Management of Diabetes and Hypertension within the Gulf Region: Updates on Treatment Practices and Therapies.

Cardiovascular disease (CVD) is a leading cause of death globally, driven by the high rates of risk factors, such as diabetes and hypertension. As the prevalence of these risk factors is particularly high in the Gulf region, better diagnosis and management of type 2 diabetes (T2D) and hypertension has the potential to dramatically reduce adverse cardiovascular outcomes for individuals in that part of the world. This article provides a summary of presentations made during the EVIDENT summit, a virtual symposium on Evidence in Diabetes and Hypertension, held in September 2021, including a review of the various guidelines for both T2D and hypertension, as well as recent findings relevant to the safety and efficacy for therapies relating to these conditions. Of relevance to the Gulf region, the risk of hypoglycaemia with sulfonylureas during Ramadan was reviewed. For the management of T2D, sulfonylureas have been a long-standing medication used to achieve glycaemic control; however, differences have emerged between early and later generations, with recent studies suggesting improvements in the safety profiles of late-generation sulfonylureas. For patients with hypertension, incremental therapy changes are recommended to reduce the risk of cardiovascular complications that are associated with increasing blood pressure. For first-line therapy, angiotensin-converting enzyme inhibitors (ACEi), such as perindopril, have been demonstrated to reduce the risk of cardiovascular and all-cause mortality. The addition of calcium channel blockers and diuretics to ACEi has been shown to be effective in patients with poorly controlled hypertension. The different renin-angiotensin-aldosterone system inhibitors are reviewed, and the benefit of combination therapies, including amlodipine and indapamide in patients with difficult-to-control hypertension, is investigated. The benefits of lifestyle modifications for these patients are also discussed, with important clinical considerations that are expected to inform patient management in daily clinical practice.

Hydration Marker Diagnostic Accuracy to Identify Mild Intracellular and Extracellular Dehydration.

Identifying mild dehydration (≤2% of body mass) is important to prevent the negative effects of more severe dehydration on human health and performance. It is unknown whether a single hydration marker can identify both mild intracellular dehydration (ID) and extracellular dehydration (ED) with adequate diagnostic accuracy (≥0.7 receiver-operating characteristic-area under the curve [ROC-AUC]). Thus, in 15 young healthy men, the authors determined the diagnostic accuracy of 15 hydration markers after three randomized 48-hr trials; euhydration (water 36 ml·kg-1·day-1), ID caused by exercise and 48 hr of fluid restriction (water 2 ml·kg-1·day-1), and ED caused by a 4-hr diuretic-induced diuresis begun at 44 hr (Furosemide 0.65 mg/kg). Body mass was maintained on euhydration, and dehydration was mild on ID and ED (1.9% [0.5%] and 2.0% [0.3%] of body mass, respectively). Urine color, urine specific gravity, plasma osmolality, saliva flow rate, saliva osmolality, heart rate variability, and dry mouth identified ID (ROC-AUC; range 0.70-0.99), and postural heart rate change identified ED (ROC-AUC 0.82). Thirst 0-9 scale (ROC-AUC 0.97 and 0.78 for ID and ED) and urine osmolality (ROC-AUC 0.99 and 0.81 for ID and ED) identified both dehydration types. However, only the thirst 0-9 scale had a common dehydration threshold (≥4; sensitivity and specificity of 100%; 87% and 71%, 87% for ID and ED). In conclusion, using a common dehydration threshold ≥4, the thirst 0-9 scale identified mild intracellular and ED with adequate diagnostic accuracy. In young healthy adults', thirst 0-9 scale is a valid and practical dehydration screening tool.

Anabolic exercise in haemodialysis patients: a randomised controlled pilot study.

