Dialysis and driving: an anonymous survey of patients receiving dialysis for end-stage kidney disease.

BACKGROUND: Driving is a complex task requiring multiple cognitive domains and the musculoskeletal system. Cognitive dysfunction is associated with driving impairment. Dialysis patients are known to have a high prevalence of cognitive impairment and other comorbidities, and may be at risk of driving impairment. No Australian guidelines address driving safety in dialysis patients. AIMS: To estimate the proportion of dialysis patients who were driving and those at risk of driving impairment, and to investigate the agreement between objective and subjective markers of risk. METHODS: This single-centre study involved dialysis patients voluntarily completing two questionnaires relating to risk of driving impairment; the first questionnaire focussed on objective markers, and the second questionnaire focussed on subjective markers. Risk of driving impairment was established using pre-determined criteria, and the agreement between objective and subjective markers was estimated using Cohen kappa. RESULTS: A total of 44.8% (99/221) of patients participated; 76.8% (76/99) of participants were driving, and 76.3% (58/76) of drivers were at risk of driving impairment. Factors associated with at-risk driving included post dialysis dizziness, leg weakness or numbness, falling asleep while driving and hypoglycaemia. Sixteen patients reported collisions since commencing dialysis. The questionnaires displayed slight agreement (Cohen kappa = 0.20) between objective and subjective markers. CONCLUSIONS: Dialysis patients are at risk of driving impairment based on self-reported questionnaire responses. Discrepancies between patients' perceptions and objective markers were apparent. Further research into appropriate risk assessments, as well as development of guidelines to aid in determining driving safety in dialysis patients, is needed.

Relationship between residual kidney function and symptom burden in haemodialysis patients.

BACKGROUND: Residual kidney function (RKF) has been associated with improved solute clearance and survival in haemodialysis (HD) patients. However, whether RKF impacts symptom burden in HD patients is unknown. AIMS: To determine the prevalence of RKF in HD patients and to explore associations between higher levels of RKF with symptom burden, as well as clinical and biochemical parameters. METHODS: This is a single-centre, retrospective, observational study. RKF was assessed as urea clearance (KRU) by interdialytic urine collection. Symptom burden was measured using the palliative care outcome scale renal questionnaire. RESULTS: A total of 90 maintenance HD patients was recruited; 31.9% had KRU ≥1 mL/min/1.73 m2 . Patients with KRU ≥1 mL/min/1.73 m2 reported fewer symptoms (5.3 ± 3.5 vs 7.7 ± 3.8) (P = 0.011), including less shortness of breath (15% vs 55%) (P = 0.0013) and vomiting (0% vs 30%) (P = 0.0016). Higher RKF was associated with lower ß2 -microglobilin (P < 0.0001), and lower serum potassium (P = 0.02), but no difference in phosphate, haemoglobin, C-reactive protein or serum albumin. CONCLUSION: Higher RKF was significantly associated with fewer symptoms, and lower serum ß2 -microglobulin and potassium, suggesting that strategies to preserve RKF may be beneficial.

Outcomes of patients commencing peritoneal dialysis with and without back-up arteriovenous fistulas.

BACKGROUND: Transitions from peritoneal dialysis (PD) to haemodialysis (HD) are often unpredictable and central venous catheters (CVCs) are frequently required. Early studies found few back-up arteriovenous fistulas (bAVFs) were ever used. The PD population's characteristics have changed over time which may have altered the likelihood of bAVFs being used. This study aimed to report use of, and outcomes associated with, bAVFs in a contemporary cohort of peritoneal dialysis patients. METHOD: A single-centre, retrospective study of PD patients commencing dialysis between 2006-2016, stratified according to presence/absence of bAVF. RESULTS: One hundred seventy-six patients were included-82 with bAVF, 94 without bAVF-of whom 156 transitioned off PD. Transitions were to HD (49%), transplantation (23%), death (15%) and renal-recovery (1%). 51% of bAVFs were successfully used and 82% of bAVFs were patent when required. Median time from creation to bAVF use was 2.5 years. More patients with a bAVF transitioned to HD (62 vs 38%, p < 0.005). However, CVC requirement at the time of transition to HD was much less common in the bAVF group (18 vs 83%, p < 0.0001), such that the overall risk of requiring a CVC was significantly lower in the bAVF group (11 vs 31%, p < 0.005). Rates of returning to PD amongst patients who transitioned to HD with a CVC or an AVF were similar (19 vs 26%, p = 0.16). CONCLUSIONS: In this cohort of PD patients, utilisation of back-up arteriovenous fistulas was higher than previously reported, and presence of a back-up arteriovenous fistula was associated with a lower rate of future CVC use.

