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.

Immediate implant placement in edentulous oral cancer patients: a long-term retrospective analysis of 207 patients.

Although the functional benefits of implants in the rehabilitation of edentulous cancer patients are well-known, most studies report on postponed implant placement. The outcome of immediate implant placement regarding successful rehabilitation, implant loading and survival is unclear. Two hundred and seven edentulous oral cancer patients that received implants during ablative surgery at the Radboud University Medical Centre between 2000 and 2011 were included. Data regarding the oncological treatment, implant placement, follow-up and prosthodontic rehabilitation were recorded retrospectively with a follow-up period of 5-17 years. Functioning implant-retained dentures were made in 73.9% of the patients. Of the surviving patients, 81.9% had functioning dentures after 2 years and 86.3% after 10 years. Patients with ASA score 1 and younger patients were rehabilitated more frequently. The median time of functioning denture placement was 336 days after surgery, with a negative influence of postoperative radiotherapy. Implant survival was 90.7%, and was lower when the implant was placed in a jaw involved in the tumour. Immediate implant placement during oral cancer surgery led to a high number of edentulous patients rehabilitated with implant-retained dentures, which are placed at an early time.

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.

Secondary hyperoxaluria due to pancreatic insufficiency.

BACKGROUND: In this article, we present two cases of patients with acute renal insufficiency with a history of exocrine pancreatic insufficiency. In one case, this was caused by pancreaticoduodenectomy; in the other, by alcohol abuse. Neither patient had considerable proteinuria or haematuria. Their renal biopsies showed tubulopathy with widespread oxalate crystals, characterised by their birefringence in light microscopy. Restricting oxalate intake and prescribing oxalate binding agents reduced serum oxalate levels. Renal function partially recovered in both patients. Oxalate nephropathy is associated with exocrine pancreatic insufficiency, gastric and pancreatic surgery, and inflammatory bowel disease. Normally, dietary calcium binds oxalate to form calcium oxalate, which is excreted in the stool. In patients with pancreatic insufficiency, fatty acids bind calcium instead, allowing oxalate to be absorbed in the colon. The resulting hyperoxaluria can cause oxalate crystal formation, tubulopathy, and renal insufficiency. Treatment relies on decreasing the amount of absorbable oxalate in the intestinal lumen, as well as lowering urinary oxalate concentrations. CONCLUSION: Secondary hyperoxaluria is a common cause of renal insufficiency and should be considered in patients with a medical history of pancreatic insufficiency and progressive kidney injury.

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.

Eculizumab Dosing Regimen in Atypical HUS: Possibilities for Individualized Treatment.

Recent studies indicate that eculizumab is often given in excess to atypical hemolytic uremic syndrome (aHUS) patients. Individualization of treatment is thus highly requested; however, data on the pharmacokinetics and pharmacodynamics of eculizumab remain limited. We analyzed 11 patients during induction (weekly), maintenance (2-weekly), and tapering (every 3-8 weeks) phases of treatment. The trough eculizumab levels increased with each additional dose during the induction phase (depending on body weight). During maintenance, high eculizumab concentrations of up to 772 µg/mL were observed. The levels decreased with each following dose during tapering (3- and 4-week intervals); however, three patients maintained target eculizumab levels over long time periods (30-48 weeks). At intervals of 6-8 weeks, target eculizumab levels were no longer attained. Serum samples with eculizumab concentrations ≥50 µg/mL showed adequate complement blockade. Our data provide essential insight for optimization of eculizumab dosing schemes and lessening of therapy burden for the patients and cost of the treatment.

Bioengineered kidney tubules efficiently excrete uremic toxins.

The development of a biotechnological platform for the removal of waste products (e.g. uremic toxins), often bound to proteins in plasma, is a prerequisite to improve current treatment modalities for patients suffering from end stage renal disease (ESRD). Here, we present a newly designed bioengineered renal tubule capable of active uremic toxin secretion through the concerted action of essential renal transporters, viz. organic anion transporter-1 (OAT1), breast cancer resistance protein (BCRP) and multidrug resistance protein-4 (MRP4). Three-dimensional cell monolayer formation of human conditionally immortalized proximal tubule epithelial cells (ciPTEC) on biofunctionalized hollow fibers with maintained barrier function was demonstrated. Using a tailor made flow system, the secretory clearance of human serum albumin-bound uremic toxins, indoxyl sulfate and kynurenic acid, as well as albumin reabsorption across the renal tubule was confirmed. These functional bioengineered renal tubules are promising entities in renal replacement therapies and regenerative medicine, as well as in drug development programs.

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.

Remote Ischemic Preconditioning To Reduce Contrast-Induced Nephropathy: A Randomized Controlled Trial.

BACKGROUND: Despite the increasing use of pre- and post-hydration protocols and low osmolar instead of high osmolar iodine containing contrast media, the incidence of contrast induced nephropathy (CIN) is still significant. There is evidence that contrast media cause ischemia reperfusion injury of the renal medulla. Remote ischemic preconditioning (RIPC) is a non-invasive, safe, and low cost method to reduce ischemia reperfusion injury. The aim of this study is to investigate whether RIPC, as an adjunct to standard preventive measures, reduces contrast induced acute kidney injury in patients at risk of CIN. METHODS: The RIPCIN study is a multicenter, single blinded, randomized controlled trial in which 76 patients at risk of CIN received standard hydration combined with RIPC or hydration with sham preconditioning. RIPC was applied by four cycles of 5 min ischemia and 5 min reperfusion of the forearm. The primary outcome measure was the change in serum creatinine from baseline to 48 to 72 hours after contrast administration. RESULTS: With regard to the primary endpoint, no significant effect of RIPC was found. CIN occurred in four patients (2 sham and 2 RIPC). A pre-defined subgroup analysis of patients with a Mehran risk score ≥11, showed a significantly reduced change in serum creatinine from baseline to 48 to 72 hours in patients allocated to the RIPC group (Δ creatinine -3.3 ± 9.8 µmol/L) compared with the sham group (Δ creatinine +17.8 ± 20.1 µmol/L). CONCLUSION: RIPC, as an adjunct to standard preventive measures, does not improve serum creatinine levels after contrast administration in patients at risk of CIN according to the Dutch guideline. However, the present data indicate that RIPC might have beneficial effects in patients at a high or very high risk of CIN (Mehran score ≥ 11). The RIPCIN study is registered at: http://www.controlled-trials.com/ISRCTN76496973.

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.