Optimal current frequency for the detection of changes in extracellular water in patients on hemodialysis by measurement of total body electrical resistance.

BACKGROUND & AIMS: Measurement of total body electrical resistance (TBER) to an alternating current is useful to monitor extracellular water (ECW) in patients on hemodialysis (HD). Which current frequency is preferable is subject of ongoing debate. The aim of this study was to quantify the implications of TBER measurements at current frequencies ranging from 0 to 1000 kHz for ECW monitoring in patients on HD. METHODS: Bioimpedance spectroscopy measurements were performed in 39 patients on HD using the Body Composition Monitor (BCM, Fresenius Medical Care). TBER data at 5, 50, 200, 500, and 1000 kHz were compared with the extrapolated TBER at 0 kHz (TBER0) assessed by Cole-Cole analysis. Sensitivity of each TBER configuration was evaluated at individual level, by assessment of the smallest ultrafiltration (UF) volume that induced a significant change in TBER, i.e. a change in TBER ≥ 2.7%. RESULTS: TBER precision was very high for all frequencies, with coefficients of variation of 0.25%-0.28%. Baseline TBER decreased with increasing current frequency. TBER was 2.9% lower at 5 kHz (P < 0.001), 11.6% lower at 50 kHz, and up to 22.0% lower at 1000 kHz. This pattern is attributed to a progressive increase in intracellular current conduction at higher frequencies. Sensitivity to volume changes induced by UF also decreased with increasing current frequency. At 0 and 5 kHz, an UF volume ≤ 0.5 L was sufficient to induce a significant increase in TBER in 87% of patients. This decreased to 69% at higher frequencies. CONCLUSION: ECW monitoring by TBER requires measurement at 5 kHz or less to ensure optimal performance.

Sensitivity of total body electrical resistance measurements in detecting extracellular volume expansion induced by infusion of NaCl 0.9.

BACKGROUND: Fluid balance management in hospitalized patients is hampered by the limited sensitivity of currently available tools. The aim of this study was to assess the sensitivity of total body electrical resistance (TBER) measurements for the detection of extracellular volume (ECV) expansion. METHODS: TBER and plasma resistivity (ρplasma) were measured during a 4-h infusion of NaCl 0.9% at a rate of 500 mL/h in 23 patients undergoing a diagnostic saline infusion test for primary hyperaldosteronism. Extracellular fluid gain (EFG) was defined as infusion volume minus urinary volume. RESULTS: Infusion of 2.0 L NaCl 0.9% was associated with a mean diuresis of 1.1 ± 0.5 L, an EFG of 0.9 ± 0.5 L, a decrease in ρplasma of 1.1 ± 0.7 Ω·cm or 1.7 ± 1.0% (P < 0.001), and a decline in TBER of 23.2 ± 10.9 Ω or 4.6 ± 2.2% (P < 0.001). At group level, infusion of 80 mL saline was sufficient to induce a statistically significant decline in mean TBER. At personal level, the decline in TBER was significant on 76% of occasions after an EFG of 0.5-0.75 L, and on all occasions after an EFG of 1.0 L or greater. CONCLUSION: Raw TBER data are very informative for the detection of ECV expansion induced by the infusion of NaCl 0.9%, with a sensitivity at a personal level that is relevant for clinical practice.

Monoclonal gammopathy of renal significance (MGRS) histopathologic classification, diagnostic workup, and therapeutic options.

Monoclonal gammopathy of renal significance (MGRS) includes all kidney disorders caused by a monoclonal protein (M-protein) secreted by a small plasma cell clone or other B-cell clones in patients who do not meet the diagnostic criteria for multiple myeloma or other B-cell malignancies. The underlying disorder in patients with MGRS is generally consistent with monoclonal gammopathy of undetermined significance (MGUS). MGRS-associated kidney disorders are various and the list is still expanding. The kidney disorders can manifest as glomerular diseases, tubulopathies, and vascular involvement with varying clinical presentations. Diagnosis is often challenging because of the wide spectrum of MGRS, and it is difficult to establish a pathogenic link between the presence of the M-protein or serum free light chains and kidney diseases; further complicating accurate diagnosis is the high incidence of MGUS and/or kidney disorders, independent of MGRS, in elderly patients. However, MGRS can significantly impair kidney function. Because treatment can stop and also reverse kidney disease, early recognition is of great importance. A combined haematologic and nephrologic approach is crucial to establish the causative role of the M-protein in the pathogenesis of kidney disease. Clone-directed therapy, which may include autologous stem cell transplantation in eligible patients, often results in improved outcomes. In this review, we discuss the histopathologic classification of MGRS lesions, provide a renal and haematologic diagnostic workup, discuss treatment options for MGRS, and introduce a Benelux MGRS Working Group.

