Search

Task-free connectivity analyses have emerged as a powerful tool in functional neuroimaging. Because the cross-correlations that underlie connectivity measures are sensitive to distortion of time-series, here we used a novel dynamic phantom to provide a ground truth for dynamic fidelity between blood oxygen level dependent (BOLD)-like inputs and fMRI outputs. We found that the de facto quality-metric for task-free fMRI, temporal signal to noise ratio (tSNR), correlated inversely with dynamic fidelity; thus, studies optimized for tSNR actually produced time-series that showed the greatest distortion of signal dynamics. Instead, the phantom showed that dynamic fidelity is reasonably approximated by a measure that, unlike tSNR, dissociates signal dynamics from scanner artifact. We then tested this measure, signal fluctuation sensitivity (SFS), against human resting-state data. As predicted by the phantom, SFS—and not tSNR—is associated with enhanced sensitivity to both local and long-range connectivity within the brain’s default mode network.

1. It has been reported that calcium antagonists lower blood pressure more effectively in salt replete hypertensive patients with a low plasma renin activity (PRA), whereas angiotensin converting enzyme (ACE) inhibitors are more effective in salt depleted patients with a high level of PRA. An inverse relationship between the antihypertensive effects of these two groups of drugs might therefore be expected. 2. Since salt retention and inappropriately high levels of PRA are said to contribute to hypertension in patients with chronic renal failure (CRF), an additive antihypertensive effect with both drugs might also be expected in such patients. 3. To test these hypotheses, we investigated the acute and chronic antihypertensive effects of the calcium antagonist nitrendipine and the new ACE inhibitor cilazapril, given alone, and in combination, in a double-blind, randomized, placebo controlled study of 11 hypertensive patients with chronic renal failure who had a mean pretreatment blood pressure of 149 +/- 3/96 +/- 2 mm Hg. Patients received nitrendipine 10 mg, cilazapril 1.25 or 2.5 mg depending on creatinine clearance, or placebo once daily orally. Nitrendipine and cilazapril were also combined at the same doses. 4. Nitrendipine and cilazapril were equally effective, with a maximal acute reduction of mean arterial pressure (MAP) of 5.3 +/- 1.8% and 8.0 +/- 1.9%, and after 1 week of treatment 5.0 +/- 2.4% and 8.1 +/- 1.8%, respectively. In individual patients no inverse relationship between the blood pressure responses to the two drugs was found.(ABSTRACT TRUNCATED AT 250 WORDS) [ABSTRACT FROM AUTHOR]

1. We have studied the diuretic and natriuretic effects and the tubular site of action of nifedipine using free water clearance (CH2O) and lithium clearance. 2. We have compared the effects of nifedipine (10 mg p.o.) with those of placebo and of frusemide (40 mg p.o.) in seven healthy volunteers during maximal water diuresis. 3. Compared with placebo, nifedipine caused a significant rise in urinary flow rate and CH2O, paralleled by significant increases in fractional excretion of sodium and lithium. The rise in sodium excretion was not accompanied by an increase in potassium excretion. 4. Frusemide caused increases in sodium and lithium excretion, comparable with the effects seen after nifedipine. CH2O did not change however. 5. Our study demonstrates that nifedipine has a clear diuretic and natriuretic effect in healthy volunteers, which is predominantly established by interference with proximal tubular sodium reabsorption. Lithium clearance did not allow us to differentiate between nifedipine and frusemide effects, thus questioning the reliability of lithium as a marker of proximal tubular sodium reabsorption. [ABSTRACT FROM AUTHOR]

Ten patients with a hypertensive crisis and a decreased renal function were treated with 10 (n = 7) or 20 (n = 3) mg nifedipine sublingually. Blood pressure was reduced in 60 min from 211 +/- 4/134 +/- 5 to 172 +/- 6/107 +/- 6 mm Hg. The decrease of blood pressure was accompanied by a rise in heart rate from 83 +/- 6 to 98 +/- 5 beats/min. In all seven patients with an encephalopathy signs of this complication were reduced. No serious side-effects were observed. [ABSTRACT FROM AUTHOR]

Serial section transmission electron microscopy (TEM) has proven to be one of the leading methods for millimeter-scale 3D imaging of brain tissues at nanoscale resolution. It is important to further improve imaging efficiency to acquire larger and more brain volumes. We report here a threefold increase in the speed of TEM by using a beam deflecting mechanism to enable highly efficient acquisition of multiple image tiles (nine) for each motion of the mechanical stage. For millimeter-scale areas, the duty cycle of imaging doubles to more than 30%, yielding a net average imaging rate of 0.3 gigapixels per second. If fully utilized, an array of four beam deflection TEMs should be capable of imaging a dataset of cubic millimeter scale in five weeks., (© 2024. The Author(s).)

