Alain Meyrier

Treatment of focal segmental glomerulosclerosis

Focal segmental glomerulosclerosis (FSGS) is not a disease, but a lesion affecting the podocyte. Secondary FSGS may be due to a host of various factors, and patients are rarely nephrotic, requiring symptomatic treatment only. The best prognostic feature of nephrotic FSGS is its response to corticosteroids. Some forms are most likely of immunological origin, relapse in a renal transplant and justify immunosuppressive treatment. In a growing number of cases, genetic profiling of molecules that contribute to the podocyte slit diaphragm permselectivity to albumin has identified defects that do not represent indications for immunosuppression. In the other forms, corticosteroids and cyclosporin A (CsA) remain the mainstay of treatment, with better efficacy when CsA is associated with steroids. The renal tolerability of CsA is reasonably good when the dosage is low. CsA dependency is not constant. Alkylating agents are reluctantly indicated in steroid-sensitive forms, which are rare. They are mostly ineffective in steroid-resistant forms. Tacrolimus seems a promising therapy with low toxicity, but it is usual for dependency on the drug to occur. Sirolimus seems to be ineffective. Azathioprine is not considered indicated, despite rare reports with favourable results, which would deserve further controlled trials. Recent publications indicate that mycophenolate mofetil might usefully find a place in the treatment. Plasmapheresis is of no avail outside the special case of relapse in a transplanted kidney. Immunoabsorption of the elusive substance that causes the nephrotic syndrome and its relapse on a transplant has not led to practical treatment options.

Treatment of focal segmental glomerulosclerosis with immunophilin modulation: when did we stop thinking about pathogenesis?

Nephrotic focal segmental glomerulosclerosis (FSGS) represents a difficult therapeutic challenge. FSGS has long been considered a subset of idiopathic nephrotic syndrome, lumping together FSGS and minimal change disease (MCD). The time-honored Shalhoub hypothesis has led to treating FSGS as a T-cell-driven condition in which a lymphokine, considered without proof as being the glomerular permeability factor, induces proteinuria and podocyte functional and structural derangement. This has led to trying, in addition to steroids, every new drug marketed in the field of organ transplantation, first cyclosporine (CsA) and then other immunophilin modulators. The fact that alkylating agents and mycophenolate mofetil have obtained a poor and inconstant favorable effect, and that rituximab may obtain remissions, although inconstantly, has not led to reconsidering the T-cell hypothesis. This wrong thinking has fostered innumerable, mostly uncontrolled, treatment trials with various immunosuppressive agents. In fact, clinicians have not considered the fact that some but not all immunophilin modulators may be effective as nonspecific antiproteinuric agents, rather than as immunosuppressive drugs, and that treatment success does not exclude a non-immunologic pathophysiology. Recent findings on the mode of action of CsA and FK-506 have lent support to this concept. This review should be considered as a plea to reconsider the pathogenesis of nephrotic FSGS, applying all efforts to the identification of the factor, or factors, responsible for nephrotic FSGS, and to fund treatment to counteract the factor, rather than pursuing costly and non-evidence-based immunosuppressive therapeutic trials.

An update on the treatment options for focal segmental glomerulosclerosis

Focal segmental glomerulosclerosis (FSGS) is not a disease but a lesion initially affecting the podocyte. Various factors may induce ‘secondary’ FSGS, including defects in molecules that contribute to the podocyte slit diaphragm permselectivity to albumin. They do not represent indications for immunosuppression and require symptomatic treatment only, comprising angiotensin 2 and endothelin antagonists. Primary (idiopathic) FSGS is possibly but not certainly of immunologic origin, owing to an elusive glomerular permeability factor (GPF), explaining relapse on a renal transplant and justifying an immunosuppressive treatment. The best prognostic feature of primary nephrotic FSGS is its response to corticosteroids. Alkylating agents are mostly ineffective in steroid-resistant forms. An association of corticosteroids and cyclosporine A (CsA) remains the mainstay of treatment, with a good tolerability when CsA dosage is low. A definite advantage of tacrolimus on CsA has not yet been established. Sirolimus appears ineffective and potentially harmful. Azathioprine is not indicated. A number of mostly uncontrolled trials indicate that mycophenolate mofetil might find an adjunctive place in the treatment. Plasmapheresis is of no avail outside the special case of relapse in a transplanted kidney. Immunoabsorption of the GPF has not led to practical treatment options. Anecdotal reports on rituximab are as yet too few to determine whether this monoclonal anti-CD20 antibody will find a place in the treatment of primary FSGS.