Changes in Symptom Burden in Dialysis Patients Assessed Using a Symptom-Reporting Questionnaire in Clinic.

INTRODUCTION: To determine the prevalence, severity, and change in symptoms experienced by dialysis patients following the introduction of use of a symptom-reporting questionnaire in nephrology clinic. METHODS: This is an observational study of 160 prevalent dialysis patients. Palliative care Outcome Scale symptom (POS-renal) questionnaires modified for patients with end-stage kidney disease were completed at baseline and follow-up (median 3 months), with results available to nephrologists at clinic appointments. FINDINGS: The baseline prevalence of individual symptoms ranged from 15% to 66%. The most common symptoms were lack of energy (66%) and poor mobility (58%). The median number of symptoms was 7/17 (interquartile range [IQR]: 4-10). Forty-nine percent of patients rated at least 1 symptom as severe or overwhelming. At follow-up, the median number of symptoms experienced was unchanged at 7/17 (IQR: 3-10). However, there was considerable flux in symptom severity. On average, individual symptoms that were present at baseline improved in 56% of patients and worsened in 18%; only 26% had stable symptom severity. Individual symptoms newly occurred in 8% to 20% of patients between time points, with 77% of patients experiencing at least 1 new symptom. The percent of patients rating at least 1 symptom as severe or overwhelming was reduced from 49% to 39% (P = .040). CONCLUSIONS: Use of the POS-renal questionnaire identified a high symptom burden. The presence and severity of symptoms changed dramatically over a short follow-up period, highlighting the need for regular surveillance of symptoms in the dialysis population. Routine use of a symptom questionnaire in clinic may be useful for the identification and management of symptoms in dialysis patients.

Phosphate nephropathy: an avoidable complication of bowel preparation for colonoscopy.

It is known that oral sodium phosphate, used as bowel preparation for colonoscopy, can cause acute phosphate nephropathy, a potentially severe and irreversible form of acute kidney injury. Due to these safety concerns, guidelines have advised against the routine use of this agent for a decade. We present a case report and biopsy series that demonstrate that oral sodium phosphate is still being used and that cases of APN are still occurring, in Australia.

The Thiazide-Sensitive Co-Transporter Promotes the Development of Sodium Retention in Mice with Diet-Induced Obesity.

BACKGROUND/AIMS: Intravascular volume expansion due to sodium retention is involved in the pathogenesis of obesity-related hypertension. Institution of high fat diet (HFD) feeding leads to an initial state of positive sodium balance due to enhanced tubular reabsorption of sodium, but which tubular sodium transporters are responsible for this remains undefined. METHODS: C57/Bl6 mice were fed control or HFD for 3 weeks. Blood pressures were recorded by tail cuff method. Sodium transporter expression and phosphorylation were determined by Western blotting. In vivo activity of NCC was determined using natriuretic responses to hydrochlorothiazide. Expression of NCC mRNA was determined using qPCR. RESULTS: At 3 weeks HFD mice had significant weight gains compared to control mice, but blood pressures were not yet elevated. There were no changes in expression or phosphorylation of the bumetanide-sensitive cotransporter, NKCC2, or in expression of subunits of the amiloride-sensitive ion channel, ENaC. However, there were significant increases in mRNA and protein expression of the thiazide-sensitive co-transporter, NCC, in kidneys from HFD mice. Consistent with this, HFD mice had increased in vivo activity of NCC. CONCLUSIONS: Increased expression of NCC promotes the sodium loading response to institution of HFD feeding before onset of hypertension.

AMPK couples plasma renin to cellular metabolism by phosphorylation of ACC1.