We present a simulation framework, called NETMORPH, for the developmental generation of 3D large-scale neuronal networks with realistic neuron morphologies. In NETMORPH, neuronal morphogenesis is simulated from the perspective of the individual growth cone. For each growth cone in a growing axonal or dendritic tree, its actions of elongation, branching and turning are described in a stochastic, phenomenological manner. In this way, neurons with realistic axonal and dendritic morphologies, including neurite curvature, can be generated. Synapses are formed as neurons grow out and axonal and dendritic branches come in close proximity of each other. NETMORPH is a flexible tool that can be applied to a wide variety of research questions regarding morphology and connectivity. Research applications include studying the complex relationship between neuronal morphology and global patterns of synaptic connectivity. Possible future developments of NETMORPH are discussed.

In previous simulations of hippocampus-dependent and prefrontal cortex-dependent tasks, we demonstrated the use of one-shot short-term buffering with time compression that may be achieved through persistent spiking activity during theta rhythm. A biophysically plausible implementation of such a first-in first-out buffer of short sequences of spike patterns includes noise and differences between the parameter values of individual model pyramidal cells. We show that a specific set of parameters determines model buffer capacity and buffer function, and individual differences can have consequences similar to those of noise. The set of parameters includes the frequency of network theta rhythm and the strength of recurrent inhibition (affecting capacity), as well as the time constants of the characteristic after-depolarizing response and the phase of afferent input during theta rhythm (affecting buffer function). Given a sufficient number of pyramidal cells in layer II of entorhinal cortex, and in each self-selected category of pyramidal cells with similar model parameters, buffer function within a category is reliable with category-specific properties. Properties include buffering of spikes in the order of inputs or in the reversed order. Multiple property sets may enable parallel buffers with different capacities, which may underlie differences of place field sizes and may interact with grid cell firing in a separate population of layer II stellate cells in the entorhinal cortex.

We propose a mechanism to explain both retrospective and prospective recall activity found in experimental data from hippocampal regions CA3 and CA1. Our model of temporal context dependent episodic memory replicates reverse recall in CA1, as recently recorded and published [Foster, D., & Wilson, M. (2006). Reverse replay of behavioural sequences in hippocampal place cells during the awake state. Nature, 440, 680-683], as well as the prospective and retrospective activity recorded in region CA3 during spatial tasks [Johnson, A., & Redish, A. (2006). Neural ensembles in ca3 transiently encode paths forward of the animal at a decision point: a possible mechanism for the consideration of alternatives. In 2006 neuroscience meeting planner. Atlanta, GA: Society for Neuroscience. (Program no. 574.2)]. We suppose that CA3 encodes episodic memory of both forward and reversed sequences of perforant path spikes representing place input. Using a persistent firing buffer mechanism in layer II of entorhinal cortex, simulated episodic learning involves dentate gyrus, layer III of entorhinal cortex, and hippocampal regions CA3 and CA1. Associations are formed between buffered episodic cues, unique temporal context specific representations in dentate gyrus, and episodic memory in the CA3 recurrent network.

Persistent neuronal firing has been modeled in relation to observed brain rhythms, especially to theta oscillations recorded in behaving animals. Models of short-term memory that are based on such persistent firing properties of specific neurons can meet the requirements of spike-timing-dependent potentiation of synaptic strengths during the encoding of a temporal sequence of spike patterns. We show that such a spiking buffer can be simulated with integrate-and-fire neurons that include a leak current even when different numbers of spikes represent successive items. We propose a mechanism that successfully replaces items in the buffer in first-in-first-out (FIFO) order when the distribution of spike density in a theta cycle is asymmetric, as found in experimental data. We predict effects on the function and capacity of the buffer model caused by changes in modeled theta cycle duration, the timing of input to the buffer, the strength of recurrent inhibition, and the strength and timing of after-hyperpolarization and after-depolarization (ADP). Shifts of input timing or changes in ADP parameters can enable the reverse-order buffering of items, with FIFO replacement in a full buffer. As noise increases, the simulated buffer provides robust output that may underlie episodic encoding.

The popular 45-year-old Dutch actress Sylvia Millecam died in August 2001 from untreated advanced breast cancer. She refused standard medical treatment and sought solace in many alternative healers, including three medical physicians. The Dutch Healthcare Inspection accused the three physicians of malpractice and asked the Medical Disciplinary Tribunal to pass judgment. In April 2006 one physician was struck from the physician register and the other two were suspended for 1 year and 6 months, respectively. These unusually severe measures were based mainly on the fact that they had neglected professional standards as defined by specialty boards, they had presented themselves as professional physicians and they had not tried hard enough to convince Millecam of the need for standard treatment. The Tribunal did not accept the strong desire of the patient to undergo only alternative treatment as a defence. Notably, the judgment of the Tribunal seems to be more severe than the present bylaws of medical-scientific bodies and the Dutch Medical Association (KNMG), which are apparently too lenient regarding the use of alternative treatments by their members.

