Murray L. Levin

Improvement of lipid abnormalities associated with proteinuria using fosinopril, an angiotensin-converting enzyme inhibitor

The nephrotic syndrome is associated with several complications including edema, hyperlipidemia, and protein malnutrition [1, 2]. These complications are largely related to the severity of the proteinuria. Elevation of the serum lipid concentrations is of major concern because it contributes to the high cardiovascular morbidity and mortality observed in patients with the nephrotic syndrome [3]. Patients with heavy proteinuria have recently been shown to have elevated levels of lipoprotein(a) (lp[a]) [4]. Lipoprotein(a) has both thrombogenic and atherogenic properties and is increasingly recognized as an independent risk factor for cardiovascular disease [5, 6]. For these reasons, reducing the hyperlipidemia associated with proteinuria could be viewed as a major therapeutic goal. In addition, recent data from animal studies suggest that hyperlipidemia may accelerate the progression of renal insufficiency, although the significance of these findings for renal disease in humans remains uncertain [7-10]. Angiotensin-converting enzyme (ACE) inhibitors slow the rate of progression of kidney disease in experimental models of renal insufficiency [11-13]. These agents have also been shown to reduce microalbuminuria in patients with incipient diabetic nephropathy [14, 15] and overt proteinuria in patients with diabetic and nondiabetic renal disease [16-18]. Taken together, these studies are suggestive of a special beneficial effect of ACE inhibitors in patients with renal disease. However, a benefit from reducing proteinuria in terms of improving the outcome of renal disease or in terms of other systemic (nonrenal) effects has not been shown in humans. One potential benefit of drug use aimed at reducing proteinuria might be the lessening of the lipid abnormalities associated with overt proteinuria. Studies in humans that have shown a reduction in proteinuria with ACE inhibitors did not focus on the effect of this intervention on the lipid profile [14-18]. We report that fosinopril, an ACE inhibitor with dual hepatic and renal elimination [19], had a prompt and sustained beneficial effect on both proteinuria and lipid profile abnormalities in patients with proteinuric renal disease enrolled in a placebo-controlled, double-blind trial of 12 weeks duration followed by an open-label trial of fosinopril of 6 months. Table. SI Units, Drug, and Abbreviations Methods Patients Twenty-eight patients with proteinuric renal disease who entered a double-blind study (fosinopril sodium compared with placebo) are reported. Two patients were withdrawn from the study during the double-blind phase; one was lost to follow-up, and the other had an increase in serum creatinine from 230 to 292 mol/L. Sixteen of the 26 patients who completed the double-blind phase were subsequently enrolled in an extended trial of fosinopril sodium. All patients except one were men; 17 were black, 8 were white, and 1 was Asian. Their ages ranged from 28 to 70 years. Diabetic nephropathy was diagnosed when overt proteinuria was documented in patients who had type 2 diabetes and clinical features consistent with diabetic nephropathy. Kidney biopsies were not done in diabetic patients. In nondiabetic patients, the diagnosis of glomerular disease was determined by kidney biopsy except in five patients who declined the procedure. The cause of their renal diseases were as follows: type 2 diabetic nephropathy in 15 patients, focal glomerular sclerosis in 3, membranous nephropathy in 2, and mesangio-capillary glomerulonephritis in 1. The cause of the renal disease in the remaining five nondiabetic patients was not determined. For a patient to be included in the study, his or her proteinuria had to exceed 2.0 g/d and serum creatinine concentration had to be 265 mol/L or less. Of the 26 patients, 21 had nephrotic-range proteinuria, defined as protein excretion exceeding 3.0 g/d [20]. Exclusion criteria were 1) treatment with converting enzyme inhibitors within 4 weeks of the baseline phase; 2) ongoing therapy with medications such as corticosteroids or immunosuppressives or with medications that could influence protein excretion such as nonsteroidal anti-inflammatory agents; 3) recent history of serum potassium concentrations exceeding 5.5 mmol/L; 4) poorly controlled diabetes mellitus; 5) uncontrolled hypertension defined as a diastolic blood pressure of 115 mm Hg or higher; 6) congestive heart failure; 7) noncompliance with medications; and 8) failure to collect 24-hour urine specimens or to keep clinic appointments. All participants gave informed written consent to participate in the study according to a protocol approved by the institutional review boards of both hospitals. Intervention Before patients entered the study, all antihypertensive medications were withdrawn. All patients received one placebo tablet daily for 3 weeks (baseline phase). After the baseline phase was completed, patients