Cyclosporin in idiopathic glomerular disease associated with the nephrotic syndrome : workshop recommendations.

Management of idiopathic glomerular disease associated with nephrotic syndrome (INS) remains controversial and one of the most complex areas relates to utilization of the drug cyclosporin. This is despite its demonstrated effectiveness in several histologic types of the INS in randomized controlled trials. Cyclosporin is effective in inducing remission of proteinuria in approximately 80% of steroid-sensitive cases of minimal change disease (MCD). Cyclosporin is also effective in both the induction of remission and long-term preservation of renal function in steroid-dependent/-resistant MCD and steroid-resistant focal segmental glomerulosclerosis (FSGS). The overall response rate in FSGS is lower than in MCD, and long-term therapy (>12 months) may be required to both achieve remission and sustain it. Cyclosporin therapy is also of benefit in reducing proteinuria in 70-80% of patients with steroid-resistant membranous nephropathy (MGN). In MGN, the maximum benefit is often delayed compared to MCD (>12 weeks). Cyclosporin is generally well tolerated and safe. The major concern remains the nephrotoxicity, but with careful monitoring of the patient's renal function; minimizing the maintenance dose and utilizing repeat renal biopsy in those receiving long-term therapy, this risk can be minimized. The algorithms have been developed derived from the best evidence in the literature in each of the histologic types to help provide a guide to the integration of cyclosporin into the management of INS for the practicing nephrologist.

Cholesterol crystal embolism: diagnosis and treatment.

Cholesterol crystal embolization (CCE) is a dreaded complication of radiology, vascular surgery, and/or anticoagulation in patients with atherosclerosis and ulcerated aortic plaques. It also represents a cause of early graft failure and of poor results of renal artery surgery. Crystals lodge in small caliber renal arteries, where they induce early, transitory thrombosis followed by delayed, definitive obstruction by endarteritis, accompanied by evidence of inflammation and eosinophilia. Massive CCE leads to early oligoanuria. In subacute forms, renal insufficiency is often delayed by weeks or months following the triggering event. A third, chronic subset of CCE is easily mistaken for atherosclerotic renal ischemia and/or nephrosclerosis. The kidney is rarely the sole organ involved in acute/subacute forms, in which the central nervous system, the coronary arteries, the spinal cord, and the mesenteric and pancreatic blood supply compromise represent the main causes of death. Cutaneous, retinal, and muscle involvement allow diagnosis by inspection or scarcely invasive biopsies in about 80% of cases, whereas renal biopsy as the only diagnostic procedure is required in 20% of cases. Prevention is based on avoidance of endovascular radiology maneuvers, vascular surgery, and excess anticoagulation in atherosclerotic patients. Treatment of acute/subacute forms of renal insufficiency consisting of stopping anticoagulation and forbidding any new radiologic and/or vascular surgery procedure; treating hypertension with angiotensin 2 antagonists and vasodilators, strict volemic control by loop diuretics and ultrafiltration, along with parenteral nutrition and prednisone, has been credited with improved outcome. Iloprost may obtain favorable results. Statins definitely ameliorate the renal and patient's prognosis.

Pharmacokinetics of quinupristin/ dalfopristin in patients with severe chronic renal insufficiency.

OBJECTIVE: To compare the pharmacokinetic profile of a single intravenous injection of quinupristin/dalfopristin, a new injectable streptogramin, in healthy young individuals and patients with severe chronic renal insufficiency. A secondary objective was to assess the relative tolerability of this dose in these patients compared with healthy individuals. PATIENTS AND PARTICIPANTS: 13 patients with severe chronic renal insufficiency (creatinine clearance 6 to 28 ml/min/1.73m2) were individually matched for gender, bodyweight and age to a healthy volunteer. METHODS: Participants received a single dose of quinupristin/dalfopristin 7.5 mg/kg bodyweight as a continuous 1-hour intravenous infusion, followed by serial blood sampling. RESULTS: The disposition profile of unchanged quinupristin was similar in the 2 groups. However, the elimination of quinupristin derivatives in patients with renal impairment tended to be decreased: mean peak plasma drug concentration (Cmax) and area under the concentration-time curve from zero to infinity (AUCinfinity) of quinupristin plus its active derivatives were about 1.4 times higher in the patients with renal impairment compared with healthy volunteers. The mean Cmax and AUCinfinity of both unchanged dalfopristin and dalfopristin plus its active derivatives were about 1.3 times higher in renally impaired patients than in healthy volunteers. Adverse events were generally mild and transient. No severe or serious adverse events were reported and no participants prematurely discontinued the study. Venous tolerability tended to be better in healthy volunteers than in the patients with renal impairment. CONCLUSION: These results suggest that no formal reduction in the dosage of quinupristin/dalfopristin is necessary in patients with severe chronic renal impairment.

