Adult macrophage activation syndrome-haemophagocytic lymphohistiocytosis: 'of plasma exchange and immunosuppressive escalation strategies' - a single centre reflection.

OBJECTIVE: In the context of systemic autoimmunity, that is systemic lupus erythematosus (SLE) or adult-onset Still's disease (AOSD), secondary haemophagocytic lymphohistiocytosis (HLH; also referred to as macrophage activation syndrome (MAS) or more recently MAS-HLH) is a rare and potentially life-threatening complication. Pathophysiological hallmarks are aberrant macrophage and T cell hyperactivation and a systemic cytokine flare, which generate a sepsis-like, tissue-damaging, cytopenic phenotype. Unfortunately, for adult MAS-HLH we lack standardized treatment protocols that go beyond high-dose corticosteroids. Consequently, outcome data are scarce on steroid refractory cases. Aside from protocols based on treatment with calcineurin inhibitors, etoposide, cyclophosphamide and anti-IL-1, favourable outcomes have been reported with the use of intravenous immunoglobulin (IvIG) and plasma exchange (PE). METHODS: Here we report a retrospective series of steroid refractory MAS-HLH, the associated therapeutic regimes and outcomes. RESULTS: In this single-centre experience, 6/8 steroid refractory patients survived (median follow-up: 54.4 (interquartile range: 23.3-113.3) weeks). All were initially treated with PE, which induced partial response in 5/8 patients. Yet, all patients required escalation of immunosuppressive therapies. One case of MAS-HLH in new-onset AOSD had to be escalated to etoposide, whereas most SLE-associated MAS-HLH patients responded well to cyclophosphamide. Relapses occurred in 2/8 cases. CONCLUSION: Together, early use of PE is at most a supportive measure, not a promising monotherapy of adult MAS-HLH. In refractory cases, conventional cytoreductive therapies (i.e. cyclophosphamide and etoposide) constitute potent and reliable rescue approaches, whereas IvIG, anti-thymoglobulin, and biologic agents appear to be less effective.

Identification and characterization of a defective CYP3A4 genotype in a kidney transplant patient with severely diminished tacrolimus clearance.

Cytochrome P450 3A4 (CYP3A4) is a major drug-metabolizing enzyme that is widely investigated. So far, no homozygous inactive variant has been described. We report on a 19-year-old kidney transplant patient suffering from Alport syndrome, who experienced unexpected high tacrolimus plasma trough levels during immunosuppressant therapy. Because nonadherence, liver failure, or drug-drug interactions could be excluded, we hypothesized a diminished metabolism of the drug caused by mutations in the main detoxification enzyme, CYP3A4. Exome sequencing revealed a novel single-nucleotide polymorphism (c.802C>T) resulting in a premature stop codon in CYP3A4 exon 5. Accordingly, no CYP3A4 protein could be detected in kidney biopsy tissue, and there was lack of expression in HepG2 cells transiently transfected with the mutated CYP3A4. In addition, the patient harbored inactive CYP3A5*3, resulting in loss of function of the entire CYP3A locus, explaining the deteriorated tacrolimus clearance. This is, to our knowledge, the first case of a complete failure of CYP3A4 in humans.

ARFI-based tissue elasticity quantification and kidney graft dysfunction: first clinical experiences.