Many patients with asymptomatic haematuria are primarily referred to urological examination. To analyse the efficiency of this strategy, we investigated the diagnostic process in 134 patients with asymptomatic haematuria (91 macroscopic and 43 microscopic) who were referred to our urology department. The frequency of diagnostic procedures was urine culture: 91%, cystoscopy: 87%, intravenous urography: 86%, ultrasound: 73%, examination of urinary sediment: 20%. In 70 patients (52%), a urological diagnosis was made. In the remaining 64 patients, the urinary sediment was examined for the presence of dysmorphic erythrocytes and erythrocyte casts in 17 patients (27%). Signs of glomerular haematuria were found in nine of them (53%). The diagnostic strategy in these patients with asymptomatic haematuria was not discordant from several published algorithms but appeared neither efficacious nor efficient. We estimate that when examination of the urinary sediment would have been performed at the start of work-up, 25% of patients could have spared from extensive urological investigation.

The orbital frontal cortex appears to be involved in learning the rules of goal-directed behavior necessary to perform the correct actions based on perception to accomplish different tasks. The activity of orbitofrontal neurons changes dependent upon the specific task or goal involved, but the functional role of this activity in performance of specific tasks has not been fully determined. Here we present a model of prefrontal cortex function using networks of integrate-and-fire neurons arranged in minicolumns. This network model forms associations between representations of sensory input and motor actions, and uses these associations to guide goal-directed behavior. The selection of goal-directed actions involves convergence of the spread of activity from the goal representation with the spread of activity from the current state. This spiking network model provides a biological implementation of the action selection process used in reinforcement learning theory. The spiking activity shows properties similar to recordings of orbitofrontal neurons during task performance.

Acetylcholine may regulate working memory for novel stimuli by activating intrinsic mechanisms for sustained spiking in entorhinal cortical neurons, which have been demonstrated in slice preparations of the entorhinal cortex. Computational modeling demonstrates that loss of the cholinergic activation of intrinsic mechanisms for sustained activity could selectively impair working memory for novel stimuli, whereas working memory for familiar stimuli could be maintained because of previously modified synapses. Blockade of muscarinic cholinergic receptors and selective cholinergic lesions has been shown to impair encoding in delayed matching tasks. However, previous studies have not compared explicitly the role of cholinergic modulation in working memory for novel versus familiar stimuli. Here, we show that lesions of the cholinergic innervation of the entorhinal cortex selectively impair delayed nonmatch to sample performance for novel odors, whereas delayed nonmatch to sample for familiar odors is spared. This indicates an important role for cholinergic innervation of the entorhinal cortex in working memory for novel stimuli.

For the past several years, there has been an advertising campaign, especially focused on dentists, to promote the so-called 'memory lymphocyte immunostimulation assay' (MELISA) for the detection of metal allergy. A study of the sparse scientific literature reveals that, as a consequence of the high number of false-positive results, this test is of no use for the diagnosis of metal allergy. Moreover, the claims of the developers of the test that metal allergy plays a role in several immune-mediated diseases, metabolic diseases and neurological or mental disorders are not based on sound scientific evidence.

Examination of the urinary sediment is a simple and indispensable tool in the diagnostic approach to patients with asymptomatic haematuria. Various glomerular and nonglomerular diseases can cause haematuria. A well-trained expert can distinguish between these two forms of haematuria by examining the urinary sediment under a simple light microscope. In glomerular haematuria, dysmorphic erythrocytes and erythrocyte casts are found, whereas in nonglomerular haematuria the erythrocytes are monomorphic and erythrocyte casts are absent. However, few people have sufficient expertise in the examination of the urinary sediment, and consequently this investigation is performed far too seldom. A few years ago, a simple method of fixation of the urinary sediment became available. Fixed specimens can be stored at room temperature for at least two weeks, which enables the sending of a fixed specimen to an expert examiner by regular mail. In this way, the urinary sediment can more frequently be used as the initial investigation in the diagnostic route of patients with asymptomatic haematuria.

