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Background The effects of pharmacological blood-pressure-lowering on cardiovascular outcomes in individuals aged 70 years and older, particularly when blood pressure is not substantially increased, is uncertain. We compared the effects of blood-pressure-lowering treatment on the risk of major cardiovascular events in groups of patients stratified by age and blood pressure at baseline. Methods We did a meta-analysis using individual participant-level data from randomised controlled trials of pharmacological blood-pressure-lowering versus placebo or other classes of blood-pressure-lowering medications, or between more versus less intensive treatment strategies, which had at least 1000 persons-years of follow-up in each treatment group. Participants with previous history of heart failure were excluded. Data were obtained from the Blood Pressure Lowering Treatment Triallists' Collaboration. We pooled the data and categorised participants into baseline age groups (Findings We included data from 358 707 participants from 51 randomised clinical trials. The age of participants at randomisation ranged from 21 years to 105 years (median 65 years [IQR 59–75]), with 42 960 (12·0%) participants younger than 55 years, 128 437 (35·8%) aged 55–64 years, 128 506 (35·8%) 65–74 years, 54 016 (15·1%) 75–84 years, and 4788 (1·3%) 85 years and older. The hazard ratios for the risk of major cardiovascular events per 5 mm Hg reduction in systolic blood pressure for each age group were 0·82 (95% CI 0·76–0·88) in individuals younger than 55 years, 0·91 (0·88–0·95) in those aged 55–64 years, 0·91 (0·88–0·95) in those aged 65–74 years, 0·91 (0·87–0·96) in those aged 75–84 years, and 0·99 (0·87–1·12) in those aged 85 years and older (adjusted pinteraction=0·050). Similar patterns of proportional risk reductions were observed for a 3 mm Hg reduction in diastolic blood pressure. Absolute risk reductions for major cardiovascular events varied by age and were larger in older groups (adjusted pinteraction=0·024). We did not find evidence for any clinically meaningful heterogeneity of relative treatment effects across different baseline blood pressure categories in any age group. Interpretation Pharmacological blood pressure reduction is effective into old age, with no evidence that relative risk reductions for prevention of major cardiovascular events vary by systolic or diastolic blood pressure levels at randomisation, down to less than 120/70 mm Hg. Pharmacological blood pressure reduction should, therefore, be considered an important treatment option regardless of age, with the removal of age-related blood-pressure thresholds from international guidelines. Funding British Heart Foundation, National Institute of Health Research Oxford Biomedical Research Centre, Oxford Martin School.

Background The effects of pharmacological blood pressure lowering at normal or high-normal blood pressure ranges in people with or without pre-existing cardiovascular disease remains uncertain. We analysed individual participant data from randomised trials to investigate the effects of blood pressure lowering treatment on the risk of major cardiovascular events by baseline levels of systolic blood pressure. Methods We did a meta-analysis of individual participant-level data from 48 randomised trials of pharmacological blood pressure lowering medications versus placebo or other classes of blood pressure-lowering medications, or between more versus less intensive treatment regimens, which had at least 1000 persons-years of follow-up in each group. Trials exclusively done with participants with heart failure or short-term interventions in participants with acute myocardial infarction or other acute settings were excluded. Data from 51 studies published between 1972 and 2013 were obtained by the Blood Pressure Lowering Treatment Trialists' Collaboration (Oxford University, Oxford, UK). We pooled the data to investigate the stratified effects of blood pressure-lowering treatment in participants with and without prevalent cardiovascular disease (ie, any reports of stroke, myocardial infarction, or ischaemic heart disease before randomisation), overall and across seven systolic blood pressure categories (ranging from

Item does not contain fulltext BACKGROUND: Change in albuminuria as a surrogate endpoint for progression of chronic kidney disease is strongly supported by biological plausibility, but empirical evidence to support its validity in epidemiological studies is lacking. We aimed to assess the consistency of the association between change in albuminuria and risk of end-stage kidney disease in a large individual participant-level meta-analysis of observational studies. METHODS: In this meta-analysis, we collected individual-level data from eligible cohorts in the Chronic Kidney Disease Prognosis Consortium (CKD-PC) with data on serum creatinine and change in albuminuria and more than 50 events on outcomes of interest. Cohort data were eligible if participants were aged 18 years or older, they had a repeated measure of albuminuria during an elapsed period of 8 months to 4 years, subsequent end-stage kidney disease or mortality follow-up data, and the cohort was active during this consortium phase. We extracted participant-level data and quantified percentage change in albuminuria, measured as change in urine albumin-to-creatinine ratio (ACR) or urine protein-to-creatinine ratio (PCR), during baseline periods of 1, 2, and 3 years. Our primary outcome of interest was development of end-stage kidney disease after a baseline period of 2 years. We defined an end-stage kidney disease event as initiation of kidney replacement therapy. We quantified associations of percentage change in albuminuria with subsequent end-stage kidney disease using Cox regression in each cohort, followed by random-effects meta-analysis. We further adjusted for regression dilution to account for imprecision in the estimation of albuminuria at the participant level. We did multiple subgroup analyses, and also repeated our analyses using participant-level data from 14 clinical trials, including nine clinical trials not in CKD-PC. FINDINGS: Between July, 2015, and June, 2018, we transferred and analysed data from 28 cohorts in the CKD-PC, which included 693 816 individuals (557 583 [80%] with diabetes). Data for 675 904 individuals and 7461 end-stage kidney disease events were available for our primary outcome analysis. Change in ACR was consistently associated with subsequent risk of end-stage kidney disease. The adjusted hazard ratio (HR) for end-stage kidney disease after a 30% decrease in ACR during a baseline period of 2 years was 0.83 (95% CI 0.74-0.94), decreasing to 0.78 (0.66-0.92) after further adjustment for regression dilution. Adjusted HRs were fairly consistent across cohorts and subgroups (ie, estimated glomerular filtration rate, diabetes, and sex), but the association was somewhat stronger among participants with higher baseline ACR than among those with lower baseline ACR (pinteraction

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.

