Otto Schück

Glomerular Filtration Rate Estimation in Patients with Advanced Chronic Renal Insufficiency Based on Serum Cystatin C Levels

Background: Cystatin C has an obvious advantage in the recognition of the initial stages of renal impairment. It is questionable whether cystatin C possesses the same benefit in follow-up of pre-dialysis patients. If cystatin C were also a sensitive marker of GFR in pre-dialysis patients, then it could be expected that, for the same degree of a decrease in GFR, the increase in S_cyst would be higher than in S_cr because of the significant increase in tubular secretion of creatinine in residual nephrons. The aim of this study was to evaluate whether S_cyst in patients with GFR ≤40 ml/min/1.73 m² provides a more accurate estimate of GFR than S_cr does. Methods: The study was performed in 67 patients (mean age 41.5 ± 7.6 years) with chronic renal insufficiency (GFR = 19.8 ± 9.9 ml/min/1.73 m²) caused by various chronic renal diseases (predominantly by chronic glomerulonephritis and chronic interstitial nephritis). GFR was measured by inulin clearance under conditions of stabilized plasma concentrations and water loading. Creatinine clearance and serum cystatin C concentration (using immunonephelometry) were measured at the same time. For statistical evaluation, linear regression analysis, receiver-operating characteristic (ROC) curves analysis and the method of Bland and Altman were used. Results: A significant correlation (r = 0.813, p < 0.001) was demonstrated between 1/S_cyst and C_in as well as between 1/S_cr and C_in (r = 0.815, p < 0.001). There were no significant differences between the regression coefficients and the intercepts of regression straight lines characterizing these relationships. ROC curves analysis using the cut-off values for C_in = 20 ml/min/1.73 m² and C_in = 10 ml/min/ 1.73 m² did not show significant differences of corresponding AUC values for S_cyst and S_cr although there was a trend for superiority of S_cyst in comparison with S_cr. The multiples of upper reference values of S_cyst and S_cr in examined patients did not differ significantly. There was a highly significant linear correlation between C_in and C_cr in pre-dialysis patients (r = 0.921, p < 0.001). The regression coefficient of this relation (1.279) was significantly higher than 1.0 (p < 0.001) and the value of intercept (6.50 ml/min/1.73 m²) was significantly higher than zero (p < 0.001). The average of C_cr/C_in in patients with C_in <10 ml/min/1.73 m² was 2.11 (± 0.29) and 1.72 (± 0.35) for those with C_in 10–20 ml/min/1.73 m². Conclusions: The findings suggest that in patients with advanced chronic renal insufficiency (CRI) for the same decrease in GFR the increase of S_cyst is not significantly higher than that of S_cr, although the tubular secretion of creatinine is significantly increased. Further studies (especially those focused on nonrenal elimination of cystatin C) are needed to elucidate the lack of difference between changes in S_cyst and S_cr in patients with CRI.

Estimation of glomerular filtration rate in obese patients with chronic renal impairment based on serum cystatin C levels.

BACKGROUND Serum cystatin C (Scyst) has an obvious advantage in recognizing the initial stages of renal impairment. However, several recent studies suggest that Scyst may also be affected by some nonglomerular factors such as thyroid dysfunction, glucocorticoid administration or metabolic status of the diabetic patient. The aim of this study was to evaluate whether obesity could affect Scyst. PATIENTS AND METHODS The study was performed in 33 patients (mean age 49.1 +/- 6.3 years) with chronic renal disease (Scr = 227 +/- 118 micromol/l) and BMI = 35.6 +/- 1.8 kg/m2, and in 78 patients (mean age 43.4 +/- 5.1 years) with chronic renal disease (Scr = 245 +/- 111 micromol/l) and BMI = 24.0 +/- 1.8 kg/m2. Glomerular filtration rate (GFR) was determined using renal inulin clearance (Cin) under conditions of stabilized plasma concentrations and water loading. Scyst was measured using immunonephelometry. For statistical evaluation, linear regression analysis and receiver-operating characteristic (ROC) curve analysis were used. RESULTS A significant correlation (r = 0.956, p < 0.001) between l/Scyst and Cin was demonstrated in patients with BMI > or = 30 kg/m2 (Group A). Similarly, a significant correlation (r = 0.900, p < 0.001) between l/Scys and Cin was found in patients with BMI < 30 kg/m2 (Group B). There was no significant difference between the regression straight lines characterizing these relationships. ROC curve analysis (using a cut-off value for Cin = 30 ml/min/1.73 m2) did not show significant differences in AUC, sensitivity and specificity for Scyst between obese and nonobese patients. CONCLUSION The results suggest that evaluation of GFR based on Scyst in obese patients need not differ from that in nonobese ones.