BACKGROUND: The anabolic response to progressive resistance exercise training (PRET) in haemodialysis patients is unclear. This pilot efficacy study aimed to determine whether high-intensity intradialytic PRET could reverse atrophy and consequently improve strength and physical function in haemodialysis patients. A second aim was to compare any anabolic response to that of healthy participants completing the same program. METHODS: In a single blind controlled study, 23 haemodialysis patients and 9 healthy individuals were randomly allocated to PRET or an attention control (SHAM) group. PRET completed high-intensity exercise leg extensions using novel equipment. SHAM completed low-intensity lower body stretching activities using ultra light resistance bands. Exercises were completed thrice weekly for 12 weeks, during dialysis in the haemodialysis patients. Outcomes included knee extensor muscle volume by magnetic resonance imaging, knee extensor strength by isometric dynamometer and lower body tests of physical function. Data were analysed by a per protocol method using between-group comparisons. RESULTS: PRET elicited a statistically and clinically significant anabolic response in haemodialysis patients (PRET-SHAM, mean difference [95 % CI]: 193[63 to 324] cm(3)) that was very similar to the response in healthy participants (PRET-SHAM, 169[-41 to 379] cm(3)). PRET increased strength in both haemodialysis patients and healthy participants. In contrast, PRET only enhanced lower body functional capacity in the healthy participants. CONCLUSIONS: Intradialytic PRET elicited a normal anabolic and strength response in haemodialysis patients. The lack of a change in functional capacity was surprising and warrants further investigation.

Renal recovery with eculizumab in atypical hemolytic uremic syndrome following prolonged dialysis.

Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy (TMA) which encompasses hemolytic anemia, thrombocytopenia, and organ impairment. Around 10% of cases are atypical HUS (aHUS), a rare disease with poor outcomes caused by uncontrolled activation of the alternative complement pathway. This case describes a young woman with clinical manifestations compatible with TMA during childhood and adolescence who was formally diagnosed with aHUS at the age of 21. She was managed with intensive plasma exchange and hemodialysis, which failed to improve her severe acute kidney injury and other hematological manifestations of aHUS. This was further compounded by several episodes of flash pulmonary edema and the posterior reversible encephalopathy syndrome (PRES). Treatment with the monoclonal anti-C5 inhibitor, eculizumab, improved all hematological parameters with almost full renal recovery following 3.5 months of dialysis. So far, long-term use of eculizumab (> 11 months) continues to be effective and without complication. Our case illustrates the difficulty but importance of early consideration of aHUS in patients presenting with TMA. More importantly, we highlight that near-normal renal recovery may be attained with eculizumab in adults even after a long dependence on dialysis - an observation that has not been reported in the literature so far.

Interaction between intradialytic exercise and hemodialysis adequacy.

BACKGROUND/AIMS: According to mathematical modeling, intradialytic exercise of sufficient intensity and duration implemented in the second half of dialysis should be as efficacious as increasing dialysis time for dialysis adequacy. This assumption has not been tested in vivo. METHODS: In this controlled trial, 11 hemodialysis (HD) patients (mean (SD) age 56 (13) years) were recruited. Each patient completed three trial arms in a randomized order: routine care (CONT), increased HD time of 30 min (TIME), and intradialytic exercise (EXER), 60 min of cycling at 90% of the lactate threshold in the last 90 min of HD. The primary outcome was eKt/Vurea. Secondary outcomes included reduction and rebound ratios of urea, creatinine, phosphate and ß2-microglobulin. Outcomes were calculated from blood sampling collected pre-, post- and 30 min post-HD and confirmed with dialysate sampling. RESULTS: Exercise was not as efficacious as increased HD time for eKt/Vurea (EXER vs. CONT, mean change (95% CI): 0.03 (-0.05 to 0.12); TIME vs. CONT: 0.15 (0.05-0.26)). Exercise was less efficacious at improving reduction ratios of urea and creatinine. However, exercise was more efficacious than increased dialysis time for phosphate reduction ratio (EXER vs. CONT: 8.6% (0.5-16.7); TIME vs. CONT: 5.0% (-1.0 to 11.1)). CONCLUSION: This study utilized a rigorously controlled in vivo design to test mathematical models and assumptions regarding dialysis adequacy. Intradialytic exercise towards the end of HD cannot replace the prescription of increased HD time for dialysis adequacy, but may be an adjunctive therapy for serum phosphate control.