Renal concentrating ability and glomerular filtration rate in lithium-treated patients.

BACKGROUND: Lithium is the most effective drug for mood stabilization in bipolar disorder. However, lithium exposure has been associated with an impaired renal concentrating ability (RCA) and glomerular filtration rate (GFR). We examined RCA and estimated GFR in a cohort of patients treated with lithium. METHODS: 134 patients (≥ 18 years of age) with a mood disorder treated with lithium were screened; 100 patients were included. Demographic and clinical characteristics and blood and urine samples were collected. Additionally, a dDAVP-test was performed to determine maximal RCA. RESULTS: A dDAVP-test was performed in 98 patients (37 males, 61 females). Mean age was 51 years (SD: 12), median duration of lithium therapy 7 years (IQR: 4-15), mean maximal urine osmolality (Uosmol) 725 mOsmol/kg (SD: 153), and median eGFR 84 ml/min/1.73 m2 (IQR: 68-95). Fifty patients (51%) had an impaired RCA and 17 patients (17%) had nephrogenic diabetes insipidus (Uosmol 600-800 and < 600 mOsmol/kg, respectively). Notably, clinical symptoms did not predict an impaired RCA. Nineteen patients (19%) had an eGFR ≤ 60 ml/min/ 1.73 m2. Multivariable regression analysis showed a significant association between the duration of lithium treatment and maximal Uosmol (B = -6.1, 95%-CI: -9.4, -2.9, p < 0.001) and eGFR (B = -0.6, 95%-CI: 0.2, -3.3; p < 0.01). CONCLUSIONS: RCA is impaired in the majority of lithium-treated patients. Both RCA and eGFR are inversely associated with the duration of lithium therapy. Prospective follow-up will enable us to evaluate if abnormalities in RCA can be used to predict the development of lithium-induced chronic kidney disease.

Assessment of Plasma Resistivity as a Surrogate for Extracellular Fluid Resistivity: Analytical Performance and Impact of Fluid Composition.

Bio-electrical impedance analysis (BIA) is frequently used to assess body composition in man. Its accuracy in patients is limited, possibly because the employed algorithms are based on the assumption that total body electrical resistance (TBER) is exclusively related to body water volume, and that variation in fluid composition and its effect on fluid resistivity can be ignored. This may introduce substantial calculation errors. The aim of this study was to develop an objective method to assess plasma resistivity (ρplasma) based on measurements by a conductivity probe, as a surrogate for extracellular fluid resistivity (ρe). Sample measurements were standardized at body temperature. Analytical variation was 0.6% within runs and 0.9% between runs. The critical difference, i.e. the smallest difference needed to consider changes within individuals significant, was 1.8% for measurements within runs and 4.3% for measurements between runs. The normal range was defined by a mean ± SD of 66.9 ± 1.8 Ω cm. Multiple regression demonstrated that ρplasma was inversely related to plasma sodium and chloride concentrations, and positively related to total protein (overall R2 = 0.92, p < 0.001). In conclusion, ρplasma measurements were sufficiently robust to be useful as a tool to examine and improve the validity of BIA in clinical settings.

Progressive kidney failure in chronic myelomonocytic leukaemia: don't forget lysozyme damage.

Kidney failure is common in haematologic malignancies. However, the nephrotoxic effect of lysozyme is seldom recognized. We present a 78-year-old male with chronic myelomonocytic leukaemia who developed progressive kidney failure due to increased production of lysozyme.

Yield of diagnostic tests in unexplained renal hypophosphatemia: a case series.