Reduction of plasma asymmetric dimethylarginine in obese patients with chronic kidney disease after three years of a low-protein diet supplemented with keto-amino acids: a randomized controlled trial

ZusammenfassungHINTERGRUND: Die Plasmaspiegel des endogenen Stickoxid-Hemmers asymmetrisches Dimethylarginin (ADMA) sind bei chronischem Nierenversagen erhöht und könnten zu den vaskulären Komplikationen beitragen. In dieser Studie wurde die Hypothese überprüft, ob diese erhöhten ADMA-Spiegel bei übergewichtigen CNV-Patienten durch eine Langzeittherapie mit einer Ketosäuren-supplementierten niedrigprotein-Diät (KA) vermindert werden könnten. PATIENTEN UND METHODEN: Insgesamt 111 CNV-Patienten (54 M/57 F) mit Adipositas (BMI ≥ 30 kg/m2), Alter 22–76 Jahre und einer Inulin-Clearance von 22–40 ml/min/1,73 m2 wurden in eine randomisiert-kontrollierte doppel-blinden Untersuchung einschlossen. Die Patienten erhielten über 336 Monate eine Niedrig-Protein-Diät (LPD) von 0,6 Protein/kg KG/Tag und 120–125/kJ/kg KG/Tag. In 66 Patienten, Gruppe I, wurde diese LPD mit KA (100 mg/kg KG/Tag) supplementiert, 65 Patienten (Gruppe II) erhielten Placebo. ERGEBNISSE: Während der Studienperiode nahm die glomeruläre Filtrationsrate leicht ab (Cin von 32,4 ± 12,6 auf 29,8 ± 8,6 ml/min/1,73m2 und 33,2 ± 12,6 auf 23,2 ± 98,4 ml/min/1,73 m2 in den Gruppen I und II; dies war ausgeprägter in Grupppe II (p < 0,01)). Der BMI verminderte sich in Gruppe I von 32.0 ± 3.3 auf 26.1 ± 4.0 kg/m2 (p < 0,01), dies war auf einen Rückgang des viszeralen Fettes gemessen mit MRI zurückzuführen (p < 0,01). Die Änderung des BMI war in Gruppe II nicht signifikant. In Gruppe I fand sich ein Rückgang des Plasmaspiegel von ADMA von 2,5 ± 0,5 auf 1,3 ± 0,4 µmol/l (p < 0,01), dieser blieb in Gruppe II unverändert. In Gruppe I fand sich auch ein Rückgang der Plasma-Konzentration von Pentosidin (von 480 ± 170 auf 320 ± 120 µg/L, p < 0,01) und der Proteinurie (von 3,8 ± 2,24 auf 1,6 ± 1,0 g / 24 h, p < 0,02). Plasma Adiponectin (ADPN) stieg in Gruppe I an (p < 0,01). Ausgeprägter in Gruppe I fand sich ein leichter Abfall von Gesamtcholesterin und LDL-Cholesterin (p < 0,02). In Gruppe I fielen die Plasma-Triglyzeride (von 3,9 ± 1,6 auf 2,2 ± 0,6 mmol/l, p < 0,01), das glykierte Hämoglobin (HbAc1) von 7,2 ± 1,4 auf 4,2 ± 0,8% (p < 0,02). ZUSAMMENFASSUNG: Bei übergewichtigen Patienten mit CNV führt eine Langzeit-Gabe von Ketosäuren zusammen mit einer LPD in Vergleich zu Placebo zu einer Verminderung des viszeralen Körperfettes und zu einer Verzögerung des Nierenfunktionsverlustes. Ein gleichzeitiger Rückgang des Plasmaspiegels von ADMA, aber auch von Pentosidin könnten zusammen mit einem Rückgang der Proteinurie