) responses in the third flicker cycle. Of venous responses to the first flicker cycle, HbA1c was linked to the maximum dilation response (p=0.004) and dilatation amplitude (p=0.017), vWf was linked to the maximum constriction response (p=0.016), and creatinine clearance to the baseline diameter fluctuation (p=0.029). In the second flicker cycle, dilatation amplitude was linked to serum creatinine (p=0.022). Conclusions: Several retinal blood vessel responses to flickering light are linked to glycaemia and renal function, but only one index is linked to endothelial function. Renal function must be considered when interpreting retinal vessel responses.

Diabetes therapies in renal impairment

Depending on age, duration of diabetes and glycaemic control, 20-40% of patients with type 2 diabetes will incur a moderate or severe deterioration of renal function. This will impact the choice of blood glucose-lowering therapy and require more frequent monitoring of both renal function and glycaemic control. Moderate renal impairment (glomerular filtration rate 30-<60 ml/min) requires consideration of dose reduction or treatment cessation for metformin, glucagon-like peptide-1 receptor agonists, some sulphonylureas and some dipeptidyl peptidase-4 inhibitors. At lower rates of glomerular filtration down to about 15 ml/min it may be appropriate to use a meglitinide, pioglitazone or certain sulphonylureas with careful consideration of dose and co-morbidities. Dipeptidyl peptidase-4 inhibitors can be used at reduced dose in patients with very low rates of glomerular filtration, and linagliptin can be used without dose reduction, and has been used in patients on dialysis. Insulin can be used at any stage of renal impairment, but the regimen and the dose must be suitably adjusted and accompanied by adequate monitoring. © The Author(s), 2012.

Tissue transglutaminase and the progression of human renal scarring

ABSTRACT. Experimental renal scarring indicates that tissue transglutaminase (tTg) may be associated with the accumulation of extracellular matrix (ECM), both indirectly via TGF-β1 activation and directly by the formation of ε(γ-glutamyl) lysine dipeptide bonds within the ECM. The latter potentially accelerates deposition and confers the ECM with resistance to proteolytic digestion. Studied were 136 human renal biopsy samples from a range of chronic renal diseases (CRD) to determine changes in tTg and ε(γ-glutamyl) lysine crosslinking. Immunofluorescence for insoluble tTg showed a 14-fold increase in the kidneys of CRD patients (5.3 ± 0.5 versus 76 ± 54 mV/cm2), which was shown to be active by a similar 11-fold increase in the ε(γ-glutamyl) lysine crosslink (1.8 ± 0.2 versus 19.3 ± 14.2 mV/cm2). Correlations were obtained with renal function for tTg and crosslink. In situ hybridization for tTg mRNA showed that tubular epithelial cells were the major source of tTg; however, both mesangial and interstitial cells also contributed to elevated levels in CRD. This mRNA pattern was consistent with immunohistochemistry for soluble tTg. Changes in renal tTg and its product, the ε(γ-glutamyl) lysine crosslink, occur in progressive renal scarring in humans independently of the original etiology and in a similar manner to experimental models. tTg may therefore play a role in the pathogenesis of renal scarring and fibrosis in patients with CRD and can therefore be considered a potential therapeutic target. E-mail: T.Johnson@sheffield.ac.uk

High-performance liquid chromatography and pharmacokinetics of some antibiotics

The principles of High Performance Liquid Chromatography (HPLC) and pharmacokinetics were applied to the use of several clinically-important drugs at the East Birmingham Hospital. Amongst these was gentamicin, which was investigated over a two-year period by a multi-disciplinary team. It was found that there was considerable intra- and inter-patient variation that had not previously been reported and the causes and consequences of such variation were considered. A detailed evaluation of available pharmacokinetic techniques was undertaken and 1- and 2-compartment models were optimised with regard to sampling procedures, analytical error and model-error. The implications for control of therapy are discussed and an improved sampling regime is proposed for routine usage. Similar techniques were applied to trimethoprim, assayed by HPLC, in patients with normal renal function and investigations were also commenced into the penetration of drug into peritoneal dialysate. Novel assay techniques were also developed for a range of drugs including 4-aminopyridine, chloramphenicol, metronidazole and a series of penicillins and cephalosporins. Stability studies on cysteamine, reaction-rate studies on creatinine-picrate and structure-activity relationships in HPLC of aminopyridines are also reported.

