Samuel Spitalewitz

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.

Remission of nephrotic syndrome in type 1 diabetes: long-term follow-up of patients in the Captopril Study.

In 1994, we reported a 3.4 +/- 0.8 year follow-up of the eight patients who experienced remission of nephrotic syndrome during the Collaborative Study Group-sponsored, multicenter trial of captopril therapy in patients with type 1 diabetes with nephropathy (Captopril Study). Of the 409 patients randomized to treatment on the Captopril Study, 108 had nephrotic syndrome (24-hour proteinuria >/= 3.5 g of protein) at baseline. Of these 108 patients, 8 experienced remission of nephrotic syndrome (proteinuria </= 1.0 g/24 h of protein). Remission was significantly associated with captopril therapy and control of systolic blood pressure. The present study describes the status of these eight patients during a follow-up of 7.7 +/- 0.3 years. Since our previous report, one patient has been lost to follow-up and one patient progressed to end-stage renal disease (ESRD) 3.7 years after completion of the Captopril Study. The remaining six patients remain in remission of nephrotic syndrome (mean 24-hour proteinuria, 1.03 +/- 0.3 g of protein) and have stable serum creatinine levels (mean, 1.58 +/- 0.3 mg/dL) and body weights (mean, 69.8 +/- 5.3 kg). Of the six patients, one has discontinued angiotensin-converting enzyme inhibitor (ACEi) therapy because of hypotension. Excluding the patient who progressed to ESRD, the current mean systolic blood pressure is 135 +/- 6 mm Hg and mean diastolic blood pressure is 78 +/- 4 mm Hg. We conclude that long-term remission of nephrotic syndrome and preservation of renal function is achievable in some patients with type 1 diabetes. Control of blood pressure and ACEi therapy appear to be important in achieving long-term remission.

Comparison of nifedipine and propranolol used in combination with diuretics for the treatment of hypertension.

One hundred patients participated in a double-blind, randomized study to compare the antihypertensive efficacy of sustained-release nifedipine and propranolol in hypertensive patients whose diastolic blood pressure exceeded 95 mm Hg while receiving diuretic therapy. Nifedipine (mean dose, 79.6 mg per day) decreased blood pressure by 11.4/10.5 mm Hg; propranolol (mean dose, 198.4 mg per day) decreased blood pressure by 13.5/10.3 mm Hg. Reduction of diastolic blood pressure to below 90 mm Hg was achieved in 63 percent of nifedipine-treated patients and in 57 percent of propranolol-treated patients. Nifedipine therapy was associated with an increase in high-density lipoprotein cholesterol levels and a decrease in serum triglyceride levels. In contrast, propranolol therapy was associated with a decrease in high-density lipoprotein cholesterol levels and an increase in serum triglyceride levels. Nifedipine is as effective as propranolol in the treatment of patients with mild to moderate hypertension whose blood pressure is inadequately controlled by diuretic therapy.

Treatment of Hyperlipidemia in the Nephrotic Syndrome: The Effects of Pravastatin Therapy

The hyperlipidemia of the nephrotic syndrome is characterized by an elevation of total cholesterol (TC) and low-density lipoprotein cholesterol (LDLC), with a normal or low high-density lipoprotein cholesterol (HDLC), and an increase in triglycerides (TGs) later in the course of the disease. If sustained, this lipid profile probably places these patients at increased risk for cardiovascular disease. Despite extensive trials of diet and drug therapy in patients with primary hyperlipidemias, few such trials exist in patients with the nephrotic syndrome. We conducted a randomized, prospective, double-blind, placebo-controlled trial to investigate the efficacy and safety of pravastatin, the newest cholesterol synthesis inhibitor, in the treatment of the hyperlipidemia of the nephrotic syndrome. After dietary modification was implemented, 13 patients received pravastatin and eight received placebo. All patients were maintained on a low-fat, low-cholesterol diet for the duration of the trial (24 weeks). The dose of pravastatin was increased from the initial 20 mg/d to 40 mg/d at week 10 or 18 if TC remained elevated (> 50th percentile). A bile acid sequestrant was added at week 18 if TC remained elevated and if the patient was already receiving the maximal pravastatin dosage. Dietary modification did not significantly change the lipid profile. Pravastatin (20 mg/d) reduced TC by 22% from a baseline of 301 +/- 28 mg/dL (P < 0.05) and LDLC by 28% from a baseline of 222 +/- 28 mg/dL (P < 0.05). When used at 40 mg/d (in six patients) no further change in the lipid profile was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Diabetic ketoacidosis presenting with atypical hemolytic uremic syndrome associated with a variant of complement factor B in an adult: a case report