were randomly assigned to either fosinopril (10 mg once every morning orally, n = 17) or matching placebo (one tablet every morning orally, n = 9) in a double-blind manner with a 2-to-1 allocation ratio for randomization. In both groups, verapamil slow-release (SR), 240 mg per day, was added after week 2 of the double-blind phase if diastolic blood pressure exceeded 95 mm Hg (nine patients in the fosinopril group and four patients in the placebo group). After 8 weeks, the dose of the blinded medications was doubled if protein excretion had not decreased by at least 30% or if the patients diastolic blood pressure exceeded 95 mm Hg. Of the 26 patients, the dose was doubled in 19 patients (12 in the fosinopril group and 7 in the placebo group). During the baseline phase and throughout the study, oral furosemide, at a dose ranging from 20 to 160 mg daily (but constant for each patient), was allowed if edema was pronounced or to help control blood pressure (eight patients in the fosinopril group and six patients in the placebo group). Four patients were receiving medications known to affect serum lipid levels: lovastatin (two patients), colestipol, and an estrogen preparation. Except when indicated, the data from these patients were excluded from analysis of the effect of fosinopril on serum lipids to avoid confounding variables. When the double-blind phase was completed, all patients were given one placebo tablet daily for 6 weeks (washout phase). During this washout phase, oral verapamil SR, 240 mg per day, was permitted only for those patients who had received it during the double-blind phase. After completion of the 6-week washout period, verapamil SR was withdrawn from all patients. A 23-week open-label trial of oral fosinopril, 10 mg once a day, was then started. Beginning at week 7 of this phase, the dose of fosinopril was increased to 20 mg every morning in all patients. Oral furosemide was given at the same dose throughout the study in 7 of the 16 patients. Dietary and Analytical Evaluations A dietary history was obtained by a registered dietitian during the baseline phase, at week 8 of the double-blind phase, and at the end of the open-label phase. Total caloric intake and the percentage of the caloric intake composed of fat, protein, and carbohydrates were recorded. All patients were instructed not to change their usual diet during the study. Patients were asked to refrain from strenuous exercise (jogging, weight lifting, vigorous aerobics) on the days when they collected 24-hour urine specimens. At each visit, the patients blood pressure was measured with a standard sphygmomanometer. After the patient rested in a seated position for 10 minutes, the blood pressure and heart rate were measured three times at 5-minute intervals; the means of the three readings were recorded. Mean arterial pressure was calculated as the diastolic blood pressure plus one third of the difference between the systolic and diastolic blood pressure. Clinical and laboratory data were recorded at the entry visit and weeks 2 and 3 of the baseline phase; weeks 1, 2, 4, 6, 8, 10, and 12 of the double-blind phase; weeks 2 and 6 of the washout phase; and weeks 1, 3, 7, 11, 15, 19, and 23 of the open-label phase. Venous blood was drawn to determine a complete blood count, fasting blood glucose, electrolytes, creatinine, urea nitrogen, total serum protein and albumin, liver function enzymes, triglycerides, and serum total cholesterol. A 24-hour urine sample was collected to measure total protein, albumin, creatinine, urea nitrogen, and sodium excretion. Urinary creatinine was measured to assess both creatinine clearance and the adequacy of the collection. Urine urea nitrogen and sodium were used as markers of protein and sodium intake, respectively. Serum total cholesterol and high-density lipoprotein (HDL) cholesterol levels were measured as previously described [21]. Serum low-density lipoprotein (LDL) cholesterol was calculated as (total cholesterol [HDL cholesterol + triglycerides/5]). This formula can be used only when triglycerides are less than 400 mg/dL. Two patients whose serum triglycerides exceeded 400 mg/dL were excluded from analysis of the effect of fosinopril on serum LDL cholesterol. Plasma lp(a) protein was measured using an assay based on sandwich enzyme-linked immunosorbent assay (ELISA) that is insensitive to the presence of plasminogen [22]. Serum ACE activity was measured 24 hours after the previous dose of fosinopril by the spectrophotometric method described by Cushman and Cheung [23]. Statistical Analysis When paired analysis was used, data are reported as mean values followed by the mean change from baseline with the associated 95% confidence intervals (CI). Where appropriate, data are also reported as mean standard error of the mean. Two-way analysis of variance (ANOVA) was used to compare the change in protein excretion and total serum cholesterol from baseline over the course of the randomized trial between the two treatment groups. Results General Data When considered as a

