Establishing Surrogate Kidney End Points for Lupus Nephritis Clinical Trials: Development and Validation of a Novel Approach to Predict Future Kidney Outcomes.

OBJECTIVE: End points currently used in lupus nephritis (LN) clinical trials lack uniformity and questionably reflect long-term kidney survival. This study was undertaken to identify short-term end points that predict long-term kidney outcomes for use in clinical trials. METHODS: A database of 944 patients with LN was assembled from 3 clinical trials and 12 longitudinal cohorts. Variables from the first 12 months of treatment after diagnosis of active LN (prediction period) were assessed as potential predictors of long-term outcomes in a 36-month follow-up period. The long-term outcomes examined were new or progressive chronic kidney disease (CKD), severe kidney injury (SKI), and the need for permanent renal replacement therapy (RRT). To predict the risk for each outcome, hazard index tools (HITs) were derived using multivariable analysis with Cox proportional hazards regression. RESULTS: Among 550 eligible subjects, 54 CKD, 55 SKI, and 22 RRT events occurred. Variables in the final CKD HIT were prediction-period CKD status, 12-month proteinuria, and 12-month serum creatinine level. The SKI HIT variables included prediction-period CKD status, International Society of Nephrology (ISN)/Renal Pathology Society (RPS) class, 12-month proteinuria, 12-month serum creatinine level, race, and an interaction between ISN/RPS class and 12-month proteinuria. The RRT HIT included age at diagnosis, 12-month proteinuria, and 12-month serum creatinine level. Each HIT validated well internally (c-indices 0.84-0.92) and in an independent LN cohort (c-indices 0.89-0.92). CONCLUSION: HITs, derived from short-term kidney responses to treatment, correlate with long-term kidney outcomes, and now must be validated as surrogate end points for LN clinical trials.

The Impact of Baseline Serum Creatinine on Complete Remission Rate and Long-Term Outcome in Patients with Severe Lupus Nephritis.

BACKGROUND/AIM: We assess the impact of serum creatinine at baseline on complete remission rate and long-term outcome in severe lupus nephritis (SLN). METHODS: A total of 86 adult patients with SLN [International Society of Nephrology/Renal Pathology Society (ISN/RPS) class IV lesions] were evaluated based on baseline serum creatinine levels (≤1.0, 1.01-1.5, 1.51-2.0, 2.01-3.0, and >3.0 mg/dl; n = 22, 23, 16, 12, and 13, respectively). The complete remission rates (serum creatinine level of ≤1.4 mg/dl and proteinuria of ≤0.33 g/day) and long-term outcomes (stable renal function, dialysis, and death) were compared. The patients were followed for 121 ± 64 months. RESULTS: The baseline clinical features were similar, but the chronicity index was significantly higher with increasing levels of serum creatinine. Complete remission rates were significantly higher in patients with lower levels of serum creatinine (86 vs. 52 vs. 19 vs. 25 vs. 0%, p < 0.0001). Patients with a baseline serum creatinine level of ≤1.0 mg/dl were >16 times as likely (OR 16.2; 95% CI: 4.2-61.5) to attain a complete remission and >6 times as likely (OR 6.1; 95% CI: 1.9-18.6) to have stable renal function at the last follow-up as compared to patients with a serum creatinine level of >1.0 mg/dl. The 15-year renal survival rate was greatest among those patients with a baseline serum creatinine level of ≤1.0 mg/dl (76 vs. 57 vs. 48 vs. 25 vs. 10%, p < 0.0001). CONCLUSION: The prognosis of SLN is significantly affected by the serum creatinine level at baseline. The complete remission rate is highest, and the long-term prognosis most favorable, in patients with a baseline serum creatinine level of ≤1.0 mg/dl. This emphasizes the importance of early diagnosis and treatment.

Severe lupus nephritis: the predictive value of a ≥ 50% reduction in proteinuria at 6 months.

