Olivera Marsenic

Glucose Control by the Kidney: An Emerging Target in Diabetes

The full significance of the kidneys role in glucose homeostasis is now well recognized. For example, it is now known that renal gluconeogenesis contributes substantially to total-body glucose release in the postabsorptive state. The kidney contributes to glucose homeostasis by filtering and reabsorbing glucose. Under normal circumstances, glucose filtered by glomeruli is completely reabsorbed, but glucosuria may occur under conditions of hyperglycemia or reduced reabsorptive capacity. The sodium-glucose cotransporter SGLT2 (encoded by the SLC5A2 gene), which is expressed almost exclusively in proximal tubules, mediates approximately 90% of active renal glucose reabsorption. This transporter can be blocked by SGLT2 inhibitors, a class of compound that may prove effective in managing type 2 diabetes. The glucosuria induced by these compounds has a naturally occurring parallel in familial renal glucosuria (FRG), a condition in which SGLT2 mutations reduce renal reabsorptive capacity. Interestingly, the chronic glucosuria of patients with FRG does not appear to be associated with other pathological changes, and patients with FRG are mostly asymptomatic. This suggests that glucosuria is not intrinsically detrimental. Selective SGLT2 inhibitors are currently in clinical trials.

Effect of Dialysis Dose on Nutritional Status of Children on Chronic Hemodialysis

It had been suggested that larger hemodialysis (HD) doses in children could result in better appetite, higher protein intake, better nutritional status and better growth. We investigated how different HD doses affect protein intake and nutritional status of children on chronic HD. Indices of nutritional status used were normalized protein catabolic rate (nPCR) calculated by formal 3-sample urea kinetic modeling and serum albumin level. Data of 38 HD sessions in 15 stable patients (6 males, 9 females) aged 14.5 ± 3.28 years (mean ± SD) were analyzed. HD sessions were divided into three groups based on delivered Kt/V: group 1 (n = 5), inadequate (Kt/V < 1.3, mean 1.05 ± 0.14); group 2 (n = 12), adequate (Kt/V = 1.3–1.6, mean 1.50 ± 0.07) and group 3 (n = 21), high (Kt/V >1.6, mean 1.94 ± 0.22). Mean nPCR and Kt/V per patient during the studied week were estimated for 11 patients in whom 3 HD sessions were available within the 38 sessions analyzed. Serum albumin level was adequate in all patients (43.77 ± 2.28 g/l). Mean overall Kt/V and nPCR were 1.68 ± 0.36 and 1.26 ± 0.23, respectively, r = 0.430. Average nPCR differed between groups depending on Kt/V. It was lowest in group 1 (1.01 ± 0.12 g/kg/day) where the highest correlation between nPCR and Kt/V was found (r = 0.648). nPCR was higher and similar in groups 2 (1.27 ± 0.23 g/kg/day) and 3 (1.31 ± 0.22 g/kg/day), with low correlation coefficients between nPCR and Kt/V in both groups (r = 0.275 and r = 0.197, respectively). A weak positive correlation (r = 0.249) between nPCR and Kt/V was found when average weekly values per patient (n = 11) were analyzed. Results of groups 1 and 2 confirm, what is already well established in adults, that adequate dialysis needs to be achieved in order to insure good protein intake. However, our data clearly show that nPCR did not increase with a further increase in delivered HD dose, i.e. Kt/V >1.6. Our results show that the nutritional status of children on chronic HD does not seem to benefit from very high HD doses (Kt/V >1.6).

Hyponatremic hypertensive syndrome

Abstract We report on a 4-year-old girl with hyponatremic-hypertensive syndrome (HHS), a rare entity in childhood. The girl was referred to us from a local hospital with a history of recurrent fever, vomiting, and seizures. On admission she was markedly dehydrated. Initial investigations revealed severe hyponatremia (serum Na 120 mmol/l), hypochloremia (serum Cl 68 mmol/l), and mild hypokalemia (serum K 3.3 mmol/l), while serum calcium and magnesium were normal. Serum urea was 5 mmol/l and serum creatinine was 62 µmol/l. Despite hyponatremic dehydration, her urine output was high (2050 ml/24 h), as was her urinary sodium (168 mmol/24 h). She had massive transient proteinuria (maximal 1642 mg/24 h) while being severely hypertensive (blood pressure 210/160 mmHg). Further investigations revealed right kidney scarring, hyper-reflexive bladder dysfunction, massive brain infarcts, and myocardial left ventricular hypertrophy. Renal arteries were normal on arteriography. Blood pressure control resulted in normalization of serum and urinary electrolytes and decrease of proteinuria. Hyponatremia and transient massive proteinuria in this patient seem to be caused by high-pressure-forced diuresis due to malignant renoparenchymal hypertension.