Exercising in a hot environment with muscle damage: effects on acute kidney injury biomarkers and kidney function.

Unaccustomed strenuous physical exertion in hot environments can result in heat stroke and acute kidney injury (AKI). Both exercise-induced muscle damage and AKI are associated with the release of interleukin-6, but whether muscle damage causes AKI in the heat is unknown. We hypothesized that muscle-damaging exercise, before exercise in the heat, would increase kidney stress. Ten healthy euhydrated men underwent a randomized, crossover trial involving both a 60-min downhill muscle-damaging run (exercise-induced muscle damage; EIMD), and an exercise intensity-matched non-muscle-damaging flat run (CON), in random order separated by 2 wk. Both treatments were followed by heat stress elicited by a 40-min run at 33°C. Urine and blood were sampled at baseline, after treatment, and after subjects ran in the heat. By design, EIMD induced higher plasma creatine kinase and interleukin-6 than CON. EIMD elevated kidney injury biomarkers (e.g., urinary neutrophil gelatinase-associated lipocalin (NGAL) after a run in the heat: EIMD-CON, mean difference [95% CI]: 12 [5, 19] ng/ml) and reduced kidney function (e.g., plasma creatinine after a run in the heat: EIMD-CON, mean difference [95% CI]: 0.2 [0.1, 0.3] mg/dl), where CI is the confidence interval. Plasma interleukin-6 was positively correlated with plasma NGAL (r = 0.9, P = 0.001). Moreover, following EIMD, 5 of 10 participants met AKIN criteria for AKI. Thus for the first time we demonstrate that muscle-damaging exercise before running in the heat results in a greater inflammatory state and kidney stress compared with non-muscle-damaging exercise. Muscle damage should therefore be considered a risk factor for AKI when performing exercise in hot environments.

Does proteinuria-inducing physical activity increase biomarkers of acute kidney injury?

AIM: We sought to determine if an acute kidney injury biomarker, neutrophil gelatinaseassociated lipocalin (NGAL), would be up-regulated by high-intensity proteinuria-inducing exercise. METHODS: A prospective cohort design was utilised. 100 healthy, active adults (mean age 24 ± 4 (SD) years) were screened for post-exercise proteinuria (PeP); 10 PeP positive and 10 PeP negative participants then completed a high-intensity exercise protocol involving an 800 meter sprint. Plasma and urinary NGAL, urinary creatinine, urinary albumin and urine volume were obtained at the following time points: pre-run, immediately post-, 25 minutes, one hour and two hours post-run. RESULTS: Following high-intensity exercise, 64% of participants had urinary NGAL concentrations above the normal range, particularly at 25 minutes post (P = 0.002). However, there was no difference in NGAL response between PeP positive and negative groups and plasma NGAL was decreased, not elevated, following exercise (P = 0.002). In some individuals normalizing urinary NGAL for urinary creatinine attenuated elevations. Urinary NGAL was also negatively correlated with urine volume (r = -0.701, P = 0.005). CONCLUSION: Proteinuria susceptibility did not influence an acute injury biomarker response to exercise. Nevertheless, urinary NGAL was elevated by exercise, possibly due to increased production by the proximal tubule, increased plasma clearance (given the decrease in plasma NGAL) and/or a concentrating effect of exercise-induced oliguria. Until correct normalisation of urinary biomarkers is determined, NGAL should be interpreted cautiously in exercise and acute kidney injury-induced oliguria. The inter-individual NGAL response to exercise also warrants further investigation.

Exertional fatigue in patients with CKD.