Proplyene glycol intake from medications used on paediatric intensive care

here is an increasing number of reports of propylene glycol (PG) toxicity in the literature, regardless of its inclusion on the Generally Recognized as Safe List (GRAS).1 PG is an excipient used in many medications as a solvent for water-insoluble drugs. Polypharmacy may increase PG exposure in vulnerable PICU patients who may accumulate PG due to compromised liver and renal function. The study aim was to quantify PG intake in PICU patients and attitudes of clinicians towards PG. Method A snapshot of 50 PICU patients oral or intravenous medication intake was collected. Other data collected included age, weight, diagnosis, lactate levels and renal function. Manufacturers were contacted for PG content and then converted to mg/kg. Excipients in formulations that compete with the PG metabolism pathway were recorded. The Intensivists' opinions on PG intake was sought via e-survey. Results The 50 patients were prescribed 62 drugs and 83 formulations, 43/83 (52%) were parenteral formulations. Median weight of the patients was 5.5 kg (range 2–50 kg), ages ranged from 1 day to 13 years of age. Eleven of the patients were classed as renally impaired (defined as 1.5 times the baseline creatinine). Sixteen formulations contained PG, 2/16 were parenteral, 6/16 unlicensed preparations. Thirty-eight patients received at least one prescription containing PG and 29/38 of these patients were receiving formulations that contained excipients that may have competed with the metabolic pathways of PG. PG intake ranged from 0.002 mg/kg/day to 250 mg/kg/day. Total intake was inconclusive for 2 patients due to a of lack of availability of information from the manufacturer; these formulations were licensed but used in for off-label indications. Five commonly used formulations contributed to higher intakes of PG, namely co-trimoxazole, dexamethasone, potassium chloride, dipyridamole and phenobarbitone. Lactate levels were difficult to interpret due to the underlying conditions of the patients. One of the sixteen intensivist was aware of PG content in drugs, 16/16 would actively change therapy if intake was above European Medicines Agency recommendations. Conclusions Certain formulations used on PICU can considerably increase PG exposure to patients. Due to a lack of awareness of PG content, these should be highlighted to the clinician to assist with making informed decisions regarding risks versus benefits in continuing that drug, route of administration or formulation.

Proplyene glycol intake from medications used on paediatric intensive care

There is an increasing number of reports of propylene glycol (PG) toxicity in the literature, regardless of its inclusion on the Generally Recognized as Safe List (GRAS).1 PG is an excipient used in many medications as a solvent for water-insoluble drugs. Polypharmacy may increase PG exposure in vulnerable PICU patients who may accumulate PG due to compromised liver and renal function. The study aim was to quantify PG intake in PICU patients and attitudes of clinicians towards PG. Method A snapshot of 50 PICU patients oral or intravenous medication intake was collected. Other data collected included age, weight, diagnosis, lactate levels and renal function. Manufacturers were contacted for PG content and then converted to mg/kg. Excipients in formulations that compete with the PG metabolism pathway were recorded. The Intensivists' opinions on PG intake was sought via e-survey. Results The 50 patients were prescribed 62 drugs and 83 formulations, 43/83 (52%) were parenteral formulations. Median weight of the patients was 5.5 kg (range 2–50 kg), ages ranged from 1 day to 13 years of age. Eleven of the patients were classed as renally impaired (defined as 1.5 times the baseline creatinine). Sixteen formulations contained PG, 2/16 were parenteral, 6/16 unlicensed preparations. Thirty-eight patients received at least one prescription containing PG and 29/38 of these patients were receiving formulations that contained excipients that may have competed with the metabolic pathways of PG. PG intake ranged from 0.002 mg/kg/day to 250 mg/kg/day. Total intake was inconclusive for 2 patients due to a of lack of availability of information from the manufacturer; these formulations were licensed but used in for off-label indications. Five commonly used formulations contributed to higher intakes of PG, namely co-trimoxazole, dexamethasone, potassium chloride, dipyridamole and phenobarbitone. Lactate levels were difficult to interpret due to the underlying conditions of the patients. One of the sixteen intensivist was aware of PG content in drugs, 16/16 would actively change therapy if intake was above European Medicines Agency recommendations. Conclusions Certain formulations used on PICU can considerably increase PG exposure to patients. Due to a lack of awareness of PG content, these should be highlighted to the clinician to assist with making informed decisions regarding risks versus benefits in continuing that drug, route of administration or formulation.