We investigated the importance of hippocampal theta oscillations and the significance of phase differences of theta modulation in the cortical regions that are involved in goal-directed spatial navigation. Our models used representations of entorhinal cortex layer III (ECIII), hippocampus and prefrontal cortex (PFC) to guide movements of a virtual rat in a virtual environment. The model encoded representations of the environment through long-term potentiation of excitatory recurrent connections between sequentially spiking place cells in ECIII and CA3. This encoding required buffering of place cell activity, which was achieved by a short-term memory (STM) in EC that was regulated by theta modulation and allowed synchronized reactivation with encoding phases in ECIII and CA3. Inhibition at a specific theta phase deactivated the oldest item in the buffer when new input was presented to a full STM buffer. A 180 degrees phase difference separated retrieval and encoding in ECIII and CA3, which enabled us to simulate data on theta phase precession of place cells. Retrieval of known paths was elicited in ECIII by input at the retrieval phase from PFC working memory for goal location, requiring strict theta phase relationships with PFC. Known locations adjacent to the virtual rat were retrieved in CA3. Together, input from ECIII and CA3 activated predictive spiking in cells in CA1 for the next desired place on a shortest path to a goal. Consistent with data, place cell activity in CA1 and CA3 showed smaller place fields than in ECIII.

A variety of approaches are available for using computational models to help understand neural processes over many levels of description, from sub-cellular processes to behavior. Alongside purely deductive bottom-up or top-down modeling, a systems design strategy has the advantage of providing a clear goal for the behavior of a complex model. The order in which biological details are added is dictated by functional requirements in terms of the tasks that the model should perform. Ideas from engineering can be mixed with those from biology to build systems in which some constituents are modeled in detail using biologically-realistic components, while others are implemented directly in software. This allows the areas of most interest to be studied within the context of a behaving system in which each component is constrained both by the biology it is intended to represent as well as the task it is required to perform within the system. The Catacomb2 modeling package has been developed to allow rapid and flexible design and study of complex multi-level systems ranging in scale from ion channels to whole animal behavior. The methodology, internal architecture, and capabilities of the system are described. Its use is illustrated by a modeling case study in which hypotheses about how parahippocampal and hippocampal structures may be involved in spatial navigation tasks are implemented in a model of a virtual rat navigating through a virtual environment in search of a food reward. The model incorporates theta oscillations to separate encoding from retrieval and yields testable predictions about the phase relations of spiking activity to theta oscillations in different parts of the hippocampal formation at various stages of the behavioral task.

In 1998, the Organ Donation Act became effective in the Netherlands. From the recent evaluation of this act, it appears that one of its important goals, the increase in organ donation, has not been achieved. The number of organ donations has decreased. Only one-third of the Dutch adult population has responded to the request to register in the Central Organ Donor Registry. All people aged 18 years and older are sent a form on which they can indicate whether or not they consent to donating their organs after death. When a non-registered person dies, the relatives will refuse organ donation in at least 75% of the cases. The most important means for improving this situation are the implementation of a presumed consent law, special attention to public education on the principle of reciprocity (quid pro quo), and an improvement of the procurement programs in the donor hospitals.

Background: There are wide national and international variations in the management of patients with end-stage renal disease (ESRD). The aim of this study was to develop, harmonize, implement, and evaluate consensus-based clinical guidelines for the management of renal anaemia and renal bone disease in patients with ESRD, and for the prevention and management of cytomegalovirus disease in renal transplant recipients across six renal centres in Europe., Methods: The trial was a prospective, multicentre, randomized balanced incomplete block design. Nephrologists from the six European renal units were randomized to develop and implement guidelines for two out of the three conditions and to act as a control for the third condition. Data were collected pre- (1 year) and post- (9 months) intervention on aspects of patient monitoring, management, and outcome., Results: Eight hundred and twenty-nine dialysis patients from the six European dialysis centres were included in the study. Multivariate analysis (adjusting for case-mix and secular trends) showed a significant increase in the number of monitoring events in the guideline group compared with control group (6%, 95% CI, 1-11%). There was no concomitant increase in either appropriate management or the number of favourable patient outcomes., Conclusions: In the first European collaboration on renal guidelines, the introduction of the guidelines improved the monitoring of the patients, but did not improve patient management or outcome. This study suggests the potential for creating clinical guidelines with the aim of standardizing treatment protocols across international boundaries, and improving the quality of the medical care provided.

