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.

Nephrosclerosis: a term in quest of a disease.

For a century, nephrosclerosis was ascribed to nonmalignant hypertension and aging. However, it was intuitively perceived that hypertension may follow rather than explain this nephrovasculopathy. Hypertensive nephrosclerosis was long considered a major cause of end-stage renal failure (ESRD). This is especially true in blacks of African descent but not in other ethnic populations. The term 'nephrosclerosis' is still an easy way out to classify a patient with renal insufficiency. This leads to neglect the possibility of an overlooked nephropathy complicated by hypertension and to believe that drastic blood pressure control may retard the progression to ESRD. Several clinical and experimental lines of evidence lead to the understanding that nephrosclerosis, especially in blacks, is a genetic renovasculopathy that precedes the rise in blood pressure. The identification of coding region variants in APOL1 encoding apolipoprotein L-1 in black but also white and Asians opens new lines of research on the genetics of nephroangiosclerosis and of FSGS. Metabolic derangements, such as obesity, oxidative stress, dyslipidemia and atherosclerosis may be considered confounding factors with regard to nephrosclerosis. Histomorphometric studies led to sorting out the lesions due to aging from those stemming from hypertension. They shed new light not only on glomerular lesions that comprise ischemic obsolescence but also on glomerulomegaly and focal-segmental sclerosis, the latter due to a loss of renal autoregulation. It appears that the control of hypertension is not credited with the expected benefit for slowing the decline of renal function. 'Nephrosclerosis' can be considered an umbrella term of poor significance that should be replaced by its pathologic description, that is, arterionephrosclerosis and incite to elucidate the various genetic and metabolic factors that lead to a lesion in quest of a specific disease.

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.

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.

[Podocytopathie and transdifferentiation of the podocytes in human glomerulonephritis. An immunomorphological study]. / Podocytose et transdifférenciation des podocytes dans les glomérulonéphrites humaines. Une etude immunomorphologique.

Transdifferentiation is characterized by a loss of normal epitopes by differentiated cells, accompanied by the acquisition of new epitopes and new functions. Podocytes are differentiated epithelial cells that cover and adhere to the outer surface of the glomerular basement membrane (GBM). The podocyte/GBM complex contributes to the selective filter function of the glomerular tuft. We have shown that, in various human glomerulonephritides, "dysregulated" podocytes acquire the potential to proliferate and multiply, undergo profound morphologic changes, detach from the GBM, and show phenotypic changes indicative of transdifferentiation. In the course of these events they lose their original epitopes and acquire macrophagic markers.

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.

Podocyte involvement in human immune crescentic glomerulonephritis.

BACKGROUND: The role of podocytes in human crescentic glomerulonephritis (GN) has been underestimated. This may be due to the confounding fact that "dysregulated" podocytes are able to proliferate, lose their markers, and acquire new epitopes. Moreover, in experimental anti-glomerular basement membrane (GBM) crescentic GN, podocytes participate in the crescent formation. The aim of this study was to investigate the involvement of podocytes in human immune crescentic GN. METHODS: Renal biopsies from 12 patients with anti-GBM disease and 14 with class IV lupus GN were studied by immunohistochemistry for the following markers: (1) synaptopodin, GLEPP1, podocalyxin, podocin, alpha-actinin-4, and vimentin for podocyte identification; (2) PCNA, Ki-67, and p57 for cell cycle assessment; (3) cytokeratins for identifying epithelial cells but not normal podocytes; (4) CD68 for tagging a macrophagic epitope; (5) alpha-smooth-muscle actin (alpha-SMA), a phenotypic marker of myofibroblasts. RESULTS: "True" (capsular) crescents lining Bowman's capsule and (tuft) "pseudocrescents" covering the glomerular tuft with a persistent patent urinary space were present in the 2 types of crescentic GN in similar percentages. Several features indicated that podocytes were involved in the formation of the both crescent types. Identifiable podocytes expressed proliferation markers. Podocyte cytoplasmic expansions and racket-like podocytes bridged between the tuft and Bowman's capsule. True and pseudocrescents contained labeled podocytes. In addition, podocytes located outside of the crescents had often lost their markers (dedifferentiation) and acquired new epitopes (cytokeratins and CD68). CONCLUSION: In human immune crescentic GN, podocytes undergo proliferation and dysregulation that are indicative of a podocytopathy. Podocytes contribute to crescent formation.

