Pituitary adenylate cyclase‐activating polypeptide deficiency associated with increased platelet count and aggregability in nephrotic syndrome

Abstract

adenylate cyclase-activating polypeptide deficiency associated with increased platelet count and aggregability in nephrotic syndrome. J Thromb Haemost 2015; 13: 755-67.Summary. Background: Pituitary adenylate cyclase-activating polypeptide (PACAP) was recently identified as an inhibitor of megakaryopoiesis and platelet aggregability. Objective: We studied PACAP levels in children with nephrotic syndrome (NS), which is associated with thrombocytosis, platelet hyperaggregability, and an increased risk of thrombosis. Patients/Methods: In four children with congenital NS (CNS) and 24 children with idiopathic NS (INS), plasma and urine levels of PACAP and ceruloplasmin were measured, as were platelet counts and platelet aggregation responses to collagen. In CNS patients, in vitro megakaryopoiesis and nuclear factor-jB expression in platelet lysates were also measured. All tests were performed during the nephrotic state and the nonnephrotic state. Results: Urinary losses of PACAP and ceruloplasmin were observed during the nephrotic state, and disappeared during the non-nephrotic state. Plasma PACAP deficiency was more pronounced in CNS patients than in INS patients. Thrombocytosis was observed in all CNS patients and in 11 of 29 INS patients during the nephrotic state. During the PACAP-deficient state, in vitro megakaryopoiesis was increased for CNS patients, and this effect could be reversed by the addition of recombinant PACAP. Platelet hyperaggregability was observed during the nephrotic state in both CNS and INS patients. In INS patients, the addition of recombinant PACAP to patients' platelets was studied, and resulted in decreased aggregation during the nephrotic state. Platelet aggregation correlated inversely with plasma PACAP levels, but not with serum albumin levels. Conclusions: We demonstrate urinary losses of PACAP and plasma PACAP deficiency in children with NS, associated with thrombocytosis and platelet hyperaggregability.

PACAP as a Potential Biomarker: Alterations of PACAP Levels in Human Physiological and Pathological Conditions

“…This was also accompanied by increased megakaryopoiesis and increased platelet aggregation [ 26 ]. Addition of PACAP inhibited the differentiation of hematopoetic stem cells into megakaryocytes during the nephrotic state, while addition of the plasma of congenital nephrotic patients during the nephrotic state directly promoted megakaryopoiesis when stem cells of healthy donors were used [ 26 ]. In a few patients, plasma PACAP levels were measured after bilateral nephrectomy, when gradually increasing levels were found together with decreased platelet count (with a strong inverse correlation in congenital nephrotic patients).…”

“…These data indicate urinary loss of PACAP and its binding protein, thus resulting in a PACAP-defi cient state. This was also accompanied by increased megakaryopoiesis and increased platelet aggregation [ 26 ]. Addition of PACAP inhibited the differentiation of hematopoetic stem cells into megakaryocytes during the nephrotic state, while addition of the plasma of congenital nephrotic patients during the nephrotic state directly promoted megakaryopoiesis when stem cells of healthy donors were used [ 26 ].…”

“…A recent study [ 26 ] has investigated PACAP levels in the plasma and urine in children with nephrotic syndrome. It was found that during the nephrotic state, PACAP was lost in the urine, compared with non-nephrotic state, when PACAP could not be reliably shown in the urine with Western blot.…”

Distribution and Function of PACAP and Its Receptors in the Healthy and Nephrotic Kidney

“…The overload of albumin and other plasma proteins in the proximal tubules causes apoptosis of proximal tubular epithelial cells and the production of proinflammatory and profibrotic substances, such as interleukin-8 and transforming growth factor-β1 (TGF-β1), causing tubulointerstitial damage and the progression of renal disease [24,25,26,27]. Since we previously found plasma PACAP deficiency due to urinary loss in infants and children with NS [23], we questioned whether PACAP would have any effect on renal proximal tubular epithelial cells simultaneously exposed to high albumin concentrations mimicking proteinuric conditions.…”

“…No data exist about the role of PACAP in proteinuric conditions [23]. Chronic proteinuria has been demonstrated as an independent disease progression factor in numerous kidney disorders [24].…”