Comparison of two methods for predicting equilibrated Kt/V (eKt/V) using true eKt/V value

Abstract Two methods have been suggested by Daugirdas and Schneditz (the rate equation), and Smye for predicting true equilibrated Kt/V (eKt/V) without the need for obtaining a blood sample 60 min after hemodialysis (HD). We compared the accuracy of these two methods when applied to pediatric HD. Thirty-eight standard pediatric HD sessions in 15 patients, (6 male, 9 female), aged 14.5±3.3 years, were analyzed. Kt/V was calculated by formal variable-volume single-pool urea kinetic model with post-HD urea taken at the end of HD (single-pool Kt/V), and with equilibrated urea (Ceq) taken 60 min after the end of HD (eKt/V). eKt/V was predicted by the rate equation from single-pool Kt/V and by the Smye method from predicted Ceq. Mean values obtained by both the rate equation (1.44±0.32, P>0.05) and by the Smye method (1.47±0.36, P>0.05) were similar to eKt/V (1.42±0.30), but correlation between results from the rate equation and eKt/V (r=0.863) was higher than between those from the Smye method and eKt/V (r=0.654). Average absolute error of the rate equation in predicting eKt/V was 0.118±0.114 (median 0.095) Kt/V units and 8.53%±8.36% (median 6.29%), while for the Smye method it was significantly higher [0.221±0.180 (median 0.190) Kt/V units, P=0.001; 16.49%±15.98% (median 11.88%) P=0.004]. High correlation between eKt/V and results from the rate equation indicates that urea rebound (expressed as ΔKt/V) is a function of the rate of dialysis (K/V). To test this, we analyzed the relationship of K/V and other parameters (session duration, body mass index, ultrafiltration rate, blood flow, and urea distribution volume) with ΔKt/V. The only significant (P<0.01) and highest correlation (r=0.442) was found for K/V. We conclude that in children on chronic HD, the rate equation is a better predictor of eKt/V than the Smye method, and that HD efficiency is the strongest determinant of postdialysis urea rebound in children.

Application of Individualized Bayesian Urea Kinetic Modeling to pediatric hemodialysis.

Incorporating urea rebound using equilibrated urea concentration (Ceq) after hemodialysis (HD) is essential for accurate assessment of HD efficiency. It is impractical to measure Ceq in clinical settings, and there are no recommended methodologies to predict Ceq in children. The objective of this work is to assess the ability of an Individualized Bayesian Urea Kinetic Model (IBKM) for predicting Ceq in children receiving HD. Developed based on adult HD data, the IBKM is a two-pool urea kinetic model that calculates Bayesian estimates of individual Ceq. Blood urea nitrogen (BUN) samples from 30 HD sessions in 13 children (age 12–18 years) were taken at pre-HD, immediately post-HD, and 60 minutes post-HD (Ceq). The IBKM and estimated population parameters from adult data were fitted to the observed data from children to predict individual Ceq using NONMEM VI software in comparison with observed Ceq (9.5 ± 3.8 mmol/L), the average individual predicted Ceq was 9.4 ± 3.8 mmol/L, with absolute individual prediction error of 6.2% ± 4.4%. For a given dialysis goal and desired dialysis duration, the required blood flow rate and dialyzer size are predicted by IBKM and confirmed by the analysis data. This study suggests that the IBKM can be used in a pediatric HD setting and accurately predict Ceq in children using only pre-HD and immediately post-HD BUN.

Prediction of equilibrated urea in children on chronic hemodialysis.

