In Acute IgA Nephropathy, Proteinuria and Creatinine Are in the Spot, but Podocyturia Operates in Silence: Any Place for Amiloride?

IgA nephropathy is the most frequent cause of primary glomerulonephritis, portends erratic patterns of clinical presentation, and lacks specific treatment. In general, it slowly progresses to end-stage renal disease. The clinical course and the response to therapy are usually assessed with proteinuria and serum creatinine. Validated biomarkers have not been identified yet. In this report, we present a case of acute renal injury with proteinuria and microscopic hematuria in a young male. A kidney biopsy disclosed IgA nephropathy. Podocyturia was significantly elevated compared to normal subjects. Proteinuria, renal function, and podocyturia improved promptly after steroids and these variables remained normal after one year of follow-up, when steroids had already been discontinued and patient continued on valsartan and amiloride. Our report demonstrates that podocyturia is critically elevated during an acute episode of IgA nephropathy, and its occurrence may explain the grim long-term prognosis of this entity. Whether podocyturia could be employed in IgA nephropathy as a trustable biomarker for treatment assessment or even for early diagnosis of IgA nephropathy relapses should be further investigated.

Increased urinary CD80 excretion and podocyturia in Fabry disease.

BACKGROUND: Certain glomerulopathies are associated with increased levels of CD80 (B7-1). We measured the urinary excretion of CD80, podocyturia and proteinuria in controls and in subjects with Fabry disease either untreated or on enzyme replacement therapy (ERT). METHODS: Cross-sectional study including 65 individuals: controls (n = 20) and Fabry patients (n = 45, 23 of them not on ERT and 22 on ERT). Variables included age, gender, urinary protein/creatinine ratio (UPCR), estimated glomerular filtration rate (eGFR), urinary uCD80/creatinine ratio (uCD80) and podocyturia. CD80 mRNA expression in response to lyso-Gb3, a bioactive glycolipid accumulated in Fabry disease, was studied in cultured human podocytes. RESULTS: Controls and Fabry patients did not differ in age, eGFR and gender. However, UPCR, uCD80 and podocyturia were significantly higher in Fabry patients than in controls. As expected, Fabry patients not on ERT were younger and a higher percentage were females. Non-ERT Fabry patients had less advanced kidney disease than ERT Fabry patients: UPCR was lower and eGFR higher, but uCD80 and podocyturia did not differ between non-ERT or ERT Fabry patients. There was a significant correlation between uCD80 and UPCR in the whole population (r 0.44, p 0.0005) and in Fabry patients (r 0.42, p 0.0046). Lyso-Gb3 at concentrations found in the circulation of Fabry patients increased uCD80 expression in cultured podocytes. CONCLUSIONS: Fabry disease is characterized by early occurrence of increased uCD80 excretion that appears to be a consequence of glycolipid accumulation. The potential for uCD80 excretion to reflect early, subclinical renal Fabry involvement should be further studied.

Podocyturia: A Clue for the Rational Use of Amiloride in Alport Renal Disease.

No specific or efficient treatment exists for Alport syndrome, an X-linked hereditary disease caused by mutations in collagen type IV, a crucial component of the glomerular basement membrane. Kidney failure is usually a major complication of the disease, and patients require renal replacement therapy early in life. Microhematuria and subsequently proteinuria are hallmarks of kidney involvement, which are due to primary basement membrane alterations that mainly cause endothelial thrombosis and podocyte contraction and ulterior irreversible detachment. Commonly drug-based approaches include angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, which are employed to reduce proteinuria and thus retard kidney disease progression and cardiovascular morbidity and mortality. However, as any hereditary disease, it is expressed as early as in the intrauterine life, and usually an index case is helpful to detect family-related cases. As no specific treatment exists, pathophysiologically based approaches are useful. The present case illustrates the reduction rate of urinary podocyte loss and proteinuria after amiloride administration and suggests the molecular pathways involved in Alport renal disease. Finally, podocyturia rather than proteinuria should be considered as an earlier biomarker of kidney involvement and disease progression in Alport disease.

Copious Podocyturia without Proteinuria and with Normal Renal Function in a Young Adult with Fabry Disease.