BACKGROUND: Fatigue is one of the most prevalent symptoms in chronic kidney disease (CKD). However, fatigue mechanisms are poorly understood due in part to nonspecific definitions. This study investigates exertional fatigue during simulated activities of daily living, focusing on oxygen delivery and utilization. STUDY DESIGN: "Explanatory" matched-cohort study. PARTICIPANTS & SETTING: 13 patients with CKD (stages 3b-4; mean age, 62 ± 13 [SD] years) and 13 healthy controls, mean matched for age, height, body mass and composition, and physical activity level. Participants completed an incremental cycle ergometer test to simulate energy expenditure of typical activities of daily living. FACTOR: 4 exercise intensities: 1, 1.8, 2.4, and 3.1 metabolic equivalent tasks (METs). OUTCOMES: The primary outcome was exertional fatigue by rating of perceived exertion (RPE) on a 6-20 scale. MEASUREMENTS: Other multidimensional measures of fatigue: UK Short Form Health Survey 36 (UK SF-36) Vitality and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) subscales. Physiologic measures of the oxygen transport and utilization chain (expired gas analysis, cardiac output, and arterial oxygen content) and blood lactate. RESULTS: RPE was increased in patients compared with controls at 2.4 (10.5 [ie, light] ± 2.7 vs 8.7 [very light] ± 1.7 units) and 3.1 (12.5 [somewhat hard] ± 2.6 vs 10.2 [light] ± 1.7 units) METs (interaction P = 0.03), which was consistent with higher chronic fatigue in patients by both the UK SF-36 Vitality (P = 0.01) and FACIT-Fatigue (P = 0.004) subscales. Arterial oxygen content was decreased in patients (P = 0.001), but cardiac output and oxygen extraction ratio were unchanged, decreasing oxygen delivery (P = 0.04). Respiratory exchange ratio (P = 0.004) and blood lactate production (P = 0.002) were increased. LIMITATIONS: Those inherent to a matched-cohort study. CONCLUSIONS: Using a novel application of the outcome measure RPE, patients with non-dialysis-dependent CKD reported considerable exertional fatigue during simulated activities of daily living. Poor compensation for mild anemia contributed to this symptom. In addition to anemia, the entire oxygen transport chain needs to be targeted to treat fatigue in patients with CKD.

Intractable malignant ascites: an alternative management option.

BACKGROUND: Recurrent malignant ascites is a common management problem in oncology and palliative care. DISCUSSION: Here, we describe a case of malignant ascites managed by insertion of a Tenckhoff Catheter (TC), which resulted in successful symptomatic control and improvement in quality of life.

When pure is not so pure: chloramine-related hemolytic anemia in home hemodialysis patients.

Worldwide, chloramines are used as the preferred disinfectant for city water supplies. Although they have distinct advantages compared with chlorine and are deemed harmless to the general population, hemodialysis (HD) patients are at risk from chloramine-induced hemolytic anemia. In recent years, this has been highlighted in regional dialysis units but not as frequently in the home HD group. We report on 2 home HD patients who succumbed to severe oxidative hemolysis due to high mains water chloramine concentrations. Both patients were extensively investigated for other cause of anemia before a definitive diagnosis was reached. Delays in diagnosing this uncommon condition can be costly in terms of significant morbidity and excessive usage of recombinant erythropoietin and blood transfusion. Prevention primarily involves enforcing strict water quality control and establishing regular communication with water supply boards and home HD patients. Double (inline) carbon filters should be installed in patient's homes as an effective means for removing high incoming chloramine concentrations.

Kidney transplantation: a systematic review of interventional and observational studies of physical activity on intermediate outcomes.