In vivo intracellular cytokine production by leukocytes during haemodialysis.

Several chronic inflammatory changes undergone during chronic haemodialysis are associated with increased pro-inflammatory cytokine production. Although generation of anaphylatoxins has been incriminated in the untoward effects of haemodialysis, it is still debated whether anaphylatoxins stimulate monocyte secretion of TNF-alpha and IL-1. We demonstrate that peripheral mononuclear cells isolated from healthy controls and cultured with complement-activated autologous serum or recombinant C5a induced high levels of IL-1, IL-1ra, IL-8 and MCP-1, low levels of TNFalpha and sTNFRII but no IL-10 and MIP-1alpha. Cytokine production by leukocytes was investigated by FACS analysis in six patients dialysed consecutively with three equivalent low permeability membranes known to activate the complement to different degrees: polysulfone (F6HPS), cellulose acetate (CA) and cuprophane (CP). Percentage of leukocytes expressing IL-1, IL-1ra, TNF-alpha and IL-8 is increased in patients dialysed with CP. Moreover, we show for the first time that haemodialysis is associated with the production of cytokines by circulating neutrophils. Predialysis plasma levels of MCP-1 and TNFRII did not increase during the dialysis session at the time when anaphylatoxin generation was highest. Dialysis with membranes that activate the complement to a high extent induce activation of leukocytes which may explain chronic complications associated with dialysing with CP.

Genetic linkage of the Muckle-Wells syndrome to chromosome 1q44.

The Muckle-Wells syndrome (MWS) is a hereditary inflammatory disorder characterized by acute febrile inflammatory episodes comprising abdominal pain, arthritis, and urticaria. Progressive nerve deafness develops subsequently, and, after several years, the disease is complicated by multiorgan AA-type amyloidosis (i.e., amyloidosis derived from the inflammatory serum amyloid-associated protein) (MIM 191900) with renal involvement and end-stage renal failure. The mode of inheritance is autosomal dominant, but some sporadic cases have also been described. No specific laboratory findings have been reported. The genetic basis of MWS is unknown. Using a genomewide search strategy in three families, we identified the locus responsible for MWS, at chromosome 1q44. Our results indicate that the gene is located within a 13.9-cM region between markers D1S2811 and D1S2882, with a maximum two-point LOD score of 4. 66 (recombination fraction.00) at D1S2836 when full penetrance is assumed. Further identification of the specific gene that is responsible for MWS will therefore provide the first biological element for characterizing MWS, other than doing so on the basis of its variable clinical expression.

[Vascular mechanisms of renal fibrosis. Vasculonephropathies and arterial hypertension]. / Mécanismes vasculaires de la fibrose rénale. Néphrovasculopathies et hypertension artérielle.

