Amanda Raff

New insights into uremic toxicity

Purpose of reviewOur concept of uremia has expanded to encompass the illness patients begin to suffer as glomerular filtration rate declines long before the onset of end-stage renal disease (ESRD) not explained by known derangements in volume status or metabolic parameters. New insights into the accumulation of uremic toxins and the loss of function of hormones and enzymes provide important information on the etiology of uremia. Recent findingsNew data are accumulating on the identity and toxicity of uremic toxins and the syndromes that encompass uremia. p-Cresol sulfate and indoxyl sulfate are small, protein-bound molecules that are poorly cleared with dialysis. These molecules have been linked to cardiovascular disease and oxidative injury. Impaired immunity plays a central role in the morbidity of ESRD and may be both the result of uremic toxicity and a contributor to oxidative stress in ESRD. Uremic cachexia is an underrecognized uremic syndrome. New insights into disordered feeding circuits in ESRD may lead to novel therapies using hormone agonists. SummaryMortality in ESRD remains unacceptably high. It is hoped that as knowledge emerges on the causes and consequences of uremia, we are embarking on an era not only of new insights but also new and effective treatments for patients with the ill effects of uremia.

Effects of Oral Sodium Bicarbonate in Patients with CKD

BACKGROUND AND OBJECTIVES Metabolic acidosis contributes to muscle breakdown in patients with CKD, but whether its treatment improves functional outcomes is unknown. The choice of dose and tolerability of high doses remain unclear. In CKD patients with mild acidosis, this study evaluated the dose-response relationship of alkali with serum bicarbonate, its side effect profile, and its effect on muscle strength. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS In this single-blinded pilot study from March of 2009 to August of 2010, 20 adults with estimated GFR 15-45 ml/min per 1.73 m(2) and serum bicarbonate 20-24 mEq/L were treated during successive 2-week periods with placebo followed by escalating oral NaHCO3 doses (0.3, 0.6, and 1.0 mEq/kg per day). At each visit, handgrip strength and time required to complete 5 and 10 repetitions of a sit-to-stand test were measured. RESULTS Each 0.1 mEq/kg per day increase in dose produced a 0.33 mEq/L (95% confidence interval=0.23-0.43 mEq/L) higher serum bicarbonate. Sit-to-stand time improved after 6 weeks of oral NaHCO3 (23.8±1.4 versus 22.2±1.6 seconds for 10 repetitions, P=0.002), and urinary nitrogen excretion decreased (-0.70 g/g creatinine [95% confidence interval=-1.11 to -0.30] per 0.1 mEq/kg per day higher dose). No statistically significant change was seen in handgrip strength (29.5±9.6 versus 28.4±9.4 kg, P=0.12). Higher NaHCO3 doses were not associated with increased BP or greater edema. CONCLUSIONS NaHCO3 supplementation produces a dose-dependent increase in serum bicarbonate and improves lower extremity muscle strength after a short-term intervention in CKD patients with mild acidosis. Long-term studies are needed to determine if this finding translates into improved functional status.

Relationship of impaired olfactory function in ESRD to malnutrition and retained uremic molecules.

BACKGROUND Olfactory function is impaired in patients with end-stage renal disease (ESRD) and may contribute to uremic anorexia. Only limited correlations of olfactory function and nutritional status were reported. This study examines the relationship of impaired olfactory function to malnutrition and levels of the retained uremic solutes monomethylamine, ethylamine, indoxyl sulfate, and P-cresol sulfate. STUDY DESIGN Cross-sectional observational study. SETTING & PARTICIPANTS 31 stable maintenance hemodialysis patients from an urban outpatient dialysis unit and 18 people with normal renal function participated. PREDICTOR Nutritional status assigned by using Subjective Global Assessment (SGA) score; SGA score of 7 indicates normal nutritional status; SGA score of 5 to 6, mild malnutrition; and SGA score of 3 to 4, moderate malnutrition. OUTCOMES & MEASUREMENTS The primary outcome is olfactory function, assessed using the University of Pennsylvania Smell Identification Test. Levels of retained uremic solutes were measured from a predialysis serum sample. Demographic data and laboratory values for nutritional status, adequacy of dialysis, and inflammation were collected. RESULTS Mean smell scores were 34.9 +/- 1.4 for controls, 33.5 +/- 3.3 for patients with SGA score of 7, 28.3 +/- 5.8 for patients with SGA score of 5 to 6, and 27.9 +/- 4.4 for patients with SGA score of 3 to 4 (P < 0.001 comparing healthy patients with all patients with ESRD). There was no difference in mean smell scores for healthy controls and patients with SGA score of 7. However, patients with lower smell scores had significantly lower SGA scores (P = 0.02) and higher C-reactive protein levels (P = 0.02). Neither smell score nor nutritional status was associated with levels of retained uremic solutes. LIMITATIONS Small sample size, only cross-sectional associations can be described. CONCLUSIONS Our results suggest an association between poor nutritional status and impaired olfactory function in patients with ESRD. Additional research is needed to discover the uremic toxins mediating these processes.