Salt reabsorption is the major energy-requiring process in the kidney, and AMP-activated protein kinase (AMPK) is an important regulator of cellular metabolism. Mice with targeted deletion of the ß1-subunit of AMPK (AMPK-ß1(-/-) mice) had significantly increased urinary Na(+) excretion on a normal salt diet. This was associated with reduced expression of the ß-subunit of the epithelial Na(+) channel (ENaC) and increased subapical tubular expression of kidney-specific Na(+)-K(+)-2Cl(-) cotransporter 2 (NKCC2) in the medullary thick ascending limb of Henle. AMPK-ß1(-/-) mice fed a salt-deficient diet were able to conserve Na(+), but renin secretion increased 180% compared with control mice. Cyclooxygenase-2 mRNA also increased in the kidney cortex, indicating greater signaling through the macula densa tubular salt-sensing pathway. To determine whether the increase in renin secretion was due to a change in regulation of fatty acid metabolism by AMPK, mice with a mutation of the inhibitory AMPK phosphosite in acetyl-CoA carboxylase 1 [ACC1-knockin (KI)(S79A) mice] were examined. ACC1-KI(S79A) mice on a normal salt diet had no increase in salt loss or renin secretion, and expression of NKCC2, Na(+)-Cl(-) cotransporter, and ENaC-ß were similar to those in control mice. When mice were placed on a salt-deficient diet, however, renin secretion and cortical expression of cyclooxygenase-2 mRNA increased significantly in ACC1-KI(S79A) mice compared with control mice. In summary, our data suggest that renin synthesis and secretion are regulated by AMPK and coupled to metabolism by phosphorylation of ACC1.

Connections between vascular calcification and progression of chronic kidney disease: therapeutic alternatives.

We have shown that renal injury and chronic kidney disease (CKD) directly inhibit skeletal anabolism, and that stimulation of bone formation decreases the serum phosphate. Most recently, these observations were rediscovered in low-density lipoprotein receptor null mice fed high-fat/cholesterol diets, a model of the metabolic syndrome (hypertension, obesity, dyslipidemia, and insulin resistance). We had demonstrated that these mice have vascular calcification (VC) of both the intimal atherosclerotic type and medial type. We have shown that VC is worsened by CKD and ameliorated by bone morphogenetic protein -7 (BMP-7). The finding that high-fat-fed low-density lipoprotein receptor null animals without CKD have hyperphosphatemia led us to examine the skeletons of these mice. We found significant reductions in bone formation rates, associated with increased VC and superimposing CKD results in the adynamic bone disorder (ABD), while VC was worsened and hyperphosphatemia persisted. A pathological link between abnormal bone mineralization and VC through the serum phosphorus was demonstrated by the partial effectiveness of directly reducing the serum phosphate by a phosphate binder that had no skeletal action. BMP-7 treatment corrected the ABD and corrected hyperphosphatemia, compatible with BMP-7-driven stimulation of skeletal phosphate deposition reducing plasma phosphate and thereby removing a major stimulus to VC. Thus, in the metabolic syndrome with CKD, a reduction in bone-forming potential of osteogenic cells leads to ABD producing hyperphosphatemia and VC, processes ameliorated by the skeletal anabolic agent BMP-7, in part through increased bone formation and skeletal deposition of phosphate, and in part through direct actions on vascular smooth muscle cells. We have demonstrated that the processes leading to vascular calcification begin with even mild levels of renal injury before demonstrable hyperphosphatemia, and they are preventable and treatable. Therefore, early intervention in CKD is warranted and may affect mortality of the disease.

Low turnover osteodystrophy and vascular calcification are amenable to skeletal anabolism in an animal model of chronic kidney disease and the metabolic syndrome.

LDL receptor (LDLR)-null mice fed high-fat/cholesterol diets, a model of the metabolic syndrome, have vascular calcification (VC) worsened by chronic kidney disease (CKD) and ameliorated by bone morphogenetic protein-7 (BMP-7), an efficacious agent in treating animal models of renal osteodystrophy. Here, LDLR-/- high-fat-fed mice without CKD were shown to have significant reductions in bone formation rates, associated with increased VC and hyperphosphatemia. Superimposing CKD resulted in a low turnover osteodystrophy, whereas VC worsened and hyperphosphatemia persisted. BMP-7 treatment corrected the hyperphosphatemia, corrected the osteodystrophy, and prevented VC, compatible with skeletal phosphate deposition leading to reduced plasma phosphate and removal of a major stimulus to VC. A pathologic link between abnormal bone mineralization and VC through the serum phosphorus was supported by the partial effectiveness of directly reducing the serum phosphate by a phosphate binder that had no skeletal action. Thus, in this model of the metabolic syndrome with CKD, a reduction in bone-forming potential of osteogenic cells leads to low bone turnover rates, producing hyperphosphatemia and VC, processes ameliorated by the skeletal anabolic agent BMP-7, in part through deposition of phosphate and increased bone formation.

