Prediction models for mortality in adult patients visiting the Emergency Department: a systematic review.

We provide a systematic overview of literature on prediction models for mortality in the Emergency Department (ED). We searched various databases for observational studies in the ED or similar setting describing prediction models for short-term mortality (up to 30 days or in-hospital mortality) in a non-trauma population. We used the CHARMS-checklist for quality assessment. We found a total of 14.768 articles and included 17 articles, describing 22 models. Model performance ranged from AUC 0.63-0.93. Most articles had a moderate risk of bias in one or more domains. The full model and PARIS model performed best, but are not yet ready for implementation. There is a need for validation studies to compare multiple prediction models and to evaluate their accuracy.

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.

Potential deleterious effects of vasopressin in chronic kidney disease and particularly autosomal dominant polycystic kidney disease.

The antidiuretic hormone vasopressin is crucial for regulating free water clearance in normal physiology. However, it has also been hypothesized that vasopressin has deleterious effects on the kidney. Vasopressin is elevated in animals and patients with chronic kidney disease. Suppression of vasopressin activity reduces proteinuria, renal hypertrophy, glomerulosclerosis and tubulointerstitial fibrosis in animal models. The potential detrimental influence of vasopressin is probably mediated by its effects on mesangial cell proliferation, renin secretion, renal hemodynamics, and blood pressure. In this review, we discuss the increasing body of evidence pointing towards the contribution of vasopressin to chronic kidney disease progression in general and to autosomal dominant polycystic kidney disease in particular. These data allude to the possibility that interventions directed at lowering vasopressin activity, for example by the administration of vasopressin receptor antagonists or by drinking more water, may be beneficial in chronic kidney disease.

Clinical significance of FGF-23 measurement in dialysis patients.

AIMS: Considering the growing relevance of fibroblast growth factor-23 (FGF-23) in the pathogenesis of chronic kidney disease bone and mineral disorder (CKD-MBD), an analysis was performed to determine the relative importance of C-terminal (cFGF-23) and intact (iFGF-23) assays in assessing CKD-MBD status in the first place and the relationship between FGF-23 and mortality as a secondary aim. METHODS: In 77 patients (15 peritoneal dialysis and 62 hemodialysis), levels of calcium, phosphate, parathyroid hormone (PTH), 25-hydroxyvitamin- D (25D), 1,25D, FGF-23 (C-terminal and intact molecule) were measured and their correlations were analyzed. The relationship between FGF-23 levels and patient survival was also analyzed. RESULTS: A significant correlation was found between cFGF-23 and 1,25D, PTH and 25D while iFGF-23 was significantly correlated with phosphate, 25D and PTH. PTH and 1,25D were independent predictors of cFGF-23, while for iFGF-23 independent predictors were phosphate and 25D. No significant relationship was found between FGF-23 and mortality. CONCLUSIONS: C-terminal or intact FGF-23 levels are weakly correlated and thus not clearly indicative of FGF-23 effects on PTH, P and vitamin D metabolism in dialysis patients. Assays for cFGF-23 and iFGF-23 showed a good correlation, but the intact molecule was not superior in defining interactions with CKD-MBD molecules. Measuring FGF-23 on a regular basis with the current assays in CKD and dialysis patients does not yet seem clinically useful.

Justification for a home-based education programme for kidney patients and their social network prior to initiation of renal replacement therapy.

In this article, an ethical analysis of an educational programme on renal replacement therapy options for patients and their social network is presented. The two main spearheads of this approach are: (1) offering an educational programme on all renal replacement therapy options ahead of treatment requirement and (2) a home-based approach involving the family and friends of the patient. Arguments are offered for the ethical justification of this approach by considering the viewpoint of the various stakeholders involved. Finally, reflecting on these ethical considerations, essential conditions for carrying out such a programme are outlined. The goal is to develop an ethically justified and responsible educational programme.

Prediction admission in the older population in the Emergency Department: the CLEARED tool.

