Ticagrelor-induced renal failure leading to statin-induced rhabdomyolysis.

Renal function deterioration is a rather frequent side effect of ticagrelor; this is especially so in patients over the age of 75, with pre-existent mild renal failure and/or taking an angiotensin receptor inhibitor. We describe a patient in whom deterioration of renal function due to ticagrelor led to a rise in serum concentration of rosuvastatin which resulted in rhabdomyolysis. The presented case emphasises the importance to check renal function routinely before and one month after starting ticagrelor and to screen carefully for possible interactions with other drugs.

Patients' representations of their end-stage renal disease: relation with mortality.

BACKGROUND: Self-regulation theory explains how patients' illness perceptions influence self-management behaviour (e.g. via adherence to treatment). Following these assumptions, we explored whether illness perceptions of ESRD-patients are related to mortality rates. METHODS: Illness perceptions of 182 patients participating in the NECOSAD-2 study in the period between December 2004 and June 2005 were assessed. Cox proportional hazard models were used to estimate whether subsequent all-cause mortality could be attributed to illness perception dimensions. RESULTS: One-third of the participants had died at the end of the follow-up. Mortality rates were higher among patients who believed that their treatment was less effective in controlling their disease (perceived treatment control; RR = 0.71, P = 0.028). This effect remained stable after adjusting for sociodemographic and clinical variables (RR = 0.65, P = 0.015). CONCLUSIONS: If we consider risk factors for mortality, we tend to rely on clinical parameters rather than on patients' representations of their illness. Nevertheless, results from the current exploration may suggest that addressing patients' personal beliefs regarding the effectiveness of treatment can provide a powerful tool for predicting and perhaps even enhancing survival.

Restrictive use of immunosuppressive treatment in patients with idiopathic membranous nephropathy: high renal survival in a large patient cohort.

BACKGROUND: Immunosuppressive treatment initiated at an early stage in patients with idiopathic membranous nephropathy (iMN) improves renal survival. Treatment should ideally be restricted to high-risk patients. AIM: To evaluate the efficacy of a restrictive immunosuppressive treatment strategy for patients with iMN. DESIGN: Prospective cohort study evaluating a predefined treatment protocol. METHODS: From 1988, we adopted a restrictive treatment strategy: immunosuppressive treatment, mainly consisting of cyclophosphamide and steroids, was advised only in patients with renal insufficiency or severe intolerable nephrotic syndrome. We evaluated this strategy in a large patient cohort. To exclude any bias, we included all adult patients with iMN biopsied in the study period with a serum creatinine (Scr) < 135 micromol/l, a proteinuria > or = 3.0 g/day and/or a serum albumin (Salb) < or = 30 g/l at the time of biopsy. Analysis was according to the intention-to-treat principle. RESULTS: We studied 69 patients. At the time of biopsy, mean age was 51 years, Scr 90 micromol/l, Salb 23 g/l and proteinuria 6.7 g/day. Average follow-up was 5.5 years. Thus far 33 (48%) patients have received immunosuppressive therapy, mainly because of renal insufficiency (n = 24). Status at the end of follow-up was: complete remission n = 22 (32%), partial remission n = 24 (35%), nephrotic syndrome n = 15 (22%), persistent proteinuria n = 1 (1.4%), ESRD n = 6 (8.7%), death n = 1 (1.4%; due to bladder carcinoma after cyclophosphamide therapy). Patient survival was 100% at 5 and 7 years. Renal survival was 94% at 5 years and 88% at 7 years. DISCUSSION: In patients with iMN, a restrictive treatment policy assures a favourable prognosis, while preventing exposure to immunosuppressive therapy in >50% of the patients.

Effect of starting with hemodialysis compared with peritoneal dialysis in patients new on dialysis treatment: a randomized controlled trial.