Background: Graft loss due to rejection is uncommon after human histocompatibility leukocyte antigen-identical living related donor (LRD) transplantation, resulting in an excellent long-term graft survival. Data on the impact of recurrence of the original disease on graft survival after LRD transplantation are scarce., Methods: We have studied the influence of recurrent glomerulonephritis in adult recipients of a human histocompatibility leukocyte antigen-identical LRD graft transplanted in our center in the period from 1968 to 1996. To that end, the data of 33 patients with proven or suspected primary glomerulonephritis and 27 patients with nonglomerular diseases were analyzed., Results: The patient survival was similar in both groups at 5, 10, and 20 years. The functional graft survival, i.e., graft survival after censoring for death, was, however, significantly worse for patients with glomerulonephritis as underlying disease (P<0.01). At 5 years graft survival was 100% vs. 88%, at 10 years 100% vs. 70%, and at 20 years 100% vs. 63%, respectively. Thus none of the patients with nonglomerular diseases lost a graft, whereas eight grafts were lost in the group of patients with glomerulonephritis. The main cause of graft loss in this patient group was recurrent glomerulonephritis (n=5), whereas chronic vascular rejection caused graft loss in two patients and occlusion of a transplant artery was the cause in one. A clinically significant proteinuria was detected in six more patients in the glomerulonephritis group: a recurrent glomerulonephritis was diagnosed in four patients and in two patients there was no biopsy. The cumulative incidence of recurrence was as high as 45% at 12 years after transplantation., Conclusion: Recipients of a human histocompatibility leukocyte antigen-identical LRD kidney have a good prognosis with respect to graft survival. After censoring for death, recurrent glomerulonephritis is the main cause of graft failure in these patients and the impact of recurrent disease on graft survival will become even more prominent with longer follow-up.

Background: Dense deposit disease (DDD) is an uncommon cause of end-stage renal disease (ESRD). As a consequence, information on the outcome of renal transplantation in patients with DDD comes from series with a limited number of patients., Methods: We present the histological and clinical data of 13 adult patients with DDD, who received their first allograft in our centre in the period between 1983 and 1994., Results: Renal transplant biopsies were performed in 11 patients, at 2.9 months after transplantation (median; range 0.4-13.8 months). The indication for taking the biopsy was in all instances a raised serum creatinine level. Five patients also had a significant proteinuria. In only one patient, light microscopy showed alterations in the capillary walls suggestive of a recurrence of DDD. However, by immunofluorescence or electron microscopy, we found glomerular deposits compatible with a recurrence of DDD in all 11 patients. Three patterns of glomerular C3 deposition were found: globular depositions only in the mesangium; mesangial accumulation with linear deposits in the capillary wall; and prominent linear presence in the capillary wall with only a few mesangial granules. The findings by electron microscopy matched the immunofluorescence results. The linear C3 accumulation in the capillary wall was visible ultrastructurally as electron-dense ribbon-like transformation of the glomerular basement membrane. Mesangial C3 deposits were seen ultrastructurally as local electron-dense deposits in the mesangium. Four patients showed a pronounced glomerular influx of neutrophils, accompanied by crescents in three patients. In these three latter patients, the recurrence of DDD was the only histological lesion. In the other patients, the recurrence was merely a coincidence, the biopsy demonstrating an additional histological lesion (three chronic vascular rejection, two acute rejection, one ischaemic necrosis and two cyclosporin A toxicity). Eight patients with a recurrence of DDD have progressed to ESRD at an average of 14 months (range 0.2-38 months) after transplantation. The recurrence was the sole cause of graft loss in the three patients with crescents. The patients in whom the C3 deposits were confined to the mesangium appeared to have a better prognosis., Conclusions: The histological recurrence rate of DDD is high. The histological picture is quite diverse, and in most patients abnormalities are only found by immunofluorescence and electron microscopy. Up to one-quarter of the patients with DDD lost their grafts because of a recurrence.

Neural networks are often employed as tools in classification tasks. The use of large networks increases the likelihood of the task's being learned, although it may also lead to increased complexity. Pruning is an effective way of reducing the complexity of large networks. We present discriminant components pruning (DCP), a method of pruning matrices of summed contributions between layers of a neural network. Attempting to interpret the underlying functions learned by the network can be aided by pruning the network. Generalization performance should be maintained at its optimal level following pruning. We demonstrate DCP's effectiveness at maintaining generalization performance, applicability to a wider range of problems, and the usefulness of such pruning for network interpretation. Possible enhancements are discussed for the identification of the optimal reduced rank and inclusion of nonlinear neural activation functions in the pruning algorithm.

The anion gap is used to evaluate disturbances in the acid-base balance, in particular metabolic acidosis. Due to the introduction of new clinical chemical techniques and modern analysers the reference range of the anion gap has changed. Clinical chemical laboratories should establish or verify their own anion gap reference range. Better communication between the laboratory and the clinician with regard to the anion gap is desirable.

