Arndt T. Petermann

DNA damage is a novel response to sublytic complement C5b-9–induced injury in podocytes

In response to Ab-complement-mediated injury, podocytes can undergo lysis, apoptosis, or, when exposed to sublytic (<5% lysis) amounts of C5b-9, become activated. Following the insertion of sublytic quantities of C5b-9, there is an increase in signaling pathways and growth factor synthesis and release of proteases, oxidants, and other molecules. Despite an increase in DNA synthesis, however, sublytic C5b-9 is associated with a delay in G(2)/M phase progression in podocytes. Here we induced sublytic C5b-9 injury in vitro by exposing cultured rat podocytes or differentiated postmitotic mouse podocytes to Ab and a complement source; we also studied the passive Heymann nephritis model of experimental membranous nephropathy in rats. A major finding was that sublytic C5b-9-induced injury caused an increase in DNA damage in podocytes both in vitro and in vivo. This was associated with an increase in protein levels for p53, the CDK inhibitor p21, growth-arrest DNA damage-45 (GADD45), and the checkpoint kinases-1 and -2. Sublytic C5b-9 increased extracellular signal-regulated kinase-1 and -2 (ERK-1 and -2), and inhibiting ERK-1 and -2 reduced the increase in p21 and GADD45 and augmented the DNA damage response to sublytic C5b-9-induced injury. These results show that sublytic C5b-9 induces DNA damage in vitro and in vivo and may explain why podocyte proliferation is limited following immune-mediated injury.

Cyclin-dependent kinase 5 is a regulator of podocyte differentiation, proliferation, and morphology.

Podocytes are highly specialized and terminally differentiated glomerular cells that play a vital role in renal physiology, including the prevention of proteinuria. Cyclin-dependent kinase 5 (CDK5) has been shown to influence several cellular processes in other terminally differentiated cells, in particular neurons. In this study, we examined the role of CDK5 in podocyte differentiation, proliferation, and morphology. In conditionally immortalized mouse podocytes in culture, CDK5 increased in association with podocyte differentiation. During mouse glomerulogenesis in vivo, CDK5 expression was predominantly detected in podocytes from the capillary loop stage to maturation and persisted in the podocytes of adult glomeruli. In contrast, CDK5 was markedly decreased in the proliferating and dedifferentiated podocytes of mice with anti-glomerular basement membrane nephritis and in human immunodeficiency virus transgenic mice. p35, the activator of CDK5, was also detected in podocytes and the p35/CDK5 complex was active. Cell fractionation studies showed that active p35/CDK5 was mainly localized to the plasma membrane. Specific inhibition of CDK5 in differentiated cultured podocytes, either pharmacologically or with siRNA, induced shape changes, with cellular elongation and loss of process formation compared to the characteristic arborized phenotype. These data suggest a role for CDK5 as a regulator of podocyte differentiation, proliferation, and morphology.

Successful application of extracorporeal membrane oxygenation due to pulmonary hemorrhage secondary to granulomatosis with polyangiitis

Extracorporeal membrane oxygenation (ECMO) is increasingly applied in adults with acute refractory respiratory failure that is deemed reversible. Bleeding is the most frequent complication during ECMO support. Severe pre-existing bleeding has been considered a contraindication to ECMO application. Nevertheless, there are cases of successful ECMO application in patients with multiple trauma and hemorrhagic shock or head trauma and intracranial hemorrhage. ECMO has proved to be life-saving in several cases of life-threatening respiratory failure associated with pulmonary hemorrhage of various causes, including granulomatosis with polyangiitis (Wegener’s disease). We successfully applied ECMO in a 65-year-old woman with acute life-threatening respiratory failure due to diffuse massive pulmonary hemorrhage secondary to granulomatosis with polyangiitis, manifested as severe pulmonary-renal syndrome. ECMO sustained life and allowed disease control, together with plasmapheresis, cyclophosphamide, corticoids, and renal replacement therapy. The patient was successfully weaned from ECMO, extubated, and discharged home. She remains alive on dialysis at 17 months follow-up.

Phosphate and FGF23 in early CKD: on how to tackle an invisible foe

In the development of ‘chronic kidney disease–mineral bone disorder’ (CKD–MBD), the current discussion ranks around the phrase ‘which comes first’ [1, 2]: calcitriol deficiency, parathyroid hormone (PTH) hypersecretion or phosphate retention, respectively? Another question that follows is related to the issue, whether and which of these obvious metabolic and biochemical derangements is meant to be adaptive or is already degenerating into maladaptation and potentially causing harm. We know that features of CKD–MBD are related to significant pathophysiological disturbances (e.g. vascular calcification, bone disease) and impaired outcomes. And as physicians, we rather favour to counteract disease development in a preventive manner than to tackle established or even advanced disease, as supported by the recent KDIGO guidelines (e.g. clinical practise recommendation 4.2.1) [3]. Current biological and epidemiological evidence suggests quite strongly that ‘invisible’ phosphate retention may be the first and the central culprit in CKD–MBD [1, 2]. Phosphate retention leads to continuous and progressive elevations of serum FGF23 levels in order to restore phosphate balance and rising FGF23 may potentially cause collateral damage (or further adaptation?) by suppressing calcitriol synthesis and pushing PTH secretion, as the second compensatory 2430 Nephrol Dial Transphant (2011): Editorial Comments

Calcimimetic Drugs and Biomarkers

The calcium-sensing receptor is expressed almost ubiquitously throughout the human body, and is essential for calcium homeostasis and is involved in several disease pathomechanisms. Mainly in nephrology, therapeutic compounds acting on the receptor are already in use in clinical routine practice. The era of calcimimetic therapy, which commenced 10 years ago with the approval of the first-in-class compound cinacalcet HCl, has recently entered into a new phase with the arrival of velcalcetide (AMG416). Since both compounds bind to different sites at the receptor molecule, genetic polymorphism panels could conceivably play a role in future for the prediction of the best choice for any given patient. If vel- calcetide, which has currently just passed phase-III-trials, is also approved for therapeutic use, this will increase the spectrum of choices and the clinician will have to make decisions about which calcimimetic drug to give to which patient. This deci- sion would probably have to be based on various considerations including biomarkers. This article summarizes the present situation regarding patents on biomarkers dealing with the calcium-sensing receptor and genetic polymorphisms.