Tissue transglutaminase:a mediator and predictor of chronic allograft nephropathy?

Background. The precise mechanisms underlying the development of chronic allograft nephropathy (CAN) and the associated renal fibrosis remain uncertain. The protein-crosslinking enzyme, tissue transglutaminase (tTg), has recently been implicated in renal fibrosis. Methods. We investigated the involvement of tTg and its crosslink product, [epsilon]-([gamma]-glutamyl) lysine, in 23 human kidney allografts during the early posttransplantation period and related these to changes of CAN that developed in 8 of them. Sequential biopsies were investigated using immunohistochemical, immunofluorescence, and in situ enzyme activity techniques. Results. From implantation, tTg (+266%) and [epsilon]-([gamma]-glutamyl) lysine crosslink (+256.3%) staining increased significantly (P <0.001) in a first renal biopsy performed within 3 months from transplantation. This was paralleled by elevated tTg in situ activity. The eight patients who developed CAN had further increases in immunostainable tTg (+197.2%, P <0.001) and [epsilon]-([gamma]-glutamyl) lysine bonds (+465%, P <0.01) that correlated with interstitial fibrosis (r=0.843, P =0.009 and r=0.622, P =0.05, respectively). The staining for both was predominantly located within the mesangium and the renal interstitium. Both implantation and first biopsies showed tTg and [epsilon]-([gamma]-glutamyl) lysine crosslinking levels in patients who developed CAN to be twice the levels of those with stable renal function. Cox regression analysis suggested the intensity of the early tTg staining was a better predictor of inferior allograft survival that other histologic markers (hazard ratio=4.48, P =0.04). Conclusions. tTg and [epsilon]-([gamma]-glutamyl) lysine crosslink correlated with the initiation and progression of scarring on sequential biopsies from renal-allograft recipients who experienced CAN. Elevated tTg may offer an early predictor of the development of CAN, whereas tTg manipulation may be an attractive therapeutic target

Pharmacotherapies to manage diabesity:an update

Several pharmacotherapies have recently become available for addition to lifestyle measures to assist the management of coexistent type 2 diabetes and obesity. These are mostly administered as add-on to metformin or as alternative therapies if metformin is not appropriate. The sodium–glucose cotransporter 2 inhibitors (dapagliflozin, canagliflozin and empagliflozin) act by eliminating excess glucose in the urine. These agents provide a non-insulin-dependent mechanism to reduce hyperglycaemia and facilitate weight loss without causing frank hypoglycaemia. Their efficacy requires the individual to have adequate renal function. The glucagon-like peptide-1 (GLP-1) receptor agonists (exenatide, liraglutide, lixisenatide, dulaglutide and albiglutide [the last at the pre-launch stage at the time of writing]) are injected subcutaneously. Different members of the class offer different time courses for their onset and duration of action. Each potentiates insulin secretion and reduces glucagon secretion in a glucose-dependent manner to address prandial glycaemic excursions while avoiding interprandial hypoglycaemia. A satiety effect of these agents assists weight reduction, but delayed gastric emptying can cause initial nausea. The dipeptidyl peptidase-4 inhibitor class now comprises sitagliptin, vildagliptin, saxagliptin, linagliptin and alogliptin. These agents offer similar glucose-lowering efficacy without weight gain or hypoglycaemia by boosting the half-life of endogenous incretins, particularly GLP-1. A fixed-ratio injected combination of insulin degludec with liraglutide (IDegLira) has recently been launched and further agents to address hyperglycaemia and assist weight loss are advancing in development.