Background: Administration of prednisolone causes an abrupt rise in proteinuria in patients with a nephrotic syndrome., Methods: To clarify the mechanisms responsible for this increase in proteinuria we have performed a placebo controlled study in 26 patients with a nephrotic syndrome. Systemic and renal haemodynamics and urinary protein excretion were measured after prednisolone and after placebo., Results: After i.v. administration of 125-150 mg prednisolone total proteinuria increased from 6.66+/-4.42 to 9.37+/-6.07 mg/min (P<0.001). By analysing the excretion of proteins with different charge and weight (albumin, transferrin, IgG, IgG4 and beta2-microglobulin) it became apparent that the increase of proteinuria was the result of a change in size selectivity rather than a change in glomerular charge selectivity or tubular protein reabsorption. Glomerular filtration rate rose from 83+/-34 ml to 95+/-43 ml/min (P<0.001) after 5 h, whereas effective renal plasma flow and endogenous creatinine clearance remained unchanged. As a result filtration fraction was increased, compatible with an increased glomerular pressure, which probably contributes to the size selectivity changes. Since corticosteroids affect both the renin-angiotensin system and renal prostaglandins, we have evaluated the effects of prednisolone on proteinuria after pretreatment with 3 months of the angiotensin-converting enzyme inhibitor lisinopril or after 2 weeks of the prostaglandin synthesis inhibitor indomethacin. Neither drug had any effect on prednisolone-induced increases of proteinuria., Conclusions: Prednisolone increases proteinuria by changing the size selective barrier of the glomerular capillary. Neither the renin-angiotensin axis nor prostaglandins seem to be involved in these effects of prednisolone on proteinuria.

In asystolic patients, kidney donation is possible by using a non-heart-beating (NHB) donation procedure. This involves in situ perfusion of the kidneys by inserting a catheter into the femoral artery and flushing cold fluid through the kidneys. The introduction of an NHB donation programme leads to ethical questions concerning the guarantees for prudent procedure: How should death of a patient be defined in case of NHB donation? Is there a strict separation of responsibilities of the medical teams in the different phases of the procedure (patient treatment and actual donation procedure)? Are sufficient attention and care given to the relatives? Does the NHB donation procedure not interfere with the care of a patient who is expected to die soon? Extensive discussion with the Medical Ethics Committee of the University Hospital Nijmegen, the Netherlands, has led to a protocol for NHB kidney donation that meets the required guarantees.

We treated patients with idiopathic membranous nephropathy (iMGN) and renal insufficiency, using: (i) (n = 15) monthly cycles of steroids (1 g methyl-prednisolone i.v. on three consecutive days, followed by oral prednisone 0.5 mg/kg/day months 1, 3 and 5) and chlorambucil (0.15 mg/kg/day months 2, 4 and 6); or (ii) (n = 17) oral cyclophosphamide (1.5-2.0 mg/kg/day for 1 year) and steroids in a comparable dose. The groups were comparable in age, renal function and levels of proteinuria. During the 6 months preceding treatment, serum creatinine levels increased from 148 +/- 50 to 219 +/- 73 mumol/l in the chlorambucil group and from 164 +/- 86 to 274 +/- 126 mumol/l in the cyclophosphamide group. Median (range) follow-ups were: chlorambucil 38 months (8-71); cyclophosphamide 26 months (5-68) (NS). Renal function improved in both groups, but the improvement was short-lived in the chlorambucil group; 12 months after starting treatment, mean serum creatinine was 6.3 mumol/l lower in the chlorambucil group and 121 mumol/l lower in the cyclophosphamide group (p < 0.01). Four chlorambucil-treated patients developed ESRD, and five needed a second course of therapy, whereas only one cyclophosphamide-treated patient developed ESRD (p < 0.05). Remissions of proteinuria occurred more frequently after cyclophosphamide treatment (15/17 vs. 5/15; p < 0.01). Side-effects necessitated interruption of treatment in six patients on cyclophosphamide and in 11 on chlorambucil (p < 0.05). In our patients, oral cyclophosphamide was better tolerated than oral chlorambucil. The suggested greater efficacy of the oral cyclophosphamide regimen needs to be ascertained by longer follow-up.

