Mitigating Drug-Target-Drug Complexes in Patients With Paroxysmal Nocturnal Hemoglobinuria Who Switch C5 Inhibitors.

Drug-target-drug complexes (DTDCs) are phenomena newly observed in patients who switch from the complement component 5 (C5) inhibitor eculizumab to crovalimab, a novel, anti-C5 antibody in development for paroxysmal nocturnal hemoglobinuria (PNH), because these agents bind to different C5 epitopes. In Part 3 of the four-part, phase I/II COMPOSER study, 19 patients with PNH switching from eculizumab received 1,000-mg crovalimab intravenously, then subcutaneous maintenance doses from Day 8 (680 mg every 4 weeks (q4w), 340 mg every 2 weeks, or 170 mg every week). Crovalimab exposure was transiently reduced, and size-exclusion chromatography and crovalimab-specific enzyme-linked immunosorbent assays revealed DTDCs in all 19 patients' sera. Additionally, self-limiting mild to moderate symptoms suggestive of type III hypersensitivity reactions occurred in two patients. Mathematical modeling simulations of DTDC kinetics and effects of dosing on DTDC size distribution using Part 3 data predicted that increased crovalimab concentrations could reduce the proportion of large, slow-clearing DTDCs in the blood. A simulation-guided, optimized crovalimab regimen (1,000 mg intravenously; four weekly, subcutaneous 340-mg doses; then 680 mg q4w from Day 29) was evaluated in Part 4. Confirming the model's predictions, mean proportions of large DTDCs in patients who switched from eculizumab to this optimized regimen decreased by > 50% by Day 22, and target crovalimab concentrations were maintained. No type III hypersensitivity reactions occurred in Part 4. Optimizing crovalimab dosing thus reduced the proportion of large DTDCs, ensured adequate complement inhibition, and may improve safety. Model-based dosing optimization to mitigate DTDC formation offers a useful strategy for patients switching to novel antibody treatments targeting soluble epitopes.

Effect of urinary glucose concentration and pH on signal intensity in magnetic resonance images.

PURPOSE: With advances in anti-diabetes drugs, increasing numbers of patients have high urinary glucose concentrations, which may alter magnetic resonance (MR) signal intensity. We sought to elucidate the effect of urinary glucose concentration and pH on transverse relaxation and MR signal intensity. MATERIALS AND METHODS: The transverse relaxation rate (R2) was measured in samples with different glucose concentrations (in vitro) and in the urinary bladder of seven patients with diabetes and nine healthy volunteers (in vivo). The glucose concentration and pH in the in vitro samples and urine were measured. The signal intensity ratio of the bladder to adjacent tissues was obtained on T2-weighted imaging (WI), T1WI, and MR urography (in vivo). To clarify the effect of pH further, the urine of two healthy subjects was adjusted with acid and/or base to obtain various pH values (ex vivo). RESULTS: R2 increased significantly with high glucose concentrations in the in vitro study. In the in vivo study, high glucose concentration (p < 0.001) and low pH (p = 0.005) were significantly associated with high R2. R2 was higher (p = 0.002) and the signal in maximum-intensity projection images of MR urography was lower (p = 0.005) in patients with diabetes than in healthy subjects. Ex vivo study revealed that a decrease in pH in acid portion resulted in increased R2. CONCLUSION: High concentrations of urinary glucose and low pH both enhance transverse relaxation, which, in turn, causes low signal intensity in urinary bladder on long echo time (TE) images, such as MR urography. Radiologists should be aware of this phenomenon when interpreting abnormally low-intensity bladders on long TE images.

Urinary mulberry bodies as a potential biomarker for early diagnosis and efficacy assessment of enzyme replacement therapy in Fabry nephropathy.