BACKGROUND: Length of stay (LOS) in the Emergency Department (ED) is correlated with an extended in-hospital LOS and may even increase 30-day mortality. Older patients represent a growing population in the ED and they are especially at risk of adverse outcomes. Screening tools that adequately predict admission could help reduce waiting times in the ED and reduce time to treatment. We aimed to develop and validate a clinical prediction tool for admission, applicable to the aged patient population in the ED. METHODS: Data from 7,606 ED visits of patients aged 70 years and older between 2012 and 2014 were used to develop the CLEARED tool. Model performance was assessed with discrimination using logistic regression and calibration. The model was internally validated by bootstrap resampling in Erasmus Medical Center and externally validated at two other hospitals, Medisch Spectrum Twente (MST) and Leiden University Medical Centre (LUMC). RESULTS: CLEARED contains 10 predictors: body temperature, heart rate, diastolic blood pressure, systolic blood pressure, oxygen saturation, respiratory rate, referral status, the Manchester Triage System category, and the need for laboratory or radiology testing. The internally validated area under the curve (AUC) was 0.766 (95% CI [0.759;0.781]). External validation in MST showed an AUC of 0.797 and in LUMC, an AUC of 0.725. CONCLUSIONS: The developed CLEARED tool reliably predicts admission in elderly patients visiting the ED. It is a promising prompt, although further research is needed to implement the tool and to investigate the benefits in terms of reduction of crowding and LOS in the ED.

Guilty as charged: unmeasured urinary anions in a case of pyroglutamic acidosis.

A patient developed an unexplained metabolic acidosis with the characteristics of renal tubular acidosis. By correcting the serum anion gap for hypoalbuminaemia and analysing the urinary anions and cations, the presence of unmeasured anions was revealed. The diagnosis of pyroglutamic acidosis, caused by a combination of flucloxacillin and acetaminophen, was established. Strategies for solving complex cases of metabolic acidosis are discussed.

[Hydration to prevent contrast-induced nephropathy]. / Hydratie ter preventie van contrastnefropathie.

In 2007, a national guideline was issued in the Netherlands to prevent contrast-induced nephropathy. This guideline recommended preventive hydration with 0.9% NaCl in patients with reduced estimated glomerular filtration rate (eGFR 30-69 ml/min/1.73 m2) prior to administration of contrast. The recent AMACING study compared hydration versus no hydration, and found that hydration did not prevent contrast-induced nephropathy but did lead to complications and higher costs. The latest 2017 guideline recommends hydration only for patients with eGFR < 30 ml/min/1.73 m2. Although this is an improvement, an even more recent study, PRESERVE, showed no differences in the incidence of contrast-induced nephropathy between sodium chloride, sodium bicarbonate, acetylcysteine, or placebo - even in patients with lower eGFRs (15-60 ml/min/1.73 m2) undergoing elective angiography. This raises the question whether preventive measures are only effective in patients with the highest risk, i.e. hospitalized patients with multiple risk factors undergoing emergency procedures.

Clinical predictors of escalating care in hepatic and renal cyst infection in autosomal dominant polycystic kidney and liver disease.

BACKGROUND: Cyst infection may occur in autosomal dominant polycystic kidney disease (ADPKD) and autosomal dominant polycystic liver disease (ADPLD). Antimicrobial agents often fail to control infection, leading to invasive action. We aimed to identify factors predicting escalation of care. METHODS: ADPKD and ADPLD patients were identified from local/national databases (2001-2013). Records were screened for patients meeting criteria for cyst infection (positive cyst aspirate and/or clinical findings). Factors that predict escalated care were identified with multivariate modified Poisson regression. RESULTS: We screened 1773 patients. A total of 77 patients with cyst infection (4.3%) were included for analysis (hepatic 36%; male 49%; age 54 ±; 13 years; ADPKD 95%; dialysis 9%, diabetes 18%, renal transplant 56%, eGFR [IQR 24-78] ml/min/1.73 m2 (excluding patients with a history of renal transplant or receiving dialysis)). A pathogen was identified in 71% of cases. Escherichia coli was the most common pathogen and accounted for 69% of cases. Initial treatment was limited to antibiotics in 87% of patients (n = 67), 40% included a fluoroquinolone. Ultimately, 48% of patients underwent some form of invasive action (escalation of care). Increasing white blood cell count (WBC) (RR 1.04 95%-CI 1.01-1.07, p = 0.008) was associated with escalating care, whereas an increase in time between transplant and infection (RR 0.92 95% CI 0.86-0.97, p = 0.005) and E. coli isolation (RR 0.55 95% CI 0.34-0.89, p = 0.02) were protective. CONCLUSION: High serum WBC, isolation of atypical pathogens and early infection after transplantation are factors that increase the risk of escalation of care in hepatic and renal cyst infection patients.

Acute and concomitant deterioration of hyponatremia and renal dysfunction associated with heart and liver failure.

