Recovery from acute renal failure after 11 months of hemodialysis.

A 46-year-old man with biopsy-proved acute tubular necrosis made a dramatic recovery after remaining oliguric and requiring maintenance hemodialysis for 11 months. The serum creatinine level declined to 5.8 mg/dL and, as hemodialysis was discontinued, a second renal biopsy showed marked regenerative changes in the renal tubules. This delayed and unexpected improvement in renal function underscores the need to avoid early renal transplantation in the patient with protracted renal failure from acute tubular necrosis.

Focal segmental glomerulosclerosis. A common entity in nephrotic black adults.

We studied 100 renal biopsy specimens from adults with the primary nephrotic syndrome in an inner city hospital serving mostly black patients and found that 47 had focal segmental glomerulosclerosis. Most of the men presented in the third decade of life, a peak distribution not seen in women. Half of the patients were hypertensive at presentation. Two thirds of the patients had not used intravenous drugs. The addicts were younger than nonaddicts (mean +/- SD age, 27 +/- 4 years vs 35 +/- 13 years), had greater proteinuria (10 +/- 5 g/d vs 6.3 +/- 5 g/d), and exhibited more glomerulosclerosis and tubulointerstitial fibrosis on biopsy. Of the 18 patients (8 addicts) remaining under our care, 4 addicts and 4 nonaddicts became uremic within 3 years. We conclude that even in the absence of drug addiction, focal segmental glomerulosclerosis is a common cause of primary glomerular disease in black adults, in whom it may represent a nonspecific glomerular reaction to injury. The prognosis in the nonaddict may not be different from that in the addict, but more patients need to be studied.

Transient and sustained recovery from renal shutdown in accelerated hypertension.

Ten black patients (eight men) with renal shutdown from accelerated hypertension were treated with hemodialysis. Renal function improved, and dialysis was discontinued after 6 +/- 2 months. Five patients (Group I) have maintained good renal function at 25 +/- 3 months of follow-up, whereas the other five (Group II) had deterioration again to advanced azotemia over 16 +/- 6 months. On admission, Group I patients had lower levels of serum creatinine (9 +/- 1.2 mg/dl [mean +/- SE] versus 13.6 +/- 1.7 mg/dl, p = 0.04) and urinary protein (0.98 +/- 0.78 g per day versus 2.17 +/- 1.5 g per day) and were more oliguric (451 +/- 145 ml per day versus 1,122 +/- 494 ml per day) than Group II. In Group I, renal shutdown was faster (8 +/- 4 days versus 38 +/- 28 days), recovery earlier (4 +/- 1.5 months versus 8 +/- 4 months) and greater (lowest serum creatinine level 1.9 +/- 0.3 mg/dl versus 5.7 +/- 1.7 mg/dl, p less than 0.05), and compliance better than in Group II. Two patients in the former group but none in the latter had peripheral schistocytes. It is concluded that the sustained recovery in Group I resulted from the resolution not only of the acute vascular lesions but also of tubular necrosis and microangiopathy, and the postrecovery deterioration in Group II is attributed to the more severe renal damage initially, the progression of the chronic vascular lesions in uncompliant patients, and possibly hyperfiltration damage in the remaining nephrons.

Appraisal of lupus nephritis by renal imaging with gallium-67.

To assess the activity of lupus nephritis, 43 patients with systemic lupus erythematosus (SLE) were studied by gallium imaging. Delayed renal visualization 48 hours after the gallium injection, a positive result, was noted in 25 of 48 scans. Active renal disease was defined by the presence of hematuria, pyuria (10 or more red blood cells or white blood cells per high-power field), proteinuria (1 g or more per 24 hours), a rising serum creatinine level, or a recent biopsy specimen showing proliferative and/or necrotizing lesions involving more than 20 percent of glomeruli. Renal disease was active in 18 instances, inactive in 23, and undetermined in seven (a total of 48 scans). Sixteen of the 18 scans (89 percent) in patients with active renal disease showed positive findings, as compared with only four of 23 scans (17 percent) in patients with inactive renal disease (p less than 0.001). Patients with positive scanning results had a higher rate of hypertension (p = 0.02), nephrotic proteinuria (p = 0.01), and progressive renal failure (p = 0.02). Mild mesangial nephritis (World Health Organization classes I and II) was noted only in the patients with negative scanning results (p = 0.02) who, however, showed a higher incidence of severe extrarenal SLE (p = 0.04). It is concluded that gallium imaging is a useful tool in evaluating the activity of lupus nephritis.