Urea rebound (UR) after hemodialysis (HD) requires the use of equilibrated urea (Ceq) instead of immediate end-dialysis urea (Ct) for correct quantification of HD, which is impractical. A new formula for predicting Ceq in children is suggested in our study. Thirty eight standard pediatric HD sessions (single pool Kt/V = 1.70 +/- 0.35, K = 4.65 +/- 1.14 ml/min/kg, UF coeff. = 3.2-6.2 ml/h/mm Hg, t = 3.80 +/- 0.46 h) in 15 children (M: 6, F: 9), ages 14.5 +/- 3.28 years were analyzed. Blood samples were taken: before, 70 min from the start, at the end, and 60 min after the end of HD sessions. After correlating UR (20.32 +/- 7.74%) to various HD parameters, we found that it was mainly determined by HD efficiency parameters. Therefore we correlated Ceq to HD efficiency parameters (Ct, urea reduction ratio, Kt/V, and K/V) and found a very high correlation between Ct and Ceq (r = 0.973). Linear regression analysis was used to further investigate this relationship, and a new formula to predict Ceq from Ct was obtained (Ceq = 1.085 Ct + 0.729, R2 = 0.946, SE = 0.49, absolute residuals = 0.38 +/- 0.29 mmol/L). In a validation study (10 HD sessions with new set of urea blood samples) the results obtained by the new formula were compared with measured values of Ceq and those obtained by the Smye formulae. Values predicted by the new formula (9.91 +/- 2.92 mmol/L) were not significantly different from the measured values (10.33 +/- 3.44 mmol/L). Absolute error of the new formula was 0.78 +/- 0.73 mmol/L, median 0.65; ie., 6.93 +/- 5.3%, median 7.7%. Ceq predicted by the Smye formulae (10.95 +/- 4.18 mmol/L) also did not significantly differ from the measured values, but absolute error of predicted values was markedly higher (1.21 +/- 0.90 mmol/L, median 0.89; 11.73 +/- 7.72%, median 10.11%; p < 0.05). When predicted Ceq was used for calculating equilibrated Kt/V (eKt/V), the new formula resulted in lower absolute error (0.09 +/- 0.07, median 0.08) than the Smye method (0.14 +/- 0.08, median 0.12). We conclude that our simple formula is sufficiently accurate in predicting Ceq in standard pediatric HD and that it is more accurate than the existing Smye formulae, while requiring only pre- and post-HD urea samples. We suggest the use of the new formula for predicting Ceq, which can then be used instead of Ct for a more accurate estimation of double pool Kt/V, URR, V, and PCR.

Effects of Postdialysis Urea Rebound on the Quantification of Pediatric Hemodialysis

Urea rebound (UR) causes single pool urea kinetic modeling (UKM), which is based on end-dialysis urea instead of its equilibrated value (Ceq), to erroneously quantify hemodialysis (HD) treatment. We estimated the impact of postdialysis UR on the results of formal variable volume single pool (VVSP) UKM [Kt/V, urea distribution volume (V), urea generation rate (G), normalized protein catabolic rate (nPCR), and urea reduction ratio (URR)] in children on chronic HD. Thirty-eight standard pediatric HD sessions in 15 stable patients (9 female, 6 male) aged 14.5 ± (SD) 3.28 years were investigated. The HD sessions lasted 3.75 ± 0.43 h. The single pool urea clearance was 4.84 ± 1.25 ml/min/kg. All HD sessions were evaluated by VVSP and URR (%) with postdialysis urea taken at the end of HD and with Ceq taken 60 min after the end of HD, incorporating double pool effects and representing true double pool values. The anthropometric V was calculated by Cheek and Mellits formulae for children. VVSP significantly overestimated Kt/V by 0.26 ± 0.18 U (1.68 ± 0.36 vs. 1.42 ± 0.30, p < 0.0001), i.e., 19.05 ± 13.07%, G/V (0.20 ± 0.04 vs. 0.18 ± 0.04, p < 0.0001), nPCR (1.26 ± 0.23 vs. 1.18 ± 0.22 g/kg/day, p < 0.0001), and URR (73.92 ± 6.49 vs. 69.22 ± 7.06, p < 0.0001). VVSP significantly underestimated kinetic V in comparison to anthropometric V (18.74 ± 4.04 vs. 20.76 ± 4.43 liters or expressed as V/body weight: 58 ± 8 vs. 65 ± 9%, p < 0.05), while double pool kinetic V was more accurate (21.45 ± 4.34 liters, V/body weight: 64 ± 6%, p > 0.05). We conclude that UR has a significant effect on all results of UKM even after standard pediatric HD, and the degree of this efffect is documented. We suggest an increase of the minimum required prescribed single pool Kt/V in children and reduction of any delivered single pool Kt/V by approxiamtely 0.26 Kt/V U. Overestimation of nPCR by approximately 0.08 g/kg/day and underestimation of V by 8.5% should be kept in mind.