BACKGROUND: Although hyponatremia with concomitant renal dysfunction has been described anecdotally, little is known about how these two conditions are related, which type of renal dysfunction usually occurs, and which patients are at risk. METHODS: From 3029 measured serum sodium (S(Na)) concentrations in 3 months, patients with at least one S(Na) < or =125 mmol/l were selected, and divided in patients with at least 1 S(Creat) > or =125 micromol/l (study group, n=20), and patients whose S(Creat) remained normal (control group, n=50). RESULTS: During the first 5 days of hospitalization, S(Creat) almost doubled in the study group from 125 +/- 40 micromol/l to 207 +/- 72 micromol/l, while S(Na) decreased concurrently from 130 +/- 2 mmol/l to 122 +/- 3 mmol/l. The peak S(Creat) and S(Na) values coincided, and the average courses were highly correlated (r = 0.88, p < 0.001). The study group more often had heart failure (10/20 vs. 1/50, p < 0.001) and liver failure (7/20 vs. 4/50, p = 0.009), and received more often loop diuretics (13/20 vs. 12/50, p = 0.002), spironolactone (11/20 vs. 7/50, p = 0.001), and/or angiotensin-converting enzyme inhibitors (5/20 vs. 2/50, p = 0.02). Four patients were admitted to the intensive care (10 in control group, p = 1.0), and 5 patients died (10 in control group, p = 0.7). CONCLUSIONS: Renal dysfunction is common in severe hyponatremia and usually develops in an acute-on-chronic fashion with concomitant deterioration of both conditions. This concourse is associated with heart failure, liver failure, and/or a renal drug regimen. Given the recent results of clinical trials, this patient group may be especially suitable for treatment with vasopressin antagonists.

Diagnostic approach to a patient with hyponatraemia: traditional versus physiology-based options.

The usual diagnostic approach to a patient with hyponatraemia is based on the clinical assessment of the extracellular fluid (ECF) volume, and laboratory parameters such as plasma osmolality, urine osmolality and/or urine sodium concentration. Several clinical diagnostic algorithms (CDA) applying these diagnostic parameters are available to the clinician. However, the accuracy and utility of these CDAs has never been tested. Therefore, we performed a survey in which 46 physicians were asked to apply all existing, unique CDAs for hyponatraemia to four selected cases of hyponatraemia. The results of this survey showed that, on average, the CDAs enabled only 10% of physicians to reach a correct diagnosis. Several weaknesses were identified in the CDAs, including a failure to consider acute hyponatraemia, the belief that a modest degree of ECF contraction can be detected by physical examination supported by routine laboratory data, and a tendency to diagnose the syndrome of inappropriate secretion of antidiuretic hormone prior to excluding other causes of hyponatraemia. We conclude that the typical architecture of CDAs for hyponatraemia represents a hierarchical order of isolated clinical and/or laboratory parameters, and that they do not take into account the pathophysiological context, the mechanism by which hyponatraemia developed and the clinical dangers of hyponatraemia. These restrictions are important for physicians confronted with hyponatraemic patients and may require them to choose different approaches. We therefore conclude this review with the presentation of a more physiology-based approach to hyponatraemia, which seeks to overcome some of the limitations of the existing CDAs.

Ultrafiltration improves aortic compliance in haemodialysis patients.

An elevated pulse pressure leads to an increased pulsatile cardiac load, and results from arterial stiffening. The aim of our study was to test whether a reduction in volume overload by ultrafiltration (UF) during haemodialysis (HD) leads to an improvement of aortic compliance. In 18 patients, aortic compliance was estimated noninvasively before and after HD with UF using a pulse pressure method based on the Windkessel model. This technique has not been applied before in a dialysis population, and combines carotid pulse contour analysis by applanation tonometry with aortic outflow measurements by Doppler echocardiography. The median UF volume was 2450 ml (range 1000-4000 ml). The aortic outflow volume after HD (39 ml; 32-53 ml) was lower (P=0.01) than before (46 ml; 29-60 ml). Carotid pulse pressure after HD (42 mmHg; 25-85 mmHg) was lower (P=0.01) than before (46 mmHg; 35-93 mmHg). Carotid augmentation index after HD (22%; 3-30%) was lower (P=0.001) than before (31%; 7-53%). Carotid-femoral pulse wave velocity was not different after HD (8.7 m/s; 5.6-28.9 m/s vs 7.7 m/s; 4.7-36.8 m/s). Aortic compliance after HD (1.10 ml/mmHg; 0.60-2.43 ml/mmHg) was higher (P=0.02) than before (1.05 ml/mmHg; 0.45-1.69 ml/mmHg). The increase in aortic stiffness in HD patients is partly caused by a reversible reduction of aortic compliance due to volume expansion. Volume withdrawal by HD moves the arterial wall characteristics back to a more favourable position on the nonlinear pressure-volume curve, reflected in a concomitant decrease in arterial pressure and improved aortic compliance.