Background Patients with membranous lupus glomerulonephritis (MLN) can present with a broad range of urine protein excretion. The glomerular lesion underlying this functional abnormality has been presumed to be immune complexes which aggregate in the subepithelial area. However, the amount of proteinuria often fails to correlate with the quantity of immune deposits demonstrable on fluorescent and electron microscopy. The purpose of this study is to determine the correlation of alterations of the morphologic components of the glomerular capillary wall with the amount of proteinuria in MLN. Design We conducted a retrospective clinicopathologic study of patients with lupus nephritis ( n = 236). In those with pure MLN and proteinuria ( n = 20), the degree of immune aggregates in the capillary walls and mesangium was detailed using fluorescent and electron microscopy. The degree of foot process effacement (FPE) was detailed using electron microscopy. Result Eleven patients had nephrotic range proteinuria (≥3 g proteinuria/g creatinine (g/g)) and nine demonstrated subnephrotic range proteinuria (Conclusions In patients with MLN, a distinguishing morphologic feature of those with nephrotic range proteinuria is diffuse visceral epithelial cell FPE. We conclude that nephrotic range proteinuria in patients with MLN may be a manifestation of concomitant glomerular visceral epithelial cell dysfunction.

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.

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 11 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.

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.

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.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.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, P0.0001). 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 and12 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 CR12 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.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 or12 months. Thus, the rate of loss of UPro at 6 months may help in predicting which patients will attain a CR.

Background: Sulodexide, a heterogenous group of sulfated glycosaminoglycans, includes low-molecular-weight heparin (similar to 80% +/- 8%), high-molecular-weight heparin (similar to 5% +/- 3%), and dermatan (similar to 20% +/- 8%), with a mean molecular weight of similar to 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 wasIntervention: The study drug was sulodexide, 200 mg/d.Outcome & Measurements: The primary end point was normoalbuminuria (ACR 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. Am J Kidney Dis. 58(5):729-736. (C) 2011 by the National Kidney Foundation, Inc.

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 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.

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.

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.

arteritis, and how these diseases related to his work with serum sickness. It was a remarkable review of a life’s work [1] . I went to Boston to Dr. Frank Austen’s lab for my research fellowship and one of the people who was working there was Dr. John David. In the mid-1960s, when I was a fellow, experimental immune diseases of the glomerulus had been studied rather well, particularly by Dr. Frank Dixon, who was at Scripps. The important pathogenetic issue regarding glomerular diseases was the immunologic activity that caused inflammation in the kidney. Two mechanisms were accepted. One was immune complex disease associated with circulating immune complexes, as occurred in serum sickness. In lupus patients there is glomerular capillary inflammation, which is attributed to deposited immune complexes. Presumably, antibodies to DNA and circulating DNA polynucleotides form a complex, which leads to their deposition and glomerular inflammation. The second mechanism was autoimmune glomerulonephritis – which Kline has spent his career studying so beautifully. The classic example of glomerulonephritis associated with antibodies to glomerular basement membrane (GBM) is Goodpasture’s syndrome. For reasons that are largely unclear, the body makes antibodies against an autoantigen in the GBM. Now I became quite involved with Dr. Rich and saw him during his multiple hospitalizations. Dr. Rich had published a Kline Bolton has made important contributions to the field of nephrology, not the least of which is his work on T-cell immunity in glomerulonephritis. I would like to take you back into the history of that subject. It is a history that few people know. In 1964, when I was a resident at the Johns Hopkins Hospital, I had the rare good fortune of participating in the care of Dr. Arnold Rich, who was the retired chairman of the Department of Pathology and one of the world’s finest experimental pathologists. That year Lyndon Johnson was running for presid ent against Barry Goldwater and Dr. Rich was a Goldwater supporter – probably the only one in the entire city of Baltimore – and there wasn’t much for us to talk about, because in those days I was actually a Democrat. Therefore, we talked about medicine. Dr. Rich was, for many years, the most prominent researcher in what we now call experimental immunologic diseases. Of course, his work was before antibiotics, so the way you treated pneumonia in those days was to inject a horse with pneumococci in order to get antibodies and you used horse serum to treat the patient. Some patients got serum sickness. Dr. Rich went into great detail in terms of the mechanism of serum sickness and how it could be related to other diseases in man. One day, after he was discharged, he sent me his Harvey Lecture from 1947 and it was about the pathogenesis of rheumatic fever, lupus, rheumatoid arthritis, and periPublished online: May 6, 2009

Background. The number of elderly patients undergoing chronic haemodialysis (HD) in the nursing home (NH) setting is growing; however, little published data exists on this group of patients. Methods. We describe our experience with 271 patients undergoing staff-assisted HD in the NH setting from 1 January 2001 to 30 June 2004. Acceptance into the programme required that the patients were mentally responsive, haemodynamically stable without sepsis and not be considered terminal or in hospice. Results. Mean age at entry was 70.5 � 12.1 years, 53% were female, 54% were white and 34% black. Main causes of end-stage renal disease (ESRD) were diabetes mellitus (DM, 48%) and hypertension (HTN, 25%). Comorbid conditions included HTN-90%, DM-65%, coronary artery disease-54%, congestive heart failure59%, cerebrovascular accident-31%, and 40% could not ambulate. The average time on chronic dialysis prior to entering the nursing programme was 18 � 27 months, and the median time was 4 months (range: 0.1–191 months). The average time in the NH programme was 2.9 � 3.6 months (median: 1.6 months, range: 0.1–24 months). During the study period 42% of the patients died, 37% were discharged from the NH, 4.4% withdrew from dialysis, and 16% remained active in the programme. Patient survival from entry into the NH programme was 82% at 1 month, 64% at 3 months, 38% at 6 months and 26% at 12 months (median survival of 4.1 months). However, the patient survival from initiation of chronic dialysis was 75% at 6 months, 66% at 12 months and 38% at 60 months with a median survival of 3.4 years. When evaluating patients based on the duration of chronic dialysis prior to entering the NH programme we found that established HD patients (on HD � 12 months prior to programme entry) had fewer myocardial infarctions (15 vs 26%, P ¼ 0.05), more amputations (19 vs 8%, P ¼ 0.01), higher creatinine (6.7 vs 4.7 mg/dl, P < 0.01), haemoglobin (11.1 vs 10.5 g/dl, P < 0.01) and albumin (3.2 vs 3.0 g/dl, P ¼ 0.09) compared with new HD patients (on HD � 3 months prior to programme entry). New HD patients had a higher mortality rate (50 vs 31%, P < 0.01) and poorer median survival (3 vs 5 months, P < 0.01) than established HD patients. Conclusion. NH dialysis provides a means for dialysing our most ill and debilitated patients in the convenience and comfort of the NH setting. The success of this programme is demonstrated by the fact that almost 40% of patients are successfully rehabilitated and discharged home. Nonetheless, healthcare providers and families must recognize that patients entering an NH HD programme are a high risk population with significant morbidity and mortality. Compared with established dialysis patients, patients entering the NH programme who are new to dialysis represent a particularly high risk group. However, it is likely that the poor survival seen in the NH programme may represent end of life care, as the overall survival from initiation of chronic dialysis in this population is consistent with that of patients entering the ESRD programme at a similar age.