[Atherosclerosis and the kidney]. / Athérosclérose et reins.

Diffuse atherosclerosis entails a 15-30% risk of plaques on renal arteries (ARAS), with a correlation with coronary atherosclerosis. Ischemia induces generation of angiotensin II (Ang II) that maintains sufficient hydrostatic pressure within the tuft to preserve the GFR. Ang II inhibition suppresses this protective mechanism. In fact, any antihypertensive drug may lead to reaching a "critical perfusion pressure". ARAS should be suspected in case of renal asymmetry. It should also be envisaged in case of "flash pulmonary edemas". Ultrasonography and renal tomography show aortic calcifications and often the outline of an abdominal aortic aneurysm. Tomodensitometry may detect large aorto-renal plaques. Spiral scanner tomography represents a progress, in terms of renal artery imaging and of renal cortical atrophy. Magnetic resonance imaging is less accurate but avoids iodine toxicity. The best noninvasive method is pulsed echo-doppler. It is particularly useful for evaluating stenoses progression. Some stenoses progress to renal atrophy and renal artery thrombosis, whereas others follow a stable course. Pulsed Doppler helps predict whether revascularization will improve renal function, according to the resistance index. Renal arteriography entails a high risk of cholesterol crystal embolism. However, it is the obligatory first step for angioplasty and stent positioning, indicated when the kidney is not atrophic. The indication for revascularization essentially depends on evaluation of the benefits vs risks of angioplasty or surgery. Some publications underscore the frequent stability of renal function and the fact that, revascularized or not, most patients will shortly die of myocardial infarction. Renal cholesterol crystal embolism (CCE) is a severe condition, which occurs when large arteries undergo surgery, aortography or interventional radiology. Anticoagulants are a frequent cause of CCE. CCE may also occur spontaneously, resulting in slowly progressive renal insufficiency. Migration of crystals in small caliber intrarenal arteries induces obstruction, followed by an inflammatory reaction. The clinical picture resembles angiitis, with laboratory evidence of inflammation along with high eosinophil counts and hypocomplementemia. Diagnosis rests on: 1) a iatrogenic event in a patient with an atherosclerotic background; 2) examination of the skin disclosing purple toes, small necrotic lesions and livedo of the lower limbs. Crystals may also be found by funduscopy. Skin or muscle biopsy are contributive in showing crystals and help avoid renal biopsy; 3) other localizations involve the mesenteric circulation and the central nervous system. Until recently, the prognosis was considered disastrous. However, a recently published treatment schedule proved efficient in reducing mortality. A last issue regarding the relationships between atherosclerosis and the kidney deserves mention. In an autopsy-based study it was shown that atherosclerosis per se is accompanied by an increase in the glomerular surface area along with a greater proportion of obsolescent glomeruli by comparison with matched controls. Finally, it should be recalled that atherogenic hyperlipidemia usually aggravates the course of any renal disease, including ARAS. Treatment with statins is indicated in all forms of atherosclerotic renal disease.

Mechanisms of disease: focal segmental glomerulosclerosis.

Focal segmental glomerulosclerosis (FSGS), a subtype of "idiopathic nephrotic syndrome", is not a single disease, but a lesion that initially affects the glomerulus followed by the tubulointerstitium and renal vessels. The term 'FSGS' does not accurately encompass the various pathologic features of the glomerulus, which are not always focal, segmental or sclerotic. Particular variants of FSGS, such as collapsing glomerulopathy and the glomerular tip lesion, exemplify the nosologic uncertainty inherent in the classification of glomerular lesions. Pathologic variation notwithstanding, all pathologic processes that affect the podocyte lead to one of the histologic subtypes of FSGS. This specialized cell type has essential roles in maintaining the integrity of glomerular architecture, resisting endocapillary hydraulic pressure and hindering egress of proteins into the urinary space. Once initiated, podocyte lesions and ensuing fibrosis are usually irreversible, at least in human forms of FSGS. Remarkable progress has been made in unraveling the mechanisms of podocyte dysregulation that accompany the cellular variants of FSGS and in identifying genetic mutations affecting proteins of the slit diaphragm. Hopefully, this progress will drastically improve treatments for what is one of the most difficult therapeutic challenges to confront the nephrologist.