Evolution of experimentally induced papillary necrosis to focal segmental glomerulosclerosis and nephrotic proteinuria.

Bromoethylamine (BEA)-induced papillary necrosis is a reproducible model for analgesic nephropathy. We induced this lesion in groups of male Sprague-Dawley rats and followed the functional and histological changes for 1 year. We found that by 1 month, necrosis of the papilla was complete, glomerular filtration rate was depressed, and urine albumin excretion was increased. There was an extensive interstitial fibrosis characterized by a mononuclear cell infiltrate and patchy tubular atrophy. By 6 months, there was re-epithelialization of the papillary stump accompanied by a marked increase in albuminuria and an improvement in concentrating ability. Changes seen at 9 months were more advanced. There was extensive cortical fibrosis manifested by pitting of the surface of the kidney. At 1 year, renal function remained impaired (creatinine clearance reduced by 65% to 0.26 mL/min/100 g), and the animals were now markedly nephrotic, with albuminuria of 254 mg of albumin/24 h. In the BEA rats, there was selective destruction of the deep nephrons leading to an increase in the volume-ratio of superficial to deep nephrons. Glomerular changes, affecting approximately 60% of the glomeruli, were characteristic of focal segmental glomerular sclerosis. This model of papillary necrosis/interstitial fibrosis is associated with chronic renal insufficiency and leads to the development of focal glomerular sclerosis and nephrotic proteinuria by 6 to 12 months after its induction.

Evaluation of a new fluorescent dye method to measure urinary albumin in lieu of urinary total protein.

Urinary total protein (UTP) determinations are notoriously inaccurate, poorly reproducible, and difficult to interpret in early renal disease, causing many investigators to measure urinary albumin instead. In this study, we compare a new nonimmunologic fluorescent dye (AB-dye) for measuring albumin with the more expensive and cumbersome radioimmunoassay. We tested 207 urine specimens from patients with variable protein concentrations and divided the results into five arbitrary ranges (0 to 20, 21 to 50, 51 to 100, 101 to 200, and 201 to 400) for chi-square analysis. There was a high degree of correlation between the two methods (chi-square = 260. 8 with 16 degrees of freedom; P < 0.001). The correlation was also high when analyzed by linear regression (R = 0.86; F < 0.01). Based on our comparison of total protein and albumin concentration in the same urine samples, we hypothesized that patients with mild proteinuria may not necessarily have microalbuminuria. Urine samples with UTP between 150 and 400 microg/mL were tested for albumin by the AB-dye. Of 41 samples in this range, 18 (44%) had normal albumin levels. We conclude that measuring urinary albumin with the AB-dye is comparable in performance to radioimmunoassay and could replace UTP determinations, especially for patients with borderline elevations of UTP, many of whom do not have microalbuminuria.

Renal disease in the inner city.

For various ethnic and socioeconomic reasons the pattern of renal disease in the inner city displays distinctive features. Hypertension is frequent, often intractable, and generally conditioned by salt sensitivity and a high sodium intake. Chronic hypertensive nephrosclerosis, found predominantly in African Americans, comprises marked cardiomegaly, renal shrinkage, and hypertensive retinopathy. It has been overdiagnosed in the past, but actually accounts for less than 20% of end-stage renal disease (ESRD) in African Americans. Malignant hypertension, less frequent nowadays, may cause renal shutdown, which is reversible in a few cases; the heart and kidneys are often of normal size. Idiopathic focal segmental glomerulosclerosis is the most common cause of the primary nephrotic syndrome in blacks, but its incidence has also been rising in whites and Hispanics; it does not respond well to treatment, and almost one half of the patients develop ESRD within 10 years. Systemic lupus erythematosus is also more common in African Americans, in whom the severe proliferative forms of lupus nephritis pursue a more virulent course: one half of such patients develop ESRD in 5 years. Cocaine, the use of which has assumed epidemic proportions, may cause accelerated hypertension, acute renal failure from rhabdomyolysis, and progression of preexisting renal disease. Heroin nephropathy has all but disappeared and has been replaced by human immunodeficiency virus (HIV) nephropathy. The prognosis of HIV-infected patients maintained by dialysis has greatly improved. Sickle glomerulopathy, consisting of mesangial expansion, basement membrane duplication, and the absence of immune deposits, may cause the nephrotic syndrome in 4% of patients with severe sickle cell anemia, heralding death within 2 years in one half of patients and ESRD in two thirds; survival has not improved with dialysis. Diabetes is now the most common cause of ESRD. Familial aggregation of ESRD is frequently encountered. Interventions useful in the general population, such as vascular bypass procedures, should be undertaken with great caution and restraint in dialysis patients.