zu einer Vermindung der Progression des Nierenversagens beitragen.SummaryBACKGROUND: Levels of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) are elevated in chronic kidney disease (CKD) and may contribute to vascular complications. In this study we tested the hypothesis that elevated ADMA can be reduced in obese CKD patients by long-term administration of a low-protein diet supplemented with keto-amino acids. PATIENTS AND METHODS: In a long-term prospective double-blind placebo-controlled randomized trial, we evaluated for a period of 36 months a total of 111 CKD patients (54 men, 57 women) aged 22–76 years with obesity (BMI ≥ 30 kg/m2) and an inulin clearance rate (Cin) of 22–40 ml/min/1.73 m2. All patients were on a low-protein diet containing 0.6 g protein/kg BW per day and 120–125 kJ/kg BW per day. The diet was randomly supplemented with keto-amino acids at a dosage of 100 mg/kg BW per day (66 patients, Group I); 65 patients received placebo (Group II). RESULTS: During the study period, the glomerular filtration rate decreased slightly in Group I (Cin from 32.4 ± 12.6 to 29.8 ± 8.6 ml/min/1.73 m2) and more markedly in Group II (from 33.2 ± 12.6 to 23.2 ± 98.4 ml/min/1.73m2, P < 0.01). BMI decreased significantly in Group I (from 32.0 ± 3.3 to 26.1 ± 4.0 kg/m2, P < 0.01) and was linked to reduced volume of visceral fat measured by MRI (P < 0.01). Reduction of BMI in Group II was not significant. In Group I, there was a significant decrease in the plasma level of ADMA (from 2.5 ± 0.5 to 1.3 ± 0.4 µmol/l, P < 0.01), but ADMA remained unchanged in Group II. A further remarkable finding in Group I was reduction in the plasma concentration of pentosidine (from 480 ± 170 to 320 ± 120 µg/l, P < 0.01) and decrease of proteinuria (from 3.8 ± 2.24 to 1.6 ± 1.0 g/24 h, P < 0.02). Plasma adiponectin rose in Group I (P < 0.01). Analysis of the lipid spectrum revealed a mild but significant decrease in total cholesterol and LPD-cholesterol (P < 0.02), more pronounced in Group I. There was also a decrease in plasma triglycerides in Group I (from 3.9 ± 1.6 down to 2.2 ± 0.6 mmol/l, P < 0.01) and a decrease in glycated hemoglobin (from 7.2 ± 1.4% to 4.2 ± 0.8%, P < 0.02). CONCLUSION: Compared with the placebo group, long term co-administration of a low-protein diet and keto-amino acids in CKD patients with obesity led to decreases of ADMA, visceral body fat and proteinuria. Concomitant decreases of glycated hemoglobin, LDL-cholesterol and pentosidine may also contribute to the delay in progression of renal failure.

Estimation of glomerular filtration rate based on the modification of diet in renal disease equation in patients with chronic renal failure.