BACKGROUND: Isolated renal hypophosphatemia may be inherited or acquired. An increasing number of patients with unexplained renal hypophosphatemia is being referred to our clinics, but the optimal diagnostic work-up is not known. Therefore, the aim of this study was to assess the diagnostic yield in these patients. METHODS: We retrospectively evaluated all patients who were referred because of unexplained isolated renal hypophosphatemia to two academic tertiary referral centers in The Netherlands in the period of 2013-2017. RESULTS: We evaluated 17 patients. In five female patients renal hypophosphatemia could be attributed to the use of oral contraceptives. The other 12 patients had a median age of 48 years (10 males). There were no other signs of tubulopathy and none of the patients used drugs known to be associated with hypophosphatemia. FGF23 levels were above normal (> 125 RU/ml) in 2/12 patients. Genetic testing, performed in all patients, did not identify a mutation in genes known to be associated with renal phosphate wasting. A scan with a radiolabeled somatostatin analogue was performed in 8 patients. In one patient, with an FGF23 level of 110 RU/ml, an increased uptake of the somatostatin analog was observed due to tumor induced osteomalacia (TIO). CONCLUSIONS: Oral contraceptive use is an important but under-recognized cause of renal hypophosphatemia. The cause of isolated renal hypophosphatemia remained unexplained in the majority of other patients despite extensive and expensive additional investigations. The pre-test probability for tumor-induced osteomalacia or inherited renal hypophosphatemia in a patient with aspecific complaints and a normal FGF23 level is low. Further research is needed to investigate which patients should be screened for TIO. At present we suggest to perform somatostatin scans only in patients with severe complaints, elevated FGF23 levels, or progressive disease.

Familial focal segmental glomerulosclerosis: mutation in inverted formin 2 mimicking Alport syndrome.

Focal segmental glomerulosclerosis (FSGS) is one of the most common patterns of glomerular injury. FSGS can be caused by mutations in genes encoding proteins that play key roles in the function of the podocyte and glomerular basement membrane. In this case report we present a family with FSGS initially suspected to be Alport syndrome. Genetic analysis according to the Dutch guidelines of FSGS revealed a mutation in INF2.

Human proximal tubule epithelial cells cultured on hollow fibers: living membranes that actively transport organic cations.

The bioartificial kidney (BAK) aims at improving dialysis by developing 'living membranes' for cells-aided removal of uremic metabolites. Here, unique human conditionally immortalized proximal tubule epithelial cell (ciPTEC) monolayers were cultured on biofunctionalized MicroPES (polyethersulfone) hollow fiber membranes (HFM) and functionally tested using microfluidics. Tight monolayer formation was demonstrated by abundant zonula occludens-1 (ZO-1) protein expression along the tight junctions of matured ciPTEC on HFM. A clear barrier function of the monolayer was confirmed by limited diffusion of FITC-inulin. The activity of the organic cation transporter 2 (OCT2) in ciPTEC was evaluated in real-time using a perfusion system by confocal microscopy using 4-(4-(dimethylamino)styryl)-N-methylpyridinium iodide (ASP(+)) as a fluorescent substrate. Initial ASP(+) uptake was inhibited by a cationic uremic metabolites mixture and by the histamine H2-receptor antagonist, cimetidine. In conclusion, a 'living membrane' of renal epithelial cells on MicroPES HFM with demonstrated active organic cation transport was successfully established as a first step in BAK engineering.

Immunosuppressive therapy in patients with IgA nephropathy.

BACKGROUND: There is limited evidence to support cytotoxic therapy in patients with IgA nephropathy and renal insufficiency. We studied the effect of cytotoxic therapy in patients with IgA nephropathy and renal insufficiency, and evaluated possible predictors of response. METHODS: Retrospective analysis of patients with IgA nephropathy who received immunosuppressive therapy. The primary outcome measure was progression of renal disease, defined as an increase in serum creatinine levels of ≥ 50% or development of end-stage renal disease. RESULTS: From 1996 to 2008, 19 patients with biopsy-proven IgA nephropathy were treated with cytotoxic agents and prednisone because of renal insufficiency and÷ or severe proteinuria. Characteristics of patients at the start of therapy: age 42±11 years, serum creatinine 208 (96-490) µmol÷l, estimated glomerular filtration rate (eGFR) 33 (12-65) ml÷min÷1.73 m2, and protein- creatinine ratio 3.8 (0.6-18.2) g÷10 mmol. Follow-up after initiation of therapy was 35 (7-133) months. Ten patients had progressive renal disease, whereas eGFR was stable in nine. Serum creatinine levels and proteinuria at the start of treatment were not significantly different between responders and non- responders. Proteinuria response at six months after start of therapy proved a good predictor: proteinuria decreased by ≥ 50% and÷or reached levels below 1 g÷day in 8÷9 responders. In contrast, proteinuria decreased by more than 50% and reached levels < 1 g÷day in only 3÷10 non-responders (p < 0.01). CONCLUSION: Prolonged immunosuppressive therapy with cytotoxic agents and prednisone may benefit a subgroup of patients with progressive IgA nephropathy. A reduction of proteinuria ≥ 50% to levels below 1 g÷day within six months predicts a favourable long-term response.