Nephrovasculopathies are an increasing cause of end-stage renal failure. Nephrosclerosis is a common finding in the hypertensive patient. However, genetic factors play a prominent role in its incidence. Nephrosclerosis is a common cause of early renal failure in blacks of African ancestry, as opposed to white Europeans, in whom hypertensive nephrosclerosis rarely and slowly leads to uremia. That primary hypertension is accompanied by arterionephrosclerosis and arteriolonephrosclerosis, by focal and segmental glomerulosclerosis leading to glomerular obsolescence and by interstitial fibrosis has been established for nearly a century. However, renal vascular lesions can be observed in animal models as well as in some humans, especially blacks, in the absence of, or preceding the onset of hypertension. This suggests that nephroangiosclerosis might stem from a genetic defect in the renal vascular bed, a defect closely associated with the hypertensive trait. Atherosclerotic renal artery stenosis is a major, potentially remediable cause of chronic renal failure, especially in whites. Its prevalence in the atherosclerotic population is in the order of 15 percent. This figure has obvious bearing in terms of health cost. Early diagnosis and treatment by angioplasty or surgery can preclude development to end-stage renal disease and maintenance hemodialysis, as renal atrophy due to chronic ischemia resulting from renal artery stenosis can be halted or partially reversed by revascularization before extensive fibrosis sets in. Finally, renal vascular lesions are commonly observed in the course of various nephropathies, even in the absence of hypertension. The relationship between fibrogenesis and these vascular lesions, which develop along with interstitial fibrosis and entail an unfavorable prognosis in various glomerulopathies, remains to be elucidated. This is especially the case for focal-segmental glomerulosclerosis, membranous glomerulopathy and IgA glomerulonephritis. The pathophysiology of renal fibrosis induced by ischemia is centered on increased generation of angiotensin II that is fibrogenic owing to interaction with endothelin 1, PDGF-BB and TGF-beta. These notions open perspectives toward pharmacologic means to retard or even prevent the development of such various ischemic conditions to end-stage renal failure.

Supportive treatment improves survival in multivisceral cholesterol crystal embolism.

Disseminated cholesterol crystal embolism (CCE) is a devastating complication of atherosclerosis that is often considered beyond therapeutic resources. We designed and implemented a treatment protocol based on an analysis of the main causes of death in disseminated CCE with renal involvement. From 1985 to 1996, we applied this protocol in 67 consecutive atherosclerotic patients admitted to our renal intensive care unit for acute renal failure (serum creatinine level, 6 +/- 2.5 mg/dL) accompanied by signs and symptoms of CCE. The other principal clinical features in these patients were cardiac failure with pulmonary edema (61%), gastrointestinal ischemia (33%), cutaneous ischemia (90%), and retinal cholesterol embolism (22%). Disseminated CCE followed one or several precipitating factors, including angiographic procedure(s) (85%), anticoagulant treatment (76%), and cardiovascular surgery (33%). Our treatment schedule systematically addressed the identified causes of death in these patients. (1) To avoid CCE recurrence, any form of anticoagulant treatment was withdrawn, and aortic catheterization and surgery were proscribed. (2) To treat or prevent cardiac failure, a high-dose vasodilator regimen was instituted, including angiotensin-converting enzyme (ACE) inhibitors. In case of cardiac failure refractory to vasodilators, loop diuretics were added and, if necessary, overhydration was corrected by ultrafiltration/hemodialysis (11 patients). (3) To avoid cachexia, severe metabolic disorders were treated by hemodialysis (41 patients), and special attention was given to providing enteral or parenteral nutritional support. Patients with declining general status and laboratory evidence of inflammation, as well as those with new episodes of CCE, were treated with corticosteroids. Statistical analysis found a significant correlation between the requirement for hemodialysis and previous anticoagulation, degree of renal insufficiency, and severity of cardiac failure. Conversely, there was no correlation between requirement for hemodialysis and ACE inhibitor treatment or presence of atherosclerotic renal artery stenosis/thrombosis. The inhospital mortality rate was 16%. There were no clinical or laboratory elements found on admission that were predictive of inhospital mortality. Among survivors, 32% had to remain on maintenance hemodialysis therapy for irreversible chronic renal failure. Including initial hospitalization, the 1-year survival rate was 87%, which compares favorably with reports in the literature indicating a first-year mortality rate of 64% to 81%. Overall follow-up was 19 +/- 20 months, ranging from 1 to 74 months. The 4-year survival rate was 52%. We conclude that an intensive-care, specific-treatment schedule reduces mortality in multivisceral cholesterol embolism.

Hypertensive nephrosclerosis pathogenesis, diagnosis and management.