BACKGROUND: A complete remission (CR) in severe lupus nephritis (SLN) is associated with a favorable long-term outcome. Initial therapy may be up to 6 months, but many patients do not achieve a CR until after 12 months. We assess the value of a ≥50% reduction in proteinuria (UPro) at 6 months in predicting the outcome in SLN patients. METHODS: We evaluated the 86 adult patients in the prospective, controlled trial of plasmapheresis (PP) in SLN (NEJM 1992). Patients with a CR (n = 12), end-stage renal disease (ESRD) or death (n = 13) at ≤6 months were excluded. The remaining 61 patients were categorized into two groups based on having attained a ≥50% reduction in UPro at 6 months: (yes) 34 patients and (no) 27 patients. The long-term outcomes were compared. A CR was defined by a serum creatinine (SCr) of ≤1.4 mg/dL and UPro of ≤0.33 g/day. RESULTS: Baseline features were similar, but the UPro was higher (7.1 ± 3.6 versus 4.6 ± 3.2, P 0.002) in the group with a ≥50% reduction in UPro at 6 months. At follow-up, a CR was attained in 56% of patients with a ≥50% reduction in UPro at 6 months compared with 22% (P = 0.009) in the group without. The 15-year renal survival (71 versus 25%, P = 0.005) and patient survival without ESRD (66 versus 18%, P = 0.004) was greatest in the patients with a ≥50% reduction in UPro at 6 months. CONCLUSION: A ≥50% reduction in UPro at 6 months predicts a favorable outcome in SLN.

Impact of glycaemic control on the effect of direct renin inhibition in the AVOID study.

INTRODUCTION: Hyperglycaemia induces development and progression of microvascular complications in diabetes. A direct link between high glucose levels and intrarenal renin-angiotensin activation has been demonstrated. This post-hoc analysis assessed the influence of baseline glycaemic control on the reduction of albuminuria with aliskiren or placebo added to losartan in the Aliskiren in the EValuation of PrOteinuria In Diabetes (AVOID) study. MATERIALS AND METHODS: In AVOID, 599 patients with type 2 diabetes, hypertension and nephropathy received 6 months' aliskiren or placebo added to losartan 100 mg and optimal antihypertensive therapy. Changes in urinary albumin creatinine ratio at end of study were assessed by tertiles of baseline HbA(1c) levels. RESULTS: Patients were divided into tertiles of HbA(1c) (<7.1%, 7.1 to <8.4% and ≥8.4%). There were no differences between tertiles, except patients in the highest tertile group more frequently used insulin. The antiproteinuric effect of aliskiren was consistent across tertiles, with the largest effect in the highest tertile (HbA(1c) ≥8.4%). CONCLUSIONS: This post-hoc analysis of the AVOID study suggests that renin inhibition with aliskiren 300 mg once daily added to losartan 100 mg once daily plus optimal antihypertensive therapy provides reductions in urinary albumin creatinine ratio that are efficacious in all, but particularly in poorly controlled, diabetic patients.

Complete remission in severe lupus nephritis: assessing the rate of loss in proteinuria.