A morphological and functional comparison of proximal tubule cell lines established from human urine and kidney tissue.

Promising renal replacement therapies include the development of a bioartificial kidney using functional human kidney cell models. In this study, human conditionally immortalized proximal tubular epithelial cell (ciPTEC) lines originating from kidney tissue (ciPTEC-T1 and ciPTEC-T2) were compared to ciPTEC previously isolated from urine (ciPTEC-U). Subclones of all ciPTEC isolates formed tight cell layers on Transwell inserts as determined by transepithelial resistance, inulin diffusion, E-cadherin expression and immunocytochemisty. Extracellular matrix genes collagen I and -IV α1 were highly present in both kidney tissue derived matured cell lines (p<0.001) compared to matured ciPTEC-U, whereas matured ciPTEC-U showed a more pronounced fibronectin I and laminin 5 gene expression (p<0.01 and p<0.05, respectively). Expression of the influx carrier Organic Cation Transporter 2 (OCT-2), and the efflux pumps P-glycoprotein (P-gp), Multidrug Resistance Protein 4 (MRP4) and Breast Cancer Resistance Protein (BCRP) were confirmed in the three cell lines using real-time PCR and Western blotting. The activities of OCT-2 and P-gp were sensitive to specific inhibition in all models (p<0.001). The highest activity of MRP4 and BCRP was demonstrated in ciPTEC-U (p<0.05). Finally, active albumin reabsorption was highest in ciPTEC-T2 (p<0.001), while Na(+)-dependent phosphate reabsorption was most abundant in ciPTEC-U (p<0.01). In conclusion, ciPTEC established from human urine or kidney tissue display comparable functional PTEC specific transporters and physiological characteristics, providing ideal human tools for bioartificial kidney development.

Living kidney transplantation in adult patients with atypical haemolytic uraemic syndrome.

BACKGROUND: Dysregulation of complement activation is the most common cause of the atypical haemolytic uraemic syndrome (aHUS). Many patients with aHUS develop end-stage renal disease and consider kidney transplantation. However, the recurrence rate after transplantation ranges from 45-90% in patients with known abnormalities in circulating complement proteins. It was recently proposed that patients with aHUS should be treated prophylactically with plasma exchange or eculizumab to prevent recurrence after transplantation. METHODS: A case series describing the successful outcome of kidney transplantation without prophylactic therapy in four adult patients with aHUS and a high risk of disease recurrence. Patients received a living donor kidney and immunosuppression consisting of basiliximab induction, low-dose tacrolimus, prednisone and mycophenolate mofetil. Patients received a statin, and were targeted to a low blood pressure preferably using blockers of the renin-angiotensin system. RESULTS: After a follow-up of 16-21 months, none of the patients developed recurrent aHUS. Also, no rejection was observed. CONCLUSIONS: Kidney transplantation in adult patients with aHUS can be successful without prophylactic eculizumab, using a protocol that minimises cold ischaemia time, reduces the risk of rejection and provides endothelial protection. Our data suggest that in patients with aHUS, controlled trials are needed to demonstrate the optimal strategy.

Iron metabolism in the pathogenesis of iron-induced kidney injury.

In the past 8 years, there has been renewed interest in the role of iron in both acute kidney injury (AKI) and chronic kidney disease (CKD). In patients with kidney diseases, renal tubules are exposed to a high concentration of iron owing to increased glomerular filtration of iron and iron-containing proteins, including haemoglobin, transferrin and neutrophil gelatinase-associated lipocalin (NGAL). Levels of intracellular catalytic iron may increase when glomerular and renal tubular cells are injured. Reducing the excessive luminal or intracellular levels of iron in the kidney could be a promising approach to treat AKI and CKD. Understanding the role of iron in kidney injury and as a therapeutic target requires insight into the mechanisms of iron metabolism in the kidney, the role of endogenous proteins involved in iron chelation and transport, including hepcidin, NGAL, the NGAL receptor and divalent metal transporter 1, and iron-induced toxic effects. This Review summarizes emerging knowledge, which suggests that complex mechanisms of iron metabolism exist in the kidney, modulated directly or indirectly by cellular iron content, inflammation, ischaemia and oxidative stress. The potential exists for prevention and treatment of iron-induced kidney injury by customized iron removal or relocation, aided by detailed insight into the underlying pathological mechanisms.