The risk and management of kidney stones from the use of topiramate and zonisamide in migraine and idiopathic intracranial hypertension

CASE HISTORY A 40-year-old woman has a 15-year history of migraine without aura that has been chronic for 5 years. While on TPM 100 mg daily for 2 years without side effects, her migraine frequency has decreased from 20 days per month to 6 days per month. She then developed a first-time kidney stone that passed spontaneously. Upon analysis, the stone was determined to be calcium phosphate. QUESTIONS What is the type of kidney stones that form and their pathophysiology? What is the frequency of kidney stones in migraineurs on TPM and ZNS and the general population? Is the risk dose and time dependent? Is a prior history of kidney stones a contraindication to use of either medication? Is formation of kidney stones a contraindication to ongoing use of TPM or ZNS? If migraineurs who develop a kidney stone(s) on TPM continue the drug, is there any way to prevent further stone formation? In patients with IIH, is the risk of kidney stone formation a contraindication to combined use of TPM and acetazolamide (ATZ)?

Olfactory function in dialysis patients: a potential key to understanding the uremic state

Impaired olfactory function is a marker of neurologic dysfunction in the uremic state. Retained uremic toxins not adequately cleared with dialysis may undermine the integrity of the olfactory epithelium and olfactory bulb and malign central olfactory processing. The evidence suggests that only renal transplantation, with its concomitant thorough reversal of uremia, truly restores olfactory function to normal in end-stage renal disease. Testing of olfactory function may emerge as an important marker for the extent and resolution of uremia.

Methylamine clearance by haemodialysis is low

BACKGROUND Dialysis adequacy is currently judged by measures of urea clearance. However, urea is relatively non-toxic and has properties distinct from large classes of other retained solutes. In particular, intracellularly sequestered solutes are likely to behave differently than urea. METHODS We studied an example of this class, the aliphatic amine monomethylamine (MMA), in stable haemodialysis outpatients (n = 10) using an HPLC-based assay. RESULTS Mean MMA levels pre-dialysis in end-stage renal disease subjects were 76 +/- 15 microg/L compared to 32 +/- 4 microg/L in normal subjects (n = 10) (P < 0.001). Mean urea reduction was 62% while the reduction ratio for MMA was 43% (P < 0.01). MMA levels rebounded in the 1 hour post-dialytic period to 85% of baseline, whereas urea levels rebounded only to 47% of baseline. MMA had a much larger calculated volume of distribution compared to urea, consistent with intracellular sequestration. Measures of intra-red blood cell (RBC) MMA concentrations confirmed greater levels in RBCs than in plasma with a ratio of 4.9:1. Because of the intracellular sequestration of MMA, we calculated its clearance using that amount removed from whole blood. Clearances for urea averaged 222 +/- 41 ml/min and for MMA 121 +/- 14 ml/min, while plasma clearance for creatinine was 162 +/- 20 ml/min (P < 0.01, for all differences). Using in vitro dialysis, in the absence of RBCs, solute clearance rates were similar: 333 +/- 6, 313 +/- 8 and 326 +/- 4 ml/min for urea, creatinine and MMA, respectively. These findings suggest that the lower MMA clearance relative to creatinine in vivo is a result of MMA movement into RBCs within the dialyser blood path diminishing its removal by dialysis. CONCLUSION In conclusion, we find that, in conventional haemodialysis, MMA is not cleared as efficiently as urea or creatinine and raise the possibility that RBCs may limit its dialysis not merely by failing to discharge it, but by further sequestering it as blood passes through the dialyser.

A zebrafish model for uremic toxicity: role of the complement pathway.

