Porous biodegradable metals for hard tissue scaffolds: a review.

Scaffolds have been utilized in tissue regeneration to facilitate the formation and maturation of new tissues or organs where a balance between temporary mechanical support and mass transport (degradation and cell growth) is ideally achieved. Polymers have been widely chosen as tissue scaffolding material having a good combination of biodegradability, biocompatibility, and porous structure. Metals that can degrade in physiological environment, namely, biodegradable metals, are proposed as potential materials for hard tissue scaffolding where biodegradable polymers are often considered as having poor mechanical properties. Biodegradable metal scaffolds have showed interesting mechanical property that was close to that of human bone with tailored degradation behaviour. The current promising fabrication technique for making scaffolds, such as computation-aided solid free-form method, can be easily applied to metals. With further optimization in topologically ordered porosity design exploiting material property and fabrication technique, porous biodegradable metals could be the potential materials for making hard tissue scaffolds.

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.

A simple method to detect an albumin permeability factor in the idiopathic nephrotic syndrome.

BACKGROUND: Several investigators have detected an albumin permeability factor in the serum of patients with the idiopathic nephrotic syndrome (INS), that is, minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS), but the methods used have been complex. METHODS: We describe here a simpler method using cultured rat glomerular epithelial cell monolayers grown to confluence on Millicell filters, which allow sampling of apical and basolateral media. 125I-labeled human serum albumin (125I-HSA) was added to the basolateral compartment, and its leakage across the epithelial cell monolayer into the apical compartment was measured. RESULTS: In untreated cells (negative control), the albumin leakage reached 5.3% at 18 hours. Cell monolayers fixed with 95% ethanol (positive control) showed 62% leakage. Sera from three out of four patients with MCD and three out of four with FSGS resulted in considerable albumin leakage, whereas sera from nine patients with other types of nephrotic renal disease and five normal subjects caused no leakage. CONCLUSION: This study shows that the Millicell system provides a simple and useful method to screen for permeability factors in the INS.

Dialysis-associated renal cystic disease resembling autosomal dominant polycystic kidney disease: a report of two cases.

Acquired renal cystic disease is common in patients receiving dialysis. Characteristically, the kidneys are small or, less often, normal in size, and the cysts are usually less than 0.6 cm in diameter. We present here 2 patients who, after 5 and 7 years on hemodialysis, developed marked renal enlargement, with large cysts in the kidneys and, in 1 patient, in the liver as well; the appearance on ultrasonography and computed tomography was indistinguishable from autosomal dominant polycystic kidney disease. Before starting dialysis the first patient was a 19-year-old man who developed renal shutdown from crescentic glomerulonephritis, and the second patient was a 33-year-old man who developed end-stage renal failure from malignant hypertension. Neither patient had renal cysts at the onset of end-stage renal failure.

Life-threatening hematuria from an arteriovenous fistula complicating an open renal biopsy.

Arteriovenous fistulae and pseudoaneurysms are not rare after renal biopsy. The majority of these lesions (80%) are asymptomatic or show only transient symptoms. We present here a patient who developed life-threatening hematuria following an open renal biopsy. Arteriovenous fistula and pseudoaneurysm were detected in the biopsied kidney by color-coded Doppler sonography, confirmed by angiography, and the fistula was sealed by superselective arterial embolization with metallic coils. Color-coded Doppler sonography successfully detects the majority of arteriovenous fistulae after renal biopsy, and selective arterial embolization obviates the need for surgical intervention in most cases.

Can total urinary protein measurements predict microalbuminuria?