Kidney transplant patients have decreased quality and longevity of life. Whether exercise can positively affect associated outcomes such as physical functioning, metabolic syndrome, kidney function, and immune function, has only been addressed in relatively small studies. Thus the aim of this systematic review was to determine effects of physical activity level on these intermediate outcomes in kidney transplant patients. We electronically and hand searched to identify 21 studies (6 retrospective assessments of habitual physical activity and 15 intervention studies including 6 controlled trials). After study quality assessment, intermediate outcomes associated with quality and longevity of life were expressed as correlations or percentage changes in addition to effect sizes. Habitual physical activity level was positively associated with quality of life and aerobic fitness and negatively associated with body fat (medium to large effect sizes). Exercise interventions also showed medium to large positive effects on aerobic capacity (10%-114% increase) and muscle strength (10%-22% increase). However, exercise programs had minimal or contradictory effects on metabolic syndrome and immune and kidney function. In kidney transplant patients, physical activity intervention is warranted to enhance physical functioning. Whether exercise impacts on outcomes associated with longevity of life requires further study.

Nandrolone decanoate as anabolic therapy in chronic kidney disease: a randomized phase II dose-finding study.

BACKGROUND/AIMS: In patients with chronic kidney disease (CKD) receiving adequate erythropoietin therapy, the ideal dose of nandrolone decanoate (ND) to enhance muscle mass is not known. METHODS: In this phase II dose-finding study, 54 patients with CKD stage 5 were randomized to either low, medium or high doses of ND (50, 100 or 200 mg/week for 24 weeks, respectively, in males; doses halved in females), while 7 patients acted as non-randomized controls. The primary outcome measure was appendicular lean mass (ALM) by dual-energy X-ray absorptiometry. Fluid overload (hydration of the fat-free mass) and indicators of physical functioning were secondary measures. Harms were also recorded. Data were analysed using Quade's (1967) non-parametric analysis of covariance. RESULTS: ND increased ALM in a dose-responsive manner (change scores = 0.3 +/- 0.3 vs. 0.8 +/- 0.3 vs. 1.5 +/- 0.5 vs. 2.1 +/- 0.4 kg, control vs. low vs. medium vs. high dose groups, respectively, p < 0.001) with no increases in fluid overload but no consistent effect on physical functioning. The highest dose of ND (100 mg/week) was intolerable in females because of virilizing effects. CONCLUSION: If goals of future studies are to improve body composition, dosing of ND up to 200 mg/week in males and 50 mg/week in females should be investigated. However, to realize improvements in physical functioning, future phase III trials of ND may require additional interventions such as exercise training.

GFR estimation using cystatin C is not independent of body composition.

BACKGROUND: Cystatin C (CysC) is an endogenous marker of glomerular filtration rate (GFR) that is claimed to be unaffected by body composition. In this study, we tested this speculation. METHODS: In 77 patients with chronic kidney disease (mean age, 65.1 +/- 11.9 [SD] years; mean indexed GFR, 45.7 +/- 28.6 mL/min/1.73 m(2) [0.76 +/- 0.48 mL/s]), we evaluated kidney function (GFR) by means of inulin clearance. CysC level was determined by using a particle-enhanced turbidimetric immunoassay. Total lean (LM) and fat masses were measured by means of dual-energy x-ray absorptiometry. Multiple regression was used to analyze relationships between absolute GFR, LM, fat mass, demographic and anthropometric variables (age, sex, height, and weight), and CysC levels. Then prediction equations were built that included only CysC level or CysC level and LM. Their performance to predict absolute GFR was evaluated in a subset of patients with extreme body composition (LM or fat mass > +/-1 SD of the entire sample). RESULTS: Only absolute GFR and LM significantly explained variance in CysC levels, and an equation including LM explained more variance in absolute GFR than an equation including CysC level alone. Consequently, the equation including LM performed better than the equation with only CysC level, especially in patients with extreme body composition, showing reduced bias and improved limits of agreement and accuracy (71.4% versus 51.4% of patients' predicted GFR did not deviate by >30% of GFR). CONCLUSION: LM is a previously unrecognized, but important, factor affecting CysC level, and GFR estimation improves when including LM. CysC level is not independent of body composition, as previously assumed, and hence accounting for body composition improves CysC-based GFR estimation.

Bioelectrical impedance can be used to predict muscle mass and hence improve estimation of glomerular filtration rate in non-diabetic patients with chronic kidney disease.