BACKGROUND: Up-until-now, the survival and health-related quality of life of hemodialysis and peritoneal dialysis patients has only been compared in observational studies. These studies have reported small and opposing differences between both modalities. The aim of this study was to compare the outcome of hemodialysis as initial chronic dialysis treatment with that of peritoneal dialysis in a randomized controlled trial. METHODS: All new dialysis patients from 38 dialysis centers in The Netherlands without indications against either modality were invited to participate. Patients were assigned to start with hemodialysis or peritoneal dialysis. The primary outcome was mean quality-adjusted life year (QALY) score. Secondary outcome was survival. RESULTS: Due to the low inclusion rate, the trial was prematurely stopped after which 38 patients had been randomized: 18 patients to hemodialysis and 20 to peritoneal dialysis. The mean QALY score in the first 2 years was 59.1 (SD 12) for hemodialysis patients versus 54.0 (SD 19) for peritoneal dialysis patients, which constitutes a small difference in favor of hemodialysis of 5.1 (95%CI -7.3 to 17.6) After 5 years of follow-up, nine hemodialysis and five peritoneal dialysis patients had died, a significant difference in survival; hazard ration of hemodialysis versus peritoneal dialysis of 3.8 (95%CI 1.1 to 12.6). After adjustment for age, comorbidity, and primary kidney disease the hazard ratio was 3.6 (0.8 to 15.4). CONCLUSION: Only a small difference in QALY score was observed between patients who started with hemodialysis compared to patients who started with peritoneal dialysis, lending support for the equivalence hypothesis. The significant difference in longer-term survival, which favored peritoneal dialysis in this small group of patients, could be used to posit that incident dialysis patients might benefit from starting on peritoneal dialysis.

Acute renal failure in patients with glomerular diseases: a consequence of tubular cell damage caused by haematuria?

We describe three patients with acute renal failure after the onset of gross haematuria. In all patients a presumptive diagnosis of rapidly progressive glomerulonephritis was made and immunosuppressive therapy initiated. A renal biopsy was performed in two patients, which showed evidence of IgA nephropathy. Extracapillary proliferation was seen in a few glomeruli. The most notable abnormality was acute tubular necrosis with intraluminal erythrocytes and cell debris. In the third patient, who was known to have longstanding glomerular haematuria, acute tubular necrosis was considered likely after review of the urinary sediment. Despite the fact that immunosuppressive therapy was stopped, renal function rapidly returned to normal in all these patients. We feel that our patients and additional literature data demonstrate that in patients with glomerular disease a reversible acute renal failure can occur that is caused by acute tubular necrosis mediated by haematuria. Recognition of this entity will prevent unnecessary long-term immunosuppressive therapy.

[Acute renal failure following treatment with intravenously administered immunoglobulins]. / Acuut nierfalen na behandeling met intraveneus toegediende immunoglobulinen.

A 74-year-old woman with insulin-dependent diabetes mellitus type 2 developed severe, reversible renal failure due probably to the administration of high doses of intravenous immunoglobulins (IVIG) for Guillain-Barré syndrome. The preparation administered did not contain sucrose or mannitol as adjuvants. The risk factors for the development of acute renal failure include pre-existent diabetes mellitus, reduced renal function and advanced age. In approximately 150 case reports in the literature, acute renal failure developed mainly after the use of sucrose-containing IVIG preparations. The course of both the onset of and the recovery from the renal failure and the histopathological findings in the described patient were in accordance with these findings. Since other causes were unlikely and in view of the supportive finding of elevated colloid osmotic pressure, it was concluded that the renal failure in this case was probably mediated by the oncotic effect of the macromolecular immunoglobulin itself.

Graft surveillance: venous pressure, access flow, or the combination?