Hypotension during hemodialysis results from an impairment of arteriolar tone and left ventricular function.

AIMS: Hypotensive episodes are a major complication of hemodialysis. Hypotension during dialysis could be directly related to a reduction in blood volume or to a decrease in cardiovascular activation as a response to decreased cardiac filling. A decreased cardiovascular activation could be due to patient-related or to dialysis-related factors. In order to study the isolated effect of a reduction in filling pressure, lower body negative pressure (LBNP) causes activation of the cardiovascular reactivity with a decrease in cardiac filling, but without the influence of the dialysis procedure that could affect cardiovascular reactivity. METHODS: We studied the relationship between relative blood volume (RBV), central venous pressure (CVP), systolic arterial pressure, heart rate, stroke volume index (SI), and total peripheral resistance index (TPRI) during a combined dialysis/ultrafiltration and during LBNP to -40 mmHg in 21 hemodialysis patients with a high incidence of hypotension. Systolic arterial pressure, heart rate, SI and TPRI were measured by Finapres. CVP was measured after cannulation of the jugular vein. During dialysis RBV was measured by a blood volume monitor (BVM). In order to study the conditions in which hypotension occurred after dialysis, we divided the patients into 2 groups: hypotensive (H) and non-hypotensive (NH) during dialysis. RESULTS: Baseline levels did not show any significant differences. During dialysis systolic arterial pressure declined gradually in the H group from 30 minutes before the onset of hypotension. There was a similar decrease of RBV and increase of heart rate in both groups with a large interindividual variation. At hypotension, H patients showed a significantly smaller increase in TPRI as compared to NH patients. The reduction in SI tended to be greater at hypotension, while CVP decreased to a similar extent in both groups. Moreover, during LBNP, a similar reduction in CVP resulted in a much smaller decrease in SI. Systolic arterial pressure was only slightly lowered due to a much greater increase in TPRI. CONCLUSION: We conclude that dialysis-related hypotension in our patient group did not result from an inability to maintain blood volume or from decreased cardiac filling. Hypotension appeared to result from the inability to adequately increase arteriolar tone and a reduction in left ventricular function. Both vascular tone and left ventricular function appeared to be impaired by the dialysis procedure.

A double-blind, placebo-controlled study of monoclonal anti-interleukin-2 receptor antibody (BT563) administration to prevent acute rejection after kidney transplantation.

In a double-blind, randomized, placebo-controlled trial, BT563, a murine IgG1 anti-IL-2R antibody, was given as a rejection prophylaxis after kidney transplantation. Drug-related side effects were not observed. During the 10-day course of BT563, no rejections (0/27) were found, whereas a rejection episode occurred in 7 patients (7/29) (P = 0.01) during placebo treatment. Within the first 4 postoperative weeks, freedom from rejection in the BT563 group and in the placebo group was 96% vs. 76% (P = 0.05). Due to rejection in the placebo group, 2 grafts were lost. At 3 months, an overall rejection incidence in the BT563 and placebo group was found of 3/27 (11%) vs. 8/29 (28%) patients (P = 0.18). Infectious complications were distributed equally between the 2 groups. CMV disease, found in 3 placebo-treated patients, occurred after rejection treatment (2/3). Within the BT563 group, 1 patient lost his graft due to renal artery thrombosis, 2 grafts were lost as a result of technical failure, and 2 patients had a squamous cell carcinoma that could be treated curatively. We conclude that the use of the anti-IL-2R mAb BT563 effectively prevents rejection after kidney transplantation without increasing infectious complications.

Cholesterol as an independent predictor of outcome after renal transplantation.