BACKGROUND: The prognosis of severe lupus nephritis (SLN) is improved in patients attaining a complete remission (CR). The time to remission ranges from 10 to 16 months with many patients not attaining a CR until after 12 months. We assessed whether the rate of loss in proteinuria (UPro) is predictive of a CR in SLN patients. METHODS: We studied 85 adult patients in the prospective controlled trial of plasmapheresis in SLN (New England Journal of Medicine 1992). All patients had International Society of Nephrology/Renal Pathology Society Class IV±Class V lesions. All patients received prednisone and oral cyclophosphamide and 39 patients received plasmapheresis. A CR was defined by a serum creatinine (SCr) of ≤1.4 mg/dL and UPro of ≤0.33 g/day. The change in UPro in gram per day per week was determined at 3 and 6 months from entry to the study. RESULTS: A CR was attained in 37 patients (44%) by 16±14 months. The level of UPro at baseline was similar in CR and no remission (NR) patients (5.5 versus 6.4 g/day), but CR patients had a lower SCr (1.2 versus 2.4, P<0.0001). At 6 months, the rate of change of UPro was higher at (-)0.224 g/day/week in CR patients and (-)0.107 g/day/week in NR patients (P=0.01) and a 50% reduction in UPro was seen in 78% of CR patients but only 42% of NR patients (P=0.009). The time to a CR was ≤12 months in 19 patients and >12 months in 18 patients. The baseline SCr was similar among the two groups. However, UPro at baseline was lower in patients with CR in ≤12 months (3.9±2.7 versus 7.2±3.0 g/day, P=0.001) but the proportion of patients with membranous glomerulonephritis was similar (16 versus 22%). The rate of change in UPro at 6 months was similar at (-)0.214 g/day/week in patients with CR ≤12 months and (-)0.235 g/day/week in those with CR>12 months (P=0.6). At 6 months, a 50% reduction in UPro was also similar in the two groups (84 versus 72%, P=0.4). Additionally, the rate of change in UPro at 3 and 6 months was similar within each group. CONCLUSIONS: The rate of change in proteinuria at 6 months is significantly greater in patients attaining a CR relative to NR patients but similar in patients with a CR in ≤12 months or >12 months. Thus, the rate of loss of UPro at 6 months may help in predicting which patients will attain a CR.

Sulodexide fails to demonstrate renoprotection in overt type 2 diabetic nephropathy.

Sulodexide, a mixture of naturally occurring glycosaminoglycan polysaccharide components, has been reported to reduce albuminuria in patients with diabetes, but it is unknown whether it is renoprotective. This study reports the results from the randomized, double-blind, placebo-controlled, sulodexide macroalbuminuria (Sun-MACRO) trial, which evaluated the renoprotective effects of sulodexide in patients with type 2 diabetes, renal impairment, and significant proteinuria (>900 mg/d) already receiving maximal therapy with angiotensin II receptor blockers. The primary end point was a composite of a doubling of baseline serum creatinine, development of ESRD, or serum creatinine ≥6.0 mg/dl. We planned to enroll 2240 patients over approximately 24 months but terminated the study after enrolling 1248 patients. After 1029 person-years of follow-up, we did not detect any significant differences between sulodexide and placebo; the primary composite end point occurred in 26 and 30 patients in the sulodexide and placebo groups, respectively. Side effect profiles were similar for both groups. In conclusion, these data do not suggest a renoprotective benefit of sulodexide in patients with type 2 diabetes, renal impairment, and macroalbuminuria.

Pyridorin in type 2 diabetic nephropathy.

Pyridoxamine dihydrochloride (Pyridorin, NephroGenex) inhibits formation of advanced glycation end products and scavenges reactive oxygen species and toxic carbonyls, but whether these actions translate into renoprotective effects is unknown. In this double-blind, randomized, placebo-controlled trial, we randomly assigned 317 patients with proteinuric type 2 diabetic nephropathy to twice-daily placebo; Pyridorin, 150 mg twice daily; or Pyridorin, 300 mg twice daily, for 52 weeks. At baseline, the mean age ± SD was 63.9±9.5 years, and the mean duration of diabetes was 17.6±8.5 years; the mean serum creatinine level was 2.2±0.6 mg/dl, and the mean protein-to-creatinine ratio was 2973±1932 mg/g. Regarding the primary end point, a statistically significant change in serum creatinine from baseline to 52 weeks was not evident in either Pyridorin group compared with placebo. However, analysis of covariance suggested that the magnitude of the treatment effect differed by baseline renal function. Among patients in the lowest tertile of baseline serum creatinine concentration, treatment with Pyridorin associated with a lower average change in serum creatinine concentration at 52 weeks (0.28, 0.07, and 0.14 mg/dl for placebo, Pyridorin 150 mg, and Pyridorin 300 mg, respectively; P=0.05 for either Pyridorin dose versus placebo); there was no evidence of a significant treatment effect in the middle or upper tertiles. In conclusion, this trial failed to detect an effect of Pyridorin on the progression of serum creatinine at 1 year, although it suggests that patients with less renal impairment might benefit.