Kidney injury during VEGF inhibitor therapy.

Antiangiogenic therapy targeting vascular endothelial growth factor (VEGF) or its receptor (VEGFR) has proven its effect in the treatment of several types of cancer, including renal cell carcinoma (RCC). However, treatment can be accompanied by notable adverse effects. Mild proteinuria and hypertension are often seen, but sometimes nephrotic range proteinuria and÷or renal insufficiency develop. In recent years insight into the toxic effects of anti-VEGF therapy in the kidney has increased. A few biopsies have been done and thrombotic microangiopathy is reported in the majority of cases. However, other patterns of kidney injury have been described as illustrated by the case of a 62-year-old patient who presented two years after initiation of the VEGFR inhibitor cediranib with a nephrotic syndrome and acute renal failure. Kidney biopsy disclosed focal segmental glomerulosclerosis (FS GS) and interstitial nephritis. Partial remission was achieved after stopping the cediranib and a short course of prednisone. We review the different forms of kidney injury that could be caused by anti-VEGF therapy.

Membranous nephropathy with predominance of C1q: another variant of C1q nephropathy?

Originally described as a proliferative glomerulonephritis, C1q nephropathy is nowadays mostly recognized as a variant of focal segmental glomerulosclerosis or minimal change disease. We describe a 30-year-old male patient with nephrotic range proteinuria. Kidney biopsy demonstrated a membranous nephropathy with predominant staining for C1q. Under conservative therapy the outcome was favorable. We suggest that this case represents another variant of C1q nephropathy, thus broadening the spectrum of the disease.

A new era in the diagnosis and treatment of atypical haemolytic uraemic syndrome.

The haemolytic uraemic syndrome (HUS) is characterised by haemolytic anaemia, thrombocytopenia and acute renal failure. The majority of cases are seen in childhood and are preceded by an infection with Shiga-like toxin producing Escherichia coli (STEC-HUS; so-called typical HUS). Non-STEC or atypical HUS (aHUS) is seen in 5 to 10% of all cases and occurs at all ages. These patients have a poorer outcome and prognosis than patients with STEC-HUS. New insights into the pathogenesis of aHUS were revealed by the identification of mutations in genes encoding proteins of the alternative pathway of the complement system in aHUS patients. Specific information of the causative mutation is important for individualised patient care with respect to choice and efficacy of therapy, the outcome of renal transplantation, and the selection of living donors. This new knowledge about the aetiology of the disease has stimulated the development of more specific treatment modalities. Until now, plasma therapy was used with limited success in aHUS, but recent clinical trials have demonstrated that patients with aHUS can be effectively treated with complement inhibitors, such as the monoclonal anti-C5 inhibitor eculizumab.

Nurse practitioners improve quality of care in chronic kidney disease: two-year results of a randomised study.

BACKGROUND: Chronic kidney disease (CKD) is associated with increased cardiovascular risk. Here we evaluate whether strict implementation of guidelines aimed at multiple targets with the aid of nurse practitioners (NP) improves management in patients with CKD. METHODS: MASTER PLAN is a randomised controlled clinical trial, performed in nine Dutch hospitals. Patients with CKD (estimated glomerular filtration rate (eGFR) 20-70 ml÷min) were randomised to receive NP support (intervention group (IG)) or physician care (control group (CG)). Patients were followed for a median of five years. Presented data are an interim analysis on risk factor control at two-year follow-up. RESULTS: We included 788 patients (532 M, 256 F), (393 CG, 395 IG), mean (±SD ) age 59 (±13) years, eGFR 38 (±15) ml÷min÷1.73m(2), blood pressure (BP) 138 (±21)÷80 (±11) mmHg. At two years 698 patients (352 IG, 346 CG) could be analysed. IG as compared with CG had lower systolic (133 vs 135 mmHg; p= 0.04) and diastolic BP (77 vs 80 mmHg; p=0.007), LDL cholesterol (2.30 vs 2.45 mmol(-l); p= 0.03), and increased use of ACE inhibitors, statins, aspirin and vitamin D. The intervention had no effect on smoking cessation, body weight, physical activity or sodium excretion. CONCLUSION: In both groups, risk factor management improved. However, changes in BP control, lipid management and medication use were more pronounced in IG than in CG. Lifestyle interventions were not effective. Coaching by NPs thus benefits everyday care of CKD patients. Whether these changes translate into improvement in clinical endpoints remains to be established.