Successful treatment of an adynamic bone disorder with bone morphogenetic protein-7 in a renal ablation model.

An adynamic bone disorder (ABD) is an important complication of chronic kidney disease (CKD) of unknown etiology for which there is no adequate treatment. Reported is an animal model of ablative CKD complicated by an ABD characterized by the absence of secondary hyperparathyroidism and its successful treatment with a skeletal anabolic factor, bone morphogenetic protein-7 (BMP-7). Adult mice were subjected to electrocautery of the right kidney followed by left nephrectomy. Animals were randomized into groups fed normal chow or fed low-phosphate chow supplemented with calcitriol to maintain normophosphatemia in CKD. All groups were maintained on the regimens for 12 wk. Hyperphosphatemia, secondary hyperparathyroidism, and a mild osteodystrophy developed in the CKD/chow-fed group, as expected. When dietary phosphorus was restricted and calcitriol was administered in the CKD low-phosphate/calcitriol group (ABD), Ca, PO(4), and parathyroid hormone levels were maintained normal. A significant ABD developed in the ABD group characterized by significant depressions in osteoblast number, perimeters, bone formation rates, and mineral apposition rates when compared with the sham-operated, chow-fed group. The abnormal skeletal histomorphometry was reversed by BMP-7 therapy to normal values and significantly improved from the ABD group (P < 0.05). The sham-operated low-phosphate/calcitriol-fed control group and the CKD low-phosphate/calcitriol/BMP-7 groups had reduced phosphate levels compared with the other groups (P < 0.05). ABD produced in mice with CKD in the absence of hyperparathyroidism was successfully reversed with a bone anabolic, BMP-7, associated with a reduction in plasma phosphorus.

BMP-7 is an efficacious treatment of vascular calcification in a murine model of atherosclerosis and chronic renal failure.

Chronic renal failure is complicated by high cardiovascular mortality. One key contributor to this mortality is vascular calcification, for which no therapy currently exists. Bone morphogenetic protein 7 is an essential renal morphogen that maintains renal tubular differentiation in the adult and is downregulated in renal failure. Several studies have demonstrated its efficacy in treating various renal diseases in rodents, and it was hypothesized that it would also be an effective treatment of vascular calcification in this setting. Uremia was imposed on LDL receptor null mice (a model of atherosclerosis), which were then treated with bone morphogenetic protein 7 for 15 wk. Uremic animals had increased vascular calcification by histology and chemical analysis. Calcification in treated animals was similar to or less than non-uremic control animals. Cells exhibiting an osteoblast-like phenotype in the vessel wall may be important in the etiology of vascular calcification. Expression of osteocalcin was assessed as a marker of osteoblastic function, and it is shown that it is increased in untreated uremic animals but downregulated to levels similar to non-uremic control animals with treatment. The data are compatible with bone morphogenetic protein 7 deficiency as a pathophysiologic factor in chronic renal failure, and they demonstrate its efficacy as a potential treatment of vascular calcification.

Bone morphogenetic protein-7: an anti-fibrotic morphogenetic protein with therapeutic importance in renal disease.

Bone morphogenetic proteins are members of the transforming growth factor-beta superfamily of cytokines and consist of a group of at least 15 morphogens involved in intracellular messaging through complex bone morphogenetic protein receptor mediated Smad signaling. Bone morphogenetic protein-7 knockout mice die shortly after birth due to uremia, demonstrating that this morphogenetic protein is essential for renal development. Recent investigations have characterized renal bone morphogenetic protein-7 receptors, shown exogenous bone morphogenetic protein-7 to prevent fibrogenesis associated with ureteral obstruction, indicated a loss of renal bone morphogenetic protein-7 associated with diabetic nephropathy, and an improvement in glomerular pathology in rodent streptozocin-induced diabetes with bone morphogenetic protein-7 treatment. In addition, this morphogenetic protein has been shown to reduce glomerulonephritis and tubulointerstitial fibrosis in a murine model of lupus nephritis as well as decrease the peritrabecular fibrosis associated with murine high turnover renal osteodystrophy. Finally, we review the effects of bone morphogenetic protein-7 on vascular calcification in an animal model, a potential complication of this therapy given its osseous morphogenetic effect.