Background: The observation that proteinuria is an important determinant of the progression of renal disease has prompted numerous studies on the effects of antihypertensive agents on protein excretion. Reports on the proteinuric effects of calcium-channel blockers are quite controversial. It has been suggested that the short-acting dihydropyridine calcium-channel blocker nifedipine increases protein excretion by interference with tubular protein reabsorption., Methods: In a randomized controlled trial 10 patients with renal disease and proteinuria were treated with a dose of 10 mg nifedipine o.d. (slow release formulation) for 1 week. The acute effects on renal and systemic haemodynamics and on urinary albumin, IgG, and beta2-microglobulin excretion were investigated during a clearance study in the supine position after the first dose. After 1 week of treatment urinary protein excretion rates were measured in 24-h urine samples collected in the ambulatory patient in consecutive fractions of 4-8 h during normal daily activities., Results: After the first dose nifedipine lowered mean arterial blood pressure in the supine position by 7+/-1 mmHg (<0.01), attenuated proximal tubular sodium reabsorption (fractional excretion of sodium 3.48+/-0.49 vs 2.62+/-0.35% during control, P<0.02), but did not affect proximal tubular protein reabsorption (fractional urinary excretion of beta2-microglobulin 0.97+/-0.30 vs 0.98+/-0.32% during control, NS). The decrease in blood pressure was not accompanied by decreases in urinary albumin or IgG excretion rates. The selectivity index as well as GFR, RPF, and FF did not change. Continued treatment for 1 week with nifedipine did not influence 24-h protein excretion. However, we observed a rise of proteinuria during daily activities in the first 4 h after drug intake compared to the start of the study with the patients in supine position. During control measurements there was a slight increase in proteinuria. During nifedipine the increase in proteinuria was more marked and correlated with the selectivity index., Conclusions: (1) Nifedipine 10 mg orally did not impair tubular protein reabsorption. (2) Nifedipine had no immediate antiproteinuric effect despite the observed blood pressure reduction. (3) Nifedipine increased proteinuria in ambulatory urine collections. This latter observation might explain the seemingly different effects of dihydropyridine calcium-channel blockers as reported in previous studies.

Background: Hypertension and nephrotoxicity are well-known side-effects of cyclosporine A (CsA). CsA-induced vasoconstriction of the afferent glomerular arteriole probably plays a role in at least the nephrotoxicity. Frequently renal transplant recipients on CsA have to be treated with antihypertensive drugs and for this purpose also beta-blockers are used. Tertatolol is a new beta-blocker with specific vasodilatory properties, and thus might be particularly useful in CsA-treated transplant recipients., Methods: We studied the systemic and renal haemodynamic effects of atenolol and tertatolol in 12 hypertensive renal transplant recipients on cyclosporine A (CsA). In a cross-over way, all patients were treated with atenolol and tertatolol for 4 weeks each, separated by a wash-out period also of 4 weeks. At the end of each period, the mean arterial pressure (MAP), heart rate, glomerular filtration rate (GFR) and renal plasma flow (RPF) were measured., Results: The mean arterial pressure was lower (P < 0.05) during atenolol (124 +/- 2 mm Hg) and tertatolol (125 +/- 2 mm Hg) treatment compared with washout (132 +/- 4 mm Hg). Also the heart rate was lower (P < 0.01) during atenolol and tertatolol (54 +/- 3 and 55 +/- 2 beats/min respectively) than in the wash-out period (65 +/- 3 beats/min). GFR and RPF were not changed by either beta-blocker., Conclusion: In CsA treated renal transplant recipients both atenolol and tertatolol effectively reduced blood pressure. In these patients we found no evidence of a specific vasodilatory effect of tertatolol. Both beta-blockers had no negative influence on renal function. Hence, these cardioprotective agents are an attractive and safe choice for the treatment of hypertension in such patients.

We describe a 50-year-old male patient with hyponatremia (serum sodium level, 128 mEq/L) discovered during routine follow-up for Henoch-Schönlein nephritis. The patient was known to have a generalized idiopathic epilepsy and was on 2,000 mg/day of sodium valproate. After exclusion of other causes such as hypothyroidism and adrenal insufficiency, we considered sodium valproate as the cause of the hyponatremia. Repeated water loading tests performed at different dosages of this drug confirmed that the ability to excrete water was reduced in a dose dependent manner. We conclude that sodium valproate can cause an SIADH-like syndrome with hyponatremia and that serum sodium levels have to be monitored during treatment with high dosages of this drug.

In a randomised prospective trial, we studied the effects of replacement of prednisone (Pred) by azathioprine (Aza), 6 months after transplantation, in stable renal allograft recipients on cyclosporine and prednisone (CsA + Pred). Out of 83 patients, 42 started treatment with CsA + Aza and 41 continued therapy with CsA + Pred. CsA was dosed to achieve a level of 150 ng/ml, the Aza dose was 3 mg/kg per day and the Pred dose was 0.15 mg/kg per day. Eighteen months after randomisation, in the CsA + Aza group 18 of the 42 patients were effectively treated with CsA + Aza. In the main, anaemia, leuco- and thrombocytopenia, and hypocorticism necessitated the reintroduction of Pred in the remaining 24 patients. Compared to the continuation of CsA + Pred, conversion of Pred to Aza resulted in a reduced number of antihypertensive drugs needed, and in lower serum total, LDL and HDL cholesterol levels; the incidence of acute rejections and graft losses was no different. In conclusion, conversion of CsA + Pred to CsA + Aza is a safe option in renal transplant patients with contraindications to long-term corticosteroid treatment.