Impact of aliskiren treatment on urinary aldosterone levels in patients with type 2 diabetes and nephropathy: an AVOID substudy.

INTRODUCTION: Aldosterone blockade reduces albuminuria in diabetic patients with chronic kidney disease (CKD), and improves prognosis in chronic heart failure. This study assessed the effects of direct renin inhibition with aliskiren in combination with losartan and optimal antihypertensive therapy on urinary aldosterone, plasma renin activity (PRA) and plasma renin concentration (PRC). MATERIALS AND METHODS: In the AVOID study, 599 patients with type 2 diabetes, hypertension and nephropathy received 6 months aliskiren (150 mg force titrated to 300 mg once daily after 3 months) or placebo added to losartan 100 mg and optimal antihypertensive therapy. Urinary aldosterone excretion, PRA and PRC were measured at baseline and after 24 weeks in a prespecified subset of 133 patients. RESULTS: Aliskiren added to losartan provided reductions from baseline in urinary aldosterone compared with adding placebo (-24% vs. -4%, p = 0.017) at week 24. There was no significant difference between the aliskiren and placebo groups in the proportion of patients with aldosterone breakthrough (aliskiren 35%, placebo 46%, p = 0.199). Aliskiren treatment reduced PRA by 90% at 24 weeks and increased PRC by 328%. CONCLUSIONS: Adding aliskiren to recommended renoprotective treatment with losartan and optimal antihypertensive therapy provided significant reductions in urinary aldosterone excretion which may attenuate decline in kidney function.

Sulodexide for kidney protection in type 2 diabetes patients with microalbuminuria: a randomized controlled trial.

BACKGROUND: Sulodexide, a heterogenous group of sulfated glycosaminoglycans, includes low-molecular-weight heparin (~80% ± 8%), high-molecular-weight heparin (~5% ± 3%), and dermatan (~20% ± 8%), with a mean molecular weight of ~9 kDa. The drug is absorbed orally and has no anticoagulant effect in the doses used. Small preliminary studies consistently showed sulodexide to be associated with decreased albuminuria in patients with diabetes. STUDY DESIGN: We conducted a multicenter placebo-controlled double-blinded study to determine the effect of sulodexide on urine albumin excretion in patients with type 2 diabetic nephropathy. SETTING & PARTICIPANTS: Patients with type 2 diabetes and urine albumin-creatinine ratios (ACRs) of 35-200 mg/g in men and 45-200 mg/g in women were enrolled. Serum creatinine level was <1.5 mg/dL. Blood pressure goal was 130/80 mm Hg. A maximum US Food and Drug Administration-approved dose of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker for a minimum of 4 months before randomization was required. INTERVENTION: The study drug was sulodexide, 200 mg/d. OUTCOME & MEASUREMENTS: The primary end point was normoalbuminuria (ACR <20 mg/g and a decrease >25%) or 50% decrease in baseline ACR. RESULTS: In 1,056 randomly assigned patients with a mean baseline ACR of 107.8 ± 83.7 mg/g, comparing the sulodexide versus placebo groups, the primary end point was achieved in 16.5% versus 18.4%; normoalbuminuria, in 7.9% versus 6.1%; and a 50% decrease in albuminuria, in 15.4% versus 17.6%. The relative probability of any given change in albuminuria was identical in both groups. LIMITATIONS: We were unable to determine whether the administered sulodexide was absorbed from the gastrointestinal tract. CONCLUSION: Sulodexide failed to decrease urine albumin excretion in patients with type 2 diabetic nephropathy and microalbuminuria.

Aliskiren in combination with losartan reduces albuminuria independent of baseline blood pressure in patients with type 2 diabetes and nephropathy.