BACKGROUND AND PURPOSE: Beyond the medical history, the clinical exam and lab findings, non-invasive ultrasound parameters such as kidney size and Doppler values (e.g. the resistive index) are important tools assisting clinical decision making in the monitoring of renal allografts. The gold standard for the diagnosis of renal allograft dysfunction remains the renal biopsy; while an invasive procedure, the justifiable necessity for this derives from its definitive nature a requirement beyond the synopses of all non-invasive tools. "Acoustic Radiation Force Impulse Imaging"(ARFI)-quantification is a novel ultrasound-based technology measuring tissue elasticity properties. So far experience related to this new method has not been reported in renal transplant follow-up. The purpose of this study was to evaluate changes in ARFI-measurements between clinically stable renal allografts and biopsy-proven transplant dysfunction. METHODS: We employed "Virtual Touch™ tissue quantification" (Siemens Acuson, S2000) for the quantitative measurement of tissue stiffness in the cortex of transplant kidneys. We performed initial baseline and later disease-evaluative ultrasound examinations in 8 renal transplant patients in a prospective study design. Patients were first examined during stable allograft function with a routine post-transplant renal ultrasound protocol. A second follow-up examination was carried out on subsequent presentation with transplant dysfunction prior to allograft biopsy and histological evaluation. All patiens were examined using ARFI-quantification (15 measurements/kidney). Resistive indices (RI) were calculated using pulsed-wave Doppler ultrasound, and transplant kidney size was measured on B-mode ultrasound images. All biopsies were evaluated histologically by a reference nephropathologist unaware of the results of the ultrasound studies. Histopathological diagnoses were based on biopsy results, taking clinical and laboratory findings into account. Finally we calculated the relative changes in ARFI-quantification, resistive indices and the absolute change of kidney size on a percentage basis at these defined assessment times and compared the results with the final pathologic diagnosis. RESULTS: Histological results enumerated five cases of acute T-cell-mediated rejection, one case of calcineurin inhibitor toxicity and two cases of acute tubular necrosis. Calcineurin inhibitor toxicity and acute tubular necrosis were subsumed as "other pathologies". Mean ARFI-values showed an average increase of more than 15% percent in transplants with histologically proven acute rejection whereas no increase was seen in transplants with other pathologies. Mean RI-values showed no increase either in the diagnostic group of acute rejection, nor in the group with other pathologies. Kidney size showed a mean absolute increase of 0.5 centimetres in allografts with acute rejection, whereas a mean decrease of 0.17 centimetres was seen in the group with other pathologies. CONCLUSION: As shown before in other studies, RI values and kidney size are of doubtful utility in the evaluation of kidney allograft dysfunction. ARFI-based elasticity measurement shows promise as a complementary non-invasive parameter in follow-on diagnosis of renal allograft rejection.

ARFI-based tissue elasticity quantification in comparison to histology for the diagnosis of renal transplant fibrosis.

BACKGROUND AND PURPOSE: Until recently clinical diagnosis of chronic renal allograft dysfunction could only be established invasively by renal biopsy. Given the risks of that procedure, a non-invasive, diagnostic test would be very advantageous. Novel ultrasound-based elasticity tools, using "Acoustic Radiation Force Impulse (ARFI)" technology are now available. Previously this technique has been utilised to quantify liver fibrosis. First results of these studies are promising. The purpose of our study was to investigate correlation between stiffness values obtained by ARFI-quantification and histological fibrosis score in renal transplants. METHODS: We employed "Virtual Touch™ tissue quantification" (Siemens Acuson, S2000) to quantitatively measure tissue stiffness in the cortex of transplant kidneys. Eighteen patients were included in this prospective study, recording close temporal ARFI-quantification and fibrosis measurements. All patients undergoing renal transplant biopsy were examined with ARFI-quantification (15 measurements per transplant kidney). Resistive indices were also calculated from pulsed-wave Doppler ultrasound. Transplant biopsies were histologically evaluated by a reference nephropathologist and graded according to the percentage of fibrosis and to the BANFF-score. Due to the non-normal distribution of the data the Spearman-correlation-coefficient (rho) was used to assess the bivariate relationship of ARFI and fibrosis in the transplant kidney. RESULTS: There was a significant positive moderate correlation between mean ARFI-values and the grade of fibrosis (rho = +0.465; p = 0.026). This correlation was also valid for the mean ARFI-values and the BANFF-category (rho = +0.468; p = 0.025). There was no significant correlation between the mean ARFI-values and the resistive indices in the transplant kidney (rho = +0.034; p = 0.904). Nevertheless, a positive correlation between the mean RI-values of the kidney and the grade of fibrosis was established (rho = +0.563; p = 0.015). CONCLUSION: The mean values of ARFI measurements and the resistive indices are potentially independent explanation variables for evaluating the grade of fibrosis in transplant kidneys.

[Acute renal failure due to rhabdomyolysis in McArdle's disease following binge drinking with seizures]. / Alkoholabusus mit Krampfanfall als Auslöser einer Rhabdomyolyse mit akutem Nierenversagen bei McArdle-Syndrom.