BACKGROUND: In this article (the second of two companion studies), we report whether bioelectrical impedance analysis (BIA) can be used to predict muscle mass in patients with chronic kidney disease (CKD), and whether using this predicted muscle mass can improve the estimation of glomerular filtration rate (GFR). METHODS: Seventy five non-diabetic patients with CKD (mean age +/- SD, 65.1 +/- 12.0 years; mean GFR 45.9 +/- 28.8 ml/min/1.73 m2) underwent body composition analysis by dual energy X-ray absorptiometry to provide a criterion marker of skeletal muscle mass (appendicular lean mass, ALM). Validity of a published BIA equation to predict ALM was evaluated and a new BIA equation was generated (ALM(BIA)) and cross-validated by the leave-one-out procedure. Renal inulin clearance provided a criterion measure of GFR (GFR(inu)). The performance of the equation including ALM(BIA) to estimate GFR(inu) was compared with demographic variables as used in the modification of diet in renal disease (MDRD) equation, by determining bias, limits of agreement and accuracy. RESULTS: The previously published BIA equation to predict ALM was not valid in these patients with CKD. In contrast, our new ALM(BIA) equation cross-validated successfully. Compared with the MDRD demographic variables, using ALM(BIA) to predict GFR(inu) improved estimation performance, showing reduced bias (4.3 vs 15.6 ml/min) and improved limits of agreement (41.1 vs 59.2 ml/min) and accuracy (69.7 vs 39.4% of patients' predicted GFR did not deviate by more than 30% of GFR(inu)). CONCLUSIONS: ALM(BIA) provides a clinically obtainable and valid method to predict muscle mass in patients with CKD, and using ALM(BIA) improves the estimation of GFR(inu). Researchers developing future GFR estimation equations should consider including ALM(BIA).

The relationship between estimated glomerular filtration rate, demographic and anthropometric variables is mediated by muscle mass in non-diabetic patients with chronic kidney disease.

BACKGROUND: In this study (the first of two related papers), we report whether the relationship between the demographic and anthropometric variables (DA, i.e. age, gender, height and weight) employed in current creatinin (Cr)-based glomerular filtration rate (GFR) estimation equations and actual GFR is mediated by muscle mass. METHODS: We studied 77 patients (mean age +/- SD, 65.1 +/- 11.9 years) with chronic kidney disease (mean GFR 45.7 +/- 28.6 ml/min/1.73 m2). Actual GFR was measured by the renal clearance of inulin (GFR(inu)). Appendicular lean mass (ALM) and its index (ALMI) by dual energy X-ray absorptiometry provided markers of muscle mass. Multiple regression analyses identified variables explaining variance in (i) GFR, (ii) ALM and (iii) Cr. RESULTS: (i) The DA variables used in the abbreviated modification of diet in renal disease (MDRD) equation accounted for only 59.6% (P < 0.001) of the variance in GFR(inu), whilst adding ALMI explained an additional 10.4% variance (P < 0.001). If ALMI was entered first, the relationship between DA variables and GFR(inu) was reduced (for weight) or completely abolished (for age, gender and height). (ii) After inputting all the commonly used DA variables, 17.2% of the variance in ALM was unexplained. (iii) All the DA variables explained only 60.6% (P < 0.001) of the variance in Cr, whilst adding ALM explained an additional 4.2% variance (P < 0.005). CONCLUSIONS: Muscle mass explained more variance in GFR(inu) than MDRD DA variables and mediated the relationship between GFR(inu) and DA variables. Furthermore, DA variables failed to account for individual differences in muscle mass or Cr. Consequently, there is a need to validate simpler, clinically obtainable measures of muscle mass and determine whether these measures will improve GFR estimation.

Intradialytic exercise as anabolic therapy in haemodialysis patients -- a pilot study.