This study assessed whether certain clinicopathologic variables could explain the impact of race on outcome in 86 patients who had severe lupus nephritis and were available for long-term follow-up after participating in a prospective, controlled, clinical trial. Fifty-four (63%) patients were white, 21 (24%) were black, and 11 (13%) were categorized as other. The proportion of patients with anti-Ro, anti-nRNP, and anti-Sm was significantly greater among black patients. Biopsies with segmental active proliferative and necrotizing lesions that involvedor=50% of glomeruli +/- membranous glomerulonephritis (class IIIor=50%+/-V) were significantly more common (white 44%, black 76%, other 36%; P0.05) and diffuse proliferative glomerulonephritis +/- membranous glomerulonephritis (class IV+/-V) was less common (white 54%, black 24%, other 64%) among black patients. Attainment of a remission was greatest among white patients (white 52%, black 29%, other 27%; P = 0.09). Features that were predictive of a remission were white race, baseline serum creatinine, and class IV+/-V lesions. Patient survival at 10 yr (white 81%, black 59%, other 73%; P = 0.029) and renal survival at 10 yr (white 68%, black 38%, other 61%; P = 0.015) were significantly poorer in black patients. Predictors of ESRD were serum creatinine, the presence of anti-Ro antibodies, class IIIor=50%+/-V lesions, and failure to achieve a remission. In conclusion, racial differences were observed in the serologic and histologic features at presentation, response to treatment, and outcome of patients with severe lupus nephritis. In a population of patients with severe lupus nephritis, black patients were significantly more likely to have a serologic profile and renal lesions that were associated with more aggressive renal disease and resulted in worse outcomes than white patients.

Fibrillary or immunotactoid nephropathy is a rare deposition disease of unknown cause in which highly organized deposits containing immunoglobulin and complement are found in the glomerular basement membrane and mesangium. These deposits are not amyloid fibrils and do not stain with Congo red. They are usually polyclonal and are not associated with monoclonal paraproteins, or with cryoglobulins or systemic lupus, distinguishing them from other non-amyloid fibrillary glomerulopathies. There is debate about whether there is a useful distinction between distinct fibrillary and rarer immunotactoid variants, the rarer immunotactoid variety being associated with larger, more organized, microtubular fibrils and possibly more commonly associated with malignancy (usually lymphoproliferative). However, clinically the conditions are similar. Patients usually present with heavy proteinuria or nephrotic syndrome. Microscopic haematuria is common and many have reduced glomerular filtration rate at presentation. Fifty per cent reach end-stage renal failure in 3–5 years and there is no convincing evidence that any treatment is effective in altering this outcome. Other organs appear to be affected only rarely (lung, liver). The disease may recur post-transplant but not always and usually more slowly, so does not preclude transplantation.

Immunotactoid glomerulopathy first was described in 1977, when Rosenmann and Eliakim (1) reported an unusual glomerular lesion in a 45-yr-old woman who presented with the nephrotic syndrome and renal insufficiency. The electron microscopy was remarkable for organized electron-dense deposits in the form of randomly arranged fibrils that measured 10 nM in diameter. The deposits were associated with mesangial expansion and immune deposits of IgG, IgM, and C3 in a mesangial pattern. Congo red stain of the deposits was negative, and there was no clinical or serologic evidence of a systemic disease. They interpreted the deposits to be “amyloid-like” and speculated that they might represent a “preamyloid” state. In 1980, Schwartz and Lewis (2) reported a case of a 49-yr-old man who presented with the nephrotic syndrome and no evidence of systemic disease and had a similar renal lesion: Immune aggregates were associated with highly organized electron-dense deposits that were composed of microtubules that were arranged in parallel bundles. During 7 yr of follow-up, the patient progressed to renal failure but never demonstrated any clinical or serologic evidence of a systemic disease. To distinguish this lesion from other disorders that have glomerular immune deposits associated with highly organized microtubular or fibrillary structures, such as amyloidosis, cryoglobulinemia, paraproteinemias, and systemic lupus erythematosus (SLE), the term immunotactoid glomerulopathy (ITG) was coined, reflecting the composition (immuno-) and polymeric morphology (tactoid) of the glomerular deposits. In the past 25 yr, >200 cases of ITG have been reported (3–5). Various synonyms have been used to refer to the lesion that is described in these reports, including fibrillary glomerulonephritis (FGN), nonamyloidotic fibrillary glomerulopathy, amyloid-like glomerulopathy, and amyloid stain–negative microfibrillary glomerulopathy, but we believe that they all represent the same or a similar disease process (6–8). The unifying feature in all of the cases …