Nephrosclerosis: update on a centenarian

Nephrosclerosis is an umbrella term defining changes in all compartments of the kidney, changes caused by hypertension and by ageing. Among other lesions, arteriolosclerosis and arteriolohyalinosis play a major role in inducing glomerular ischaemic shrinking and sclerosis along with glomerulomegaly and focal-segmental glomerulosclerosis (FSGS). These lesions are accompanied by tubulointerstitial inflammation and fibrosis that predict the decline of renal function. Nephrosclerosis is a major cause of renal insufficiency in blacks of African descent with a severe, early form of renovasculopathy and a rapid course to renal failure with predominant lesions of FSGS. It seems that in blacks, separate genetic factors independently lead to vascular lesions and to hypertension with a different time-scale of their onset and of their progression, nephroangiosclerosis preceding the onset of hypertension. Conversely, true and histologically identified nephrosclerosis in white Europeans rarely leads to end-stage renal disease in the absence of malignant hypertension. Various animal models demonstrate that renal vascular lesions may exist in the absence of hypertension. These experiments also point to a major role of angiotensin II and of a number of independent and overlapping cellular and molecular pathways in a cascade of inflammatory events that end in renal fibrosis. Two pathophysiologic mechanisms are at work in inducing glomerular lesions and tubulointerstitial fibrosis: a loss of autoregulation of the renal blood flow caused by an arteriolohyalinosis of the glomerular afferent arteriole and ischaemia that fosters the generation of hypoxia inducible-fibrosing factors. Not all antihypertensive drugs equally protect the kidney from nephrosclerosis. Angiotensin II antagonists exert a favourable effect on hyperfiltration. Conversely, dihydropyridine calcium-channel blockers and vasodilators do not withstand the derangement of renal autoregulation.

Focal and Segmental Glomerulosclerosis: Multiple Pathways Are Involved

Focal segmental glomerulosclerosis (FSGS) is not a disease but a clinicopathologic entity. The term FSGS itself is a misnomer because its lesions are not always focal, segmental, or sclerotic. Its clinical expression also widely varies and is nonspecific. Confronted with such diversity, one cannot but translate the title of this contribution into a unifying version focusing on the podocyte, initial culprit, or victim of multiple processes leading to FSGS. Some have been identified in human glomerulopathies and/or in animal or cell culture models, and are classified as secondary. Genetic forms, nonsyndromic or syndromic, have adduced a wealth of knowledge on the slit diaphragm architecture and explain the reason for their steroid resistance. Others, mostly expressed by a nephrotic syndrome, will be considered as idiopathic until the offending factor(s) that affect the molecular array of the slit diaphragm filtration barrier are identified and counteracted. Recent research has lead to suggesting that FSGS is not a T-cell-driven autoimmune glomerulopathy. Thus, treatments considered as etiologic, including glucocorticoids and calcineurin inhibitors, are in fact endowed with a mode of action on podocytes that suggests that drugs used such as immunosuppressors also might be considered as antiproteinuric agents.

Report from the Editorial Office

On behalf of all our staff and the publisher OUP, we would like to convey our best wishes for the New Year to our readers, editors and reviewers and want to thank them all for their continuing support of the journal. With this editorial, we also provide an update on last years achievements.

A farewell editorial from the Clinical Kidney Journal's former Editor-in-Chief.