Propylene glycol intake from medications used on paediatric intensive care

Background: There are increasing reports of propylene glycol (PG) toxicity, which is used in many medications as a solvent for water-insoluble drugs. Polypharmacy may increase PG exposure in vulnerable PICU patients who may accumulate PG due to compromised liver and renal function. The study aim was to quantify PG intake in PICU patients and attitudes of clinicians towards PG. Methods: A snapshot of 50 patients’ medication intake was collected. Other data collected included age, weight, diagnosis, lactate levels and renal function. Manufacturers were contacted for PG content and then converted to mg/kg. Excipients in formulations that compete with the PG metabolism pathway were recorded. The Intensivists opinions on PG intake was sought via e-survey. Results: The 50 patients were prescribed 62 drugs and 83 formulations, 43/83 (52 %) were parenteral formulations. Sixteen formulations contained PG, 2/16 were parenteral, 6/16 unlicensed preparations. Thirty-eight patients received drugs with PG. PG intake ranged from 0.002 mg/kg/day to 250 mg/kg/day, with 29/38 receiving formulations with concomitant pathway competing excipients. The total amount could not be quantified in two cases due to lack of availability of information from the manufacturer. Four commonly used formulations contributed to higher intakes of PG. Only 1/16intensivists was aware of PG content in drugs, 16/16 would actively change therapy if intake was above European Medicines Agency recommendations. Conclusions: Certain formulations used on PICU can considerably increase PG exposure to patients. These should be highlighted to the clinician to make an informed decision regarding risks versus benefits in continuing that drug or formulation.

Diabetes in the very elderly:need for an individualised approach

Background: Intensive risk factor management is recommended for individuals with diabetes. However, it is not known if such an approach is appropriate in the elderly with multiple comorbidities and limited life expectancy. The aim of this study was to characterise a cohort of very elderly individuals with diabetes and assess the impact of known risk factors on mortality. Methods: This was a retrospective audit approved by the clinical audit lead. All patients aged >80 years who attended diabetes outpatient clinics 2 years prior to the date of the audit (April 2012) were identified from clinic records. A detailed history including demographics, comorbidities and treatment were collected. Blood pressure readings, HbA1c, cholesterol and renal function were extracted and the mean of these readings was recorded. Survival status at 2 years was recorded for all patients. Statistical analysis was performed using SPSS19. Results: Data were available for 864 (381 male, 483 female) patients. The majority (75%) lived in their own home. More than 60% had multiple comorbidities and 25% had a prior history of cardiovascular disease. Two-thirds of the patients had more than one hospital admission in 2 years and a third had more than three admissions. 60% were on either insulin or a sulfonylurea. Mean HbA1c was 7.6%, cholesterol 4.2mmol/l, systolic blood pressure 145mmHg and eGFR 53ml/min. Over 2 years, 174 (20%)had died. Age, creatinine and previous coronary heart disease were significant predictors of death. Conclusion: The benefits of intensive diabetes management appear to be uncertain in very elderly patients. The need for intensive treatment must therefore be individualised to each patient.

Renal glucose reabsorption inhibitors to treat diabetes

Current therapies to reduce hyperglycaemia in type 2 diabetes mellitus (T2DM) mostly involve insulin-dependent mechanisms and lose their effectiveness as pancreatic ß-cell function declines. In the kidney, filtered glucose is reabsorbed mainly via the high-capacity, low-affinity sodium glucose cotransporter-2 (SGLT2) at the luminal surface of cells lining the first segment of the proximal tubules. Selective inhibitors of SGLT2 reduce glucose reabsorption, causing excess glucose to be eliminated in the urine; this decreases plasma glucose. In T2DM, the glucosuria produced by SGLT2 inhibitors is associated with weight loss, and mild osmotic diuresis might assist a reduction in blood pressure. The mechanism is independent of insulin and carries a low risk of hypoglycaemia. This review examines the potential of SGLT2 inhibitors as a novel approach to the treatment of hyperglycaemia in T2DM.