Can murine diabetic nephropathy be separated from superimposed acute renal failure?

Can murine diabetic nephropathy be separated from superimposed acute renal failure?BackgroundStreptozotocin (STZ) is commonly used to induce diabetes in experimental animal models, but not without accompanying cytotoxic effects. This study was undertaken to (1) determine an optimal dose and administration route of STZ to induce diabetic nephropathy in wild-type mice but without the concurrent acute renal injury resulting from cytotoxic effects of STZ and (2) evaluate the pattern of tubular injury and interstitial inflammation in this model.MethodsMale Balb/c mice received either (1) STZ (225mg/kg by intraperitoneal injection.); or (2) two doses of STZ 5 days apart (150mg/150mg/kg; 75mg/150mg/kg; 75mg/75mg/kg; and 100mg/100mg/kg by intravenous injection). Another strain of mice, C57BL/6J, also received STZ (200mg/kg intravenously or intraperitoneally). Renal function and histology were examined at weeks 1, 2, 4, and 8 after induction of diabetes. In initial optimization studies, animals were sacrificed at week 1 or week 2 and histology examined for acute renal injury.ResultsFollowing a single intraperitoneal injection of 225mg/kg of STZ, only two thirds of animals developed hyperglycemia, yet the model was associated with focal areas of acute tubular necrosis (ATN) at week 2. ATN was also observed in C57BL/6J mice given a single intravenous or intraperitoneal dose of STZ (200mg/kg), at week 2 post-diabetes. At an optimal diabetogenic dose and route (75mg/150mg/kg by intravenous injection 5 days apart), all mice developed diabetes and no ATN was observed histologically. However, even with this regimen, glomerular filtration rate (GFR) was significantly impaired from week 2. This regimen was accompanied by progressive histologic changes, including tubular and glomerular hypertrophy, mesangial area expansion, as well as interstitial macrophage, CD4+ and CD8+ T-cell accumulation.ConclusionBy careful optimization of STZ dose, a stable and reproducible diabetic murine model was established. However, even in this optimized model, renal functional impairment was observed. The frequency of ATN and functional impairment casts doubt on conclusions about experimental diabetic nephropathy drawn from reports in which ATN has not been excluded rigorously

Psychosocial factors in patients with kidney failure and role for social worker : a secondary data audit

Background: People with kidney failure face a multitude of psychosocial stressors that affect disease trajectory and health outcomes. Objectives: To investigate psychosocial factors affecting people with kidney failure before or at start of kidney replacement therapy (KRT) and kidney supportive and palliative care (KSPC) phases of illness and to explore role of social worker during the illness trajectory. Methods: We conducted a secondary data audit of patients either before or at start of KRT (Phase 1) and at the KSPC (Phase 2) of illness and had psychosocial assessments between March 2012 and March 2020 in an Australian setting. Results: Seventy-nine individuals, aged 70 ± 12 years, had at least two psychosocial assessments, one in each of the two phases of illness. The median time between social worker evaluations in Phase 1 and Phase 2 was 522 (116−943) days. Adjustment to illness and treatment (90%) was the most prevalent psychosocial issue identified in Phase 1, which declined to 39% in Phase 2. Need for aged care assistance (7.6%−63%; p < 0.001) and carer support (7.6%−42%; p < 0.001) increased significantly from Phase 1 to Phase 2. There was a significant increase in psychosocial interventions by the social worker in Phase 2, including supportive counselling (53%−73%; p < 0.05), provision of education and information (43%−65%; p < 0.01), and referrals (28%−62%; p < 0.01). Conclusion: Adults nearing or at the start of KRT experience immense psychosocial burden and adaptive demands that recognisably change during the course of illness. The positive role played by the nephrology social worker warrants further investigation

Prevention of recurrent calcium nephrolithiasis

Calcium-containing renal calculi are the most common stone type in reported series and recur in 26-53% of patients over a 10 year period. Because of this tendency, interventions aimed at reducing or preventing recurrence are an important strategy for reducing the morbidity associated with stone disease. This guideline uses an evidence-based review of the published literature with the purpose of examining current interventions aimed at reducing the recurrence of calcium stones. The approach to this and the other related CARI guidelines is to score interventions on the quality of the evidence available. Formal guidelines are made when Level I or II evidence is available (i.e. randomized controlled trial (RCT) or meta-analysis). It is appreciated that not all interventions used for stone prevention may be adequately represented by this approach. Part of the funcion of this review is therefore to highlight where the available evidence for treatment of this condition can be improved. Similarly, detailed discussion of the different metabolic abnormalities seen in patients with recurrent calcium stones is beyond the scope of this review. Where applicable, however, the role of different interventions in the presence of different metabolic abnormalities is discussed. Evidence based recommendations for the interventions considered in this review were only made where data available for their effect on stone recurrence. Recommendations were not made when the effect of an intervention on surrogate markers of stone risk (e.g. urinary parameters) was reported