Role of nitric oxide in cocaine-induced acute hypertension.

Cocaine causes acute hypertension by blocking catecholamine reuptake. There is evidence that it also impairs the peripheral endothelial nitric oxide system, which is normally vasodilatory. We further explored the role of nitric oxide in cocaine-induced vasoconstriction in anesthetized rats, and in vitro by using isolated carotid artery segments. Cocaine administered intravenously in rats increased mean arterial pressure by 30 to 40 mm Hg within 1 min. This effect was dose dependent and the maximum effect was observed at a dose of 1.25 mg/kg. The prototype catecholamine norepinephrine induced a similar increase in blood pressure. When rats were pretreated with NG-monomethyl-L-arginine (L-NMMA, a blocker of nitric oxide) and challenged with cocaine, the increase in blood pressure was blocked by 80%, whereas pretreatment with L-NMMA did not block norepinephrine-induced vasoconstriction. Both cocaine and norepinephrine also induced an immediate vasoconstriction in isolated carotid artery preparations. The in vitro vasoconstriction induced by cocaine was blocked by pretreatment with L-NMMA, whereas L-NMMA did not block the norepinephrine-induced vasoconstriction in vitro. Furthermore, carotid artery stripped of endothelium responded to norepinephrine but failed to respond to L-NMMA or cocaine. S-nitroso-N-acetyl-D,L-penicillamine (SNAP)-a precursor of nitric oxide- stimulated nitric oxide production in control coronary artery fragments. When these fragments were incubated with cocaine there was a 20% reduction in the production of nitrite oxide. These results suggest that cocaine exerts its peripheral vasoconstriction at least in part by inhibiting local vasodilator nitric oxide.

Prevalence of hypertension in chronic cocaine users.

The association of cocaine and acute hypertension is well known; however, cocaine use has not generally been linked to chronic hypertension. We hypothesized that chronic use of cocaine over time would increase the prevalence of hypertension and that cocaine induced vasoconstriction would result in urine protein leakage, manifested by microalbuminuria. Therefore, we studied a population of predominantly black male patients admitted for addiction treatment whose drug of dependence was cocaine. A urine toxicology screen was considered positive if cocaine was detected within 24 h prior to or during admission to the hospital. A total of 301 patients with normal renal function were observed over their 2 week hospitalization. The majority (62%) of the patients were normotensive regardless of the status of their initial urine toxicology screen. Twenty percent of the population had acutely elevated blood pressure that normalized within 1 day, whereas 18% had blood pressure chronically >140/90 mm Hg (chronic hypertension). Levels of systolic and diastolic blood pressures were examined at age deciles and compared to the NHANES III (Third National Health and Nutrition Examination Survey) data for a predominantly black population. There was no significant difference in blood pressure with age in the cocaine users compared to the NHANES groups. Random urine samples were screened for the presence of microalbuminuria and no significant elevation was detected in any of the samples tested. We conclude that chronic cocaine use is associated with acute but not chronic hypertension in middle-aged black males. Cocaine use does not cause microalbuminuria.

Purification and biochemical characterization of xanthopterin from patients with chronic renal failure. II. Biochemical elucidation and structural analysis.

