G. Ligtenberg

Sudden dialysis-related hypotension is characterized by paradoxical vasodilation, suggestive of sympathoinhibition. A similar hypotensive reaction can be evoked by lower body negative pressure (LBNP), which thus allows the study of the numerous factors involved in dialysis hypotension separately. This article examines the influence of changes in volume status on the hemodynamic response to LBNP (45 mmHg up to the iliac crest, maximum 60 min) in 12 healthy subjects. LBNP caused a decrease in cardiac index and pulse pressure, and an increase in heart rate and total peripheral resistance, most of which developed within the first 3 min of LBNP. Six subjects developed sudden hypotension characterized by vasodilation after 9 +/- 4 min of LBNP. After saline expansion (25 ml/kg), which increased blood volume by approximately 8%, five subjects endured LBNP for the full 60 min. However, after 60 min of LBNP, the circulatory parameters suggested a similar critical situation as that observed before presyncope in their first experiment. The other six subjects endured the full 60 min of LBNP. After furosemide-induced volume reduction associated with 1.6 +/- 0.2 kg weight loss and approximately 7% blood volume reduction, five of them developed vasodilatory presyncope after 17 +/- 5 min of LBNP. Comparison of presyncopal and nonpresyncopal experiments within subjects, as well as between subjects, showed that the early (3 min) response to LBNP was different: Despite similar decreases in cardiac index, the values for systolic pressure, pulse pressure, peripheral resistance, and stroke volume were lower, and the heart rate was higher in the experiments ending in presyncope. It is concluded that the volume status is a determinant of the tolerance to LBNP, probably by affecting the vasoconstrictive response. By inference, this study suggests that the vasoconstrictive response to the hemodynamic stress of hemodialysis is also influenced by the volume status.

OBJECTIVES: To describe renal outcomes of the lupus nephritis (LN) population of the University Medical Centre Groningen (UMCG) in the Netherlands and to identify predictors for renal flares and long-term renal outcome in daily clinical practice. METHODS: A retrospective analysis of biopsy-proven LN patients with induction and maintenance treatment in the UMCG between 1982 and 2016 was performed. Data were collected at time of diagnosis, after 6 months and every year up to 10 years after diagnosis. Outcome measures were renal relapse (biopsy proven), progression to chronic kidney disease (CKD) stage 3 or 4 and chronic renal replacement therapy. The ability of serum creatinine, proteinuria, creatinine clearance, serum anti-double stranded DNA (anti-dsDNA) antibodies, serum complement 3 (C3) and serum complement 4 (C4), as well as biographic data and histopathological class to predict long-term renal outcome was assessed. RESULTS: Seventy-one patients were included, with median follow-up of 120 months (IQR 48-120 months). During follow-up - up to 10 years - twenty-one (30%) patients experienced at least one relapse. Eleven (15%) patients had CKD stage 3 or 4, of whom eight showed persistent CKD since baseline and two (3%) patients required chronic renal replacement therapy. At baseline, low levels of serum C3 were a significant predictor of renal relapse. Low levels of C3 and C4 at 6 and 12 and proteinuria and high levels of anti-dsDNA at 12 months were significant predictors of renal relapse. At baseline, 6 months and 12 months serum creatinine and creatinine clearance were significant predictors for persistent or newly developed CKD 3 or 4, and need for chronic renal replacement therapy. CONCLUSIONS: Almost one-third of LN patients experience at least one renal relapse during long-term follow up, but only 3% need chronic renal replacement therapy. Our data suggests that early serological remission is associated with a low risk of renal relapse. Decreased renal function at onset and the first year after diagnosis is predictive for decreased renal function at a later stage.

BACKGROUND: The haemodynamic response to progressive hypovolaemia, whether simulated by lower body negative pressure (LBNP) or head-up tilt, or induced by haemorrhage or haemodialysis, has a typical biphasic pattern: a first, sympathoexcitatory, phase of vasoconstriction, tachycardia, and stable blood pressure, and a second, sympathoinhibitory, phase of vasodilatation, bradycardia, and hypotension. The opioid system is involved in this response, since animal studies showed that opioid antagonism by naloxone can attenuate hypovolaemic hypotension. In humans, this finding could not be confirmed. We hypothesized that this could result from inadequate dosing. METHODS: Six healthy subjects underwent LBNP at -45 mmHg until presyncope before and after administration of naloxone 2 mg/kg. During the study, blood pressure, heart rate, vascular resistance, cardiac output, and plasma beta-endorphin were measured. RESULTS: LBNP caused an immediate increase in vasoconstriction and heart rate, resulting in stable blood pressure. After 12 +/- 3.5 min, vasodilatory hypotension followed, accompanied by a modest increase in plasma beta-endorphin. Naloxone did not alter the first or the second phase of the circulatory response, and tolerance to LBNP even tended to decrease (hypotension after 7.5 +/- 2.0 min, NS). Pre-LBNP plasma beta-endorphin as well as hypotensive levels were increased after naloxone. CONCLUSIONS: Our results suggest that naloxone, in a sufficient dose to interfere with the opioid system, does not influence the circulatory response to simulated hypovolaemia in humans is not influenced by naloxone. Given the mechanistic resemblance of LBNP hypotension to dialysis-induced hypotension, we propose that high-dose naloxone is not useful to treat the latter form of hypotension.