We re-addressed the question of whether routine total urinary protein determinations can be used to predict the presence of microalbuminuria by studying 61 patients who attended a diabetic clinic and tested negative or had one positive protein by dipstick. Total urinary protein was measured by the Biorad dye-binding method in undialyzed urine (UND), in dialyzed urine (DIAL), and in dialyzed urine in which albumin and globulins were separated, measured separately with albumin and globulin standards and the results added together to obtain total urinary protein (A + G). The results were compared with albumin measurements obtained by radioimmunoassay (RIA). Compared to DIAL, urinary protein measurements were 43% higher with A + G and 22% higher with UND. Microalbuminuria correlated moderately with UND (r =0.81) and better with the other methods (r=0.87 for DIAL, r=0.91 for A + G). None of the methods predicted microalbuminuria reliably. Taking a protein-to-creatinine ratio of 0.15 and an albumin-to-creatinine ratio of 0.03 as upper limits of normal, we found that UND had a 72% positive predictive value (28% false positives) and 85 % negative predictive value (15% false negatives). DIAL had 90% positive predictive value (10% false positives) and 78% negative predictive value (22% false negatives). A + G had 65% positive predictive value (35% false positives) but 91% negative predictive value (9% false negatives). A + G, which uses the correct standards, would be the most suitable method for screening, having the least number of false negatives, but has more false positives because it is more sensitive. In practice, most routine chemical laboratories find it expedient to use only UND, but physicians interpreting the results of this method should be aware of its limitations.

Simplified screening for microalbuminuria.

BACKGROUND: Screening for microalbuminuria is increasingly advocated as a way to diagnose early renal involvement in diabetes and other diseases. It usually entails the use of a radioimmunoassay that is expensive and not always readily available. OBJECTIVE: To assess the efficacy of three simple and inexpensive tests for ruling out microalbuminuria. DESIGN: Cross-sectional study. SETTING: Outpatient clinics. PATIENTS: 221 patients from primary care clinics and a diabetes clinic. MEASUREMENTS: Random urine specimens were tested for albumin by using Micral-Test immunoassay strips (Boehringer Mannheim, Mannheim, Germany) and for protein by using sulfosalicylic acid testing and impregnated dipsticks (Chemstrips, Boehringer Mannheim). Radioimmunoassay for albumin was used for all specimens as standard for comparison. RESULTS: When less than 20 mg/L was considered the upper limit of normal for albumin concentration, Micral-Test, sulfosalicylic acid testing, and Chemstrips had negative predictive values of 99%, 95%, and 96%, respectively. Seventy-four specimens tested negative on both sulfosalicylic acid and Chemstrips; the negative predictive value of these two tests combined was 99%. CONCLUSIONS: The combination of sulfosalicylic acid testing and Chemistrips was as good as and less expensive than Micral-Test in ruling out microalbuminuria.

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.

Drugs of abuse and renal disease.

The complications of drug abuse encompass a spectrum of glomerular, interstitial, and vascular diseases. They comprise the heroin-associated nephropathy seen in African-American intravenous drug addicts, which, however, has given way in the 1990s to HIV-associated nephropathy. Infections with methicillin-resistant Staphylococcus aureus may cause acute glomerulonephritis by releasing bacterial superantigens. Hepatitis C has supplanted hepatitis B and may give rise to membranoproliferative glomerulonephritis and cryoglobulinemia. Addicts who inject drugs subcutaneously ('skin popping') may develop amyloidosis. Cocaine causes rhabdomyolysis, severe hypertension, occasionally renal failure in the absence of rhabdomyolysis, and may hasten progression to uremia in patients with underlying renal insufficiency. 'Ecstasy', an amphetamine-like recreational drug, has caused acute renal failure, electrolyte disturbances, and malignant hypertension. In Belgium and some other European countries, women taking Chinese herbs in a slimming regimen have developed a severe and irreversible interstitial fibrosis that is assuming epidemic proportions.

Role of cocaine in end-stage renal disease in some hypertensive African Americans.

During a period of 1 year we observed 12 African American patients who had smoked or sniffed cocaine for several years and presented to inner city hospitals with accelerated hypertension and renal insufficiency. Ten required maintenance dialysis; 1 recovered partially after a brief period of dialysis, and 1 had moderate renal insufficiency. In the absence of striking proteinuria, cardiomegaly or renal shrinkage, the probable diagnosis in most of the patients was primary accelerated hypertension. The clinical history suggested that the habitual use of cocaine had worsened the hypertension, made it more difficult to control or triggered an accelerated phase resulting in renal shutdown. At a time when billions of dollars are being spent on the treatment of end-stage renal disease, the harmful role of cocaine in susceptible individuals requires due attention.

