Outcomes from the International Society of Nephrology Haemolytic Uraemic Syndromes International Forum.

The haemolytic uraemic syndromes (HUS) are a heterogeneous group of conditions only some of which are mediated by complement (CaHUS). We report the outcome of the 2023 International Society of Nephrology HUS International Forum where a global panel of experts considered the current state of the art, identified areas of uncertainty, and proposed optimal solutions. Areas of uncertainty and areas for future research included: the nomenclature of HUS; novel complement testing strategies; identification of biomarkers; genetic predisposition to aHUS; optimal dosing and withdrawal strategies for C5 inhibitors; treatment of kidney transplantation recipients; disparity of access to treatment; and the next generation of complement inhibitors in CaHUS. The current rationale for optimal patient management is described.

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.

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.

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.

An overview of immunosuppressive therapy in idiopathic membranous nephropathy.

Idiopathic membranous nephropathy is the most common cause of nephrotic syndrome. In patients who present with nephrotic range proteinuria the clinical course is variable, with 50% of patients developing end stage renal disease after extended follow-up without therapy. We review the various immunosuppressive treatment modalities. The efficacy of alkylating agents is demonstrated in randomized trials, although side effects are a major drawback. Calcineurin inhibitors, rituximab and possibly adrenocorticotropic hormone (ACTH) are able to induce remission of proteinuria, which portends a good prognosis. However, the efficacy of these agents must be confirmed in randomized trials with adequate renal end points. Immunosuppressive treatment should be restricted to high risk patients. The use of immunosuppressive therapy has improved outcome of patients with iMN, with nowadays less than 10% of patients progressing to end stage renal disease (ESRD).

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.

Continuation of cinacalcet immediately after renal transplantation: a prospective cohort study.

BACKGROUND: Cinacalcet is used for treating secondary hyperparathyroidism in dialysis patients, but it is currently unknown whether it can safely be continued immediately after renal transplantation. METHODS: We prospectively studied renal transplant recipients with secondary hyperparathyroidism who were receiving cinacalcet before transplantation and continued treatment afterwards (n = 29) at a dose of 30 mg/day. Cinacalcet dose was titrated to serum calcium. Patients were followed for 6 months. Incidence of hypercalcemia, serum calcium and intact PTH (iPTH) were analyzed. Tacrolimus levels, acute rejection rate and renal function were compared with an age and sex matched control group. RESULTS: In 16 patients hypercalcemia was observed after transplantation. Severe hypercalcemia (>= 2.87 mmol/l) (n = 4) and hypocalcemia (n = 2) were infrequent. No difference in acute rejection rate or renal function between the cinacalcet and the control group was found. There also was no clinically relevant influence of cinacalcet on tacrolimus levels. CONCLUSIONS: Our study shows that cinacalcet can safely be continued immediately after renal transplantation. Studies are needed to determine if continuation of cinacalcet is better than early withdrawal. Also, the optimum dose of cinacalcet and the long-term effects of cinacalcet after renal transplantation must be defined.

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.

Urinary excretion of low-molecular-weight proteins as prognostic markers in IgA nephropathy.