Effects of proactive iron and erythropoiesis-stimulating agent protocol implementation on achieving clinical guideline targets for anaemia in a satellite haemodialysis patient cohort

Aim: Anaemia management with erythropoiesis-stimulating agents (ESA) and i.v. iron replacement in haemodialysis patients poses several clinical challenges, including maintaining stable haemoglobin (Hb) levels within target ranges while achieving lowest effective ESA dose. This manuscript describes the effect of implementing proactive protocol-driven adjustments for iron and ESA in maintenance haemodialysis patients. Methods: This was a cohort study of 46 satellite haemodialysis patients examined from 2004 to 2006 with protocol implementation in 2005. Baseline haemoglobin, transferrin saturations (TSAT), ferritin values and ESA administration were obtained during 2004. Follow-up data was collected in 2006 and compared to baseline values in reference to specified targets in the 2004 Caring for Australasians with Renal Impairment (CARI) guidelines. Results: Fifty-four percent of patients achieved haemoglobin targets during follow up versus 43% patients during baseline. Seventy-nine percent of patients achieved TSAT targets during follow up versus 67% patients during baseline. Ninety percent of patients achieved ferritin targets during follow up versus 75% patients during baseline. Odds ratios for values falling within target ranges during follow up compared to baseline were 1.63 (Hb: P = 0.037; 95% confidence interval (CI), 1.03–2.57), 1.90 (TSAT: P = 0.006; 95% CI, 1.20– 3.01) and 3.72 (ferritin: P = 0.003; 95% CI, 1.57–8.83). There was a trend toward lower average ESA dose (P = 0.07). Conclusion: This study demonstrates the successful implementation and efficacy of a proactive protocol for iron and ESA treatment in haemodialysis patients. Benefits include increased concordance with historical guideline targets and decreased haemoglobin variability. Improved iron status and optimizing ESA response allows for lower ESA doses, limiting both potential side-effects of ESA (hypertension) and the burgeoning costs of anaemia management

Diameter of inflow as a predictor of radiocephalic fistula flow

Introduction: The optimal method for vascular access surveillance is largely unknown. A previous case–control study suggested a simplified anatomical measure obtained by Doppler ultrasound—the narrowest segment of the circuit or “minimal luminal diameter” may identify patients with a dysfunctional radiocephalic arteriovenous fistula. The relationship between minimal luminal diameter and access flow (Qa) in the radiocephalic arteriovenous fistula has not previously been studied. Methods: Patients undergoing Doppler ultrasound of a radiocephalic arteriovenous fistula over an 8-month period were identified retrospectively. Minimal luminal diameter was identified and demographic and clinical data were collected. Qa was estimated by Doppler estimation of brachial artery flow. The relationship between minimal luminal diameter and Qa was examined by correlation and using different levels of minimal luminal diameter as a simplified measure to detect or exclude low Qa (3.2 mm largely excludes a low-flow radiocephalic arteriovenous fistula in this cohort. Brachial artery flow is a reasonable measure of Qa in comparison with indicator dilution

The hidden burden of high-flow fistulae in a home haemodialysis programme : outcomes of initiating arteriovenous fistula monitoring in the home haemodialysis population

Home haemodialysis (HHD) is common in Australia. The majority of these patients dialyse using an arteriovenous fistula (AVF). AVFs are a potential source of morbidity: low fistula flow may result in inadequate dialysis; high flow may lead to cardiac failure. Whilst intradialytic measures of fistula performance are available in many haemodialysis centres, HHD patients are particularly vulnerable to unrecognised access dysfunction. To address the needs of this population for access monitoring, a structured programme of surveillance utilising ultrasound dilution was introduced. This allowed us to determine the prevalence and type (high/low flow) of access dysfunction. Over a three-year period, 141 patients had flow measurements, with cardiac output (CO) also measured where possible. All patients dialysed through an AVF. Forty-one patients (29%) were identified with access dysfunction. Nineteen patients (13.5%) had low-flow AVF (access flow (Qa) 2L/min, CO >8L/min or Qa:CO >0.3). Upper arm AVF were more likely to be high flow than radiocephalic (p<0.001). Most patients with low-flow AVF underwent stenting (17/19), and 10 patients with high-flow AVF had banding to reduce the size. We identified a high prevalence of undetected AVF dysfunction that could result in significant morbidity, particularly related to high-flow AVF that may be clinically silent. We support the use of regular AVF surveillance in the HHD population using ultrasound dilution as a simple and effective way of identifying dysfunctional AVF to allow early intervention and reduced future morbidity

Protein Z is reduced in chronic kidney disease and not elevated in patients on haemodialysis