We have identified the primary endogenous fluorescent substance, which has characteristic excitation/emission maxima at 380/440 nm and 400/460 nm, found in the sera of patients with chronic renal failure (Clin Chem 32: 1276, 1988). Preliminary studies, using thin layer chromatography (with cellulose) in conjunction with pteridine standards, indicated that the compound is an unconjugated pteridine. Characterization by gas chromatography-mass spectrometry (electron impact), direct probe-mass spectrometry (electron impact/chemical ionization), and Fourier Transform Infrared analysis showed this compound to be xanthopterin (2-amino 4,6 pteridinedione), an unconjugated pteridine known to be present in man in trace quantities. An authentic sample of this compound had a retention time with high-performance liquid chromatography (HPLC) identical to that of the purified fluorophore. The physiological role of xanthopterin in the pathogenesis of uremia has yet to be elucidated.

Purification and biochemical characterization of xanthopterin from patients with chronic renal failure. I. Isolation, purification and preliminary characterization.

We describe the purification and initial characterization of a hitherto unrecognized fluorescence (excitation/emission maxima at 380/440 nm and 400/460 nm) reported from this laboratory in patients with chronic renal failure (Clin Chem 31: 1988, 1985). Purification was achieved using Sephadex G-10 gel chromatography combined with reverse phase and ion exchange high-performance liquid chromatography (HPLC). Purity of the "blue-green" fluorescent compound was determined to be greater than 99% by HPLC, and two-dimensional thin layer chromatography using an acidic and basic solvent system. The excitation/emission maxima were shown to be 390 nm/456 nm, and ultraviolet scans, at pH 1.0, 7.0, and 13.0, gave absorbance optima at 261 nm/356 nm, 278 nm/390 nm, and 255 nm/394 nm, respectively. The isoelectric point of 4.05 in conjunction with the fluorescent and ultraviolet spectra suggests that the fluorophore belongs to the class of compounds known as pteridines.

Focal segmental glomerulosclerosis in adult African Americans.

We have previously shown that idiopathic focal segmental glomerulosclerosis (FSGS) is the most common non-proliferative primary glomerulopathy in adult African Americans. In this report we present our experience with treated FSGS in 15 such patients followed over five years. They were all treated with prednisone 60 mg daily for three months, followed by a slow tapering. In addition, two patients later had cyclophosphamide, and five had enalapril. At entry hypertension was present in 73% of the patients, nephrotic syndrome in 87%, and elevated serum creatinine (> or = 1.4 mg/dl) in 40%. Five of the 15 patients (33%) developed end-stage renal failure (ESRF), one of them having a "malignant" course after the advent of pregnancy. Two patients (13%) have chronic renal insufficiency (CRI; serum creatinine > 2.5 mg/dl); three (20%) have mild renal insufficiency (serum creatinine 1.4-2.5 mg/dl), and five patients (33%) have normal renal function. The cumulative renal survival was 93% at five years, but only 26% at eight years. At last follow-up all the ten patients who did not develop ESRF were in partial remission (urinary protein of 1.3 g/day +/- 1.21), but 4 of the 5 patients who did not develop ESRF had no prolonged partial remission of nephrotic syndrome. Neither the initial clinical parameters not the use of enalapril correlated with the renal outcome (univariate analysis). However, 4 of the 5 patients who developed ESRF had elevated serum creatinine at entry, versus only 2 of the 10 not developing ESRF (p = 0.09 by two-sided, and 0.045 by one-sided Fisher's exact test). We conclude that the short-term renal outcome in nephrotic adult African Americans with treated FSGS is comparable to that of the non-African Americans, but their long-term prognosis may be poorer. Patients developing ESRF were more likely to present with elevated serum creatinine. Enalapril did not seem to modify the course of renal disease, but its utility and that of other ACE inhibitors in the treatment of FSGS must await prospective randomized studies.

Hyperaluminemia in renal failure: the influence of age and citrate intake.