HISTORY AND ADMISSION FINDINGS: A 36-year-old gardener was admitted for tonic-clonic seizures after binge drinking. The next days he developed massive rhabdomyolysis with acute renal failure. Past medical history was unremarkable except for a similar episode of acute renal failure 14 years ago. At that time he had consumed alcohol as well. Furthermore, the patient complained of exercise-related painful muscle cramping and swelling. INVESTIGATIONS: The serum creatinine peaked at 8.5 mg/dl, blood urea at 126 mg/dl and the maximal level of serum creatinine kinase was 108 300 U/l. Because of the massive rhabdomyolysis and the patient inverted question marks past medical history a metabolic myopathy was suspected and a muscle biopsy was performed. Histochemical staining of muscle frozen sections for phosphorylase revealed no activity which is typical for myophosphorylase deficiency (McArdle inverted question marks disease). Additional biochemical analysis of the muscle biopsy specimen confirmed the diagnosis. TREATMENT AND COURSE: By vigorous intravenous hydration and forced alkaline diuresis, the patient had a sufficient urinary output and lacked uremic signs. The serum creatinine and urea fell continuously and reached normal levels after 6 weeks. At that time serum creatinine kinase was still elevated (867 U/l), which is typical for McArdle inverted question marks disease. Avoiding alcohol, a new episode of rhabdomyolysis and acute renal failure did not occur. CONCLUSIONS: Besides exercise alcohol is likely to be a further possible trigger of rhabdomyolysis and acute renal failure in McArdle inverted question marks disease. Postulated mechanisms by which alcohol induces muscle injury include direct muscle toxicity and inhibition of gluconeogenesis, as these patients are probably more dependent on the gluconeogenetic pathway for muscle cell metabolism.

[Mycoplasma hominis. A rare causative agent of acute pyelonephritis]. / Mycoplasma hominis. Ein seltener Erreger der akuten Pyelonephritis.

HISTORY AND CLINICAL FINDINGS: A 23-year-old woman was admitted with typical signs of an acute urinary tract infection: fever, pain on tapping over both renal areas and in both flanks, urgency and dysuria. She had a history of renal colic with spontaneous passage of a renal stone. INVESTIGATIONS: There was marked leukocytosis and raised C-reactive protein, leukocyturia and haematuria, but no nitrites or protein in the urine. All blood and urine cultures were sterile and renal ultrasound was unremarkable. DIAGNOSIS, TREATMENT AND COURSE: As signs and laboratory data indicated acute pyelonephritis (PN) she was treated with gyrase inhibiting antibiotics. But while symptoms improved, fever, leukocyturia and haematuria continued; no micro-organism could be demonstrated. Mycoplasma was therefore considered as a rare cause of PN. Special urine cultures then grew M. hominis, > 10(5) organisms/ml. On the basis of sensitivity tests doxycycline was administered. All symptoms quickly improved and all inflammation parameters and urine sediments became normal. CONCLUSION: In rare instances M. hominis may be isolated as the causative organism of PN. If, in cases with appropriate symptoms, routine tests fail to demonstrate the causative agent, M. hominis should be included in the differential diagnosis.

Dietary salt, intracellular ion homeostasis and hypertension secondary to early-stage kidney disease.

Abnormal salt metabolism plays a central role in the pathogenesis of hypertension caused by early-stage renal disease. The mechanisms by which alterations in salt balance and the vasoconstrictor state are related are unclear. We studied the effects of three different salt diets (3, 6-9 and 12 g sodium chloride) on cellular ion homeostasis in platelets in 20 patients with renal hypertension. Compared to normal subjects, patients with renal hypertension had raised cytosolic sodium and calcium concentrations. The platelet sodium pump activity was significantly depressed and calcium ATPase activity increased. These abnormalities of cellular ion metabolism were aggravated by salt overload. On the other hand, dietary salt restriction tended to normalise these parameters. The data presented indicate that a circulating inhibitor of the sodium pump plays a central role in the pathogenesis of salt-induced renal hypertension and that the final common pathway of hypertension secondary to early-stage parenchymal renal disease is an elevation of resting cytosolic calcium followed by an elevation of peripheral vascular resistance.