The time for starting a patient with Fabry disease on enzyme replacement therapy is still a matter of debate, particularly when no overt classical clinical signs or symptoms are present. With respect to Fabry nephropathy, a dual problem coexists: the reluctance of many nephrologists to start enzyme replacement infusion until signs of renal disease appear as the appearance of proteinuria or an elevation in serum creatinine and the lack of validated biomarkers of early renal damage. In this regard, proteinuria is nowadays considered as an early and appropriate marker of kidney disease and of cardiovascular morbidity and mortality. However, in this report we demonstrate that podocyturia antedates the classical appearance of proteinuria and could be considered as an even earlier biomarker of kidney damage. Podocyturia may be a novel indication for the initiation of therapy in Fabry disease.

Lupus eritematoso sistémico inducido por interferón-α pegilado en un paciente con infección por VHC / Pegylated interferon-α induced lupus in a patient with chronic hepatitis C

El Lupus inducido por drogas tiene una prevalencia estimada del 10%, debe sospecharse frente al antecedente de la exposición a un farmaco y están relacionado en forma temporal al uso del mismo. Generalmente, luego de suspender la droga el cuadro se resuelve. El Interferón-α puede ser responsable tanto de gatillar una respuesta inmune en pacientes predispuestos como de exacerbarla en aquellos con patologías autoinmunes previas. Comunicamos el caso de un varón de 54 años con infección por virus de hepatitis C que desarrolló LES inducido por IFN-α pegilado y realizamos una revisión de la literatura.(AU)

Lupus eritematoso sistémico inducido por interferón-α pegilado en un paciente con infección por VHC / Pegylated interferon-α induced lupus in a patient with chronic hepatitis C

El Lupus inducido por drogas tiene una prevalencia estimada del 10%, debe sospecharse frente al antecedente de la exposición a un farmaco y están relacionado en forma temporal al uso del mismo. Generalmente, luego de suspender la droga el cuadro se resuelve. El Interferón-α puede ser responsable tanto de gatillar una respuesta inmune en pacientes predispuestos como de exacerbarla en aquellos con patologías autoinmunes previas. Comunicamos el caso de un varón de 54 años con infección por virus de hepatitis C que desarrolló LES inducido por IFN-α pegilado y realizamos una revisión de la literatura.

Complex heterodyne for undersampled chirped sinusoidal signals.

We describe a method for analyzing frequency-chirped sinusoidal signals using a complex heterodyne, sometimes also known as complex demodulation on the digitized waveform. This method allows one to use prior knowledge of the signal to reduce the effective bandwidth of the signal. The method can be used to extract a frequency-chirped signal even when it is sampled well below the Nyquist criterion. Accordingly, the method facilitates the use of less-expensive data acquisition and signal processing hardware than has traditionally been used for these applications. This technique is particularly useful for high-precision (parts in 10(9)) interferometer applications in which there exists a differential acceleration between the two arms (commonly found in absolute gravity meters or gradiometers).

Persistent increase in plasma thrombomodulin in patients with a history of lupus nephritis: endothelial cell activation markers.

OBJECTIVE: To investigate the presence of continuing endothelial cell activation in patients with systemic lupus erythematosus (SLE) and its relationship with lupus nephritis. METHODS: We measured plasma concentrations of soluble thrombomodulin (sTM), vascular cellular adhesion molecule-1 (sVCAM-1), von Willebrand factor (vWf), sP-selectin, and ED1-fibronectin in 75 SLE patients with a median SLE disease activity index (SLEDAI) of 4. Forty patients with a history of lupus nephritis, confirmed by renal biopsy in 33, were compared with 35 patients without lupus nephritis and 25 controls. For subgroup analysis in patients with clinically stable remission we excluded patients with a SLEDAI > 6 or with evidence of renal disease activity. RESULTS: In the total SLE patient group sTM, sVCAM-1, vWf, and sP-selectin were significantly elevated compared with controls. In patients with a history of lupus nephritis plasma levels of sTM and vWf were significantly increased compared with SLE patients without nephritis. After adjustment for significantly associated variables, especially creatinine clearance and age, in a multivariate linear regression analysis, sTM remained significantly elevated in patients with a history of lupus nephritis (difference 28.9 ng/ml, 95% CI 11.5-46.4). In the subgroup analysis of 57 patients, the results remained unchanged. CONCLUSION: The increase of sVCAM-1, sP-selectin, sTM, and vWf reflects a state of persistent endothelial cell activation. Multivariate regression analysis shows that the elevated sTM levels are strongly associated with a history of lupus nephritis, independent of creatinine clearance or disease activity, suggesting endothelial cell activation specifically localized in the kidneys.