The list of indications for initiating regular dialysis treatment includes residual glomerular filtration rate (GFR). Under the current European Best Practice Guidelines for Hemodialysis, residual GFR (and the presence of one or more symptoms of uremia) should not decrease below 15 ml/min. The present article seeks to determine to what extent the modification of diet in renal disease (MDRD) equation enables the detection of this decrease in GFR. We tried to answer this question using a more detailed analysis of the relationship between MDRD and renal inulin clearance (Cin). Residual GFR based on Cin (under conditions of stable plasma levels and water loading) and GFR calculated using the MDRD equation was measured in 79 individuals with chronic renal failure (with mean Cin = 19.1 ± 10.1 ml/min/1.73 m2). Statistical evaluation was performed using regression analysis, the interchangeability of both methods (Bland-Altman) and receiver-operating characteristic (ROC) curve analysis. Regression analysis demonstrated a significant correlation between MDRD and Cin (r = 0.892; p < 0.001). However, the regression equation line for the correlation differs significantly from the identity line (p < 0.001). The value of the regression coefficient (0.722) is significantly lower than 1.0 (CI50 0.63; 0.81). The mean MDRD – Cin difference was 3.26 ± 4.46 ml/min/1.73 m2 and the value was significantly different from zero (p < 0.001). The mean difference +2 SD was 12.2 ml/min/1.73 m2, and the mean – 2 SD was –5.7 ml/min/1.73 m2. ROC curve analysis (for a cutoff Cin = 15 ml/min/1.73 m2) indicates an area under the curve (AUC) of 0.954 ± 0.023. The best combination of sensitivity and specificity was obtained for a MDRD of 19.7 ml/min/1.73 m2, with a sensitivity of 90.5% and specificity of 87.5%. For cutoff value of Cin = 10 ml/min/1.73 m2, the AUC was 0.939 ± 0.026 (CI95 0.863–0.890). A combination of maximum sensitivity and specificity was obtained with an MDRD of 16.5 ml/min/1.73 m2. With this value, MDRD sensitivity was 100% and specificity 81.5%. A significant correlation between the MDRD equation and the measured creatinine clearance (Ccr) was found (r = 0.883, p < 0.001). The mean difference of MDRD – Ccr was –7.2 ± 6.5 ml/min/1.73 m2. This is significantly different from that of MDRD – Cin (p < 0.001). Our results suggest that MDRD and Cin in individuals with chronic renal failure are not interchangeable methods for a GFR <15 ml/min/1.73 m2 determination. However, MDRD may furnish valuable information in terms of detecting a critical decrease in GFR; but, the MDRD equation for this decrease in GFR (15 ml/min/1.73 m2) will provide a somewhat higher value (19.7 ml/min/1.73 m2).

The Association between Left Ventricular Diastolic Function and a Mild-to-Moderate Decrease in Glomerular Filtration Rate in Patients with Type 2 Diabetes Mellitus

This prospective study evaluated the relationship between echocardiography parameters of left ventricular (LV) diastolic function and mild-to-moderate renal function impairment in 82 patients with type 2 diabetes mellitus. The mean age of the patients was 61.1 years. A significant correlation was found between estimated glomerular filtration rate (eGFR) and the ratio of peak velocity of early transmitral flow (E) to peak velocity of early diastolic mitral annular motion (E′). Cluster analysis revealed two subgroups of patients with different E′ values but comparable eGFRs. The correlation between eGFR and E/E′ was significant in 38 patients with E′ ≤ 7.1 cm/s, but not significant in 44 patients with E′ > 7.1 cm/s. The results suggest that the deterioration of LV relaxation (E′) represents the underlying condition for the association between mild-to-moderate renal function impairment and the non-invasive parameter of LV end-diastolic pressure (E/E′), in patients with type 2 diabetes without any previous cardiovascular event and with well-controlled blood pressure.

Plasma Adrenomedullin and Subclinical Cardiorenal Syndrome in Patients with Type 2 Diabetes Mellitus

OBJECTIVE: To evaluate whether plasma adrenomedullin is involved in the previously reported significant inverse correlation between left ventricular (LV) end-diastolic pressure (peak velocity of early transmitral flow/peak velocity of early diastolic mitral annular motion ratio [E/E′]) and estimated glomerular filtration rate (eGFR) in patients with type 2 diabetes mellitus, mild-to-moderate renal function impairment and LV relaxation impairment (E′ ≤ 7.1 cm/s). METHODS: Plasma adrenomedullin concentration, E/E′ and eGFR were assessed in 82 patients with type 2 diabetes. RESULTS: Plasma adrenomedullin concentration was positively correlated with eGFR in patients with or without LV relaxation impairment, and inversely correlated with E/E′ in patients with LV relaxation impairment. Multivariate linear regression analysis supported a role for plasma adrenomedullin in the association between E/E′ and eGFR. CONCLUSION: These results support the hypothesis that adrenomedullin modulates the interaction between the heart and kidneys in early subclinical cardiorenal syndrome in patients with type 2 diabetes mellitus.