We investigated a series of patients with systemic lupus erythematosus (SLE), who had sparse subepithelial and mesangial immune deposits. Our goal was to determine structure: function correlation. We examined whether proteinuria correlated with either capillary wall immune aggregate formation or abnormal podocyte morphology. Renal biopsies from patients with sparse (two or fewer subepithelial or intramembranous electron dense deposits per glomerular capillary loop) immune deposits and podocyte effacement were studied. Patients fulfilled criteria for the diagnosis of SLE. Cases were excluded if the biopsy showed endocapillary proliferation or necrosis. Eighteen biopsies were studied, five from patients with nephrotic range proteinuria (≥3 g/day) and 13 from patients with non-nephrotic proteinuria (

The US Food and Drug Administration currently accepts halving of glomerular filtration rate (GFR), assessed as doubling of serum creatinine level, as a surrogate end point for the development of kidney failure in clinical trials of kidney disease progression. A doubling of serum creatinine level generally is a late event in chronic kidney disease (CKD); thus, there is great interest in considering alternative end points for clinical trials to shorten their duration, reduce sample size, and extend their conduct to patients with earlier stages of CKD. However, the relationship between lesser declines in GFR and the subsequent development of kidney failure has not been well characterized. The National Kidney Foundation and Food and Drug Administration sponsored a scientific workshop to critically examine available data to determine whether alternative GFR-based end points have sufficiently strong relationships with important clinical outcomes of CKD to be used in clinical trials. Based on a series of meta-analyses of cohorts and clinical trials and simulations of trial designs and analytic methods, the workshop concluded that a confirmed decline in estimated GFR of 30% over 2 to 3 years may be an acceptable surrogate end point in some circumstances, but the pattern of treatment effects on GFR must be examined, specifically acute effects on estimated GFR. An estimated GFR decline of 40% may be more broadly acceptable than a 30% decline across a wider range of baseline GFRs and patterns of treatment effects on GFR. However, there are other circumstances in which these end points could lead to a reduction in statistical power or erroneous conclusions regarding benefits or harms of interventions. We encourage careful consideration of these alternative end points in the design of future clinical trials. (C) 2014 by the National Kidney Foundation, Inc.

Elevated arterial pressure is a major risk factor for progression to ESRD in diabetic nephropathy. However, the component of arterial pressure and level of BP control for optimal renal outcomes are disputed. Data from 1590 hypertensive patients with type 2 diabetes in the Irbesartan Diabetic Nephropathy Trial (IDNT), a randomized, double-blind, placebo-controlled trial performed in 209 clinics worldwide, were examined, and the effects of baseline and mean follow-up systolic BP (SBP) and diastolic BP and the interaction of assigned study medications (irbesartan, amlodipine, and placebo) on progressive renal failure and all-cause mortality were assessed. Other antihypertensive agents were added to achieve predetermined BP goals. Entry criteria included elevated baseline serum creatinine concentration up to 266 micromol/L (3.0 mg/dl) and urine protein excretion >900 mg/d. Baseline BP averaged 159/87 +/- 20/11 mmHg. Median patient follow-up was 2.6 yr. Follow-up achieved SBP most strongly predicted renal outcomes. SBP >149 mmHg was associated with a 2.2-fold increase in the risk for doubling serum creatinine or ESRD compared with SBP

The molecular mechanisms of heparan sulfate proteoglycan downregulation in the glomerular basement membrane (GBM) of the kidneys with diabetic nephropathy remain controversial. In the present study, we showed that the expression of heparanase-1 (HPR1), a heparan sulfate–degrading endoglycosidase, was upregulated in the renal epithelial cells in the kidney with diabetic nephropathy. Urinary HPR1 levels were elevated in patients with diabetic nephropathy. In vitro cell culture studies revealed that HPR1 promoter–driven luciferase reporter gene expression, HPR1 mRNA, and protein were upregulated in renal epithelial cells under high glucose conditions. Induction of HPR1 expression by high glucose led to decreased cell surface heparan sulfate expression. HPR1 inhibitors were able to restore cell surface heparan sulfate expression. Functional analysis revealed that renal epithelial cells grown under high glucose conditions resulted in an increase of basement membrane permeability to albumin. Our studies suggest that loss of heparan sulfate in the GBM with diabetic nephropathy is attributable to accelerated heparan sulfate degradation by increased HPR1 expression.

Elevated arterial pressure enhances the risk for cardiovascular (CV) events in patients with diabetic nephropathy. The optimal BP and the component of the elevated BP that affect the risk have not been defined. A post hoc analysis was performed to assess the impact of achieved systolic, diastolic, and pulse pressures on CV outcomes in 1590 adults who had overt diabetic nephropathy and were enrolled in the Irbesartan Diabetic Nephropathy Trial (IDNT) and had a baseline serum creatinine above the normal range, up to 266 micromol/L (3.0 mg/dL), 24-h urine protein >900 mg/d, and at least 6 mo of follow-up. Patients were randomized to irbesartan, amlodipine, or placebo, with other antihypertensive agents to a BP goal of < or =135/85 mmHg. Progressively lower achieved systolic BP (SBP) to 120 mmHg predicted a decrease in CV mortality and congestive heart failure (CHF) but not myocardial infarctions (MI). A SBP below this threshold was associated with increased risk for CV deaths and CHF events. Achieved diastolic BP

Despite clinical and experimental data suggesting a direct relationship between antineutrophil cytoplasmic antibodies (ANCAs) and disease activity in patients with microscopic polyangiitis (MPA), the causal relationship between perinuclear ANCAs specific for myeloperoxidase (MPO-ANCA) and disease manifestations has been controversial. We describe the case of a woman with a history of pulmonary-renal syndrome caused by MPA whose disease became clinically and serologically active during pregnancy. Forty-eight hours after delivery, the newborn developed pulmonary hemorrhage and abnormalities in renal function. The newborn's cord blood showed an immunoglobulin G MPO-ANCA level identical to that of the mother's serum, indicating passive transfer of the antibody to the neonate. Our findings represent the first human model supporting the interpretation that MPO-ANCAs were immunopathogenic.