Following the occurrence of aluminum encephalopathy in four patients with chronic renal failure, we studied 34 azotemic patients seen during the same year and five volunteers who took varying combinations of aluminum hydroxide and an alkalinizing citrate (Shohl's) solution. We found that the four encephalopathic cases were older than the 34 azotemic patients (68 years +/- 14 SD, vs 50 +/- 13, p less than 0.05), had a higher mean serum aluminum value (727 micrograms/l +/- 320 vs 92 +/- 73, p less than 0.005), had taken more aluminum hydroxide (5 g/day +/- 0.9 vs 1.6 +/- 1.8, p less than 0.01), and more Shohl's solution (64 ml/day +/- 19 vs 20 +/- 29, p less than 0.01). In all 38 patients the serum aluminum values correlated directly with age (p = 0.01), aluminum hydroxide (p = 0.001) and concomitant citrate intake (p = 0.004). In the five healthy volunteers the 24-hour urinary aluminum excretion increased from a baseline of 22 micrograms +/- 19 SD to 167 +/- 109 (p = 0.05) during aluminum hydroxide intake, rising to 580 +/- 267 (p = 0.01) during the simultaneous intake of citrate and aluminum hydroxide. Corresponding serum aluminum values were 11 micrograms/l +/- 2 SD, 44 +/- 34 (p = 0.1), and 98 +/- 58 (p less than 0.05). Thus citrate seems to enhance aluminum absorption and may cause encephalopathy in patients with chronic renal failure, especially the elderly.

Effect of acute and chronic glutathione depletion on renal function in the rat.

Renal function was evaluated in normal and acid-loaded rats following acute and chronic depletion of glutathione (GSH) by buthionine sulfoximine (BSO). Creatinine clearance and fractional excretion of electrolytes were normal. There was no acidification or concentration defect detected in animals with acute or chronic GSH depletion.

Biochemical elucidation and HPLC fractionation of fluorescent peptides in patients with chronic renal failure.

We evaluated the biochemical characteristics of endogenous fluorescent substances, Ex 380 nm/Em 440 nm and Ex 400 nm/Em 460 nm, present in sera of patients with chronic renal failure (Clin. Chem. 31:1988, 1985). Sera from 23 patients with chronic renal failure (CRF) and from 10 normal subjects were filtered through ultrafiltration membranes (cutoff limit of 500 Da). Fluorescence intensity of the aforementioned substances was significantly elevated as compared to normals (p less than 0.001). Fluorescence characteristics of these substances remained unaltered after ultrafiltration and treatment with beta-glucuronidase. Extraction of these fluorescent compounds with organic solvents (dichloromethane, ethyl acetate, chloroform:methanol) could not be achieved after ultrafiltrates were subjected to 6N hydrochloric acid (HC1) hydrolysis. In addition, treatment with 6N HC1 enhanced fluorescence intensity without altering fluorescence excitation/emission maxima. Removal of fluorescence could be accomplished in toto by adsorption onto activated charcoal with subsequent recovery from charcoal by treatment with sodium hydroxide, pH 12 (Ex 380 nm: 51.1%, Ex 400 nm: 91.8%). Analysis of alkali-treated specimens by high performance liquid chromatography demonstrated that peptides associated with these fluorescent substances were denatured, although fluorescence at these previously described excitation/emission maxima persisted. Our studies indicate that the unique fluorescence observed in the sera of patients with CRF is not an intrinsic characteristic of a specific peptide or its amino acids, but rather an inherent property of fluorescent molecules which may bind to these peptides.

Amino acid composition of uremic middle and low molecular weight retention products.

In order to characterize the spectrum of small peptides retained in chronic renal failure, we carried out high pressure liquid chromatography (HPLC) of serum ultrafiltrates from patients with chronic renal failure (CRF), acute renal failure (ARF), and normal subjects. HPLC patterns in CRF resolved into more than twenty peaks; those in ARF contained fewer peaks and resembled that of normals. We carried out amino acid analysis of HPLC fractions after hydrolysis with 6N HC1 of four patients with CRF, one patient with ARF, and one normal subject. Following hydrolysis each HPLC fraction yielded several amino acids. Glycine, leucine, serine, phosphoserine, glutamic acid, and phenylalanine were found in greatest frequency in the four CRF patients.

Once weekly intravenous calcitriol suppresses hyperparathyroidism in hemodialysis patients.