Protein Z (PZ) is a vitamin K dependent serine protease inhibitor, which along with its cofactor Protein Z-dependant protease inhibitor (ZPI) has anti-Xa activity. PZ has previously been reported to be elevated in patients with end-stage chronic kidney disease (CKD) on haemodialysis but not in non-dialysed CKD patients raising the possibility that PZ may have a role in the bleeding diathesis of patients on haemodyalisis. PZ was measured in controls (n = 18), CKD on haemodialysis (n = 23) and CKD not on dialysis (n = 23). Patients on vitamin K antagonists, with acute inflammatory conditions (as measured by CRP) or liver dysfunction were excluded PZ levels were reduced in CKD patients when compared to levels in the control group (1.35 μg/mL vs 1.80 respectively, p = 0.022). Subgroup analysis revealed a trend toward reduction in mean PZ in the CKD subgroups (non-dialysed CKD group 1.37 (p = 0.08); haemodialysis 1.33 (p = 0.12)). There were no significant differences in the PZ levels for different stages of non-dialysed CKD patients when stratified by the level of glomerular filtration rate (GFR). These data show that PZ levels were reduced in patients with CKD, and not elevated in patients on haemodialysis, arguing against a role for PZ in the bleeding diathesis of renal failure. This finding is in contradiction to a previous report which found PZ to be elevated in patients on haemodialysis

'My Kidneys, My Choice, decision aid' : supporting shared decision making

Background: For patients with chronic kidney disease (CKD) who are progressing to end-stage kidney disease (ESKD) a decision of whether to undertake dialysis or conservative care is a critical component of the patient journey. Shared decision making for complex decisions such as this could be enhanced by a decision aid, a practice which is well utilised in other disciplines but limited for nephrology. Methods: A multidisciplinary team in Australia and New Zealand (ANZ) utilised current decision-making theory and best practice to develop the 'My Kidneys, My Choice', a decision aid for the treatment of kidney disease. Results: A patient-centred, five-sectioned tool is now complete and freely available to all ANZ units to support the ESKD education and shared decision-making process. Distribution and education have occurred across ANZ and evaluation of the decision aid in practice is in the first phase. Conclusions: Development of a new tool such as an ESKD decision aid requires vision, multidisciplinary input and ongoing implementation resources. This tool is being integrated into ANZ, ESKD education practice and is promoting the philosophy of shared decision making

Danaparoid use for haemodialysis in a morbidly obese patient with heparin-induced thrombocytopenia : need for a higher than recommended weight-based dosing

What is known and objective: Heparin is widely used to prevent clotting of the extracorporeal circuit during haemodialysis (HD). Heparin-induced thrombocytopenia (HIT) is a potentially devastating immune mediated adverse drug reaction caused by the emergence of antibodies that activate platelets in the presence of heparin, leading to a pro-thrombotic state. Danaparoid is an alternative anticoagulant used in patients on HD with HIT but its dosing recommendations in obese patients on HD are relatively scarce. Case summary: We report a case of a 48-year-old morbidly obese patient who received weight-based dosing of danaparoid for HD with monitoring of anti-Xa activity. However, despite the patient's anti-Xa level being within the therapeutic range at various time points, the circuit lines kept clotting during HD. What is new and conclusion: The report provides evidence that the manufacturer's recommendations on dosing danaparoid based on body weight may lead to sub-optimal therapeutic benefit and highlight the need for higher than recommended weight-based dosing in obese individuals on dialysis

HIF-1alpha expression follows microvascular loss in advanced murine adriamycin nephrosis

Cellular hypoxia has been proposed as a major factor in the pathogenesis of chronic renal injury, yet to date there has been no direct evidence to support its importance. Therefore, we examined cortical hypoxia in an animal model of chronic renal injury (murine adriamycin nephrosis; AN) by assessing nuclear localization of the oxygen-dependent alpha-subunit of hypoxia-inducible factor-1 (HIF-1alpha) in animals 7, 14, and 28 days after adriamycin. Results were assessed in conjunction with quantitation of the cortical microvasculature (by CD34 immunostaining) and cortical expression of VEGF. Cortical apoptosis was also examined by terminal deoxynucleotidyl transferase dUTP nick-end labeling staining. A dramatic and significant increase in nuclear localization of HIF-1alpha was seen 28 days after adriamycin in the context of severe glomerular and tubulointerstitial damage. Areas of nuclear HIF-1alpha staining did not colocalize with areas of cellular apoptosis. AN was also associated with a significant attenuation of the peritubular capillaries that was significant at 14 and 28 days after adriamycin. Cortical VEGF expression fell in a stepwise manner from day 7 until day 28 after adriamycin. In conclusion, these data are consistent with a significant increase in cellular hypoxia occurring in the advanced stages of murine AN. Increased cortical hypoxia was preceded by significant reductions in both the number of peritubular capillaries (i.e., oxygen supply) and the angiogenic cytokine VEGF. Apart from providing the first direct evidence for cellular hypoxia in a model of chronic renal disease, these results suggest that a primary dysregulation of angiogenesis may be the cause of increased hypoxia in this model