Effect of the decrease in dialysate sodium in pediatric patients on chronic hemodialysis

Optimal dialysate sodium (dNa) is unknown, with both higher and lower values suggested in adult studies to improve outcomes. Similar studies in pediatric hemodialysis (HD) population are missing. This is the first report of the effect of two constant dNa concentrations in pediatric patients on chronic HD. 480 standard HD sessions and interdialytic periods were studied in 5 patients (age 4–17 years, weight 20.8–66 kg) during a period of 6–11 months per patient. dNa was 140 mEq/L during the first half, and 138 mEq/L during the second half of the study period for each patient. Lowering dNa was associated with improved preHD hypertension, decreased interdialytic weight gain, decreased need for ultrafiltration, lower sodium gradient and was well tolerated despite lack of concordance with predialysis sNa, that was variable. Further studies are needed to verify our findings and to investigate if an even lower dNa may be more beneficial in the pediatric HD population.

Use of ionic dialysance to calculate Kt/V in pediatric hemodialysis

Online clearance (OLC) monitor measures conductivity difference between dialysate entering and leaving the dialyser. Derived ionic dialysance (ID) represents effective urea clearance from which Kt/V is calculated, allowing Kt/V monitoring at every treatment without blood sampling. We tested ID accuracy in children and provide recommendations for its use. Using Fresenius machines 2008 K with built‐in OLC monitors, we studied 45 hemodialysis (HD) sessions and 168 calculated Kt/V results in 11 patients. Urea distribution volume (V), needed to calculate Kt/V from ID, was estimated using three methods: Mellits and Cheek (MC), KDOQI recommended total body water nomograms (TBWN) and OLC‐derived independent from tested HD sessions. Reference spKt/V from pre‐ and post‐HD BUN (Daugirdas) was compared with Kt/V calculated from ID using three different estimated Vs. ID was accurate in calculating Kt/V in children when V derived from OLC was used (P = 0.42), with absolute error 0.14 ± 0.12. If TBWN‐derived V was used, Kt/V was consistently underestimated by 0.32 ± 0.22. TBWN‐derived V can still be recommended for use with OLC for monitoring trend in Kt/V, if underestimation of spKt/V of average 0.3 is accounted for. MC‐derived V results in even greater underestimation of spKt/V and therefore cannot be recommended for use with OLC.

Comparison of cystatin C and Beta‐2‐microglobulin kinetics in children on maintenance hemodialysis

Middle‐molecules (MM) are not monitored in children on hemodialysis (HD), but are accumulated and increase the risk of cardiovascular disease and mortality. Molecular properties of Cystatin C (CyC), 13 kDa, potentially make it a preferred MM marker over Beta‐2‐Microglobulin (B2M), 12 kDa. We compared CyC and B2M kinetics to investigate if CyC can be used as preferred MM marker. CyC (mg/L) and B2M (μg/mL) were measured in 21 low‐flux HD sessions in seven children. Blood samples were taken at HD start (pre), 1 and 2 hours into HD and at end of HD (post) for all sessions and 60 minutes after the first HD (Eq). PreCyC (9.85 ± 2.15) did not differ (P > 0.05) from postCyC (10.04 ± 2.83). PostB2M (38.87 ± 7.12) was higher (P < 0.05) than preHD B2M (33.27 ± 7.41). There was no change in CyC at 1 and 2 hours into HD, while B2M progressively increased. CyC or B2M changes did not significantly correlate with spKt/V (2.09 ± 0.86), ultrafiltration (4.61 ± 1.98%) or HD duration (218 ± 20 minutes). EqCyC was not different from postCyC (11.07 ± 3.14 vs. 10.71 ± 2.85, P > 0.05), while EqB2M was lower than postB2M (36.48 ± 7.68 vs. 41.09 ± 8.99, P < 0.05). MMs as represented by B2M and CyC are elevated in children on standard HD. Intensified HD modalities would be needed for their removal. B2M is affected by the dialytic process with a rise during HD independent of ultrafiltration and decrease 1 hour after, while CyC remains unchanged. We suggest that CyC be used as preferred marker of MM removal and as a marker of adequacy of intensified HD regimens.