A series of patients with systemic lupus erythematosus (SLE) and proteinuria were studied to determine whether nephrotic-range proteinuria was associated with diffuse epithelial cell foot process effacement in the absence of peripheral glomerular immune aggregate deposition. Biopsies from patients with known or suspected SLE and a histologic diagnosis of (1) normal by light microscopy, (2) mesangial proliferative glomerulonephritis, or (3) focal segmental glomerulosclerosis were studied. Biopsies were excluded when they demonstrated endocapillary proliferation or necrosis by light microscopy or electron-dense glomerular basement membrane deposits by electron microscopy. Patients were required to fulfill four of 11 American Rheumatologic Association criteria for the diagnosis of SLE, and proteinuria could not be associated with nonsteroidal anti-inflammatory drug use. Eighteen biopsies were studied, eight from patients with nephrotic-range proteinuria (>/=3 g/d) and 10 from patients with non-nephrotic proteinuria. The time from diagnosis of SLE to biopsy was shorter for nephrotic patients that for nonnephrotic patients. Seven of eight biopsies from nephrotic patients demonstrated at least 80% foot process effacement, whereas no biopsy from a nonnephrotic patient exhibited >20% effacement. There were no other significant pathologic differences between the nephrotic and nonnephrotic patients. The single common morphologic feature associated with nephrotic proteinuria was diffuse visceral epithelial cell foot process effacement. It is concluded that the development of nephrotic-range proteinuria in patients with SLE without peripheral immune aggregate deposition or endocapillary proliferation on renal biopsy is more likely a manifestation of SLE than the coexistence of idiopathic minimal-change glomerulopathy and SLE.

Historically diabetic nephropathy has been a devastating complication of both type I and type II diabetes. The past 2 decades have seen enormous conceptual advances in understanding the pathogenesis of diabetic nephropathy. The genetic determinants of diabetic renal disease have also been elucidated as well as biochemical events and cytokine interactions. Most importantly, key clinical trials have identified therapeutic interventions which can slow or halt the progression of diabetic nephropathy, specifically the therapeutic use of angiotensin-converting enzyme inhibition and intensive blood sugar control. Multiple treatment modalities for patients once they reach end-stage renal disease are also available and great strides have been improving outcomes in these areas as well.

In 1992, we published the results of a prospective, controlled trial of aggressive therapy (high-dose prednisone plus oral cyclophosphamide alone or with plasmapheresis) in 86 patients with severe lupus nephritis. During this study, remission (serum creatinine < or =1.4 mg/dL [< or =123 micromol/L] and proteinuria < or =330 mg/d of protein) in renal disease occurred in 37 patients (43%). To assess the long-term effect of remission on patient and renal survival, we now report the results of our extended follow-up of these patients. After an average of 10 years of follow-up in the 86 patients, patient survival rates at both 5 and 10 years were 95% in the group that had a remission and 69% at 5 years and 60% at 10 years in the no-remission group (P < 0.001). Renal survival rates were 94% at both 5 and 10 years in the remission group compared with 46% at 5 years and 31% at 10 years in the no-remission group (P < 0. 0001). Features predictive of remission included stable renal function after 4 weeks on therapy, category IV lesion, lower chronicity index, white race, lower urine protein excretion level at baseline, and lower baseline serum creatinine level. The features predictive of end-stage renal disease were higher baseline serum creatinine level, presence of anti-Ro antibodies, and failure to attain a remission. Thus, in patients with the most severe forms of lupus nephritis, a remission of clinical renal abnormalities is associated with dramatic improvement in long-term patient and renal survival.

mmHg/85±11 mmHg, serum creatinine 150±53 mmol/l (1.7±0.6 mg/dl ), creatinine clearance Background. Diabetic nephropathy is the most common cause of end-stage renal disease in the 66±34 ml/min and 24 h urine protein 4.0±3.5 g/day. developed world. Angiotensin-converting enzyme Keywords: angiotensin II receptor antagonist; diabetic inhibitors have been demonstrated to be renoprotective nephropathy; renoprotection; type II diabetes in type I diabetes and are now the standard of care for both hypertensive and non-hypertensive type I diabetic patients with any level of proteinuria. The role of blockade of the renin-angiotensin system in type II Introduction diabetic patients is not defined. The Collaborative Study Group has initiated the Irbesartan Type II Diabetic nephropathy is the most common end-stage Diabetic Nephropathy Trial (IDNT ), studying the renal disease ( ESRD) diagnosis in most of the eVect of the angiotensin II receptor antagonist irbesar- developed world, and is responsible for 43% of all new tan on progression of renal disease and mortality in patients requiring renal replacement therapy in the type II diabetic patients with overt nephropathy and USA (1). The incidence rate of diabetic ESRD is hypertension. Here we report the study design and increasing by 10% a year (1). This near epidemic baseline patient characteristics. growth occurs despite recent advances in the under- Methods. To qualify, hypertensive type II patients, age standing of the roles that glycaemic, blood pressure 30-70 years, must have a 24 h urinary protein excretion and dietary control, and angiotensin-converting of >900 mg and a serum creatinine 90-265 mmol/l enzyme inhibitors (ACEIs) play in the development (1.0-3.0 mg/dl ) in women and 110-265 mmol/l and progression of this disorder (2). The majority of (1.2-3.0 mg/dl ) in men. Three treatment arms include research to date has focused on type I diabetes, despite irbesartan, placebo and amlodipine, with every attempt the fact that the majority of patients with diabetes and made to achieve similar blood pressure levels in all ESRD have type II diabetes (3). treatment arms. A total of 1650 patients will be enrolled ACEIs play a unique role because of the 'renoprotec- utilizing ~225 clinics worldwide. The primary outcome tion' that they aVord: the property of slowing progres- measure is time to event to the composite end-point sion of renal disease independently of their eVect on of doubling of serum creatinine, end-stage renal disease blood pressure (4-8). They are now considered the or death. The secondary outcome measure is time to standard of care for type I patients with both incipient composite end-point of fatal or non-fatal cardiovas- (microalbuminuria) and overt nephropathy. Their role cular events. The average length of patient follow-up in patients with type II diabetes and nephropathy is is expected to be ~36 months. undefined (9). The present trial is being undertaken Results. The baseline characteristics of the study sub- predominantly in order to evaluate in a high risk jects are: age 59±8 years, duration of diabetes 15±9 hypertensive population whether blockade of the renin- years, height 168±11 cm (5 ft 6 in), weight 87±19 kg -angiotensin system with the angiotensin II receptor (192 lb), body mass index 31± 7k g/m2, blood pressure antagonist (AIIRA) irbesartan aVords similar renopro