BACKGROUND AND OBJECTIVES: Elevated BP contributes to development and progression of proteinuria and decline in renal function in patients with type 2 diabetes. Our post hoc analysis assessed the baseline BP influence on the antiproteinuric effect in the Aliskiren in the Evaluation of Proteinuria in Diabetes (AVOID) study. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In the AVOID study, 599 hypertensive type 2 diabetic patients with nephropathy received 6 months of aliskiren (150 mg force titrated to 300 mg daily after 3 months) or placebo added to losartan (100 mg) daily and optimal antihypertensive therapy. Changes in early morning urinary albumin:creatinine ratio and eGFR at week 24 were assessed by subgroups of baseline BP: Group A (prespecified target), <130/80 mmHg (n=159); Group B, <140/90 mmHg but ≥130/80 mmHg (n=189); and Group C (insufficient BP control), ≥140/90 mmHg (n=251). RESULTS: Mean baseline BP (mmHg) levels for Groups A, B, and C were 120/71, 133/78, and 145/81, respectively. BP during the trial was nearly identical to baseline levels in all groups. The antiproteinuric effects of aliskiren were consistent across subgroups of baseline BP (19 to 22% reduction versus placebo). In Group C, the decline in eGFR was significantly lower with aliskiren than with placebo (P=0.013). CONCLUSIONS: Aliskiren (300 mg) added to losartan (100 mg) plus optimal antihypertensive therapy provides antiproteinuric effects independent of BP in patients with type 2 diabetes and nephropathy. Renal function was better preserved with aliskiren in patients with insufficient BP control.

Impact of baseline renal function on the efficacy and safety of aliskiren added to losartan in patients with type 2 diabetes and nephropathy.

OBJECTIVE: Proteinuric diabetic patients with reduced glomerular filtration rate (GFR) are at high risk of renal and cardiovascular disease progression and treatment-related adverse events. This post hoc analysis assessed the efficacy and safety of aliskiren added to the maximal recommended dose of losartan according to baseline estimated GFR (eGFR) (stage 1-3 chronic kidney disease [CKD]). RESEARCH DESIGN AND METHODS: In the Aliskiren in the Evaluation of Proteinuria in Diabetes (AVOID) study, 599 hypertensive patients with type 2 diabetes and nephropathy received 6 months of aliskiren (150 mg daily titrated to 300 mg daily after 3 months) or placebo added to 100 mg losartan and optimal antihypertensive therapy. Exclusion criteria included eGFR<30 ml/min per 1.73 m2 and serum potassium>5.1 mmol/l. RESULTS: Baseline characteristics were similar between treatment groups in all CKD stages. The antiproteinuric effects of aliskiren were consistent across CKD stages (19, 22, and 18% reduction). In the stage 3 CKD group, baseline serum creatinine levels were equal, but renal dysfunction, prespecified as a postrandomization serum creatinine elevation>176.8 µmol/l (2.0 mg/dl) occurred more frequently in the placebo group (29.2 vs. 13.6%, P=0.032). Serum potassium elevations>5.5 mmol/l (based on a single measurement) were more frequent with aliskiren (22.5 vs. 13.6%) in stage 3 CKD. Adverse event rates were similar between treatments, irrespective of CKD stage. CONCLUSIONS: Aliskiren added to losartan reduced albuminuria and renal dysfunction and was well tolerated, except for hyperkalemia (stage 3), independent of baseline CKD stage in patients with type 2 diabetes, hypertension, and nephropathy.

Pathogenetic features of severe segmental lupus nephritis.