Three years of age in the human species applies to a toddler. In primates, as for a medical publication like the Clinical Kidney Journal, turning 36 months means maturity. It is time, now that he has reached the end of his tenure, that the former Editor-in-Chief takes a look back at his dear journals conception, its birth, its achievements and its promises. n nIts conception stemmed from the retirement of a predecessor, NDT-Plus, the honourable sister journal to Nephrology, Dialysis, Transplantation. In fact, this title seemed to point to some superiority of the younger member of the kindred, whereas its goal was to assist NDT in providing clinical matters to a younger readership. Moreover, NDT and NDT-Plus had the same Editor-in-Chief, a driver with a two-in-hand harnessing. The coachman did a splendid job of it, but when his 6-year tenure came to an end, it was time to change one of the horses. There were long deliberations on a title—‘Journal’, of course, ‘Kidney’, evidently, and what about ‘Clinical’? That was it! Invert the terms and you come up with a good title … Clinical Kidney Journal. n nTo assist in the birth, an obstetrician of sorts was chosen—that is, a new Editor-in-Chief. The EDTA-ERA Council elected yours truly, which I considered an honour but also a frightening responsibility for a beginner in medical editing. I bit the bullet and proposed to start with a new blue glossy cover—as blue is my favourite colour—displaying three symbolic pictures (nephrology, dialysis and transplantation, respectively), a new layout and a new editorial board. This was approved by the council and by our publisher, Oxford University Press. n nThen, the new EIC had to elaborate the first issue, which appeared in February 2012. It was well received (at least this was what I was indulgently told), which was an encouragement to pursue my vision and help the newborn thrive. Now the cart had to work its weary way along the rough road of gathering reviews—in-depth-and mini ones—original articles, exceptional cases, clinical reports and other papers such as historical contributions. The content was to interest young as well as seasoned nephrologists, not be too clinical nor too scientific … yet still, clinical and scientific. It came as a rewarding acknowledgement to receive up to 120 submissions per month from all continents. This allowed a rejection rate of ∼60% of all submitted papers, so that the high quality of the journal could be maintained, but this in no way hindered a steady increase in page number. I am confident that year-in, year-out, CKJ will fulfil its promises and continue to progress to the satisfaction of its readers, clinicians and nephrologists. n nLooking back at these achievements, I cannot help but express my heartfelt gratitude to all who contributed to putting and keeping CKJ on track, the colleagues who accepted to offer reviews of outstanding quality, authors of so many interesting and teaching papers, subject editors who assigned reviewers and often added their touch to polish the revised version to perfection. Lastly, CKJ owes much to the dedication of our secretarial assistants who, one in Ghent and the other in Bonn, guided me all along the winding and bumpy roads of managing the journal. They also helped me out with the arcanum of the ScholarOne computerized system that rules the process of medical editing from some remote star in the scientific Milky Way. Their modesty precludes telling their names. You will find them on the Editorial Board page. n n‘Tiiiime!’, utters the umpire calling the next set in tennis matches. Yes, time it is to close this farewell editorial with a treat for our faithful readership. Reader, you will find below, with our compliments, a selection of 19 free in-depth reviews that appeared in the journal over its 3 years of existence. n nAppreciate, enjoy and chant with me: Long live the Clinical Kidney Journal!