Many organic solutes accumulate in end-stage renal disease (ESRD) and some are poorly removed with urea-based prescriptions for hemodialysis. However, their toxicities have been difficult to assess. We have employed an animal model, the zebrafish embryo, to test the toxicity of uremic serum compared to control. Serum was obtained from stable ESRD patients predialysis or from normal subjects. Zebrafish embryos 24 h postfertilization were exposed to experimental media at a water:human serum ratio of 3:1. Those exposed to serum from uremic subjects had significantly reduced survival at 8 h (19 ± 18 vs. 94 ± 6%, p < 0.05, uremic serum vs. control, respectively). Embryos exposed to serum from ESRD subjects fractionated at 50 kDa showed significantly greater toxicity with the larger molecular weight fraction (83 ± 11 vs. 7 ± 17% survival, p < 0.05, <50 vs. >50 kDa, respectively). Heating serum abrogated its toxicity. EDTA, a potent inhibitor of complement by virtue of calcium chelation, reduced the toxicity of uremic serum compared to untreated uremic serum (96 ± 5 vs. 28 ± 20% survival, p < 0.016, chelated vs. nonchelated serum, respectively). Anti-factor B, a specific inhibitor of the alternative complement pathway, reduced the toxicity of uremic serum, compared to untreated uremic serum (98 ± 6 vs. 3 ± 9% survival, p < 0.016, anti-factor B treated vs. nontreated, respectively). Uremic serum is thus more toxic to zebrafish embryos than normal serum. Furthermore, this toxicity is associated with a fraction of large size, is inactivated by heat, and is reduced by both specific and nonspecific inhibitors of complement activation. Together these data lend support to the hypothesis that at least some uremic toxicities may be mediated by complement.

Group observed structured encounter (GOSCE) for third-year medical students improves self-assessment of clinical communication

Abstract Objectives: This study assesses the effectiveness of a GOSCE in teaching medical students clinical communication, as well as group collaboration and peer feedback. Methods: The GOSCE was administered during the Internal Medicine clerkship. Groups consisted of 4–6 students and one faculty member. Students completed pre- and post-GOSCE surveys to assess confidence in clinical communication and a GOSCE evaluation to rate the overall experience. Pre- and post-GOSCE program survey scores were compared, and the mean score and standard deviation of the GOSCE evaluation was calculated. Results: Students perceived improvement in their general (Mean 4.49–4.57, p < .0001), case-specific (3.61–3.84, p < .0001) and group clinical communication (3.75–4.09, p < .0001) skills. Students agreed or strongly agreed that the GOSCE taught them something new (91.20%), made them more comfortable in giving (64.31%) and receiving (66.57%) feedback and working with a group (64.22%). Students found the GOSCE to be as effective as an OSCE (70.97%). Conclusions: A GOSCE is a valuable resource for use in formative assessment of clinical communication, and it offers the benefit of group collaboration and peer feedback. These findings support the broader use of GOSCEs in undergraduate medical education.

Four-Station Group Observed Structured Clinical Encounter for Formative Assessment of Communication Skills for Internal Medicine Clerks

Introduction Communication with patients and among colleagues is critical to effective clinical care. A group observed structured clinical encounter (GOSCE) is an effective and resource-saving tool for teaching communication skills to medical students. While objective structured clinical exams (OSCEs) are a well-established assessment tool for communication skills, a GOSCE allows for formal observation of communication skills while also providing an opportunity for peer observation and feedback. Additionally, a GOSCE costs less and requires fewer faculty per learner than a traditional OSCE. Methods This is a four-station GOSCE to teach advanced communication skills to medical students. The stations are smoking cessation, difficult doctor-patient encounter, shared decision making, and delivering bad news. A group is made up of four to six students and one faculty member. At each station, one student takes the lead in the patient interview, followed by a group interview and ending with feedback by all participants. Results In the pilot phase, a total of 44 students were administered the GOSCE and were surveyed about their experience. Students felt the GOSCE was an enjoyable and educational experience. The GOSCE has subsequently been administered to more than 600 students, and 25 internal medicine faculty have participated. Discussion Our work demonstrates that the GOSCE is a feasible curricular enhancement for formative assessment of communication skills during the internal medicine clerkship. It is easy to implement and has been well received by all participants, with minimal impact on limited medical school and faculty resources.

Topiramate and Nephrolithiasis: A Response

1. Jion YI, Raff A, Grosberg BM, Evans RW. The risk and management of kidney stones from the use of topiramate and zonisamide in migraine and idiopathic intracranial hypertension. Headache. 2015; 55: 161–166. 2. Kaplon DM, Penniston KL, Nakada SY. Patients with and without prior urolithiasis have hypocitraturia and incident kidney stones while on topiramate. Urology. 2011; 77:295-298. 3. Vega D, Maalouf NM, Sakhaee K. Increased propensity for calcium phosphate kidney stones with topiramate use. Expert Opin Drug Saf. 2007; 6:547– 557. 4. Maalouf NM, Langston JP, Van Ness PC, Moe OW, Sakhaee K. Nephrolithiasis in topiramate users. Urol Res. 2011; 39:303-307.