Pharmacokinetics of furosemide in advanced renal failure

The pharmacokinetics of furosemide were studied in 12 patients with advanced renal failure. The elimination half‐life of furosemide averaged 9.7 hours. Renal furosemide clearance was reduced, but furosemide elimination by non renal mechanisms was unimpaired in uremic patients without liver disease and accounted for 86% to 98% of total elimination. Nonrenal furosemide clearance also was reduced in 3 uremic patients with liver cirrhosis, and elimination half‐life was prolonged to 20 hours in 1 of these patients. The diuretic response to intravenous furosemide appeared to be adversely affected by poor renal function and dehydration. Diuretic response was always less after oral than after intravenous furosemide, and the slow, intravenous infusion of this drug is recommended for maximal efficacy in uremic patients.

Outcomes and Native Renal Recovery Following Simultaneous Liver-Kidney Transplantation

With the increase in patients having impaired renal function at liver transplant due to MELD, accurate predictors of posttransplant native renal recovery are needed to select candidates for simultaneous liver–kidney transplantation (SLK). Current UNOS guidelines rely on specific clinical criteria for SLK allocation. To examine these guidelines and other variables predicting nonrecovery, we analyzed 155 SLK recipients, focusing on a subset (n = 78) that had post‐SLK native GFR (nGFR) determined by radionuclide renal scans. The 77 patients not having renal scans received a higher number of extended criteria donor organs and had worse posttransplant survival. Of the 78 renal scan patients, 31 met and 47 did not meet pre‐SLK UNOS criteria. The UNOS criteria were more predictive than our institutional criteria for all nGFR recovery thresholds (20–40 mL/min), although at the most conservative cut‐off (nGFR ≤ 20) it had low sensitivity (55.3%), specificity (75%), PPV (67.6%) and NPV (63.8%) for predicting post‐SLK nonrecovery. On multivariate analysis, the only predictor of native renal nonrecovery (nGFR ≤ 20) was abnormal pre‐SLK renal imaging (OR 3.85, CI 1.22–12.5). Our data support the need to refine SLK selection utilizing more definitive biomarkers and predictors of native renal recovery than current clinical criteria.

Hiv-associated nephropathy occurring before HIV antibody seroconversion.

It currently is thought that human immunodeficiency virus-associated nephropathy (HIVAN) occurs late in the course of HIV infection. Although HIVAN may be the presenting manifestation of acquired immunodeficiency syndrome (AIDS), it usually occurs after a prolonged period of viral infection often associated with high levels of HIV viremia. The patient described here developed HIVAN as a manifestation of acute retroviral syndrome. A 41-year-old black man presented with nephrotic range proteinuria, renal insufficiency, and acute gastrointestinal and pulmonary symptoms. He recently had been treated for primary syphilis. Two HIV serologic tests, performed 3 months apart, were negative. Renal biopsy was consistent with HIVAN. After the biopsy, the patient was discovered to have more than 700,000 viral copies per mL in his blood. CD4(+) count was greater than 500/mm(3). Six weeks later, enzyme-linked immunosorbent assay and Western blot analyses for HIV antibody became positive. HIVAN can occur early in the course of HIV infection, even during acute infection before seroconversion, and prolonged exposure to virus is not necessary for this renal involvement to occur in the susceptible host.

Plasma protein biomarkers enhance the clinical prediction of kidney injury recovery in patients undergoing liver transplantation

Biomarkers predictive of recovery from acute kidney injury (AKI) after liver transplantation (LT) could enhance decision algorithms regarding the need for liver‐kidney transplantation or renal sparing regimens. Multianalyte plasma/urine kidney injury protein panels were performed immediately before and 1 month post‐LT in an initial test group divided by reversible pre‐LT AKI (rAKI = post‐LT renal recovery) versus no AKI (nAKI). This was followed by a larger validation set that included an additional group: irreversible pre‐LT AKI (iAKI = no post‐LT renal recovery). In the test group (n = 16), six pre‐LT plasma (not urine) kidney injury proteins (osteopontin [OPN], neutrophil gelatinase‐associated lipocalin, cystatin C, trefoil factor 3, tissue inhibitor of metalloproteinase [TIMP]‐1, and β‐2‐microglobulin) were higher in rAKI versus nAKI (P < 0.05) and returned to normal values with renal recovery post‐LT. In the validation set (n = 46), a number of proteins were significantly higher in both rAKI and iAKI versus nAKI. However, only pre‐LT plasma OPN (P = 0.009) and TIMP‐1 (P = 0.019) levels were significantly higher in rAKI versus iAKI. Logistic regression modeling was used to correlate the probability of post‐LT rAKI, factoring in both pre‐LT protein markers and clinical variables. A combined model including elevated OPN and TIMP‐1 levels, age <57, and absence of diabetes had the highest area under the curve of 0.82, compared to protein‐only and clinical variable–only models. Conclusion: These data suggest that plasma protein profiles might improve the prediction of pre‐LT kidney injury recovery after LT. However, multicenter, prospective studies are needed to validate these findings and ultimately test the value of such protein panels in perioperative management and decision making. (Hepatology 2014;60:2016–2025)