The renoprotective effect of captopril on progression of diabetic nephropathy was demonstrated by the Collaborative Study Group Captopril Trial and might be independent of blood pressure. Because angiotensin II is known to stimulate the prosclerotic cytokine, transforming growth factor-beta (TGF-beta), we postulated that the renoprotective effect may be due to inhibition of TGF-beta1 production. TGF-beta1 levels were measured in serum at baseline and 6 months from patients in the captopril trial. TGF-beta1 analyses were performed on all available patient sera. Analysis was performed between the percent change in TGF-beta1 levels during the first 6 months versus the percent change in glomerular filtration rate (GFR) in the subsequent 2 years. TGF-beta1 levels increased by 11% (P = 0. 003) in the placebo group (n = 24), whereas there was a decrease of 14% (P = 0.01) in the captopril group (n = 34). There was an inverse correlation between the percent change in TGF-beta1 levels during the first 6 months and the percent change in GFR over the ensuing 2-year period in patients from both the placebo (r = -0.55, P = 0. 005) and captopril groups (r = -0.45, P = 0.008). In patients with initial GFR below 75 mL/min, there was an even stronger correlation in percent change in TGF-beta1 levels and percent change in GFR in both placebo (n = 9, r = -0.69, P = 0.03) and captopril groups (n = 21, r = -0.73, P = 0.0001). Our data suggest that captopril decreases TGF-beta1 levels in diabetic nephropathy and that changes in TGF-beta1 levels may predict the course of diabetic nephropathy.

Diabetic nephropathy is the most common cause of end-stage renal disease in the United States. We undertook a study to assess the impact of assignment to different levels of blood pressure control on the course of type 1 diabetic nephropathy in patients receiving angiotensin-converting enzyme (ACE) inhibitor therapy. We also examined the long-term course of this well-characterized cohort of patients receiving ACE inhibitor therapy. One hundred twenty-nine patients with type 1 diabetes and diabetic nephropathy who had previously participated in the Angiotensin-Converting Enzyme Inhibition in Diabetic Nephropathy Study who had a serum creatinine level less than 4.0 mg/dL were randomly assigned to a mean arterial blood pressure (MAP) goal of 92 mm Hg or less (group I) or 100 to 107 mm Hg (group II). Patients received varying doses of ramipril as the primary therapeutic antihypertensive agent. All patients were followed for a minimum of 2 years. Outcome measures included iothalamate clearance, 24-hour creatinine clearance, creatinine clearance estimated by the Cockcroft and Gault formula, and urinary protein excretion. The average difference in MAP between groups was 6 mm Hg over the 24-month follow-up. The median iothalamate clearance in group I was 62 mL/min/1.73 m(2) at baseline and 54 mL/min/1.73 m(2) at the end of the study compared with a baseline of 64 mL/min/1.73 m(2) and final 58 mL/min/1.73 m(2) in group II. There were no statistically significant differences in the rate of decline in renal function between groups. There was a significant difference in follow-up total urinary protein excretion between group I (535 mg/24 h) and group II (1,723 mg/24 h; P = 0.02). Thirty-two percent of 126 patients achieved a final total protein excretion less than 500 mg/24 h. Patients from groups I and II had equivalent rates of adverse events. In patients with type 1 diabetes mellitus and diabetic nephropathy, the MAP goal should be 92 mm Hg or less for optimal renoprotection, if defined as including decreased proteinuria. With the combination of ACE inhibition and intensive blood pressure control, many patients can achieve regression or apparent remission of clinical evidence of diabetic nephropathy.

had glomerular changes characteristic of the diabetic state including enlarged glomeruli and an increase in Background. The glomerular and retinal vessels are both aVected in patients with type I and type II mesangial matrix without Kimmelstiel‐Wilson nodules (mesangial sclerosis lesion); and two had other primary diabetes mellitus. However, the prevalence of the nodular form of diabetic glomerular sclerosis glomerular diseases (IgA and membranous nephropathy). Patients with Kimmelstiel‐Wilson nodules ( Kimmelstiel‐Wilson lesion) and other forms of glomerular pathology including diVuse mesangial sclerosis had elevated serum creatinines compared to patients with mesangial sclerosis lesions, but there were no and their clinical correlates in type II diabetes are less well known. In addition, although recent studies have other significant diVerences. Patients with Kimmelstiel‐ Wilson nodules had more severe overall retinopathy suggested that non-diabetic glomerular disease was a common cause of proteinuria in type II diabetes, the than those with mesangial sclerosis lesions (P=0.0043): six of seven with proliferative retinopathy had prevalence of other diseases is unknown. The literature on this subject is clouded by clinical bias regarding Kimmelstiel‐Wilson nodules, and seven of the eight patients without retinopathy had mesangial sclerosis patients with diabetes who undergo renal biopsy. Methods. Glomerular and retinal pathology and clin- lesions. Conclusions. The two discrete patterns of glomerular ical correlates were studied in 36 patients enrolled in a prospective clinical trial of patients with type II pathology and the correlation between diabetic retinopathy and the Kimmelstiel‐Wilson lesion but not diabetes mellitus, proteinuria, renal insuYciency, and hypertension. the mesangial sclerosis lesion suggest that the Kimmelstiel‐Wilson and mesangial sclerosis lesions of