Nephrovasculopathies are an increasing cause of end-stage renal failure. Hypertensive nephroscierosis is an old concept. In fact, the renal vascular lesions corresponding to this term can result from aging or a host of parenchymal renal diseases in the absence of elevated blood pressure. Nephrosclerosis is overdiagnosed. The diagnosis should rest only on renal biopsy, which is not usually done in an elderly patient with chronic renal insufficiency, hypertension and atrophic kidneys. Atherosclerotic renal disease and renal cholesterol crystal embolism are often misdiagnosed for nephro-sclerosis. The classical picture of nephrosclerosis is the patient with primary hypertension accompanied by arterio-and arteriolonephrosclerosis, focal and segmental glomerulo-sclerosis leading to glomerular obsolescence, interstitial fibrosis and inflammatory infiltrates. However, similar lesions can be observed in animal models as well as in some humans, especially blacks, in the absence of, or preceding the onset of hypertension. This suggests that nephrosclerosis might stem from a genetic defect in the renal vascular bed, a defect closely associated with the hypertensive trait. Recent data regarding the link between low birthweight and hypertension of early onset might have bearing on future developments in understanding the pathogenesis of nephrosclerosis. Treatment pursues two goals: normalizing blood pressure according to international recommendations and retarding sclerosis with a regimen essentially based on angiotensin II antagonists.

Fixed low-dose perindopril-indapamide combination in hypertensive patients with chronic renal failure.

The angiotensin converting enzyme inhibitor perindopril and the diuretic indapamide have been shown to be effective antihypertensive agents in patients with chronic renal failure. A fixed low-dose combination of these two agents has been proposed in the treatment of hypertension. We evaluated this combination in 26 patients with mild to moderate essential hypertension and mild to severe chronic renal failure that did not require dialysis. This was a multicenter, open trial consisting of a 2-week single-blind placebo washout period followed by 12 weeks of active treatment. At week 0, the patients received 2 mg perindopril/0.625 mg indapamide once a day or every other day, with the possibility of dosage adjustment to perindopril 4 mg/indapamide 1.25 mg at week 2, week 4, or week 8. A pharmacokinetic analysis using a population pharmacokinetic approach was performed at week 8. Twenty-three patients completed the 12-week study, at which time 14 patients were receiving 2 mg perindopril/0.625 mg indapamide daily, three were receiving 2 mg perindopril/0.625 mg indapamide every other day, and six perindopril 4 mg/indapamide 1.25 mg. Blood pressure readings (supine) decreased from 170.4+/-19.2 / 101.5+/-6.7 mm Hg before active treatment to 146.5+/-19.7 / 86.5+/-10.6 mm Hg at the end of treatment (P < .0001). Pharmacokinetic analysis showed that for indapamide and perindoprilat (the active metabolite of perindopril) the area under the curve (AUC24) increased with the severity of renal failure. No interaction was noted between the two drugs. Mean serum creatinine and sodium and serum potassium levels remained stable during the study. Impairment of renal function occurred in one patient and was considered unrelated to treatment. We conclude that a fixed low-dose perindopril-indapamide combination as first-line treatment has a good safety/efficacy ratio in hypertensive patients with chronic renal failure.

Germ-line mutation analysis in patients with multiple endocrine neoplasia type 1 and related disorders.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant syndrome predisposing to tumors of the parathyroid, endocrine pancreas, anterior pituitary, adrenal glands, and diffuse neuroendocrine tissues. The MEN1 gene has been assigned, by linkage analysis and loss of heterozygosity, to chromosome 11q13 and recently has been identified by positional cloning. In this study, a total of 84 families and/or isolated patients with either MEN1 or MEN1-related inherited endocrine tumors were screened for MEN1 germ-line mutations, by heteroduplex and sequence analysis of the MEN1 gene-coding region and untranslated exon 1. Germ-line MEN1 alterations were identified in 47/54 (87%) MEN1 families, in 9/11 (82%) isolated MEN1 patients, and in only 6/19 (31.5%) atypical MEN1-related inherited cases. We characterized 52 distinct mutations in a total of 62 MEN1 germ-line alterations. Thirty-five of the 52 mutations were frameshifts and nonsense mutations predicted to encode for a truncated MEN1 protein. We identified eight missense mutations and five in-frame deletions over the entire coding sequence. Six mutations were observed more than once in familial MEN1. Haplotype analysis in families with identical mutations indicate that these occurrences reflected mainly independent mutational events. No MEN1 germ-line mutations were found in 7/54 (13%) MEN1 families, in 2/11 (18%) isolated MEN1 cases, in 13/19 (68. 5%) MEN1-related cases, and in a kindred with familial isolated hyperparathyroidism. Two hundred twenty gene carriers (167 affected and 53 unaffected) were identified. No evidence of genotype-phenotype correlation was found. Age-related penetrance was estimated to be >95% at age >30 years. Our results add to the diversity of MEN1 germ-line mutations and provide new tools in genetic screening of MEN1 and clinically related cases.

