Continental variations in IgA nephropathy among Asians.

BACKGROUND/AIMS: Local variations in patient demographics and medical practice can contribute to differences in renal outcomes in patients with IgA nephropathy. We report the experiences of two groups of Asians with IgA nephropathy across continents. MATERIALS AND METHODS: We retrospectively examined two cohorts of Asian patients with IgA nephropathy from The King Chulalongkorn Memorial Hospital registry, Thailand (1994 - 2005), and The Metropolitan Toronto Glomerulonephritis registry, Canada (1975 - 2006), and compared their baseline characteristics. Slope of estimated glomerular filtration rate (eGFR) in each group was approximated using separate repeated measures regression models for each country. RESULTS: There were 152 Canadian and 76 Thai patients. At the time of first presentation, Thai patients were more likely to be female (63.2 vs. 44.1%, p = 0.01), have less baseline proteinuria (1.2 vs. 1.7 g/d, p = 0.08) and more likely to receive angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin receptor blockers (ARB) (64.0 vs. 15.2%, p < 0.01), or prednisone (41.3 vs. 4.6%, p < 0.01). The annual change in estimated glomerular filtration rate (eGFR) for the Thai and Canadian groups were -0.82 ml/min/1.73 m2/year and -3.35 ml/min/1.73 m2/year, respectively, after adjustment for age, sex, mean arterial pressure (MAP), proteinuria, body mass index, Haas histological grade, chronicity scores and baseline medications. CONCLUSIONS: Although disease severity was similar among IgA nephropathy patients in Canada and Thailand, more Thai patients were on ACE-I/ARB or prednisone therapy at baseline. Further prospective research is needed to explore international differences in demographic and environmental factors, health resources, and disease management to determine how they may impact long-term outcomes in Asians with IgA nephropathy.

Rituximab treatment of idiopathic membranous nephropathy.

Idiopathic membranous nephropathy is a common cause of nephrotic syndrome whose pathogenesis may involve B-cell functions. Rituximab is a monoclonal antibody that binds to the CD20 antigen on B cells thereby deleting them. We conducted an open-label pilot trial of rituximab treatment in 15 severely nephrotic patients with proteinuria refractory to angiotensin-converting enzyme inhibition and/or receptor blockade but with adequately controlled blood pressure. Rituximab was given 2 weeks apart and, at 6 months, patients who remained proteinuric but had recovered B-cell counts were given a second course of treatment. Proteinuria was significantly decreased by about half at 12 months. Of the 14 patients who completed follow-up, full remission was achieved in two and partial remission in six patients based upon the degree of proteinuria. Side effects were minor; however, we found no relationship between the response and number of B cells in the blood, CD20 cells in the kidney biopsy, degree of tubulointerstitial fibrosis, starting proteinuria or creatinine values. Rituximab appears effective in reducing proteinuria in some patients with idiopathic membranous nephropathy but prospective identification of responsive patients was not possible.

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.

Renal pathology in idiopathic membranous nephropathy: a new perspective.

Histology findings in idiopathic membranous nephropathy (MGN) have been associated with the risk of renal failure, but whether they are independent of the clinical variables at the time of biopsy, predict rate of progression, or should guide therapy is uncertain. Renal biopsies of 389 adult MGN patients were evaluated semiquantitatively for interstitial fibrosis, tubular atrophy, vascular sclerosis, focal and segmental glomerulosclerosis lesions (FSGS), complement deposition, and stage and synchrony of deposits by electron microscopy (EM). Associations were tested between these findings and the rate of renal function decline (slope), renal survival, remission in proteinuria, and response to immunosuppression. Patients with a greater degree of tubulo-interstitial disease, vascular sclerosis, and secondary FSGS were older, had a higher mean arterial pressure, and a lower creatinine clearance at presentation. Although these histologic features were associated with a reduced renal survival, they did not predict this outcome independently of the baseline clinical variables nor did they correlate with the rate of decline in function or with baseline proteinuria. Furthermore, the severity of tubulo-interstitial and vascular lesions did not preclude a remission in proteinuria in those who received immunosuppressive therapy. Neither stage nor synchronicity of EM deposits nor the amount of complement deposition predicted renal survival but the latter did correlate with progression rate. In MGN, certain histologic changes are associated with renal survival outcome. However, the indicators of chronic injury are associated with age, blood pressure, and creatinine clearance at presentation and not with rate of disease progression or initial proteinuria.