Predictors of the progression of renal insufficiency in patients with insulin-dependent diabetes and overt diabetic nephropathy. We designed a prospective, double-blind controlled trial to determine predictors of loss of renal function in patients with insulin dependent diabetes and established nephropathy. A total of 409 insulin-dependent diabetic patients with established nephropathy enrolled in a trial on the effect of Captopril on the rate of progression of renal disease. Baseline demographic, clinical (history and physical) and laboratory parameters were analyzed as risk factors for time to progression. Dichotomous characteristics were compared by Fisher's exact test and continuous characteristics with the Wilcoxon rank-sum test. Univariate proportional hazards regression analysis was used to estimate relative risk of nephropathy progression, and bivariate proportional hazard regression to identify interactions with the treatment group assignment. Multivariate proportional hazard regression was employed to determine which characteristics were independent risk factors. We found that a number of demographic and clinical characteristics were significantly associated with nephropathy progression even after adjustment for treatment group. However, after multivariate analysis, the risk factors that independently predicted progression were onset of IDDM later in life, parental diagnosis of IDDM, the presence of edema, increased mean arterial pressure, and an abnormal electrocardiogram. Likewise, a number of laboratory characteristics were also predictive of nephropathy progression. A low hematocrit, high blood sugar, and higher protein excretion predicted nephropathy progression as did a higher serum creatinine, particularly in the face of a normal serum albumin. In conclusion, this study identifies a number of clinical and laboratory risk factors that can predict which patients with insulin-dependent diabetes with established nephropathy are more likely to sustain a clinically important decrease in renal function over a median follow-up of three years.

Diabetic nephropathy is the inevitable long term complication of prolonged hyperglycaemia for up to 40% of patients with diabetes mellitus. Most patients with renal involvement have a number of comorbid conditions including hypertension, coronary artery disease. peripheral vascular disease and retinopathy. These complications utilise considerable healthcare expenditures. In addition, end-stage renal disease (ESRD) therapies are extremely expensive (>$US40 000 per patient per year in the US»)II However, ESRD is associated with an accelerated course to death (5-year survival

The purpose of this study was to determine the usefulness of a random urine specimen protein to creatinine (P/C) ratio in predicting 24-hour urine protein excretion (24 UP) in type 1 diabetic patients with overt nephropathy. Two hundred twenty-nine outpatient diabetic subjects enrolled in the Collaborative Study Group's multicenter clinical trial of "Angiotensin-Converting Enzyme Inhibition in Type 1 Diabetic Nephropathy" provided specimens for study, which encompassed a wide range of proteinuria (0.05 to 13.3 g/d). Twenty-four hour urine collections for total protein and creatinine (g/d) were obtained in the outpatient setting. This was followed shortly thereafter by an untimed single urine specimen for protein and creatinine (mg/dL). For longitudinal analysis, 33 patients provided two 24-hour urine collections with concomitant random urine specimens, separated by at least a 3-month period. Across the range of proteinuria that we studied, the log random urine P/C ratio correlated to log 24 UP (r = 0.90). The regression line was almost identical to the line of unity, which indicates that a patient's 24 U/P (in g/d) can be predicted directly from the random urine specimen P/C ratio (P/C = 24 UP in g/d). However, the standard deviations associated with these predictions were large, especially at the higher 24 UP values. Of the 33 patients who provided two time-separated specimens, the direction of change in P/C ratio was discordant with the direction of change in 24 UP in 14 of the 33 repeat specimens.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Item does not contain fulltext AIMS/HYPOTHESIS: The content of heparan sulphate is reduced in the endothelium under hyperglycaemic conditions and may contribute to the pathogenesis of atherosclerosis. Heparanase-1 (HPR1) specifically degrades heparan sulphate proteoglycans. We therefore sought to determine whether: (1) heparan sulphate reduction in endothelial cells is due to increased HPR1 production through increased reactive oxygen species (ROS) production; and (2) HPR1 production is increased in vivo in endothelial cells under hyperglycaemic and/or atherosclerotic conditions. METHODS: HPR1 mRNA and protein levels in endothelial cells were analysed by RT-PCR and Western blot or HPR1 enzymatic activity assay, respectively. Cell surface heparan sulphate levels were analysed by FACS. HPR1 in the artery from control rats and a rat model of diabetes, and from patients under hyperglycaemic and/or atherosclerotic conditions was immunohistochemically examined. RESULTS: High-glucose-induced HPR1 production and heparan sulphate degradation in three human endothelial cell lines, both of which were blocked by ROS scavengers, glutathione and N-acetylcysteine. Exogenous H(2)O(2) induced HPR1 production, subsequently leading to decreased cell surface heparan sulphate levels. HPR1 content was significantly increased in endothelial cells in the arterial walls of a rat model of diabetes. Clinical studies revealed that HPR1 production was increased in endothelial cells under hyperglycaemic conditions, and in endothelial cells and macrophages in atherosclerotic lesions. CONCLUSIONS/INTERPRETATION: Hyperglycaemia induces HPR1 production and heparan sulphate degradation in endothelial cells through ROS. HPR1 production is increased in endothelial cells from a rat model of diabetes, and in macrophages in the atherosclerotic lesions of diabetic and non-diabetic patients. Increased HPR1 production may contribute to the pathogenesis and progression of atherosclerosis. 01 juni 2011

Background Renal function declines progressively in patients who have diabetic nephropathy, and the decline may be slowed by antihypertensive drugs. The purpose of this study was to determine whether captopril has kidney-protecting properties independent of its effect on blood pressure in diabetic nephropathy. Methods We performed a randomized, controlled trial comparing captopril with placebo in patients with insulin-dependent diabetes mellitus in whom urinary protein excretion was > or = 500 mg per day and the serum creatinine concentration was Results Two hundred seven patients received captopril, and 202 placebo. Serum creatinine concentrations doubled in 25 patients in the captopril group, as compared with 43 patients in the placebo group (P = 0.007). The associated reductions in risk of a doubling of the serum creatinine concentration were 48 percent in the captopril group as a whole, 76 percent in the subgroup with a baseline serum creatinine concentration of 2.0 mg per deciliter (177 mumol per liter), 55 percent in the subgroup with a concentration of 1.5 mg per deciliter (133 mumol per liter), and 17 percent in the subgroup with a concentration of 1.0 mg per deciliter (88.4 mumol per liter). The mean (+/- SD) rate of decline in creatinine clearance was 11 +/- 21 percent per year in the captopril group and 17 +/- 20 percent per year in the placebo group (P = 0.03). Among the patients whose base-line serum creatinine concentration was > or = 1.5 mg per deciliter, creatinine clearance declined at a rate of 23 +/- 25 percent per year in the captopril group and at a rate of 37 +/- 25 percent per year in the placebo group (P = 0.01). Captopril treatment was associated with a 50 percent reduction in the risk of the combined end points of death, dialysis, and transplantation that was independent of the small disparity in blood pressure between the groups. Conclusions Captopril protects against deterioration in renal function in insulin-dependent diabetic nephropathy and is significantly more effective than blood-pressure control alone.