BACKGROUND: The inability of enzyme replacement therapy (ERT) to prevent progression of Fabry nephropathy (FN) in the presence of >1 g/day proteinuria underscores the necessity of identifying effective biomarkers for early diagnosis of FN preceding proteinuria. Here we attempted to identify biomarkers for early detection of FN. METHODS: Fifty-one Fabry disease (FD) patients were enrolled. Urinary mulberry bodies (uMBs) were immunostained for globotriaosylceramide (Gb3) and renal cell markers to determine their origin. The association between semiquantitative uMB excretion and the histological severity of podocyte vacuolation was investigated in seven patients using the vacuolated podocyte:glomerular average area ratio. The association between the semiquantitative estimate of uMB excretion and duration of ERT was analyzed. A longitudinal study was conducted to assess the effect of ERT on uMB excretion. RESULTS: Thirty-two patients (63%) had uMBs, while only 31% showed proteinuria. The uMBs were positive for Gb3, lysosomal-associated membrane protein 1 and podocalyxin, suggesting they were derived from lysosomes with Gb3 accumulation in podocytes. We observed more severe podocyte vacuolation with increased uMB excretion (P = 0.03 for trend); however, the same was not observed with increased proteinuria. The percentage of patients with substantial uMB excretion increased with shorter ERT duration (P = 0.018). Eighteen-month-long ERT reduced uMB excretion (P = 0.03) without affecting proteinuria. CONCLUSIONS: uMB excretion, implying ongoing podocyte injury, preceded proteinuria in most patients. Semiquantitative uMB estimates can serve as novel biomarkers for early FN diagnosis and for monitoring the efficacy of FD-specific therapies.

A Food Debris-Like Component in the Urine Sediment From a Urostomy Pouch.

Microscopic examination of urine sediment is a basic, common method of detecting diseases of the urinary tract. We experienced a case involving a patient who had developed a fever after undergoing a urinary-diversion operation. Results of the microscopic examination of the urine collected from the urostomy pouch of the patient showed a food debris-like component. Based on this finding, we suspected a fistula between the urinary and intestinal tracts. However, after performing an experiment to verify the results, we determined that no fistula was present. Instead, we discovered that the food debris-like component originated from the urostomy skin barrier. To our knowledge, ours is the first report in the literature to demonstrate that the urostomy skin barrier can dissolve and mimic food debris in urine sediment, leading to incorrect assumptions regarding the presence of fistulas. We believe that it is important to derive a correct diagnosis when an unfamiliar component is observed in urinary sediment. We further believe that the findings from this case are valuable to professionals who administer clinical treatment and perform laboratory testing.

[Diagnosis of hematuria from red blood cells in urinary sediment].

Urinalysis is classical noninvasive test for urological disease, kidney disease, infection, bone metabolic disorders, doping tests, and many other diseases. Urinalysis is also important as a screening test to diagnose diseases. Hematuria diagnostic guidelines in Japan were published in 2006. It is described in them that the examination of urinary sediment may indicate hematuria. Urinary red blood cells in urinary sediments are useful to differentiate hematuria of glomerular origin from that of non-glomerular origin. The urinary sediment test is one of the very important tests to investigate the origin of hematuria. Here, we show a method for determining the urinary red blood cell morphology and obtaining information on hematuria.

[Analysis of the causal relations between serum ferritin elevation and latent pathologic factors by structural equation modeling].

Serum ferritin increases in various disorders and clinical conditions such as iron overload, tissue disorders, and inflammation. However causal associations between the serum ferritin level and clinical factors that influence serum ferritin level or between these factors are not well characterized. We analyzed the ferritin level and other laboratory data including transferrin saturation (TF%), enzyme activities, and inflammatory protein levels in the sera of 124 patients with hyperferritinemia. We identified latent pathologic factors representing cell damage and inflammatory status and assumed causal relations between serum ferritin elevation and these factors. Structural equation modeling was used to verify causal relations and the adequacy of latent factors. A model that quantitatively explained serum ferritin elevation was identified. The direct effect of the cell damage factor on serum ferritin indicated cell destruction and decreased ferritin clearance. In contrast, the inflammation factor directly increased the ferritin level, but indirectly decreased it via TF%. These causal relations may quantitatively explain the mechanism of serum ferritin levels in patients with hyperferritinemia.