In membranous nephropathy it would be of great value to be able to identify in an early phase patients at highest risk for disease progression, since potentially toxic treatment could then be restricted to these patients only. We measured renal hemodynamics, serum proteins and urinary protein excretion in 22 patients with membranous nephropathy, nephrotic syndrome and normal renal function (endogenous creatinine clearance > 85 ml/min). These patients were followed for a mean of 56 months. Renal function deteriorated in nine patients. When using univariate analysis, deterioration of renal) function appeared to be associated with a low serum albumin and transferrin, high urinary transferrin, beta-microglobulin, and IgG excretion, but not with renal hemodynamics. A step-up procedure, used for selecting variables associated with survival, showed that IgG excretion was independently associated with renal function deterioration. In patients with membranous nephropathy and normal renal function, the urinary excretion rate of IgG predicts future renal function outcome.

Kidney transplantation guarantees a better quality of life than dialysis and is less costly. Transplantation without preceding dialysis is an attractive option. However, transplantation long before end-stage renal failure prolongs the period of exposure to immunosuppressive therapy, thereby increasing the risk of malignancy. Transplantation at one year before dialysis-dependency is expected would seem an acceptable compromise. Unfortunately, this option is purely theoretical because there is a long waiting-list due to the existing donor shortage. Patients are usually put on the waiting-list after dialysis has already been started. Extension of the list with pre-dialysis patients is currently only justifiable in exceptional cases. These limitations do not apply to patients who have received an offer of kidney donation from a living (related or unrelated) donor. In these patients transplantation can be done as soon as the creatinine clearance has reached a level of 10-12 ml per minute. More attention should be paid to this form of transplantation, because it can help to decrease the donor shortage.

Background: Intravenous administration of clodronate (dichloromethylene bisphosphate)-containing liposomes (clodro-L) has been reported to induce selective depletion of tissue macrophages (M phi) with little or no effect on polymorphonuclear granulocytes (PMN). Therefore, we used clodro-L treatment to study the role of M phi in a PMN-dependent model of anti-glomerular basement membrane (GBM) nephritis., Methods: C57BL/6J mice received clodro-L i.v. at days -2 and -1 before i.v. injection of anti-GBM antibodies. The albuminuria of the first 24 h was measured by radial immunodiffusion in 18 hour urine samples and glomerular changes were studied histologically and immunohistologically., Results: Treatment with clodro-L, in doses that adequately destroyed the Kupffer cells, failed to reduce glomerular M phi numbers, but markedly inhibited glomerular PMN accumulation. Compared to control mice, clodro-L-pretreated C57BL/6J mice showed considerable reduction of both albuminuria and glomerular damage at day 1 after injection of rabbit anti-GBM antibody., Conclusions: In this PMN-dependent model, the inhibitory effect of clodro-L treatment on the development of nephritis very likely due to the inhibition of glomerular PMN accumulation. Our results indicate the clodro-L treatment as a method of selective M phi depletion has its limitations, especially in models in which PMN are involved as effector cells.

Background: The information in the medical literature on the incidence of recurrence of type I membranoproliferative glomerulonephritis (MPGN) after renal transplantation and its impact on graft survival is limited because most data are derived from case reports or from studies involving a small number of patients., Methods: We analyzed the data from our transplant center. Among 1097 adult patients receiving their first allograft between 1977 and 1994, we identified 32 patients with type I MPGN., Results: A recurrence was detected in 9 of the 27 recipients of a first cadaveric graft (33%). The cumulative incidence reached 48% at 4 years after transplantation when patients with graft failure from other causes were censored. All patients with recurrent MPGN had clinically significant proteinuria (>1 g/24 hr) that was first observed at a median time of 20 months (range, 1.5-42 months) after transplantation. Graft survival was significantly worse in patients with recurrence as compared with patients without recurrence. Mean duration of graft survival after the diagnosis of recurrence was 40 months. We could not detect any clinical characteristics of patients or donors that were associated with recurrent disease. However, an increased risk of recurrence was observed in patients with the HLA haplotype B8DR3. Four patients received an HLA-identical graft from a living related donor. Recurrence occurred in three patients (75%), with ensuing graft loss in two. The only patient with a haploidentical living related graft did not have a recurrence. Five patients with a recurrence in the first graft received a second transplant. Recurrence was observed in four of these patients (80%)., Conclusions: Type I MPGN recurred after renal transplantation in half of the patients. The incidence may be even higher in recipients of an identical living related donor graft and in patients receiving a second transplant after having experienced a recurrence in their first graft. Recurrence of type I MPGN has a detrimental effect on graft survival.