Histological indices of renal pathology in lupus nephritis have been proposed as prognostic signs and as a method to quantitate therapeutic response. We tested the reproducibility of the activity (AI) and chronicity indices (CI) in the renal biopsies from 83 patients with lupus nephritis, enrolled in a controlled therapeutic trial. The AI/CI were calculated separately by four renal pathologists using published criteria. Pair-wise Spearman's rank correlation coefficient was used to examine the relationship among the scores of the four raters, and their degree of reproducibility was evaluated using the coefficient of reliability. The mean Cl scores ranged from 2.84 to 4.61, and the mean AI ranged from 9.64 to 12.89. The correlation among the different pathologist's scores ranged from 0.44 to 0.63 for the AI and 0.60 to 0.76 for the CI. One pathologist (M.M.S.) rated the biopsies twice, and the correlation between the two ratings was 0.58 for the AI and 0.74 for the CI. Thus, the Al and Cl calculated by different pathologists and the temporally separate observations of a single observer were only moderately correlated. The reproducibility of a single rating was low, showing a reliability coefficient of 0.48 for the Al and 0.57 for the Cl. The low reliability coefficient suggests that the variability among pathologists was the result of interpretative differences. We conclude that the AI/CI are too subjective to be used as therapeutic guides or as prognosticators.

The level of renal function at biopsy is predictive of outcome in patients with severe lupus nephritis (SLN). While renal function has been based on serum creatinine (SCr) alone, measuring the estimated glomerular filtration rate (eGFR) utilizing the Modification of Diet in Renal Disease (MDRD) Study equation has been found to be more accurate. The MDRD eGFR (ml/min/1.73 m2) at biopsy was calculated in 86 patients with SLN and patients were categorized based on eGFR: ≥60 (33 pts), 59–30 (33 pts) and

Role of pathology indices in the management of severe lupus glomerulonephritis. The principal value of the renal biopsy in patients with SLE is as a therapeutic guide. Although semiquantitative indices of nephron loss (chronicity = CI) and acute potentially reversible inflammation (activity = AI) are reported by some to have separate values from traditional classifications of glomerular pathology as predictors of outcome and therapeutic guides, this point remains controversial. We have tested the predictive value of the AI and CI in a large group of patients with severe lupus glomerulonephritis (SLE GN) and a mean follow-up of 281 weeks ± 116 (mean ± SD). A total of 86 patients entered into the study of plasmapheresis in severe SLE GN by the Lupus Nephritis Collaborative Study Group, and long-term follow-up was available in 83. The predictive value of the AI and the CI was described over the entire range of cut-off points by the method of receiver operator characteristics (ROC). ROC analysis demonstrated that there was no level of either AI or CI that predicted the outcome of death or renal failure with sufficient sensitivity and specificity to be useful in the individual patient. The CI signifies renal damage and nephron loss, whereas the AI describes potentially reversible pathology. Neither the CI nor the AI taken by itself predicts individual outcomes of renal failure or death in patients with aggressively treated SLE GN. Since the indices fail to identify the patient whose disease will progress to renal failure, they are both insufficient as therapeutic guides and add little to the management of the patient with severe SLE GN.

Background. The prognosis of patients with systemic lupus erythematosus who have glomerulonephritis is poor, despite treatment with immunosuppressive therapy. Plasmapheresis therapy has been used, but there have been few controlled clinical observations of its efficacy. Methods We carried out a randomized, controlled trial comparing a standard-therapy regimen of prednisone and cyclophosphamide (standard therapy) with a regimen of standard therapy plus plasmapheresis in 86 patients with severe lupus nephritis in 14 medical centers. The patients underwent plasmapheresis three times weekly for four weeks. Drug therapy was standardized, with strict adherence to nine detailed medical-management protocols. Results Forty-six patients received standard therapy, and 40 patients received standard therapy plus plasmapheresis. The mean follow-up was 136 weeks. Six patients (13 percent) in the standard-therapy group and eight patients (20 percent) in the plasmapheresis group died. Renal failure developed in 8...

The purpose of this study is to determine whether two distinct histopathological–immunopathological lesions, which have been reported in severe lupus nephritis, diffuse global glomerulonephritis (GN) (WHO IV) and a segmental and necrotising GN (WHO III) can be reported to coexist in a single patient. We examine the evidence of coexistence of these disparate lesions and the prognostic significance in a group of patients with severe lupus nephritis who have been subjected to a common therapeutic regimen by protocol. The simple, reproducible parameter indicating the presence of glomerular capillary necrosis was the presence of crescents. We, therefore, reviewed 39 renal biopsies with diffuse global lupus GN (WHO IV) (Churg, J, Sobin, LH. Lupus nephritis. Renal disease, classification and atlas of glomerular diseases. New York: Igaku-Shoin; 1982. p. 127–149). and used crescents as a surrogate for glomerular necrosis. Peripheral capillary immune deposits were less prominent in WHO IV with crescents compared with those without and resembled the reduced immune deposits seen in severe segmental GN (WHO III ≥ 50%). Patients with WHO IV with crescents had decreased survival without end-stage renal disease ( P = 0.02), fewer remissions ( P = 0.04) and more adverse outcomes (12/22 vs 3/17) ( P = 0.02) than those without crescents, and this was similar to patients with WHO III ≥50%. We conclude that, on the basis of immunological and morphological features, WHO IV with crescents appears to be the result of two distinct pathogenetic mechanisms. We propose that diffuse global lupus GN, associated with crescents, is best described as WHO class IV + WHO class III.