BACKGROUND: Accumulating evidence supports the notion that the pathogenesis of severe lupus glomerulonephritis is multifactorial and not solely an immune complex-mediated glomerular disease. Alternate mechanisms for glomerular destruction may exist. METHODS: We conducted a retrospective clinicopathologic analysis of 213 patients with lupus nephritis. Twenty-six patients had severe segmental glomerulonephritis (SSGN) and 15 patients had diffuse proliferative glomerulonephritis (DPGN). Patients with pure mesangial lupus nephritis [mesangial glomerulonephritis (MesGN)] (N = 13) were used as histologic controls. The degree of immunologic activity detailed by histologic data including light, fluorescent (IF) and electron microscopy (EM) on kidney biopsies and clinical data from patients with severe lupus nephritis were analysed. RESULTS: Biopsies from patients with SSGN had fewer glomeruli with wire loops (3 +/- 6% versus 35 +/- 34% P = 0.005) and hyaline thrombi (0.8 +/- 3% versus 16 +/- 22%, P = 0.02) compared to DPGN. The amount of IgG by IF was less in SSGN lesions compared to DPGN lesions, and IgG was absent in 30% of the SSGN group compared to none of the DPGN group (P = 0.04). There was no difference in mesangial deposits among the three groups (SSGN, DPGN and MesGN). The EM data supported the IF data. Anti-neutrophil cytoplasmic antibodies (ANCA) were essentially negative in all three groups and the C3 values tended to be lower in DPGN compared to SSGN (48 +/- 15 mg/dl versus 60 +/- 26 mg/dl, P = 0.09). CONCLUSIONS: The findings in DPGN involve a classic immune complex-mediated glomerulonephritis as demonstrated by the abundant immune aggregates witnessed in the peripheral capillary wall. In contrast, a paucity of peripheral immune aggregates is seen in SSGN implying a different pathogenesis. Our data support a mechanism of glomerular injury in SSGN that is separate from the generally accepted unitary concept of immune complex deposition in lupus nephritis.

[Aliskiren combined with losartan in type 2-diabetes and nephropathy - secondary publication]. / Kombination af aliskiren og losartan hos patienter med type 2-diabetes og nefropati - Sekundaerpublikation.

We evaluated the renoprotective effects of adding aliskiren to treatment with losartan in hypertensive patients with type 2 diabetes and nephropathy. A total of 599 patients were randomized to six months of treatment with placebo or aliskiren in addition to losartan 100 mg and optimal antihypertensive therapy. The primary outcome was a reduction in the urinary albumin-creatinine ratio. Aliskiren 300 mg daily reduced the mean urinary albumin-creatinine ratio by 20% (p < 0.001) compared with placebo. The number of adverse events was similar between groups. Aliskiren is renoprotective independently of its blood pressure lowering effect.

The value of post-biopsy ultrasound in predicting complications after percutaneous renal biopsy of native kidneys.

BACKGROUND: Clinically significant bleeding complications occur in >30% of patients undergoing percutaneous renal biopsy (PRB) of native kidneys and can be severe in up to 10% of patients. A noninvasive measure that would reliably predict which patients will do well with an uncomplicated post-biopsy course or which patients may be at risk of developing a clinically significant complication is in great demand. METHODS: PRB of native kidneys was performed in 162 adult patients from February 2002 through February 2007 using real-time ultrasound and automated needle. Renal ultrasound (US) was performed at 1-h post-PRB to assess biopsy-related bleeding. Patients were observed for 24 h post-PRB to monitor clinically apparent biopsy-related complications. The value of the post-biopsy ultrasound in predicting complications was assessed. RESULTS: A clinically apparent complication was observed in 26 (16%) patients post-PRB (13 minor not requiring any intervention and 13 major requiring intervention). In patients with complicated courses, a haematoma at 1 h was seen in 77% (69% with minor and 87% with major complications). However, only 27 (20%) of 136 patients without complications (P < 0.0001) had a haematoma at 1 h. The presence of a haematoma 1-h post-PRB had a sensitivity of 77%, specificity of 80%, positive predictive value of 43% but a negative predictive value of 95% for predicting clinical complications. CONCLUSIONS: We find that with the use of renal ultrasound 1-h post-PRB, the absence of perinephric bleeding is predictive of an uncomplicated course while the presence of a perinephric haematoma is not reliably predictive of a clinically significant complication post-renal biopsy.

Aliskiren combined with losartan in type 2 diabetes and nephropathy.