Mycophenolate mofetil in the treatment of focal segmental glomerulosclerosis.

AIMS: Primary focal segmental glomerulosclerosis (FSGS) is a common cause of end-stage renal disease in both children and adults. Our current treatments are suboptimal, and a significant percentage of cases are resistant to current therapy. PATIENTS AND METHODS: We performed an open-label, 6-month trial of the new immunosuppressive agent mycophenolate mofetil (MMF) in 18 biopsy-proven patients resistant to a course of corticosteroids therapy. Seventy-five percent had also failed to respond to a cytotoxic agent and/or a calcineurin inhibitor. RESULTS: A substantial improvement in proteinuria was seen in 44% (8/18) of the patients by 6 months. This was sustained for up to 1 year post treatment in 50% (4/8) of this group. No patient had a complete remission. No deterioration in renal function was observed in any patient over the treatment period, but 3 progressed to chronic kidney failure during follow-up. Adverse effects were mild. Only 1 patient required a dose reduction due to an intercurrent infection. CONCLUSIONS: MMF appears safe to use in this group of patients and did lower proteinuria in 44% of this cohort resistant to other forms of treatment. Relapses were common, suggesting more prolonged or combination therapy may be required. More rigorous trials utilizing this medication should be considered to further assess the risk-benefit ratio of treatment with MMF in patients with FSGS.

Predicting progression in IgA nephropathy.

Immunoglobulin A (IgA) nephropathy is one of the most common primary types of glomerulonephritis to progress to end-stage renal disease. Its variable and often long natural history makes it difficult to predict outcome. We investigated the association of the rate of renal function decline based on the slope of creatinine clearance over time with demographic, clinical, laboratory, and histological data from 298 patients with biopsy-proven IgA nephropathy with a mean follow-up of 70 months. Using univariate analysis, urinary protein excretion at baseline and Lee pathological grading, as well as mean arterial pressure (MAP) and urinary protein excretion during follow-up, were associated with the rate of deterioration in renal function. Of these, only MAP and urinary protein excretion during follow-up were identified as independent factors by multiple linear regression analysis. The combination of best accuracy of prediction and shortest observation time using these two parameters was reached between the second and third years of follow-up. A semiquantitative method of estimating the rate of progression by using these factors was developed. These results indicate that MAP and severity of proteinuria over time are the most important prognostic indicators of IgA nephropathy. The potential relevance of the algorithm in patient management is shown.

Cyclosporine in patients with steroid-resistant membranous nephropathy: a randomized trial.

BACKGROUND: A clinical trial of cyclosporine in patients with steroid-resistant membranous nephropathy (MGN) was conducted. Although MGN remains the most common cause of adult-onset nephrotic syndrome, its management is still controversial. Cyclosporine has been shown to be effective in cases of progressive MGN, but it has not been used in controlled studies at an early stage of the disease. METHODS: We conducted a randomized trial in 51 biopsy-proven idiopathic MGN patients with nephrotic-range proteinuria comparing 26 weeks of cyclosporine treatment plus low-dose prednisone to placebo plus prednisone. All patients were followed for an average of 78 weeks, and the short- and long-term effects on renal function were assessed. RESULTS: Seventy-five percent of the treatment group versus 22% of the control group (P < 0.001) had a partial or complete remission of their proteinuria by 26 weeks. Relapse occurred in 43% (N = 9) of the cyclosporine remission group and 40% (N = 2) of the placebo group by week 52. The fraction of the total population in remission then remained almost unchanged and significant different between the groups until the end of the study (cyclosporine 39%, placebo 13%, P = 0.007). Renal function was unchanged and equal in the two groups over the test medication period. In the subsequent follow-up, renal insufficiency, defined as doubling of baseline creatinine, was seen in two patients in each group, but remained equal and stable in all of the other patients. CONCLUSION: This study suggests that cyclosporine is an effective therapeutic agent in the treatment of steroid-resistant cases of MGN. Although a high relapse does occur, 39% of the treated patients remained in remission and were subnephrotic for at least one-year post-treatment, with no adverse effect on filtration function.