BACKGROUND: Immunoglobulin A nephropathy (IgAN) is characterised by high variability in clinical course and outcome. Accurate prediction of prognosis is needed to optimise treatment. Urinary alpha1-microglobulin and beta2-microglobulin are markers of tubulointerstitial injury and predict the risk of end-stage renal disease (ESRD) in idiopathic membranous nephropathy. We questioned the relevance of these markers in IgAN. METHODS: We included patients with biopsy proven IgAN, who were evaluated for proteinuria in our centre between 1995 and 2007. Data were analysed using univariate and multivariate Cox regression for the outcome variables ESRD and progression (rise in serum creatinine of >50% or start of immunosuppressive therapy). RESULTS: Seventy patients (71% men) were selected. Median age was 39 years, median serum creatinine 140 micromol/l, and median proteinuria 2.4 g/day. Median urinary alpha1-microglobulin excretion was 23.5 microg/min (range 3.5-275.3) and median urinary beta2-microglobulin excretion was 0.4 microg/min (range 0.1-62.1). Both alpha1m and beta2m correlated significantly with serum creatinine (r = 0.65, p<0.01 and r = 0.62, p<0.01) and total proteinuria (r = 0.35, p<0.01 and r = 0.28, p<0.05). During follow-up (median 75 months) 25 patients (36%) developed ESRD , and 46 patients (66%) showed progression. 19 patients (27%) were treated with immunosuppressive agents. In univariate analysis urinary alpha1- and beta2-microglobulin predicted ESRD and progression. In multivariate analysis only serum creatinine and urinary protein were independent predictors of both outcomes. CONCLUSION: Urinary excretion of low molecular weight proteins did not offer an advantage over total proteinuria and serum creatinine in predicting prognosis in patients with IgAN.

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.

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.

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.

Toxicity of contrast media: an update.

Renal toxicity of iodinated radiocontrast media (contrastinduced nephropathy; CIN) is a major cause of acute renal failure in hospitalised patients. Magnetic resonance imaging (MRI) is applied as an alternative technique but the use of gadolinium (Gd) containing contrast media carries the risk of nephrogenic systemic fibrosis (NSF), a potentially lethal disorder that occurs especially in patients with renal failure. In this article we give an update of the literature on toxicity of radiocontrast media and on preventive measures. Risk of nephrotoxicity of iodinated contrast media can be reduced by identification of high-risk patients. In these patients pre- and post-hydration with isotonic saline should be applied. When there is insufficient time to prehydrate, a short infusion protocol with sodium bicarbonate is preferable. There is a lack of evidence to support the use of oral or intravenous N-acetylcysteine or iso-osmolar contrast media. In order to prevent NSF , linear gadolinium chelates should not be used in patients with an estimated glomerular filtration rate (eGFR) of less than 30 ml/min. In patients with eGFR between 10 and 30 ml/min the small chance of NSF with cyclic Gd-containing chelates must be balanced against the high risk of developing CIN, and the morbidity and mortality associated with the start of dialysis. In patients without residual renal function, the small chance of developing NSF after macrocyclic Gd-enhanced MRI imaging may tip the balance to the use of iodine containing contrast media.

Oscillometric blood pressure measurements: differences between measured and calculated mean arterial pressure.

Mean arterial pressure (MAP) is often used as an index of overall blood pressure. In recent years, the use of automated oscillometric blood pressure measurement devices is increasing. These devices directly measure and display MAP; however, MAP is often calculated from systolic blood pressure (SBP) and diastolic blood pressure (DBP) as displayed by the device. In this study we have analysed measured and calculated MAP, obtained by two different oscillometric BP measurement devices in two different patient cohorts. The first cohort included 242 healthy subjects (male 40.5%, 50+/-13 years). BP measurements were performed with a Welch Allyn 5300P device. We found a small but significant difference between measured MAP and calculated MAP (MAP(m-c:) -1.8 mmHg, range -5.7 to 12.9 mmHg, p < 0.001). MAP(m-c) showed a significant, but weak correlation with DBP and SBP. The second cohort included included 134 patients with glomerular diseases (male 63%, 50+/14 years). BP measurements were performed with a Dinamap 487210 device. In this group we also observed a small difference between measured MAP and calculated MAP (+1.7 mmHg, range -15.3 to 28.2 mmHg, p<0.001). MAP (m-c) correlated with age, all blood pressure indices and heart rate. An overall analysis showed that age, SBP, DBP, and type of device are all independently related to MAP (m-c). There is a significant difference between measured and calculated MAP. The difference is small on average; however, this MAP(m-c) can be large in the individual patient. Moreover, there are differences of reported MAP between devices. Our data suggest that calculated and measured MAP cannot be used interchangeably.

Review on diagnosis and treatment of focal segmental glomerulosclerosis.

