Water and Salt: from renal mechanisms to clinical disorders

Chapter 1 is a brief introduction to the renal mechanisms and clinical disorders of water and sodium balance. The aims of the thesis are presented. The thesis is divided into two parts. Part A (Chapters 2 – 6) presents studies investigating the renal mechanisms of water and sodium balance regulation, while Part B (Chapters 7 – 14) presents studies investigating clinical disorders of water and sodium balance. Chapter 2, the first chapter of Part A, is an introduction to the proteomics technique Difference Gel Electrophoresis (DIGE). Proteomics is a promising new technique with the ability to study cellular signaling pathways and identify clinical disease biomarkers. DIGE is currently one of the few techniques to perform quantitative proteomics, generating a statistical output to differences in protein abundances. The chapter discusses the principles of DIGE-based proteomics, including sample preparation, two-dimensional electrophoresis (2-DE), stat

Intravenous fluids: balancing solutions

The topic of intravenous (IV) fluids may be regarded as “reverse nephrology”, because nephrologists usually treat to remove fluids rather than to infuse them. However, because nephrology is deeply rooted in fluid, electrolyte, and acid-base balance, IV fluids belong in the realm of our specialty. The field of IV fluid therapy is in motion due to the increasing use of balanced crystalloids, partly fueled by the advent of new solutions. This review aims to capture these recent developments by critically evaluating the current evidence base. It will review both indications and complications of IV fluid therapy, including the characteristics of the currently available solutions. It will also cover the use of IV fluids in specific settings such as kidney transplantation and pediatrics. Finally, this review will address the pathogenesis of saline-induced hyperchloremic acidosis, its potential effect on outcomes, and the question if this should lead to a definitive switch to balanced solutions

From ARB to ARNI in Cardiovascular Control

Coexistence of hypertension, diabetes mellitus and chronic kidney disease synergistically aggravates the risk of cardiovascular and renal morbidity and mortality. These high-risk, multi-morbid patient populations benefit less from currently available anti-hypertensive treatment. Simultaneous angiotensin II type 1 receptor blockade and neprilysin inhibition (‘ARNI’) with valsartan/sacubitril (LCZ696) might potentiate the beneficial effects of renin-angiotensin-aldosterone inhibition by reinforcing its endogenous counterbalance, the natriuretic peptide system. This review discusses effects obtained with this approach in animals and humans. In animal models of hypertension, either alone or in combination with myocardial infarction or diabetes, ARNI consistently reduced heart weight and cardiac fibrosis in a blood pressure-independent manner. Additionally, LCZ696 treatment reduced proteinuria, focal segmental glomerulosclerosis and retinopathy, thus simultaneously demonstrating favourable effects on microvascular complications. These results were confirmed in patient populations. Besides blood pressure reductions in hypertensive patients and greatly improved (cardiovascular) mortality in heart failure patients, ventricular wall stress and albuminuria w

Serum bicarbonate is associated with kidney outcomes in autosomal dominant polycystic kidney disease

BACKGROUND: Metabolic acidosis accelerates progression of chronic kidney disease, but whether this is also true for autosomal dominant polycystic kidney disease (ADPKD) is unknown. METHODS: Patients with ADPKD from the DIPAK (Developing Interventions to halt Progression of ADPKD) trial were included [n = 296, estimated glomerular filtration rate (eGFR) 50 ± 11 mL/min/1.73 m(2), 2.5 years follow-up]. Outcomes were worsening kidney function (30% decrease in eGFR or kidney failure), annual eGFR change and height-adjusted total kidney and liver volumes (htTKV and htTLV). Cox and linear regressions were adjusted for prognostic markers for ADPKD [Mayo image class and predicting renal outcomes in ADPKD (PROPKD) scores] and acid–base parameters (urinary ammonium excretion). RESULTS: Patients in the lowest tertile of baseline serum bicarbonate (23.1 ± 1.6 mmol/L) had a significantly greater risk of worsening kidney function [hazard ratio = 2.95, 95% confidence interval (CI) 1.21–7.19] compared with patients in the highest tertile (serum bicarbonate 29.0 ± 1.3 mmol/L). Each mmol/L decrease in serum bicarbonate increased the risk of worsening kidney function by 21% in the fully adjusted model (hazard ratio = 1.21, 95% CI 1.06–1.37). Each mmol/L decrease of serum bicarbonate was also associated with further eGFR decline (−0.12 mL/min/1.73 m(2)/year, 95% CI −0.20 to −0.03). Serum bicarbonate was not associated with changes in htTKV or htTLV growth. CONCLUSIONS: In patients with ADPKD, a lower serum bicarbonate within the normal range predicts worse kidney outcomes independent of established prognostic factors for ADPKD and independent of urine ammonium excretion. Serum bicarbonate may add to prognostic models and should be explored as a treatment target in ADPKD