Ischemic renal diseases: new insights into old entities.

Vascular nephropathies are a steadily increasing cause of end-stage renal failure. Arterionephrosclerosis and arteriolonephrosclerosis are common features in the hypertensive patient. This is especially true for blacks of African descent, in whom hypertension and nephrovasculopathies are a major cause of renal insufficiency. That primary hypertension leads to renal vascular lesions, glomerular obsolescence and interstitial fibrosis has long been established. It should not, however, obscure the fact that renal vascular lesions can be observed in animal models as well as in some humans, especially young blacks, in the absence of, or anticipating the onset of hypertension. This leads to considering the hypothesis that nephroangiosclerosis might stem from a genetic defect in the renal vascular bed and that this defect is strongly associated with the hypertensive trait. Atherosclerotic renal disease is a major, potentially treatable cause of chronic renal disease is a major, potentially treatable cause of chronic renal failure, especially in whites. It leads to renal atrophy, but the ischemic kidney retains a vigorous potential for tubular cell regeneration, which pleads for early recognition and treatment. Recent data suggest that renal ischemia, be it due to renal artery stenosis or to cholesterol crystal embolism, ranks among the multiple causes of secondary focal segmental glomerulosclerosis. Irrespective of its initial mechanism, ischemia induces renal fibrosis, the pathophysiology of which is centered on increased generation of angiotensin II. Finally, renal vascular lesions are commonly observed in the course of various nephropathies, even in the absence of hypertension, and the relationship between these lesions and the unfavorable prognosis of glomerulopathies, especially primary focal-segmental glomerulosclerosis, membranous glomerulopathy and IgA glomerulonephritis, remains to be elucidated. Expanding knowledge of the spectrum of nephrovasculopathies opens perspectives for investigating, understanding and treating a major mechanism of progressive renal insufficiency.

Long-term outcome according to renal histological lesions in 118 patients with monoclonal gammopathies.

BACKGROUND: The prognosis of monoclonal gammopathies with multiple myeloma and renal involvement is poor, and the indication for renal replacement therapy is controversial. Few studies address the value of renal histology for determining prognosis according to initial pathology findings. METHODS: We studied the course of 118 patients with multiple myeloma according to renal biopsy lesions. The monoclonal component was identified and quantified in serum and urine. Tumor cell mass was classified as stage 1, 2 or 3, according to Durie and Salmon. End-points were death, or survival on dialysis, or serum creatinine level at last examination. RESULTS: Renal biopsy showed myeloma kidney in 48 cases (41%), AL-amyloidosis in 35 (30%), light chain deposit disease in 22 (19%), chronic tubulointerstitial nephritis in 12 (10%) and cryoglobulinaemic kidney with multiple myeloma in 1. Maintenance haemodialysis was required in 46 patients (39%), earlier (P<0.0001) in myeloma kidney (mean: 3 months after diagnosis) than in AL-amyloidosis (mean: 15 months) and light chain deposit disease (mean: 18 months). Median survival was 12 months in myeloma kidney, 24 months in AL-amyloidosis and 48 months in light chain deposit disease. Dialysis increased survival in light chain deposit disease, in contrast with myeloma kidney and AL-amyloidosis patients whose survival was shorter when dialysed. The main cause of death during first year of dialysis was cardiac involvement in AL-amyloidosis, and sepsis or cardiac insufficiency in myeloma kidney. There was a trend to increased survival with multidrug chemotherapy which seemed to slow progression to end-stage renal failure. At last follow-up (median: 12 months, range 1-297), 65 (55%) patients had died. By multivariate analysis, independent predictors of survival were: age < 70, serum creatinine < or = 300 micromol/l, and serum calcium < or = 2.5 mmol/l. CONCLUSIONS: Initial renal biopsy helps predict prognosis in patients with multiple myeloma and renal involvement. Maintenance haemodialysis is a reasonable indication in light chain deposit disease and AL-amyloidosis, especially in patients aged < 70. Multidrug therapy tends to prolong survival and slow progression to end-stage renal disease.