BACKGROUND: Diabetic nephropathy is the leading cause of end-stage renal disease in developed countries. We evaluated the renoprotective effects of dual blockade of the renin-angiotensin-aldosterone system by adding treatment with aliskiren, an oral direct renin inhibitor, to treatment with the maximal recommended dose of losartan (100 mg daily) and optimal antihypertensive therapy in patients who had hypertension and type 2 diabetes with nephropathy. METHODS: We enrolled 599 patients in this multinational, randomized, double-blind study. After a 3-month, open-label, run-in period during which patients received 100 mg of losartan daily, patients were randomly assigned to receive 6 months of treatment with aliskiren (150 mg daily for 3 months, followed by an increase in dosage to 300 mg daily for another 3 months) or placebo, in addition to losartan. The primary outcome was a reduction in the ratio of albumin to creatinine, as measured in an early-morning urine sample, at 6 months. RESULTS: The baseline characteristics of the two groups were similar. Treatment with 300 mg of aliskiren daily, as compared with placebo, reduced the mean urinary albumin-to-creatinine ratio by 20% (95% confidence interval, 9 to 30; P<0.001), with a reduction of 50% or more in 24.7% of the patients who received aliskiren as compared with 12.5% of those who received placebo (P<0.001). A small difference in blood pressure was seen between the treatment groups by the end of the study period (systolic, 2 mm Hg lower [P=0.07] and diastolic, 1 mm Hg lower [P=0.08] in the aliskiren group). The total numbers of adverse and serious adverse events were similar in the groups. CONCLUSIONS: Aliskiren may have renoprotective effects that are independent of its blood-pressure-lowering effect in patients with hypertension, type 2 diabetes, and nephropathy who are receiving the recommended renoprotective treatment. (ClinicalTrials.gov number, NCT00097955 [ClinicalTrials.gov].).

Abnormal glomerular permeability characteristics in diabetic nephropathy: implications for the therapeutic use of low-molecular weight heparin.

The physicochemical characteristics of the glomerular capillary filtration membrane restrict the passage of macromolecules on the basis of molecular weight, charge, and shape. The proposed ionic charge permselectivity characteristics of the glomerular basement membrane (GBM) are determined by its chemical composition, primarily the highly sulfated glycosaminoglycan heparan. In diabetic nephropathy, the heparan sulfate content of the GBM is diminished. It has been proposed that decreased GBM heparan sulfate content causes decreased permselectivity to negatively charged macromolecules such as albumin, allowing this protein to leak into the urinary space. One possible explanation for decreased GBM heparan sulfate content in diabetic nephropathy is the observation that heparanase, an enzyme capable of degrading heparan sulfate, is upregulated in the glomerular epithelial cell (GEC) in response to increased glucose. Increased GEC heparanase activity has been demonstrated in glomeruli in diabetic kidneys, and increased urine heparanase has been observed in diabetic nephropathy. In vitro studies have shown that GEC heparanase activity depends on the glucose concentration of the culture medium. GEC heparanase activity can be inhibited by heparin compounds. Sulodexide, an orally active low-molecular weight heparin, has been shown to lower urine albumin excretion. The working hypothesis that has emerged is that sulodexide may be an in vivo heparanase inhibitor that reaches the glomerular capillary wall and prevents heparan sulfate degradation, thus allowing reconstruction of heparan sulfate content and restoration of GBM ionic permselectivity. Two clinical trials are currently being carried out to determine whether sulodexide is renoprotective in diabetic nephropathy.

The prognosis and pathogenesis of severe lupus glomerulonephritis.