High-flux hemodialysis postpones clinical manifestation of dialysis-related amyloidosis.

Amyloidosis due to the retention of beta 2-microglobulin (beta 2-MG) is a frequent complication of hemodialysis (HD). Significant amounts of beta 2-MG can be removed from the body by highly permeable HD membranes, whereas conventional low-flux membranes are impermeable for the molecule. In a prospective and controlled study we investigated whether high-flux HD could delay the onset of dialysis-related amyloidosis (DRA). Twenty patients treated with cuprophane low-flux HD membranes were matched for age and previous time on HD either to continue their HD regimen or to receive HD treatment with high-flux polysulfone membranes. For 6 years each patient was examined for manifestations of DRA once a year or upon individual needs, additionally, serum beta 2-MG levels were monitored. After 6 years of follow-up no clinical signs of DRA were found in any of the patients dialyzed with high-flux polysulfone membranes, whereas 8/10 of the conventionally dialyzed patients had CTS and/or osteoarticular lesions. Serum levels of beta 2-MG were significantly reduced in patients treated with high-flux polysulfone membranes.

Biocompatible intermittent hemodialysis.

Since intermittent hemodialysis was first used systemically during the Korean war, the mortality of acute renal failure (ARF) in critically ill patients has remained high ( > or 50%). The lack of improvement may be a result of better resuscitation techniques and intensive care management that allow more severely ill patients to survive long enough to develop ARF. The concept that those patients with ARF die with, but not of, renal failure was challenged recently by the results of three prospective randomized trials. Each tested the hypothesis that the course of ARF and the fate of critically ill patients may be affected adversely by bioincompatibility reactions due to the dialysis membrane used (activation of complement and neutrophils). Schiffl and colleagues were the first to publish a full report on the results of their investigation comparing bioincompatible cuprophane (CUP) and biocompatible acrylonitrile AN 69 (Hospal, Lyon, France) membranes in 52 patients with ARF following cardiovascular surgery. The AN 69 group had a lower death rate (38% vs. 65%, p = 0.052), a lower proportion of patients dying from Gram-negative sepsis (40% vs. 71%, p = 0.0162), and an improved recovery of renal function. A similar trial comparing the use of CUP with biocompatible polymethyl-methacrylate (PMMA) was performed in 72 patients with medical categories of ARF. Again, the use of a biocompatible membrane resulted in an improved survival rate (57% vs. 37%, p = 0.11) and better recovery of renal function (62% vs. 37%, p = 0.04). Of the 20 patients in each group who initially had nonoliguric ARF, the survival rates were 80% with PMMA and 40% with CUP (p = 0.01). The preliminary results of another multicenter study including 121 patients dialyzed with either bioincompatible cellulosic membranes or PMMA or polysulfone membranes seem to confirm these findings. The management of critically ill patients is sophisticated and expensive. The use of biocompatible membranes adds little to the overall costs and appears to be justified.

Leflunomide (HWA 486), a novel immunomodulating compound for the treatment of autoimmune disorders and reactions leading to transplantation rejection.

Leflunomide has been shown to be very effective in preventing and curing several autoimmune animal diseases. Further, this agent is as effective as cyclosporin A in preventing the rejection of skin and kidney transplants in rats. Preliminary results from patients suffering from severe cases of rheumatoid arthritis demonstrated that clinical and immunological parameters could be improved with leflunomide therapy. Mode of action studies revealed that this substance antagonizes the proliferation inducing activity of several cytokines and is cytostatic for certain cell types. In this light, we could show that tyrosine phosphorylation of the RR-SRC peptide substrate and the autophosphorylation of the epidermal growth factor (EGF) receptor were, dose dependently, inhibited by leflunomide. EGF activates the intrinsic tyrosine kinase of its receptor, which stimulates the phosphorylation of a variety of peptides, the amino acid residue in all cases is tyrosine. These results indicate that much of leflunomide's activity could be due to the inhibition of tyrosine-kinase(s), which is an important general mechanism for the proliferation of various cell types. Thus, leflunomide, which is effective against autoimmune diseases and reactions leading to graft rejection, would seem to have a mode of action separating it from known immunosuppressive drugs.