Haemodialysis (HD) patients are characterized by muscle wasting and consequently decreased physical functioning and poor outcome. This pilot study investigated if a novel intradialytic exercise programme could increase lean mass via up-regulation of the insulin-like growth factor (IGF) system. Nine HD patients were assessed before (w-12) and after a 3-month control phase (w0), after a three-month intradialytic interval training programme using high intensity cycle exercise (w12), and after a withdrawal of treatment phase (w24). Body composition was determined by dual energy X-ray absorptiometry (DEXA) and bioelectrical impedance spectroscopy (BIS); physical functioning by knee extensor strength (KES) and 30-s sit stand test (SST); and IGF-I and IGFBP-3 in serum and muscle by radioimmunoassay. Despite significant increases in training load (+274%, P<0.001), peak power output (+71%, P<0.001) and physical function (KES: +19%, P<0.05; SST: +20%, P<0.05) following the intervention phase, lean masses by DEXA, intra cellular water by BIS (a surrogate measure of body cell mass) and serum and muscle IGFs remained unchanged following training. Although this novel exercise programme, utilizing high intensity interval training, was safe, clinically feasible and beneficial in terms of physical functioning, the 12 weeks of intradialytic cycle exercise failed to reverse the muscle atrophy characteristic of this population. Future studies, using primary outcome measures similar to those employed in the present study, should investigate other anabolic interventions to determine potential treatments for the muscle wasting associated with end stage renal disease.

Muscle insulin-like growth factor status, body composition, and functional capacity in hemodialysis patients.

BACKGROUND: Hemodialysis (HD) patients typically have reduced muscle mass and diminished functional capacity. The role of the muscle insulin-like growth factors (IGFs), a principal anabolic system that is involved in protein synthesis and that has downregulation that is implicated in muscle loss in animal models of uremia, has previously not been assessed in vivo in HD patients. METHODS: Seventeen HD patients were compared cross-sectionally with 17 age-, sex-, and body mass index-matched healthy controls. Body composition was assessed by dual energy x-ray absorptiometry and bioelectrical impedance spectrometry; functional capacity by hand grip strength, quadriceps strength, and 30-second sit-to-stand test; systemic inflammation by tumor necrosis factor-alpha (TNF-alpha) and TNF receptor 1 (TNFR1); serum and muscle IGF-I and IGFBP-3 by radioimmunoassay; and fragmentation of serum IGFBP-3 by Western immunoblotting. RESULTS: Appendicular lean mass was significantly decreased in HD patients compared with controls (17.6 +/- 0.9 versus 21.5 +/- 1.5 kg, P < .05), as were all measures of functional capacity (P < .01 to .001), and highly significant positive correlations between appendicular lean mass and functional capacity were evident (appendicular lean mass and hand-grip strength, quadriceps strength, 30-second sit-to-stand test, all P < .001). TNF-alpha and TNFR1 were elevated in patients (P < .001). Although serum IGF-I and IGFBP-3 levels did not differ between the groups (P = .295 and .379 respectively), fragmented IGFBP-3 levels were increased (53.1 +/- 16.0 versus 29.81 +/- 15.3%, P < .005). In contrast, muscle IGF-I was substantially diminished in the patient group (n = 7) relative to control (n = 5) levels (0.84 +/- 0.06 versus 2.78 +/- 1.80 pg/microg, P < .05). CONCLUSIONS: We provide evidence of reduced IGF-I in HD patients' skeletal muscle that may be a causal factor in the muscle wasting characteristic of this population. Future research should determine the exact consequences and causes of alterations to the muscle IGF system in HD patients.

Painful cutaneous lesions, renal failure and urgent parathyroidectomy.

We describe two patients with end stage renal failure who presented with painful skin lesions, which rapidly progressed to become necrotic and gangrenous. The diagnosis was calciphylaxis, a rare disorder due to calcification and luminal fibrosis of small and medium sized cutaneous and systemic vessels. Both patients had tertiary hyperparathyroidism. An urgent parathyroidectomy was performed on one patient, which relieved her symptoms; the other required local surgery but refused parathyroidectomy and died.