Urinary markers of intrarenal renin-angiotensin system activity in vivo

Recent interest focuses on urinary renin and angiotensinogen as markers of renal renin-angiotensin system activity. Before concluding that these components are independent markers, we need to exclude that their presence in urine, like that of albumin (a protein of comparable size), is due to (disturbed) glomerular filtration. This review critically discusses their filtration, reabsorption and local release. Given the close correlation between urinary angiotensinogen and albumin in human studies, it concludes that, in humans, urinary angiotensinogen is a filtration barrier damage marker with the same predictive power as urinary albumin. In contrast, in animals, tubular angiotensinogen release may occur, although tubulus-specific knockout studies do not support a functional role for such angiotensinogen. Urinary renin levels, relative to albumin, are >200-fold higher and unrelated to albumin. This may reflect release of renin from the urinary tract, but could also be attributed to activation of filtered, plasma-derived prorenin and/or incomplete tubular reabsorption

Serum uric acid and chronic kidney disease: The role of hypertension

Background: There are inconsistent findings on the role of hyperuricemia as an independent risk factor for chronic kidney disease (CKD). Hypertension has been implicated as a factor influencing the association between serum uric acid and CKD. In this population-based study we investigated the association between serum uric acid and decline in renal function and tested whether hypertension moderates this association. Methods: We included 2601 subjects aged 55 years and over from the Rotterdam Study. Serum uric acid and estimated glomerular filtration rate (eGFR) were assessed at baseline. After average 6.5 years of follow-up, second eGFR was assessed. CKD was defined as eGFR<60 ml/min/1.73 m2. All associations were corrected for socio-demographic and cardiovascular factors. Results: Each unit (mg/dL) increase in serum uric acid was associated with 0.19 ml/min per 1.73 m2 faster annual decline in eGFR. While the association between serum uric acid and incidence of CKD was not significant in our study population (Hazard Ratio: 1.12, 95% confidence interval [CI]: 0.98-1.28), incorporating our results in a meta-analysis with eleven published studies revealed a significant association (Relative Risk: 1.18, 95%CI: 1.15-1.22). In the stratified analyses, we observed that the associations of serum uric acid with eGFR decline and incident CKD were stronger in hypertensive subjects (P for interaction = 0.046 and 0.024, respectively). Conclusions: Our findings suggest that hyperuricemia is independently associated with a decline in renal function. Stronger association in hypertensive individuals may indicate that hypertension mediates the association between serum uric acid and CKD

Measurement and interpretation of skin prick test results

Background: There are several methods to read skin prick test results in type-I allergy testing. A commonly used method is to characterize the wheal size by its 'average diameter'. A more accurate method is to scan the area of the wheal to calculate the actual size. In both methods, skin prick test (SPT) results can be corrected for histamine-sensitivity of the skin by dividing the results of the allergic reaction by the histamine control. The objectives of this study are to compare different techniques of quantifying SPT results, to determine a cut-off value for a positive SPT for histamine equivalent prick -index (HEP) area, and to study the accuracy of predicting cashew nut reactions in double-blind placebo-controlled food challenge (DBPCFC) tests with the different SPT methods. Methods: Data of 172 children with cashew nut sensitisation were used for the analysis. All patients underwent a DBPCFC with cashew nut. Per patient, the average diameter and scanned area of the wheal size were recorded. In addition, the same data for the histamine-induced wheal were collected for each patient. The accuracy in predicting the outcome of the DBPCFC using four different SPT readings (i.e. average diameter, area, HEP-index diameter, HEP-index area) were compared in a Receiver-Operating Characteristic (ROC) plot. Results: Characterizing the wheal size by the average diameter method is inaccurate compared to scanning method. A wheal average diameter of 3 mm is generally considered as a positive SPT cut-off value and an equivalent HEP-index area cut-off value of 0.4 was calculated. The four SPT methods yielded a comparable area under the curve (AUC) of 0.84, 0.85, 0.83 and 0.83, respectively. The four methods showed comparable accuracy in predicting cashew nut reactions in a DBPCFC. Conclusions: The 'scanned area method' is theoretically more accurate in determining the wheal area than the 'average diameter method' and is recommended in academic research. A HEP-index area of 0.4 is determined as cut-off value for a positive SPT. However, in clinical practice, the 'average diameter method' is also useful, because this method provides similar accuracy in predicting cashew nut allergic reactions in the DBPCFC