A randomized trial of cyclosporine in patients with steroid-resistant focal segmental glomerulosclerosis. North America Nephrotic Syndrome Study Group.

UNLABELLED: A randomized trial of cyclosporine in patients with steroid-resistant focal segmental glomerulosclerosis. BACKGROUND: A clinical trial of cyclosporine in patients with steroid-resistant focal segmental glomerulosclerosis (FSGS) was conducted. Despite the fact that it is the most common primary glomerulonephritis to progress to renal failure, treatment trials have been very limited. METHODS: We conducted a randomized controlled trial in 49 cases of steroid-resistant FSGS comparing 26 weeks of cyclosporine treatment plus low-dose prednisone to placebo plus prednisone. All patients were followed for an average of 200 weeks, and the short- and long-term effects on renal function were assessed. RESULTS: Seventy percent of the treatment group versus 4% of the placebo group (P < 0. 001) had a partial or complete remission of their proteinuria by 26 weeks. Relapse occurred in 40% of the remitters by 52 weeks and 60% by week 78, but the remainder stayed in remission to the end of the observation period. Renal function was better preserved in the cyclosporine group. There was a decrease of 50% in baseline creatinine clearance in 25% of the treated group compared with 52% of controls (P < 0.05). This was a reduction in risk of 70% (95% CI, 9 to 93) independent of other baseline demographic and laboratory variables. CONCLUSIONS: These results suggest that cyclosporine is an effective therapeutic agent in the treatment of steroid-resistant cases of FSGS. Although a high relapse rate does occur, a long-term decrease in proteinuria and preservation of filtration function were observed in a significant proportion of treated patients.

Prognosis after a complete remission in adult patients with idiopathic membranous nephropathy.

This review of the long-term outcome after a complete remission of proteinuria includes 82 adult patients with biopsy-proven idiopathic membranous glomerulonephritis (IMGN), who represented 25% of the total cases (82 of 323 cases) of IMGN in our registry. Complete remission was defined as at least two consecutive follow-up evaluations showing proteinuria of 0.3 g/d or less of protein. Before remission, 70% of the patients had nephrotic-range proteinuria (61% at presentation, 9% during follow-up), and 30% were always subnephrotic (protein level < 3.5 g/d). Mean total observation time was 101 +/- 56 months, with a postremission period of 69 +/- 60 months. Seventy-one percent of the patients remained in remission and 29% relapsed. In the relapse group, 46% relapsed to nephrotic-range proteinuria and 54% relapsed to subnephrotic levels. The plasma creatinine level remained stable in 86% of the patients (71 of 82 patients) but became or remained elevated despite a period of complete remission in the remaining 14% (8 of 82 patients). No patient went on to end-stage renal disease. Seventy-seven percent of the patients had no specific treatment within 6 months of remission, whereas 23% had steroid therapy alone or in combination with an immunosuppressive agent. In a multivariate analysis, the factors that favored both remission and its durability were persistent lower levels of proteinuria and female sex. Complete remission indicates an excellent long-term prognosis in patients with IMGN, but relapses are common and, in a small percentage, chronic renal insufficiency occurs. Thus, our data suggest that even this group of patients should be monitored on a regular basis.

Impact of gender on the renal response to angiotensin II.