RELATIVE NEPHROTOXICITY OF TACROLIMUS VERSUS CYCLOSPORINE The cyclic oligopeptide, cyclosporine, has been the pivotal immunosuppressive agent since its anti-T-cell properties were discovered in 1972. On its introduction in the 1980s, it improved 1-year kidney survival rates from 64% to 80% by reducing acute rejection rates (1). The use of this potent calcineurin blocker spread rapidly to all fields of transplantation, and it has proven phenomenally successful in preventing early graft loss. However, the major problems facing long-term use of this agent in all spheres is its nephrotoxicity. The initial launch of tacrolimus, a macrolide-calcineurin inhibitor, onto the world of transplantation in the 1980s was heralded by initial claims that tacrolimus was less toxic than cyclosporine. It was launched at a time when drug monitoring was still being optimized and at a high initial dose with intravenous protocols during the induction stage. This led to the rapid realization that nephrotoxicity was as bad as, if not worse, in patients treated with tacrolimus. However, as time has moved on, the dose of tacrolimus used has been decreased, such that current recommended oral doses are effective and safe. Cyclosporine and tacrolimus both have acute and chronic toxic effects. Acute toxic effects are reversible and dose related, causing a rapid reduction of renal blood flow and glomerular filtration rate after administration. With respect to cyclosporine, many mediators have been proposed to account for this effect, including adenosine, thromboxane A2, cysteinyl leukotrienes, endothelin-1, angiotensin II, and platelet-derived growth factor (2). In addition, altered activity of the sympathetic nervous system or the synthesis of vasodilatory prostaglandins or nitric oxide may also play a part. Although most work has been performed with regard to cyclosporine, most studies suggest that similar changes are seen with tacrolimus (3). Histology and clinical data are poorly correlated, but histological changes of vascular toxicity involve demonstration of light microscopical changes in afferent arterioles, showing endothelial swelling and nodular hyaline thickening and narrowing of the vascular lumen. This is often seen with evidence of downstream damage with ischemic-looking collapsed glomeruli and gross tubular vacuolation. Cyclosporine- and tacrolimus-induced chronic nephrotoxicity is progressive and leads to interstitial scarring that starts in the outer medulla and “striped fibrosis.” It is not known whether this is the result of recurrent and subclinical vascular microischemia or has a separate pathology. Certainly there is histological data to suggest that at least some of the chronic lesions have their basis in ischemia. However the tubulointerstitial lesions are patchy and not always in the territory supplied by affected arterioles. Implicating calcineurin inhibitors as the immediate cause of renal dysfunction in transplant patients is not always easy due to the complex nature of things, such as pretransplant conditions, preexistent renal dysfunction, drug interactions, and the use of drugs with nephrotoxic potential. Animal studies suggest that cyclosporine or tacrolimus are the most likely causative agents. However, there are problems extrapolating animal data to humans, because animals are relatively resistant to cyclosporine nephrotoxicity (4). Most studies have suggested that the nephrotoxic potential of both tacrolimus and cyclosporine is similar, and the recognition that nephrotoxicity is a major problem in transplantation medicine has led to the introduction of calcineurin blocking-free regimes as standard in many liver units. Other approaches of using calcium antagonists and other agents to protect the kidney against these vascular effects have been tried but with variable results. In this issue of Transplantation, Klein et al. (5) reported their data in a simple but clear study comparing the acute effects of tacrolimus and cyclosporine in normal human subjects. This study confirmed previous data showing that cyclosporine is vasoactive at these doses, with increases in baseline creatinine and blood pressure and a reduction in renal plasma flow and glomerular filtration rate in otherwise in normal kidneys. However, this is the first study to show that tacrolimus does not share these vasoconstrictor properties at the current recommended doses. This slightly surprising result may be related to the relative doses and potencies. The “guilt by association” usually linking these agents may be unfair, because the real differences between the two agents are now becoming clearer. Most data now suggests that tacrolimus may have a cleaner vascular side-effect profile at currently recommended trough levels than cyclosporine. This study did not address the effects of these agents on lipid or glucose metabolism, areas in which concerns have been raised and which may be pertinent to long-term graft survival. Does the current evidence suggest that we should keep a long-term place for cyclosporine in allograft immunosuppression regimes? In this respect, the link between acute reduction in renal blood flow and chronic nephrotoxicity is crucial. If one takes the view that chronic toxicity is due at least in part to microischemia, then patients should probably be transferred onto agents that cause less vasoconstriction. The problem with this approach is that in some studies there were appreciable rejection episodes associated with cyclosporine removal (6). In other studies, some benefit was derived from the switch from cyclosporine to tacrolimus (7). Although the study by Klein et al. (5) was small and concentrated on the acute period, it highlighted the relative vasoactive potency in the normal kidney. However, it may be that these data merely highlight the inadequacy of our current therapeutic monitoring using trough concentrations. Perhaps the side effects of cyclosporine could be ameliorated by better tailoring of doses. Measurement of cyclosporine concentrations at 2 hours post-administration, rather than the trough levels, gives a better indication of peak concentrations, and has been advocated by the manufacturer. However, many units have found the practical difficulties of switching to monitoring at 2 hours post-dose to be overwhelming. Moreover, because all patients differ in their T-cell sensitivity to calcineurin blocking agents, we urgently need an inexpensive and reliable lymphocyte sensitivity assay, which may allow a much more individual dosing regime than current therapy allows. In summary, because the vascular effects of cyclosporine are likely to be contributory to its nephrotoxicity, they remain the major drawback to its use in transplantation and autoimmune disease. This study showed that tacrolimus seems to be less vasoactive in normal subjects. Although it is difficult to extrapolate this data to transplant patients, there is now more of an argument for replacing cyclosporine with tacrolimus in the short term. In the long term, replacing calcineurin blocking agents completely with drugs such as rapamycin or switching early to mycophenolate mofetil-based regimes may be the way ahead.