Focal segmental glomerulosclerosis (FSGS) is one the most important causes of the nephrotic syndrome in adult patients. FSGS is not a disease entity. The identification of underlying causes of FSGS (secondary FSGS) has increased our insight into the pathogenesis of FSGS. Moreover, differentiating between primary (idiopathic) and secondary forms of FSGS is important to allow appropriate treatment. Recently a new pathological classification of FSGS was proposed, expanding FSGS to include nonsclerotic lesions. In this review we discuss the current diagnostic and therapeutic options in patients with FSGS.

Rituximab in minimal change nephropathy and focal segmental glomerulosclerosis: report of four cases and review of the literature.

Minimal change nephropathy (MCNS) and focal segmental glomerulosclerosis (FSGS) are the main causes of the idiopathic nephrotic syndrome. MCNS usually responds to steroids and the long-term prognosis is generally good. However, some patients require prolonged treatment with immunosuppressive agents. FSGS generally follows a less favourable course: patients do not always respond to steroids and may progress to end-stage renal disease. Recurrence of FSGS after renal transplantation is frequently observed and may result in graft loss. Recently, anecdotal case reports have described long-term resolution of nephrotic syndrome due to MCNS or FSGS after treatment with rituximab. We present four patients with nephrotic syndrome due to MCNS, FSGS or recurrence of FS GS after kidney transplantation, who were treated with rituximab with variable success. A review of the recent literature suggests that anti-CD20 antibodies may be a promising therapy, especially for patients with MCNS or idiopathic FSGS. Controlled studies are required to determine the efficacy of rituximab and to define which patients will benefit.

Thyroid function in patients with proteinuria.

BACKGROUND: Patients with proteinuria may suffer from substantial losses of functional proteins such as hormones and hormone-binding proteins. A limited number of studies have reported urinary losses of thyroid hormones and thyroxin-binding globulin. Overt hypothyroidism attributable to these urinary losses has been described. However, the impact of proteinuria on thyroid function parameters has not been studied in a large patient cohort. METHODS: We evaluated thyroid function parameters in patients with proteinurea who are negative to thyroxine peroxidase antibodies (TPOAbs). Values of free thyroxin and thyroid-stimulating hormone (TSH) were compared with data from age- and gender-matched controls derived from the Nijmegen Biomedical Study, a population-based survey conducted in our hospital. RESULTS: We evaluated 159 patients. There were 111 males and 48 females. Median (IQR) age was 52 (40 to 62) years, serum creatinine concentration 99 (82 to 134) micromol/l, serum albumin concentration 29 (22 to 35) g/l, and proteinuria 6.6 (3.1 to 10.9) g/10 mmol creatinine. Median TSH was significantly higher in the patients than the controls (1.81 mU/l vs 1.34 mU/l, p.<0.001); however, overt hypothyroidism was observed in only one patient. CONCLUSION: Patients with proteinuria have higher TSH levels, consistent with urinary loss of thyroid hormones. However, these urinary losses do not result in overt, clinically relevant, hypothyroidism. The role of subclinical hypothyroidism in these patients needs further evaluation.

Cholesterol in end-stage renal disease: the good, the bad or the ugly?

The incidence of cardiovascular disease is markedly increased in patients with end-stage renal disease (ESRD). High serum cholesterol is widely recognised as a cardiovascular risk factor in the general population. However, in patients with ESRD high concentrations of cholesterol are associated with a better survival. This reverse epidemiology is, amongst others, caused by confounding due to malnutrition and chronic inflammation. In this population, treatment with statins to lower the serum cholesterol remains a matter of debate. In ESRD, LDL cholesterol is modified by increased oxidative stress. These altered LDL particles play a pivotal role in the development of atherosclerosis. Treatment with the antioxidant vitamin E has not equivocally been shown to be beneficial in this population. This review tries to put data from literature on dyslipidaemia and oxidative stress in ESRD in perspective.