Activated platelets release two types of membrane vesicles: microvesicles by surface shedding and exosomes derived from exocytosis of multivesicular bodies and alpha-granules.

Platelet activation leads to secretion of granule contents and to the formation of microvesicles by shedding of membranes from the cell surface. Recently, we have described small internal vesicles in multivesicular bodies (MVBs) and alpha-granules, and suggested that these vesicles are secreted during platelet activation, analogous to the secretion of vesicles termed exosomes by other cell types. In the present study we report that two different types of membrane vesicles are released after stimulation of platelets with thrombin receptor agonist peptide SFLLRN (TRAP) or alpha-thrombin: microvesicles of 100 nm to 1 microm, and exosomes measuring 40 to 100 nm in diameter, similar in size as the internal vesicles in MVBs and alpha-granules. Microvesicles could be detected by flow cytometry but not the exosomes, probably because of the small size of the latter. Western blot analysis showed that isolated exosomes were selectively enriched in the tetraspan protein CD63. Whole-mount immuno-electron microscopy (IEM) confirmed this observation. Membrane proteins such as the integrin chains alpha(IIb)-beta(3) and beta(1), GPIbalpha, and P-selectin were predominantly present on the microvesicles. IEM of platelet aggregates showed CD63(+) internal vesicles in fusion profiles of MVBs, and in the extracellular space between platelet extensions. Annexin-V binding was mainly restricted to the microvesicles and to a low extent to exosomes. Binding of factor X and prothrombin was observed to the microvesicles but not to exosomes. These observations and the selective presence of CD63 suggest that released platelet exosomes may have an extracellular function other than the procoagulant activity, attributed to platelet microvesicles.

Generation of HER-2/neu-specific cytotoxic neutrophils in vivo: efficient arming of neutrophils by combined administration of granulocyte colony-stimulating factor and Fcgamma receptor I bispecific antibodies.

Abs are able to induce inflammatory antitumor responses by recruiting IgG Fc receptor (FcgammaR)-bearing cytotoxic effector cells. We recently described the capacity of the high affinity FcgammaRI (CD64) to trigger cytotoxic activity of neutrophils (PMN) during granulocyte CSF (G-CSF) treatment. To take advantage of FcgammaRI as a cytotoxic trigger molecule on PMN, two Ab constructs were prepared. We show that a chimeric human IgG1 Ab (Ch520C9) and an anti-FcgammaRI bispecific Ab (BsAb; 22x520C9), both directed to the proto-oncogene product HER-2/neu, interact with FcgammaRI. In addition, both Ab constructs mediate enhanced lysis of HER-2/neu-expressing tumor cells by G-CSF-primed PMN. However, engagement of FcgammaRI by Ch520C9 was inhibited by human serum IgG, thereby abrogating the enhanced Ch520C9-mediated cytotoxicity. BsAb 22x520C9, which binds FcgammaRI outside the ligand binding domain, effectively recruits the cytotoxic potential of FcgammaRI on G-CSF-primed PMN regardless of the presence of human serum. These results indicate that under physiologic conditions, serum IgG impairs activation of FcgammaRI-mediated cytotoxicity by conventional antitumor Abs. The IgG blockade can be circumvented with anti-FcgammaRI BsAbs. Using human FcgammaRI transgenic mice we demonstrate that BsAb 22x520C9 is able to engage FcgammaRI in vivo. BsAb 22x520C9 injected i.v. was readily detected on circulating PMN of G-CSF-treated transgenic animals. In addition, we showed that PMN remain "armed" with BsAb 22x520C9 during migration to inflammatory sites, and that after isolation such PMN specifically lyse HER-2/neu-expressing tumor cells. These results point to the possibility of targeting anti-FcgammaRI BsAbs to G-CSF-primed PMN in vivo, endowing them with specific anti-tumor activity.

Attitude of schizophrenics to computer videogames.

We investigated the initial attitude of 10 chronic, defected schizophrenic patients to a computer videogame session. Six of them enjoyed the experience and wanted to repeat it. Cooperation and performance were compared by means of videogames and a standard psychometric test (WAIS). Videogame performance correlated with the execution test IQ more than with the verbal test IQ. Computer games could be useful in these patients for evaluation of attitudes and responses, psychologic testing, motivation and reward.