BACKGROUND: The debate on the role of high serum cholesterol levels in cardiovascular disease or chronic vascular rejection in kidney-transplanted patients has not yet been settled. METHODS: We studied the influence of serum cholesterol at 1 year after transplantation on the failure risk in all 676 kidney graft recipients who survived with a functioning graft. Other variables included in this analysis were donor/recipient age and gender, original disease, race, number of HLA-A and -B mismatches, previous transplants, postmortal or living-related transplantation, and transplantation year. At 1 year after transplantation, we included: serum cholesterol, serum creatinine, proteinuria, and hypertension. RESULTS: In the Cox proportional hazards analysis, serum cholesterol at 1 year after transplantation turned out to be an important, independent variable influencing all end points (adjusted for all other variables in the model). The influence on graft failure censored for death was log-linear, and there was interaction with serum creatinine at 1 year. The adverse effect of elevated serum cholesterol levels on the graft failure rate decreased with increasing serum creatinine levels. The influence of serum cholesterol on the rate ratio (RR) for patient failure was linear too, and here there was interaction with recipient age. The negative influence of serum cholesterol on the RR for patient failure decreased with increasing recipient age. The risk for over-all graft failure was influenced by increasing serum cholesterol levels, and there was interaction with recipient age. Because recipient age had interaction with donor age and serum creatinine, the influence of all four variables together on the RR was estimated. It is shown that whereas the RR for over-all graft failure in young recipients of a renal transplant increases significantly with higher cholesterol levels, there is very little influence on the RR of elderly recipients. The risk increases proportionally with increasing serum creatinine levels. CONCLUSION: Serum cholesterol levels have an independent influence on graft, patient, and over-all graft failure.

The vanishing importance of age in renal transplantation.

BACKGROUND: The growing number of patients awaiting a kidney transplant raises questions about allocation of kidneys to the elderly and about the use of elderly donors. In all reported studies analyzing the influence of age on the outcome after renal transplantation, age is investigated as a categorical variable. METHODS: We studied age both as a categorical (Kaplan-Meier) and as a continuous (Cox) variable in a total of 509 cyclosporine-treated recipients of a primary cadaveric kidney graft who underwent transplantation between July 1983 and July 1997. For the Kaplan-Meier analysis, the population was divided into three comparably sized age groups: 17-43 years (n=171), 44-55 years (n=169), and 56-75 years (n=169). RESULTS: Patient survival was better and graft survival censored for death was worse in the younger patients. Overall graft survival (end point was death or graft failure) was not significantly influenced by age. In the Cox proportional hazards analysis, transplantation year turned out to be an important, independent variable influencing all end points. Because the influence was not linear, three periods were defined in which the relative risk remained stable: 1983-1990, 1991-1993, and 1994-1997. In the second period, the relative risk for transplant failure or death was 49% of that in the first period. In the third period, the relative risk had decreased to 22% of that in the first period. Recipient age and donor age were significant predictors of overall transplant failure. There was no interaction between these variables and transplantation year. Within each transplantation period, an increase in recipient age by 1 year increased the relative risk for overall graft failure by only 1.44%. The influence of donor age followed a J-shaped curve with a minimum at 30 years. The influence of increasing either recipient or donor age was counteracted by the improving results over time. CONCLUSION: Considering the improving results over time, there are, at this moment, no arguments for an age restriction for kidney transplant recipients or donors.

A randomized trial comparing safety and efficacy of OKT3 and a monoclonal anti-interleukin-2 receptor antibody (BT563) in the prevention of acute rejection after heart transplantation.

In a prospective randomized trial, BT563, a murine IgG, anti-interleukin-2 receptor antibody, was compared with OKT3 for use as an early rejection prophylaxis after heart transplantation. Patients received either BT563 (n=31) or OKT3 (n=29) during the first 7 days after transplantation; cyclosporine was started on day 3. Median follow-up was 34 months. A cytokine release syndrome occurred in the majority of patients of the OKT3-treated group but in none of the BT563 recipients. The mean duration of electrical stimulation of the heart in the BT563 group was longer than in the OKT3 group (5.1 vs. 2.1 days). In both groups, one patient required insertion of a permanent pacemaker. Freedom from acute rejection at 3 months was not significantly different between the two groups (BT563: 5/29, 17%; OKT3: 6/29, 21%). In the BT563 group, however, rejection tended to occur earlier after transplantation. There was no difference in the overall incidence of rejection. The incidence of infectious complications was evenly distributed in both groups. Malignancies occurred in two patients, both in the OKT3 group. In conclusion, the use of this anti-interleukin-2 receptor monoclonal antibody in heart transplant recipients is safe and devoid of the side effects that accompany the use of OKT3. OKT3 and BT563 result in a similar freedom from rejection at 3 and 12 months after heart transplantation.

Proteinuria after renal transplantation affects not only graft survival but also patient survival.