Sodium-Chloride Difference as a Simple Parameter for Acid-Base Status Assessment

To the Editor: We read with great interest the recent article by Adrogué and Madias and agree with all its conclusions. However, the article did not comment on a simple and useful parameter for assessing acid-base status; namely, the difference between 2 major serum ions, sodium and chloride. The relationship between serum bicarbonate, sodium-chloride difference, and the anion gap (AG) can be expressed by the equation: AG 5 Na 2 Cl 2 HCO3 ; modified to HCO3 5 (Na 2 Cl) – AG. It implies that if sodium-chloride difference remains constant, there is an inverse linear relationship between bicarbonate and the AG. If the AG is unchanged, a relationship must exist between bicarbonate and sodium-chloride difference. Therefore, a decrease in sodium-chloride difference is associated with bicarbonate loss or dilution acidosis. Serum sodium and

A “Lingering Mystery” of Postdialysis Serum Bicarbonate Concentration

References 1. Riccio E, Sabbatini M, Esposito G, Pisani A. Catheter-based renal denervation in ADPKD: just for pain control? Am J Kidney Dis. 2014;64(6):999. 2. Krum H, Schlaich M, Whitbourn R, et al. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet. 2009;373(9671):1275-1281. 3. Esler MD, Krum H, Sobotka PA, et al. Renal sympathetic denervation in patients with treatment-resistant hypertension (the Symplicity HTN-2 trial): a randomised controlled trial. Lancet. 2010;376(9756):1903-1909. 4. Bhatt DL, Kandzari DE, O’Neill WW, et al. A controlled trial of renal denervation for resistant hypertension. N Engl J Med. 2014;370(15):1393-1401. 5. Harrison JL, Hildreth CM, Callahan SM, Goodchild AK, Phillips JK. Cardiovascular autonomic dysfunction in a novel rodent model of polycystic kidney disease. Auton Neurosci. 2010;152(1-2):60-66. 6. Klein IH, Ligtenberg G, Oey PL, Koomans HA, Blankestijn PJ. Sympathetic activity is increased in polycystic kidney disease and is associated with hypertension. J Am Soc Nephrol. 2001;12(11):2427-2433. 7. Shetty SV, Roberts TJ, Schlaich MP. Percutaneous transluminal renal denervation: a potential treatment option for polycystic kidney disease-related pain? Int J Cardiol. 2013;162(3): e58-e59. 8. Prejbisz A, Kadziela J, Lewandowski J, et al. Effect of percutaneous renal denervation on blood pressure level and sympathetic activity in a patient with polycystic kidney disease. Clin Res Cardiol. 2014;103(3):251-253. 9. Walsh N, Sarria JE. Management of chronic pain in a patient with autosomal dominant polycystic kidney disease by sequential celiac plexus blockade, radiofrequency ablation, and spinal cord stimulation. Am J Kidney Dis. 2012;59(6): 858-861. 10. Riccio E, Esposito G, Franzone A, Imbriaco M, Santangelo M, Pisani A. Renal sympathetic-nerve ablation for uncontrolled hypertension in a patient with single-kidney autosomal dominant polycystic kidney disease. J Clin Hypertens (Greenwich). 2014;16(5):385-386.

Acid-base balance in peritoneal dialysis patients: a Stewart-Fencl analysis.

