Marc A. Pohl

Independent and Additive Impact of Blood Pressure Control and Angiotensin II Receptor Blockade on Renal Outcomes in the Irbesartan Diabetic Nephropathy Trial: Clinical Implications and Limitations

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 <134 mmHg. Progressive lowering of SBP to 120 mmHg was associated with improved renal and patient survival, an effect independent of baseline renal function. Below this threshold, all-cause mortality increased. An additional renoprotective effect of irbesartan, independent of achieved SBP, was observed down to 120 mmHg. There was no correlation between diastolic BP and renal outcomes. We recommend a SBP target between 120 and 130 mmHg, in conjunction with blockade of the renin-angiotensin system, in patients with type 2 diabetic nephropathy.

Impact of achieved blood pressure on cardiovascular outcomes in the Irbesartan Diabetic Nephropathy Trial.

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 <85 mmHg was associated with a trend to increase in all-cause mortality, significant increase in MI, but decreased risk for strokes. Increased pulse pressure predicted increased all-cause mortality, CV mortality, MI, and CHF. It is concluded that achieved SBP approaching 120 mmHg and diastolic BP of 85 mmHg are associated with the best protection against CV events in these patients. BP < or =120/85 may be associated with an increase in CV events.

Critical perfusion pressure for renal function in patients with bilateral atherosclerotic renal vascular disease

We studied renal plasma flow and glomerular filtration rate during graded blood pressure reduction induced with sodium nitroprusside infusion in 16 hypertensive patients with atherosclerotic renovascular disease. Eight patients with unilateral disease tolerated pressure reduction from 205 +/- 9 (SE)/103 +/- 2 mm Hg to 146 +/- 6/84 +/- 3 mm Hg (p less than 0.01) with no change in total renal function. In 8 other patients with bilateral renal arterial stenosis (all arteries 70% or more stenosed), similar pressure reduction produced marked but reversible decrements in plasma flow (152 +/- 28 mL/min to 66 +/- 13 mL/min; p less than 0.01) and glomerular filtration rate (38 +/- 8 mL/min to 16 +/- mL/min; p less than 0.01). In 4 patients restudied after revascularization, sensitivity of renal function to pressure changes was no longer present. These data indicate that vascular stenosis to the entire renal mass may limit function and provide a means for evaluating patients at risk for loss of renal function during antihypertensive therapy.

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.

Revascularization for preservation of renal function in patients with atherosclerotic renovascular disease

Fifty-one patients with atherosclerotic renovascular disease have undergone elective revascularization primarily to preserve renal function. In all patients the blood pressure was well controlled preoperatively with medical therapy and was not an indication for revascularization. The preoperative serum creatinine value was 2.0 mg./dl. or more in 35 patients and less than 2.0 mg./dl. in 16. Vascular reconstruction was technically successful in all patients, with postoperative followup ranging from 4 to 76 months. The current level of over-all renal function is improved in 34 patients (67 per cent), unchanged in 14 (27 per cent) and deteriorated in 3 (6 per cent). In selected patients with atherosclerotic renal artery disease revascularization can achieve preservation or improvement of renal function.

Natural History of Atherosclerotic and Fibrous Renal Artery Disease: Clinical Implications

Atherosclerotic renal artery disease and the fibrous renal artery diseases are described with respect to their radiographic and clinical characteristics. In a retrospective review, serial renal arteriograms of 85 patients with atherosclerotic renal artery disease and 66 patients with the medial fibroplasia type of fibrous renal artery disease were analyzed to characterize their natural history. Atherosclerotic renovascular disease progressed in 37 patients (44%) with total arterial occlusion occurring in 14 patients (16%). Medial fibroplasia of the renal artery progressed in 22 patients (33%) with no patient progressing to complete occlusion. Reduction in kidney size and increase in serum creatinine were good clinical markers for progressive atherosclerotic renal artery disease, but failed to discriminate between progressive and nonprogressive medial fibroplasia. The adequacy of BP control did not correlate with progressive occlusive disease in patients with either renal artery atherosclerosis or medial fibroplasia. The clinical implications of these observations are discussed with a view toward renal revascularization or transluminal angioplasty for preservation of renal 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.