BACKGROUND: Increased venous pressure (VP) and decreased access flow (Qa) are predictors of dialysis access graft thrombosis. VP is easily obtainable. Qa assessment requires a special device and takes more time. The aims of our randomized multicenter studies were to compare outcome in patients with grafts monitored by VP or Qa (study A) or monitored by VP or the combination of VP and Qa (study B). METHODS: We performed VP measurements consisting of weekly VP at a pump flow of 200 mL/min (VP200) and the ratio of VP0/MAP. Qa was measured every eight weeks with the Transonic HD01 hemodialysis monitor. Threshold levels for referral for angiography were VP200> 150 mm Hg or VP0/MAP> 0.5 (both at 3 consecutive dialysis sessions) or Qa <600 mL/min. Subsequent therapy consisted of either percutaneous transluminal angioplasty (PTA) or surgery. RESULTS: Total follow-up was 80.5 patient-years for 125 grafts. The vast majority of a total of 131 positive tests was followed by angiography and corrective intervention. In study A, the rate of thromboses not preceded by a positive test was 0.19 and 0.24 per patient-year (P = NS), and in study B, it was 0.32 versus 0.28 per patient-year (P = NS). Survival curves were not significantly different between the subgroups. CONCLUSIONS: These data demonstrate that standardized monitoring of either VP or Qa or the combination of both and subsequent corrective intervention can reduce thrombosis rate in grafts to below the recommended quality of care standard (that is, 0.5 per patient-year, NKF-DOQI). These surveillance strategies are equally effective in reducing thrombosis rates.

Neurotoxicity caused by valacyclovir in a patient on hemodialysis.

The authors report toxicity caused by valacyclovir in a patient on hemodialysis. After initial recuperation resulting from treatment with hemodialysis, the patient experienced a relapse of neurologic symptoms, again necessitating hemodialysis. Although acyclovir and its analogues are generally safe drugs, they should be used with caution in patients with end-stage renal disease. Therapeutic drug monitoring may be indicated.

Decreased PMN accumulation and glomerular damage by clodronate liposome treatment in PMN-dependent anti-GBM nephritis in mice.

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.

Different mediator systems in biphasic heterologous phase of anti-GBM nephritis in mice.

BACKGROUND: After the injection of rabbit anti-mouse glomerular basement membrane (GBM) antibody into normal C57BL/6J mice severe albuminuria develops, which reaches a peak at 24 h. This early albuminuria is dependent on polymorphonuclear granulocytes (PMN) and is completely absent in the congenic beige mutant strain (C57BL/6J, bg/bg), which is genetically deficient in leukocytic neutral proteinase activity. We now studied the development of anti-GBM nephritis in beige mice during the later heterologous phase. METHODS: In untreated beige mice we assessed the albuminuria and glomerular lesions on days 1-5 after i.v. injection of anti-GBM antibody. Secondly, effector mechanisms involved in the later days of the heterologous phase were studied by substitution of whole anti-GBM antibodies by F(ab')2 fragments, by leukocyte depletion (total body irradiation), scavenging of reactive oxygen metabolites (dimethylsulfoxide treatment), and complement depletion (cobra venom factor treatment). RESULTS: In the later part of the heterologous phase (days 2-5), when there is still no sign of autologous antibody formation, i.v. injection of anti-GBM antibodies in beige mice induces nephritis with gradually increasing albuminuria, that reaches levels similar to those in non-deficient, congenic controls by day 3. This late albuminuria did not occur after injection of F(ab')2 fragments of the antibody, could be prevented by leukocyte depletion, and was greatly reduced by treatment with dimethylsulfoxide, a scavenger of hydroxyl radicals. The late albuminuria was not influenced by complement depletion with cobra venom factor. Histologic and immunohistologic studies gave no indication for a role of glomerular macrophages or lymphocytes. CONCLUSIONS: The heterologous phase in murine anti-GBM nephritis is a biphasic process, with sequential involvement of different and independent mediating systems: both phases are PMN-dependent, but only the early albuminuria depends on leukocytic neutral proteinase activity, whereas the albuminuria and the glomerular damage at later days are effected by reactive oxygen metabolites, most probably originating from PMN accumulating in the glomerulus.

Role of macrophages and colony-stimulating factor-1 in murine antiglomerular basement membrane glomerulonephritis.