Background. Evaluation of acid-base disorders using the Stewart-Fencl principle is based on assessment of independent factors: strong ion difference (SID) and the total concentration of non-volatile weak acids (Atot). This approach allows for a more detailed evaluation of the cause of acid-base imbalance than the conventional bicarbonate-centered approach based on the Henderson-Hasselbalch principle, which is a necessary yet insufficient condition to describe the state of the system. The aim of our study was to assess acid-base disorders in peritoneal dialysis (PD) patients using both of these principles. Methods. A total of 17 patients with chronic renal failure (10 men), aged 60.7 (22–84) years, treated by PD for 25.7 (1–147) months were examined. A control group included 17 healthy volunteers (HV) (8 males), with a mean age of 42.7 (22–77) years and normal renal function. Patients were treated with a solution containing bicarbonate (25 mmol/L) and lactate (15 mmol/L) as buffers; eleven of them used, during the nighttime dwell, a solution with icodextrin buffered by lactate at a concentration of 40 mmol/L. The following equations were employed for calculations of acid-base parameters according to the Stewart-Fencl principle. The first is SID = [Na+] + [K+] + 2[Ca2+] + 2[Mg2+] − [Cl−] − [UA−], where SID is the strong ion difference and [UA−] is the concentration of undetermined anions. For practical calculation of SID, the second equation, SID = [HCO3−] + [Alb−] + [Pi−], was used, where [Alb−] and [Pi−] are the charges carried by albumin and phosphates. The third is Atot, the total concentration of weak non-volatile acids, albumin [Alb] and phosphates [Pi]. Results. The capillary blood pH in PD group was 7.41 (7.27–7.48), [HCO3−] levels 23.7 (17.6–29.5) mmol/L, SID 36.3 (29.5–41.3) mmol/L, sodium-chloride difference 39.0 (31.0–44.0) mmol/L, [Pi] 1.60 (0.83–2.54) mmol/L, and [Alb] 39.7 (28.8–43.4) g/L (median, min-max). Bicarbonate in blood correlated positively with SID (Rho = 0.823; p < 0.001), with the sodium-chloride difference (Rho = 0.649; p < 0.01) and pH (Rho = 0.754; p < 0.001), and negatively with residual renal function (Rho = −0.517; p < 0.05). Moreover, the sodium-chloride difference was also found to correlate with SID (Rho = 0.653; p < 0.01). While the groups of PD and HV patients did not differ in median bicarbonate levels, significantly lower median value of SID were observed in PD patients, 36.3 vs. 39.3 mmol/L (p < 0.01); additionally, PD patients were shown to have significantly lower mean value of serum sodium levels, 138 vs. 141 mmol/L (p < 0.01), and serum chlorides levels, 100 vs. 104 mmol/L (p < 0.001). Despite the higher [UA−] levels in PD patients, 9.1 vs. 5.4 mmol/L (p < 0.001), this parameter was not found to correlate with bicarbonate levels. Conclusions. The results suggest that the decreased bicarbonate in PD patients results from a combination of decreased sodium-chloride difference and mildly increased unmeasured anions.

Effects of high-tone external muscle stimulation on renal function in healthy volunteers.

OBJECTIVE AND DESIGN Hightone external muscle stimulation (HTEMS) ameliorates pain and discomfort of patients with polyneuropathy. Since some patients reported about an urge to urinate during these treatments, the potential effects of HTEMS application on renal function were investigated. For this purpose in healthy subjects, we analyzed in the current study the acute effects of electrotherapy on parameters of renal function. INTERVENTIONS 24 healthy volunteers (14 women and 10 men), mean age 26 ± 4 years, were enrolled. The protocol was composed of a run-in period, a pre-treatment period, the active HTEMS treatment period of both lower extremities and the post-treatment period. The duration of each period was 60 min. Urine collection and blood samples were taken at the beginning and end of each period. To achieve a sufficient diuresis, the fluid intake was adapted to the amount of diuresis. Parameters of renal function included diuresis, glomerular filtration rate (endogenous creatinine clearance) and absolute and fractional sodium excretion. Moreover blood pressure and heart rate were monitored. RESULTS HTEMS led to a significant increase of creatinine clearance and fractional sodium excretion which was limited to the active treatment period. CONCLUSION These findings show for the first time that HTEMS can transiently increase glomerular filtration rate associated with a decreased tubular sodium reabsorption. The underlying mechanisms are to be elucidated.