NDT Plus introduces the Clinical Kidney Journal

Four years ago, the Council of the ERA-EDTA took the wise decision to publish a sister journal to Nephrology, Dialysis, Transplantation. The goal was to issue a bimonthly educational publication for young as well as seasoned nephrologists. Following some brainstorming, the title of the new journal was chosen as ‘NDT Plus’. It was indeed a ‘Plus’ that soon attracted a soaring number of submissions: comprehensive in-depth reviews, catching clinical reports, thoughtful teaching points, puzzling nephroquizzes and seductive images in nephrology. The Editorin-Chief was the same for NDT and NDT Plus, with the hard task of leading a ‘two-in-hand’ harness. The coach and pair worked their way successfully along. They still do. However, considering the fast pace of evolving interests among nephrologists, the coach driver and his team of editors wondered about a change. Would it not be a good idea to create more individuality for the two journals? A difficult quandary: the two horses got along well. The number of submissions had been growing. The readership was content. However, some voices ruffled this complacency. NDT Plus was educational alright, but not sufficiently ‘academic’. In fact, there was increasing demand for more and better. Reader, you can imagine the turmoil. More? Better? This was not asking for a revolution but rather for a complete change over. After some hesitancy the ERA-EDTA Council and Oxford University Press decided to go ahead without further stalling. New name. New cover. New editorial team. New content. This does not mean that NDT Plus has died. It is merely evolving, and we are confident that the first issue of the Clinical Kidney Journal, which you will discover in February 2012, will more than fulfil your expectations.

Acute Kidney Failure and Minimal Change Disease

MCD represents 95% of all cases of childhood idiopathic nephrotic syndrome (INS) and 30% of INS in adults of all ages and is not exceptional after 60 years. Albuminuria and hypoalbuminemia are accompanied by massive edema without reduction of blood volume. Renal function is moderately altered in 1/3 of patients with MCD, as foot process fusion impairs filtration of small molecules. The GFR returns to normal with remission of proteinuria. Since the early 1960s, a number of publications reported cases of acute oliguric kidney insufficiency complicating the course of MCD in adults. AKI mostly affects older patients with massive proteinuria, severe hypoalbuminemia, a background of hypertension, and arterial/arteriolar lesions on kidney biopsy. Histology reveals ischemic tubular necrosis. AKI may require dialysis for several weeks or months until treatment-induced remission allows resolution of oliguria. In rare cases AKI does not recover. Factors causing AKI in patients with MCD are diuretic-induced hypovolemia, NSAIDs, iodinated contrast media, and nephrotoxic drugs. AKI is not frequent in children with MCD in the absence of intercurrent complications. Conversely when steroid-resistant nephrotic children are hospitalized for an acute episode of hypovolemia, sepsis, peritonitis, and exposure to nephrotoxic medications and/or ACE inhibitors, AKI complicates NS in about half of them. The main goal of supportive therapy is to buy time until corticosteroids obtain a remission of proteinuria. Persistent oliguria may require a long period of dialysis. Prevention is based on early detection and treatment of infection, limited use of diuretics, and avoidance of nephrotoxic agents.

Acute kidney injury complicating nephrotic syndrome of minimal change disease

Minimal change disease accounts for 70% to 90% of cases of nephrotic syndrome in children. It also causes nephrotic syndrome in adults, including patients older than age 60. Renal function is altered moderately in approximately 20% to 30% of patients because foot-process fusion impairs filtration of water and solutes. The glomerular filtration rate is reduced by approximately 20% to 30% and returns to baseline with remission of proteinuria. Over the past 50 years, a number of publications have reported cases of acute kidney injury occurring in approximately one-fifth to one-third of adult cases in the absence of prior or concomitant renal disease. Clinical attributes point to a male predominance, age >50, massive proteinuria, severe hypoalbuminemia, a background of hypertension and vascular lesions on kidney biopsy, along with ischemic tubular necrosis. Acute kidney injury may require dialysis for weeks or months until remission of proteinuria allows resolution of oliguria. In some cases, renal function does not recover. An effect of endothelin-1-induced vasoconstriction at the onset of proteinuria has been proposed to explain tubular cell ischemic necrosis. The main factors causing acute kidney injury in patients with minimal change disease are diuretic-induced hypovolemia and nephrotoxic agents. Acute kidney injury is uncommon in children in the absence of intercurrent complications. Infection, nephrotoxic medication, and steroid resistance represent the main risk factors. In all patients, the goal of supportive therapy is essentially to buy time until glucocorticoids obtain remission of proteinuria, which allows resolution of renal failure.