BACKGROUND: Proteinuria is associated with an increased risk of renal failure. Moreover, proteinuria is associated with an increased death risk in patients with diabetes mellitus or hypertension and even in the general population. METHODS: One year after renal transplantation, we studied the influence of the presence of proteinuria on the risk of either graft failure or death in all 722 recipients of a kidney graft in our center who survived at least 1 year with a functioning graft. Proteinuria was analyzed both as a categorical variable (presence versus absence) and as a continuous variable (quantification of 24 hr urine). Other variables included in this analysis were: donor/recipient age and gender, original disease, race, number of HLA-A and HLA-B mismatches, previous transplants, postmortal or living related transplantation, and transplantation year. At 1 year after transplantation, we included: proteinuria, serum cholesterol, serum creatinine, blood pressure, and the use of antihypertensive medication. RESULTS: In the Cox proportional hazards analysis, proteinuria at 1 year after transplantation (both as a categorical and continuous variable) was an important and independent variable influencing all endpoints. The influence of proteinuria as a categorical variable on graft failure censored for death showed no interaction with any of the other variables. There was an adverse effect of the presence of proteinuria on the graft failure rate (RR=2.03). The influence of proteinuria as a continuous variable showed interaction with original disease. The presence of glomerulonephritis, hypertension, and systemic diseases as the original disease significantly increased the risk of graft failure with an increasing amount of proteinuria at 1 year. The influence of proteinuria as a categorical variable on the rate ratio for patient failure was significant, and there was no interaction with any of the other significant variables (RR=1.98). The death risk was almost twice as high for patients with proteinuria at 1 year compared with patients without proteinuria. The influence of proteinuria as a continuous variable was also significant and also without interaction with other variables. The death risk increased with increasing amounts of proteinuria at 1 year. Both the risks for cardiovascular and for noncardiovascular death were increased. CONCLUSION: Proteinuria after renal transplantation increases both the risk for graft failure and the risk for death.

Contrasting response to cyclosporin in refractory nephrotic syndrome.

We studied the effects of cyclosporin A (CsA), given for three months, in 14 patients with nephrotic syndrome refractory to treatment with prednisone and/or other immunosuppressants. CsA was given in a starting dose of 6 mg/kg and plasma through levels (RIA) were kept between 50 and 150 ng/ml. Diagnosis included: idiopathic membranous glomerulonephritis (n = 6), focal segmental glomerulosclerosis (n = 3), minimal change disease (n = 3) and membranoproliferative glomerulonephritis (n = 2). Three patients with non-immunologically mediated nephrotic syndrome due to Alport's syndrome were studied as well. Considering all patients and diagnostic groups together, proteinuria decreased from 9.0 +/- 4.3 to 4.7 +/- 3.8 g/24 h during CsA treatment (mean +/- SD; p less than 0.01). However, serum creatinine increased from 121.8 +/- 60.5 to 150.4 +/- 64.6 mol/l (p less than 0.01) and glomerular filtration rate as estimated by 24-hour creatinine clearance fell from 85.5 +/- 33.7 to 72.1 +/- 37.2 ml/min (p less than 0.05). When compared to other diagnostic groups, fractional excretion of protein, i.e. protein excretion corrected for changes in glomerular filtration rate, fell only in IMGN (ANOVA, p less than 0.05). We conclude that CsA reduced proteinuria in patients with refractory nephrotic syndrome. In the majority of these patients this reduction could be due to a renal hemodynamic, rather than an immunomodulatory effect of the drug. Only in IMGN the latter action of the drug may be of importance.

Optimising glomerular filtration rate and effective renal plasma flow measurements using a simple pharmacokinetic model.

We applied an open one compartment pharmacokinetic model for the determination of glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) based on a rapid intravenous loading dose followed by a constant infusion of 125I-iothalamate and 131I-orthoiodohippurate in order to ensure constant plasma levels of the two clearance markers. The loading dose was based on the assumption that the volume of distribution of the two markers equals the extracellular volume (25% of the body weight). The infusion rate as calculated after the clearance of thalamate was estimated from body weight, age, sex and serum creatinine using Cockcrofts formula. The clearance of hippurate was assumed to be four times that of thalamate. We studied the reliability of this model in 212 patients with insulin dependent diabetes mellitus (IDDM; n = 74), nephrotic syndrome (NS; n = 18) and heart (HTX; n = 69) or kidney (KTX; n = 51) transplants. A steady state concentration was obtained in all patient groups, even when GFR was markedly depressed. In patients with diabetes, we observed more variance between plasma and urinary clearances of thalamate, which could be due to inaccuracies in urine sampling. In these patients, GFR should be measured using a method that is not dependent on urine collection. Also, the estimation of GFR by means of Cockcrofts equation seems to underestimate GFR in diabetic subjects.