Immunoallergic granulomatous interstitial nephritis following treatment with omeprazole.

A 69-year-old male who had a long history of ocular myasthenia was treated with omeprazole for 3 months. Progressive renal insufficiency was discovered fortuitously. There were no clinical or laboratory manifestations of immunoallergy. Renal biopsy revealed severe granulomatous interstitial nephritis, tubular injury and fibrosis. Histology of a liver nodule disclosed hepatic granulomatous involvement. Withdrawal of omeprazole and a short course of corticosteroids were followed by improvement but not normalization of renal function. This is the eighth report of omeprazole-induced interstitial nephritis. In the present case as in 2 others in the literature, the patients had been followed up for an autoimmune disease previously, which suggests that in patients with such a background, patients should be examined regularly for renal functional impairment during treatment with omeprazole.

Podocytes undergo phenotypic changes and express macrophagic-associated markers in idiopathic collapsing glomerulopathy.

Collapsing glomerulopathy (CG), a severe form of focal segmental glomerulosclerosis (FSG), is characterized by tuft retraction and consolidation in numerous glomeruli and changes in podocyte morphology and topography. Other glomeruli are less affected. Collapsing glomerulopathy is also characterized by tubulointerstitial atrophy and fibrosis. The pathophysiology of the glomerular and tubulointerstitial lesions is poorly understood. We studied renal tissue of five Black and three White patients, all human immuno-deficiency virus (HIV) negative, with nephrotic syndrome, renal failure, and histological evidence of CG. Immunohistochemistry identified normal podocyte phenotypes by podocalyxin, vimentin and complement receptor 1 (CR1) labeling. Three monoclonal antibodies were used to further characterize podocyte epitopes: anti-CD68 clone KP1, anti-CD68 clone PG-M1 and anti-M130 clone M18 (Ber-MAC3). Light microscopy of collapsed glomeruli showed podocyte swelling, vacuolization, multinucleation, "cobblestone-like" alignment around the glomerular tuft, and pseudo-crescent formation in Bowman's space. In collapsed glomeruli, podocalyxin, vimentin and CR1 labeling tagged both normal and vacuolated podocytes still attached to the GBM, but labeling was not found in cobblestone-like podocytes or in podocytes detached from the GBM. Conversely, numerous podocytes undergoing detachment and shedding into Bowman's space expressed macrophagic-associated epitopes. Cells with macrophagic-associated epitopes clumped in cystically dilated tubules and were aligned in tubules of smaller caliber. Their appearance was that of viable cells. There was no morphologic indication that these cells expressing macrophage-associated antigens originated from outside the glomeruli or outside the tubules. We conclude that in CG podocytes detach from the GBM, lose their normal podocytic phenotype and acquire macrophage differentiation antigens. The presence of cells with such antigens in tubular lumens suggests that detached metaplastic podocytes progress along the tubule or, alternatively, that CG tubular cells also undergo metaplastic changes into macrophage-like cells.

Pentagastrin testing in patients with renal insufficiency: normal responsivity of mature calcitonin.

Calcitonin (CT) is the most sensitive tumor marker for medullary thyroid carcinoma available, but it lacks specificity. Chronic renal failure (CRF) is known to be associated with elevations of serum immunoreactive calcitonin. Using an immunoradiometric assay to detect only mature CT, we evaluated the basal CT level and its response to pentagastrin in 30 patients with CRF and compared these data with those obtained in 71 controls. Basal mature CT was significantly higher (p < 0.05) in patients with CRF (3.55 pg/mL) than in controls (2.00). Among these patients, 20% had basal CT levels more than 10 pg/mL with a maximum of 51 pg/mL. Peak CT values (highest value obtained 3 or 5 minutes after pentagastrin) were comparable in the two groups. Among patients with CRF, 10% had peak CT values greater than 30 pg/mL with a maximum of 53 pg/mL. In this group of patients, no correlation was found between CT (at any time during the test) and parathyroid hormone, calcium, phosphate, or creatinine clearance. Men had significantly higher CT values compared with women at each time point tested, including peak values. Patients with CRF, who have not yet undergone dialysis, have moderately elevated basal CT levels, but have normal pentagastrin-stimulated peak CT levels.