Macrophages have been shown to mediate glomerular injury in antiglomerular basement membrane (anti-GBM) glomerulonephritis in rats and rabbits. To evaluate the role of macrophages and the macrophage-related cytokines, colony stimulating factor-1 (CSF-1), monocyte chemoattractant protein-1 (MCP-1) and RANTES, accelerated anti-GBM nephritis was studied in op/op mutant mice, which lack CSF-1 and are severely macrophage deficient, and in heterozygous op/+ control mice. Observations were made 24 h and 3 days after the injection of rabbit anti-mouse GBM antibody in mice preimmunized with rabbit immunoglobulin G. Proteinuria rose progressively in both groups but did not differ between them (urine protein/creatinine ratio at 3 days: 1.01 +/- 0.38 in op/op versus 1.45 +/- 0.43 in op/+; P, not significant). In both op/op and op/+ mice, anti-GBM nephritis was associated with renal expression of mRNA for RANTES and MCP-1 and barely detectable levels of mRNA for CSF-1. In contrast, these cytokines were not expressed in sham-injected mice. Morphologic lesions appeared earlier in op/op mice but were comparable by Day 3. Glomerular injury consisted of capillary thrombosis and endothelial cell damage associated with mild to moderate leukocyte infiltration. Despite enhanced expression of mRNA for RANTES and MCP-1, glomerular macrophage infiltration was not increased in op/+ mice. It was concluded that, in mice, in contrast to rats and rabbits, accelerated anti-GBM nephritis may develop in the absence of both CSF-1 and macrophage infiltration.

Lack of albuminuria in the early heterologous phase of anti-GBM nephritis in beige mice.

Passive anti-glomerular basement membrane (GBM) nephritis in the mouse is accompanied by acute massive albuminuria in the early heterologous phase. As we have previously shown, this albuminuria does not occur in the beige mutant of the C57BL/6J strain which is deficient for the leukocytic neutral proteinases elastase and cathepsin G. To address the question whether an intrinsic defect in the polymorphonuclear granulocyte (PMN) or local factors in the beige kidney are responsible for the lack of albuminuria in the beige mouse strain, we conducted reciprocal bone marrow transplantations (BMT) in beige and congenic control mice. Injection of anti-GBM antibody resulted in only slight albuminuria (89 +/- 47 micrograms/18 hours; N = 6) in normal (that is, non-irradiated, non-reconstituted) beige mice. By contrast, in beige mice, reconstituted with bone marrow (BM) from control mice, acute albuminuria developed (3032 +/- 1408 micrograms/18 hours; N = 8), to a degree comparable to that in non-irradiated control mice (4411 +/- 3405 micrograms/18 hours; N = 6, P < 0.01). Albuminuria in control mice, reconstituted with beige BM, was in the range of the normal beige mice (112 +/- 55 micrograms/18 hours; N = 9). Reconstitution with syngeneic bone marrow demonstrated that BMT by itself did not influence the level of albuminuria. All mice showed similar morphological lesions, with comparable influx of PMN in the glomeruli two hours after antibody injection. Elastase activities of PMN extracts in BMT groups were not different from those in donor mice. We conclude that the absence of albuminuria in beige mice is caused by an intrinsic defect in leukocytic neutral proteinase activity.

A peculiar variation of the musculature of the front of the forearm.

On the front of the right forearm of an adult male individual a hitherto undescribed supernumerary muscle was observed. This fusiform muscle originated from the lateral aspect of the coronoid process of the ulna and the lateral margin of the radius, distal to the attachment of the supinator muscle, and inserted - through the intermediary of an aponeurotic structure enveloping the synovial sheaths of the flexor digitorum superficialis and profundus and flexor pollicis longus muscles as well as of the extensor pollicis brevis and abductor pollicis longus muscles - to the pisiform bone, the pisohamate ligament and the tubercles of the trapezium and the scaphoid bone. It is argued that the muscle belongs to the group of the deep flexor muscles.