BackgroundNon-Shiga toxin-associated hemolytic uremic syndrome is known to be caused by dysregulation of the alternative complement pathway. Infections, drugs, pregnancy, bone marrow transplantation, malignancy, and autoimmune disorders have all been reported to trigger episodes of atypical hemolytic uremic syndrome. To the best of our knowledge, there have been no previous reports of an association between diabetic ketoacidosis and atypical hemolytic uremic syndrome.Case presentationWe describe a case of a 26-year-old Spanish man who presented with diabetic ketoacidosis and was found to have the triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. The patient had a normal ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity level, and his renal biopsy demonstrated predominant changes of diabetic glomerulosclerosis with an area compatible with thrombotic microangiopathy suggestive of superimposed atypical hemolytic uremic syndrome. Complement sequencing subsequently revealed a potential causative mutation in exon 12 of complement factor B with changes of lysine at amino acid position 533 to an arginine (CFB p.K533R).ConclusionsTo the best of our knowledge, this is the first case report of diabetic ketoacidosis presenting with atypical hemolytic uremic syndrome associated with a variant of complement factor B in an adult patient.

Hypercalcemia-Induced Hypokalemic Metabolic Alkalosis in a Multiple Myeloma Patient: The Risk of Furosemide Use.

Hypercalcemia is often seen in patients with malignancies, and in the past treatment for this has traditionally included loop diuretics. Clinically, patients with hypercalcemia frequently present with polyuria and volume contraction which may be further exacerbated by diuretic therapy. In the lab, hypercalcemia has been shown to activate the calcium-sensing receptor in the thick ascending limb of Henle and inactivate the 2 chloride sodium potassium co-transporter and induce a hypokalemic metabolic alkalosis, an effect similar to that of the loop diuretic furosemide. We now report what may well be the first clinical correlate of this laboratory finding in a patient who developed a hypokalemic metabolic alkalosis as a consequence of severe hypercalcemia due to multiple myeloma and whose metabolic derangement was corrected without the use of a loop diuretic which may have exacerbated the electrolyte abnormalities.

Treatment of Hypertensive Patients with Chronic Renal Insufficiency

The prevalence of hypertension in patients with chronic renal insufficiency (CRI) from all causes increases linearly as renal function deteriorates, reaching approx 95% as patients approach end-stage renal disease (ESRD) (1–3). There is now substantial evidence that controlling blood pressure (BP) will slow the inexorable decline in renal function in patients with CRI (4). Nevertheless, at a time when morbidity and mortality from cardiovascular disease is declining, the incidence of ESRD is increasing dramatically, particularly in African Americans, the elderly, and diabetics (5). There is no single explanation for this fact, but pertinent issues are as follows (6, 7): 1. Should the general therapeutic approach to hypertension (nonpharmacologic and/or pharmacologic) differ in patients with CRI vs essential hypertensive patients without renal insufficiency? 2. Will lowering BP to levels below current standards (140/90 mmHg; mean arterial pressure [MAP] = 107) better preserve renal function without increasing adverse consequences? 3. Are there specific classes of antihypertensive drugs that are renoprotective over and above their effect on BP?