BACKGROUND: The International Society of Nephrology/ Renal Pathology Society classification (ISN/RPS) of lupus glomerulonephritis (GN) divides diffuse GN (>/=50% involvement) into diffuse segmental (IV-S) and diffuse global GN (IV-G). This division tests whether the pathogenesis and clinical outcomes are the same as when similar patients are classified using the World Health Organization (WHO) classification into severe segmental (WHO III >/=50%) and diffuse global (WHO-IV) GN. METHODS: Thirty-nine renal biopsies with WHO class IV and 44 with WHO III >/= 50% were reclassified using the ISN/RPS and were correlated with pathogenesis and outcome. RESULTS: There were 22 biopsies with ISN/RPS class IV-S. ISN/RPS class IV-G comprises two morphologically discrete classes of renal biopsies: 39 biopsies originally classified as WHO class IV (WHO-IV) and 22 that switched from WHO III >/=50% to ISN/RPS class IV-G (IV-Q). We will analyze IV-S, IV-Q and WHO-IV separately. WHO-IV had significantly more immune aggregate deposition than IV-S and IV-Q. WHO-IV had lower serum complements C3 (P = 0.05) and C4 (P = 0.05) than patients with IV-Q. Patients with WHO-IV had more remissions (56%) than IV-Q (23%) (P = 0.01), and stable renal function at the last follow-up was less frequent in patients with IV-Q (18%) than IV-S (50%, P = 0.05) and WHO-IV (62%, P = 0.001). Renal survival and renal survival without end-stage renal disease were different when the patients were diagnosed as WHO classes III >/=50% and IV, but the outcomes for ISN/RPS class IV-S and IV-G (WHO-IV plus IV-Q) were not different. CONCLUSIONS: WHO III >/=50% and WHO-IV lupus GN are not congruent with ISN/RPS IV-S and IV-G. The ISN/RPS minimizes pathological and outcome differences between classes IV-S and IV-G which results in the loss of informational content from the renal biopsies. ISN/RPS does not detect pathogenetic or clinical differences among patients with severe lupus GN.

Value of a complete or partial remission in severe lupus nephritis.

BACKGROUND AND OBJECTIVES: The value of a complete remission in severe lupus nephritis is well known but little is known about the impact of a partial remission in this patient population. The purpose of this study was to evaluate the long-term prognosis of achieving a complete or partial remission in a well-defined group of patients with severe lupus nephritis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this study, 86 patients with diffuse lupus glomerulonephritis were reviewed for assessment of the value of a partial remission (50% reduction in baseline proteinuria to < or =1.5 g/d and < or =25% increase in baseline creatinine) and complete remission (proteinuria < or =0.33 g/d and serum creatinine < or =1.4 mg/dl) on outcomes compared with patients who did not attain a remission. These well-characterized patients were entered into a prospective therapeutic trial conducted by the Collaborative Study Group and were followed for more than 10 yr. RESULTS: All biopsies showed diffuse lupus nephritis. A complete remission was attained in 37 (43%) patients, a partial remission in 21 (24%) patients, and no remission in 28 (32%) patients. Baseline clinical and serologic features were similar among the groups, but patients with a complete remission had a lower serum creatinine and chronicity index compared with patients with partial or no remission. The patient survival at 10 yr was 95% for complete remission, 76% for partial remission, and 46% for no remission. The renal survival at 10 yr was 94% for complete remission, 45% for partial remission, and 19% for no remission, and the patient survival without end-stage renal disease at 10 yr was 92% for complete remission, 43% for partial remission, and 13% for no remission. CONCLUSION: Even a partial remission in lupus nephritis is associated with a significantly better patient and renal survival compared with no remission.

Treating hypertension in the patient with overt diabetic nephropathy.

Arterial blood pressure is a major determinant of renal and cardiovascular outcomes in diabetic nephropathy. There is a proportional relationship between the systolic blood pressure and renal and mortality outcomes. Decreasing the diastolic pressure does not significantly decrease these outcomes. Irrespective of the magnitude of pretreatment systolic hypertension in the patient with type 2 diabetic nephropathy, the systolic pressure achieved with antihypertensive therapy is the important determinant of renal and cardiovascular risk. Achieving a lower systolic pressure down to 120 mm Hg is associated with substantial risk reduction. Although the data are limited, systolic blood pressure less than 120 mm Hg may be associated with increased all-cause mortality in this patient population, increasing the possibility of a J-curve response. A marked decrease in diastolic pressure, which is a danger when undertaking aggressive therapy with the goal of decreasing the systolic pressure to 130 mm Hg, can be associated with an increased risk of cardiac events. The renoprotective and proteinuria-decreasing effects of angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers recommend these agents as the standard of care in type 2 diabetic nephropathy. In addition to angiotensin-converting enzyme inhibitor and angiotensin-receptor blocker therapy, controlling the systolic blood pressure in this difficult to control patient population may require the use of 3 or more antihypertensive agents.