BACKGROUND: It is clear that women with renal disease progress to end stage at a slower rate than do men. We hypothesized that this protection may result from gender-mediated differences in responses to angiotensin II (Ang II), which has known hemodynamic effects that are thought to promote renal disease progression. We examined sex differences in renin-angiotensin system (RAS) function by measuring renal hemodynamic function and circulating plasma components of the RAS at baseline and in response to graded infusions of Ang II. METHODS: We studied two groups of normal healthy subjects, 24 men and 24 women, mean age 28 +/- 1 years, ingesting a controlled sodium and protein diet. We examined baseline concentrations of angiotensin converting enzyme, plasma renin activity, Ang II, and aldosterone. Inulin and paraaminohippurate clearance techniques were used to estimate effective renal plasma flow (ERPF) and glomerular filtration rate (GFR) at baseline and in response to graded Ang II infusion (0.5, 1.5, and 2.5 ng/kg/min). RESULTS: Mean baseline values for mean arterial pressure and aldosterone were lower in women, whereas values for plasma Ang II, GFR, ERPF, and filtration fraction (FF) did not differ. In response to Ang II, both groups exhibited a similar increase in mean arterial pressure and a decline in ERPF. GFR was maintained during Ang II infusion only in men, resulting in an augmentation of FF. In women, GFR declined in parallel with ERPF, and the FF response was significantly blunted. 17beta-Estradiol plasma concentrations influenced the ERPF response to Ang II infusion, with higher levels predicting a blunting of the decrease. The GFR response was not affected. CONCLUSIONS: The renal microcirculation in sodium-replete women may respond differently to Ang II than that of men, with the female sex predicting a lesser augmentation of FF and possibly a blunted increase in intraglomerular pressure. The mechanism remains obscure, but these contrasting responses may help to explain gender-mediated differences in renal disease progression.

Steroid therapy and prognosis of focal segmental glomerulosclerosis in the elderly.

Idiopathic focal segmental glomerulosclerosis (FSGS) is an infrequent renal biopsy diagnosis in the elderly. In our single-centre referral registry there were only 17 cases seen in 822 biopsies performed in patients aged 60 or over giving an incidence of 2%. These seventeen patients ranged from age 61 to 78 at the time of biopsy and were followed a median period of 29.5 months. The incidence of nephrotic syndrome at baseline was similar to younger adults (70.5%), but both hypertension (71%) and renal insufficiency (53%) were higher. Fifty-three percent (9/17) of the patients were treated with either steroids or a combination of steroids and cytotoxic therapy. A complete remission in proteinuria was observed in 44% of the treated patients versus none in the untreated patients. No relapses were seen in those that had a complete remission. As well, none of the patients with a complete remission, versus 9/14 (63%) of the untreated or non-responsive patients progressed to renal failure during the observation period. One patient who was treated with cytotoxic therapy and steroids subsequently died of a pancreatic carcinoma. Idiopathic FSGS is an infrequent glomerulopathy in the elderly but it is important given its malignant natural history. Alternate day prednisone for up to 6 months may be a reasonable approach since a complete remission in proteinuria was seen in 44% of our treated patients and this response was closely linked to a good long-term prognosis. The risks of therapy however must be carefully weighed against the potential benefit in each case because of the advanced age of these patients.

A randomized controlled trial of prednisone in patients with idiopathic membranous nephropathy.

We conducted a prospective randomized study in which patients with biopsy-confirmed idiopathic membranous nephropathy were assigned to receive either a six-month course of prednisone given on alternate days (45 mg per square meter of body-surface area; n = 81) or no specific treatment (n = 77). The mean duration of follow-up was 48 months. Patients in the prednisone group (median age, 46 years) entered with a mean disease duration of 15 months, a median creatinine clearance of 1.2 ml per second per 1.73 m2 (range, 0.25 to 2.6), and a median rate of urinary protein excretion of 6.8 g per day (0.3 to 26). The annual change in the corrected creatinine clearance at six months did not differ between the prednisone group and the control group (0.10 vs. 0.06 ml per second; P = 0.8), or at the last follow-up evaluation (-0.07 vs. -0.02 ml per second; P = 0.2; 95 percent confidence interval on the difference, -0.03 to 0.13). The proportion of patients with complete remission of proteinuria was also similar in the groups at 6 and 12 months and after a mean of 48 months. Outcomes were similar in the two groups with respect to progression to renal failure (3 vs. 4 patients), death (3 vs. 1 patient), complete remission of proteinuria at 36 months (16 vs. 19 patients), and a decline of 25 percent or more in the creatinine clearance at 60 months (32 vs. 25 percent of patients). A multivariate analysis, which adjusted for differences at entry in sex distribution, urinary protein excretion, and creatinine concentration, as well as other prognostic variables, failed to provide an explanation for the lack of effect of prednisone. We conclude that a six-month course of therapy in which prednisone is given on alternate days is of no benefit to patients with idiopathic membranous nephropathy.