Although thrice weekly intravenous calcitriol therapy suppresses parathyroid hormone in end-stage renal disease patients, the efficacy of once weekly administration is not known. Sixty-three patients hemodialyzed for a mean duration of 44 +/- 4 months were treated with once weekly intravenous calcitriol at a mean dose of 2.8 +/- 1 microgram/week. Parathyroid hormone was significantly suppressed from a mean baseline level of 471 +/- 38 to 342 +/- 46 at 5 months and 220 +/- 40 pg/ml at 7 months of therapy. Plasma calcium levels rose from 9.0 +/- 0.1 to 9.4 +/- 0.1 and 9.9 +/- 0.2 mg/dl, respectively. Plasma phosphate level was unchanged. No untoward side effects were observed. The same mean dose of calcitriol achieved a comparable degree of parathyroid hormone suppression regardless of whether patients were on prior thrice weekly or no prior therapy. In patients who had been treated with thrice weekly bolus injections, switching to a once weekly bolus injection achieved a comparable suppression with a 36% reduction in the cumulative dose. Thus, once weekly intravenous bolus administration of calcitriol resulted in a rapid and marked suppression of parathyroid hormone, similar in adequacy to thrice weekly boluses but at a considerably lower cumulative weekly dose. Results were particularly impressive in patients recently starting dialysis, suggesting that once weekly administration is safe, cost effective, and should become standard therapy.

Suppression of hyperparathyroidism by calcitriol therapy.

We reviewed the charts of 160 patients on hemodialysis and identified 33 with parathyroid hormone (PTH) > 800 pg/ml at any time during the last 3 years to confirm our impression that patients with PTH elevations for short durations of time require significantly smaller doses of calcitriol than those with prolonged PTH elevations. We divided the patients into two groups: 18 with PTH > 800 pg/ml on three or fewer occasions (Group 1, short-term hyperparathyroidism) and 15 with PTH > 800 pg/ml more than three times (Group 2, long-term hyperparathyroidism). Most patients received once weekly intravenous calcitriol, but if this failed to suppress PTH, the dose was increased gradually to three times a week, PTH was measured at mid-week, calcitriol was held if serum calcium rose to >11 mg/dl, and calcitriol was started again when calcium fell to <11 mg/dl. We found that the duration of dialysis was generally shorter in Group 1, as were maximal PTH levels. Calcitriol suppressed PTH levels to <200 pg/ml in both groups. However, the weekly dose of calcitriol needed to suppress PTH was significantly lower in Group 1 (5.4 +/- 1.2 microg in Group 1 and 11.4 +/- 1.8 microg in Group 2; p < 0.001). Further follow-up of seven patients for 1 more year showed continued suppression of PTH, and the dose of calcitriol required to maintain the suppression was lower than the initial dose. Thus patients with longer histories of dialysis and prolonged hyperparathyroidism required higher doses of calcitriol to suppress PTH to the same level as patients who were new on dialysis or with transient hyperparathyroidism. A protocol of three times weekly, high dose calcitriol with strict monitoring of serum calcium will avoid parathyroidectomy in most cases.

Chromatographic studies of uremic plasma.

In order to characterize the spectrum of possibly toxic retention compounds in uremia we have developed a simple reproducible method of separating fractions of uremic serum by Sephadex G-15 column chromatography. This technique, which requires no prior deproteinisation and is carried out at ambient temperatures, allowed the separation of uremic serum into several well defined fractions. Subsequent thin layer chromatography (TLC) showed that each peak represented a mixture of peptides, and that there were qualitative and quantitative differences between the plasma of normal and uremic patients as well as between patients with acute renal failure and chronic renal failure.

Intra-dialytic oral iron therapy.

In order to test the limits of what can be achieved with oral iron therapy and eliminate the factor of noncompliance, we conducted a series of observational studies in an 140-patient inner city dialysis unit. In these studies the patients received supervised iron therapy as 3-4 ferrous sulfate (325 mg) tablets during each dialysis. Acceptance and tolerance was high, less than 10% refusing to take the tablets. In two separate observational studies oral intradialytic iron yielded a hematocrit 28% in 69% of patients and 30% in 42-52%. There was no correlation between the final hematocrit and serum ferritin or transferrin saturation. The response to iron therapy could frequently not be predicted by the ferritin levels or transferrin saturation. We conclude that in view of the known hazards of intravenous iron dextran, oral intradialytic therapy should be tried first and that a good response can be expected in one half to two thirds of hemodialysis patients.