Sudden Fatal Pulmonary Calcification Following Renal Transplantation

A 42-year-old male was hemodialyzed for 2 years with excellent control of calcium-phosphate metabolism. He received a cadaveric renal transplant but experienced a prolonged episode of acute tubular necrosis during which he could not tolerate phosphate-binding antacids. His calcium X phosphate product became markedly elevated for 20 days. Following a brief period of function, the homograft was removed on the 45th post-transplant day after severe rejection and subsequent infection. Chest X-ray was normal. Six days after graft nephrectomy, he became acutely dyspneic and markedly hypoxemic. Diffuse, flocculent pulmonary infiltrates appeared on the chest film. The patient expired 1 day later. At postmortem examination, there was severe, diffuse pulmonary alveolar calcification demonstrated by chemical and histologic examination. Although unlikely, the prolonged post-transplant period characterized by elevated calcium X phosphate product may have played a pathogenetic role. Calciphylaxis may have occurred, with hyperparathyroidism as the sensitizing agent and any of several drugs acting as challenger.

Intractable Renovascular Hypertension in an Adult Recipient of a Pediatric Cadaveric Renal Transplant

Renovascular hypertension developed in an anephric 37-year-old patient after he received a cadaveric renal transplant from a 2-year-old donor. Despite adequate homograft function, a transplant nephrectomy was perfomed because of intractable, lifethreatening hypertension. There was relative stenosis throughout the course of the transplanted renal artery. Pathologic examination of the kidney did not demonstrate evidence of technical failure or immunological or hypertensive damage. Atrophic changes in the media of the renal artery may have resulted from radiation damage. The hypertension appears to have been caused by disproportionate growth between the parenchyma in the hypertrophying pediatric homograft and its renal artery.

Acute renal failure followed by protracted, slowly resolving chronic uremia

Abstract A case of acute tubular necrosis which resulted in prolonged renal insufficiency accompanied by severe complications is described. After 1 yr partial spontaneous recovery of renal function occurred with improvement in the patients neuropathy, anemia and secondary hyperparathyroidism. The possible mechanisms for this unusual course are discussed.

Physician Prevention of Acute Kidney Injury

BACKGROUND The frequency of acute kidney injury has become substantially greater over the recent past. Acute kidney injury, moreover, is associated with increased mortality and morbidity over both the short and long term. Despite these facts, its therapy has not changed significantly for many decades. Currently, therefore, prevention is the only action that can reduce the frequency and consequences of acute kidney injury. METHODS Charts of 492 patients were reviewed retrospectively for the presence of acute kidney injury based on creatinine elevation. One hundred seventy patients were found to have acute kidney injury defined as a sustained elevation of serum creatinine ≥ 0.3 mg/dL for 48 hours or more. An agent or event was determined to be responsible for renal injury if there was the defined increase in serum creatinine within 48 hours of exposure. Charts were reviewed to determine if the renal injury was preventable. RESULTS Fifty-one cases were considered to be preventable. Of these, 16 had not received saline prophylaxis for intravenous contrast when appropriate, 15 were not treated appropriately for hemodynamic instability or for hypertension, 9 had inappropriate use of medications, and 11 received multiple nephrotoxic agents. CONCLUSIONS In a retrospective analysis of 170 hospitalized patients who developed acute kidney injury during admission, 30% of episodes could have been avoided if physicians had taken appropriate preventive actions.

Unilateral renal papillectomy via laser or incisional techniques: Chronic functional effects in the dog

OBJECTIVE To determine if selective renal papillectomy would impair urinary concentrating ability, thereby decreasing urinary calcium concentration. METHODS Left papillectomy was performed in dogs using either incisional (n = 6) or Neodymium:yttrium-aluminum-garnet (Nd:YAG) laser (n = 5) techniques. Split renal function studies were then performed four months postoperatively to determine the effect on multiple parameters including inulin and para-aminohippurate (PAH) clearance, free water reabsorption, and calcium concentrations. Partially infarcted kidneys (n = 6) were evaluated in a similar fashion to determine the role of impaired glomerular filtration rate (GFR) in the observed concentrating defect occurring after papillectomy. RESULTS Papillectomized kidneys demonstrated impaired free water reabsorption, resulting in a decreased urinary osmolality and an increased fractional excretion of water. Osmolar clearance [Na+] and Na+ excretion were unaffected by papillectomy, whereas [Ca++] was significantly reduced. While a slight defect in free water reabsorption existed following partial infarction, urinary osmolality was only minimally decreased, fractional excretion of water was unchanged, and Na+ excretion was decreased. CONCLUSIONS The concentrating defect induced by papillectomy via either sharp excision or laser ablation is due to loss of medullary tissue and is greater than the defect resulting from impaired GFR, which is presumably due to decreased medullary solute delivery and increased flow of water in remaining nephrons. Since the physiologic consequences of papillectomy (formation of less concentrated urine with decreased [Ca++]) have potential clinical applicability, further study of this concept is warranted.