Plasmapheresis Does Not Increase the Risk for Infection in Immunosuppressed Patients with Severe Lupus Nephritis

OBJECTIVE To determine whether plasmapheresis increases the risk for infection in immunosuppressed patients. DESIGN Randomized, controlled trial. SETTING Multicenter. PATIENTS Eighty-six patients enrolled in a trial of plasmapheresis for severe diffuse proliferative lupus nephritis. INTERVENTIONS Forty-six of the patients received high-dose steroid therapy plus cyclophosphamide therapy for 8 weeks. Thereafter, cyclophosphamide therapy was discontinued, and steroid therapy was tapered (standard treatment group). Forty patients received identical treatment and had 12 plasmapheresis procedures during the first 4 weeks of the treatment. MEASUREMENTS Patients were examined for the development of infection. MAIN RESULTS No statistical difference in age, sex, race, serum creatinine level, proteinuria, or complement levels was found between the two groups. Over a follow-up period of 5376 patient-weeks, 74% of patients in the standard treatment group had 62 infections, yielding an aggregate infection rate of 1.15 infections per 100 weeks (median individual infection rate, 1.08; 25th and 75th percentiles, 0.0 and 2.44). This rate was comparable to that seen in the plasmapheresis-treated patients who were followed for 4187 patient-weeks: 68% had 51 infections, for an aggregate infection rate of 1.22 infections per 100 weeks (median individual infection rate, 0.94; 25th and 75th percentiles, 0.0 and 2.32). The infection rate was also comparable in the initial acute phase of the study, despite the fact that patients who received plasmapheresis then had significantly lower immunoglobulin (IgG) levels (P less than 0.001). Neither the site (superficial compared with systemic) nor the nature (conventional compared with unconventional) of infection differed statistically between the two groups. Of 14 patient deaths, 7 were from infection (4 in control group and 3 in the plasmapheresis group). CONCLUSION Plasmapheresis did not increase the risk for infection in immunosuppressed patients with severe lupus nephritis.

Reversible renin mediated massive proteinuria successfully treated by nephrectomy.

We report on a patient with severe hypertension and nephrotic range proteinuria, which were renin mediated in origin. Aortography demonstrated occlusion of the right renal artery and renal vein renin measurements lateralized strongly to the right kidney. Removal of the right kidney led to amelioration of hypertension and proteinuria. Massive proteinuria in this setting is due to high levels of intrarenal angiotensin II and is reversible with deactivation of the renin-angiotensin system.

Dipstick Pseudohematuria: Unnecessary Consultation and Evaluation

PURPOSE While many primary care providers advocate routine screening urinalyses, a heme positive dipstick test often leads to a false-positive diagnosis of hematuria, or pseudohematuria. Thus, American Urological Association guidelines recommend urological evaluation for asymptomatic patients only for at least 3 red blood cells per high power field in 2 of 3 microscopic urinalyses. We determined the percentage of patients referred for asymptomatic hematuria undergoing unnecessary consultation and studies. MATERIALS AND METHODS Patients were retrospectively identified if seen for initial consultation associated with CPT 599.7X, hematuria. Among these patients those referred for evaluation of asymptomatic nonmacroscopic hematuria were identified, and referral patterns, ancillary tests, procedures and findings were examined. RESULTS Of 320 new patient visits with diagnosis code 599.7X, 91 were referred for asymptomatic, nonmacroscopic hematuria. Of these patients only 37 (41%) had microscopic urinalyses before referral and only 22 (24%) had microscopic urinalyses showing 3 or more red blood cells per high power field. Of the 69 patients referred without confirmed microhematuria approximately 25% had true microhematuria and 15 with no true hematuria had undergone imaging before referral. The Medicare reimbursement value for the evaluation of these 69 patients was