Early function as the principal correlate of graft survival. A multivariate analysis of 200 cadaveric renal transplants treated with a protocol incorporating antilymphocyte globulin and cyclosporine.

We examined the factors determining graft survival in 200 consecutive cadaveric renal transplants managed on a quadruple-therapy protocol: Minnesota antilymphoblast globulin, cyclosporine, azathioprine, and low-dose prednisone. Perioperative central venous pressure monitoring and volume expansion were emphasized. To avoid CsA nephrotoxicity in the early posttransplant period, patients were treated with ALG until renal function was established (a mean of 7 days). Therapeutic CsA levels were achieved before ALG was discontinued. Azathioprine was used to supplement CsA in patients with nephrotoxicity or rejection. Twelve-month graft survival was 85% (first transplants 86%, retransplants 79%), with patient survival of 95%. ALG was not associated with excessive clinical cytomegalovirus infections, which occurred in 5% of patients, or with malignancy. When 3 technical failures were excluded, an analysis of numerous factors in the pretransplant and peritransplant period revealed that the strongest correlate of one-year graft survival was early renal function. Grafts with delayed function (DF) had 75% survival, compared with 91% for grafts with good early function (EF). A multivariate analysis confirmed this association: the relative risk of graft loss was increased 2.86 times for DF compared with EF. The mechanism of the deleterious effect of DF was apparently multifactorial: the DF group, by definition, contained all the kidneys that never functioned, but some risk also persisted in kidneys that achieved function. One reason for this may be that DF kidneys that achieved function had higher mean serum creatinine values at 1 month: elevated serum creatinine values at 1 month were strongly associated with increased risk of graft loss regardless of initial function. There was also a higher number of rejection episodes diagnosed in the DF group. These observations suggest that early renal function is a major determinant of graft outcome and should be a target for efforts to further improve renal graft survival.

Plasmapheresis and antiplatelet agents in the treatment of the hemolytic uremic syndrome secondary to mitomycin.

Four patients with the hemolytic uremic syndrome secondary to mitomycin therapy were treated with intense plasmapheresis and antiplatelet agents. All four patients had a hematologic response and three had slow, but steady, improvement in renal function. These results suggest an important role for these agents in mitomycin-induced hemolytic uremic syndrome.

Anemia of chronic renal failure: inhibition of erythropoiesis by uremic serum.

The pathogenesis of anemia in patients with end-stage renal disease was studied by assessing the effect of uremic serum on the proliferation and maturation of erythroid progenitor cells, BFU-E and CFU-E, into colonies in vitro. Nucleated peripheral blood cells from 10 anemic patients produced normal or increased numbers of BFU-E colonies in response to added erythropoietin when cultured in control serum, but declined a mean of 63% when autologous uremic serum was substituted. Uremic sera from 90 patients cultured with normal human marrow produced a mean decrease in BFU-E colony growth of 72%, and of CFU-E colony growth of 82%, compared to control serum. Neither hemodialysis nor peritoneal dialysis was effective in removing the inhibitor. We conclude that patients with uremia have adequate circulating erythroid progenitors that respond to erythropoietin normally when removed from the uremic environment, and that uremic serum is toxic and inhibitory to erythropoiesis. This may be an important mechanism in the anemia of chronic renal failure.

Monthly plasmapheresis for systemic lupus erythematosus with diffuse proliferative glomerulonephritis: a pilot study.

Twelve patients with systemic lupus erythematosus and biopsy-proved diffuse proliferative glomerulonephritis were randomly allocated to a control group (to continue receiving conventional therapy only) or to a plasmapheresis group (to receive conventional therapy along with one 4-I plasma exchange a month). The six patients treated with plasmapheresis had better preservation of renal function, reduced disease activity, fewer admissions to hospital and less need for steroid and immunosuppressive therapy than the six control patients. The patients treated with plasmapheresis also showed evidence of reduced immunologic activity and had no side effects attributable to the plasma exchange. These results suggest that monthly plasma exchange should be assessed in a controlled randomized trial as a possible therapeutic adjunct in patients with systemic lupus erythematosus and diffuse proliferative glomerulonephritis.