The prognosis of lupus nephritis in African-Americans: a retrospective analysis.

To fully describe the clinical course of lupus nephritis in an African-American population, we report our experience with 54 patients seen at a large inner-city hospital over a period of 14 years. The patients were divided into five histopathologic groups. Group MES (n = 3) represented mesangial nephritis (World Health Organization [WHO] class II) and group FOC (n = 11) represented mild and moderate focal segmental proliferative glomerulonephritis (WHO class III). Group DIF (n = 9) included patients with severe segmental proliferative, diffuse proliferative, membranoproliferative, and membranous and severe superimposed proliferative lesions (WHO classes III, IV, and Vd). Group CRES (n = 9) combined all the patients with cellular crescents in more than 40% of the glomeruli and included patients in WHO classes III (severe), IV, and Vc and d. Group MEM (n = 22) represented membranous nephritis occurring alone or with superimposed mesangial or mild segmental proliferative lesions (WHO class Va and b). Groups DIF and CRES received intensive treatment with high-dose prednisone and cytotoxic drugs. Groups FOC and MEM received lower doses of prednisone, but half of the patients later received intensive treatment largely for severe systemic manifestations. The three patients in group MES remained well. End-stage renal failure (ESRF) developed in 11 of 18 patients in groups DIF and CRES combined, and in two of 22 patients in group MEM. Three of 11 patients in group FOC, five in groups DIF and CRES, and one in group MEM died. The actuarial 5- and 10-year survival rates were, respectively, 78% and 78% for FOC, 80% and 0% for DIF and CRES, and 100% and 100% for MEM (P < 0.03 v DIF/CRES). Five- and 10-year survival rates without ESRF were, respectively, 78% and 78% for FOC, 52% and 0% for DIF and CRES (P < 0.05), and 94% and 85% for MEM (P = 0.002 v DIF/CRES). Univariate proportional hazards regression analysis, uncontrolled for histopathologic groups, showed a significant association between ESRF and severe thrombocytopenia (P = 0.003), serum creatinine above 1.4 mg/dL at entry (P = 0.04), and severe systemic manifestations (P = 0.05). After controlling for histopathologic groups, only thrombocytopenia remained strongly associated with ESRF, both by univariate (P = 0.01) and multivariate (hazard ratio = 14.19, P = 0.05) analyses. We conclude that severe proliferative lupus nephritis in African-Americans has a poor prognosis. For mild and moderate focal proliferative nephritis and uncomplicated membranous lupus nephritis the prognosis is as good as in white patients. Severe thrombocytopenia predicts ESRF.

Acute renal failure in hepatitis A.

A 21-year-old man developed acute renal failure early in the course of hepatitis A infection and recovered after 17 days. There was no evidence of pre-renal azotemia, the hepato-renal syndrome, ischemic acute tubular necrosis, rhabdomyolysis, or thrombotic microangiopathy. There was, however, transient proteinuria and hypocomplementemia. It would appear that the renal failure resulted from viral-induced injury, either direct or mediated by immune complexes.

A study of xanthopterin in chronic renal failure.

Xanthopterin, a metabolic end product of the nonconjugated pterins dihydrobiopterin and tetrahydrobiopterin, is present in many organs and is known to inhibit the proliferation and growth of conconavalin-stimulated lymphocytes. We have developed a simple fluorometric method to measure xanthopterin in the blood and have validated the method by high pressure liquid chromatography (HPLC). Serum levels were 14 +/- 7 nmol/l in normal subjects and 141 +/- 51 nmol/l in hemodialysis patients (p < 0.02). Intermediate levels from patients with renal insufficiency not on dialysis correlated with serum creatinine levels (p < 0.001). Xanthopterin (MW 179) was cleared by hemodialysis at a slightly lower rate than creatinine. It is bound to protein, but the binding, 90 +/- 5% in normal subjects, is decreased in uremia to 60 +/- 15%, p < 0.01. Red cell levels of xanthopterin were five times higher than those of plasma in normal subjects (69 +/- 15 vs. 14 +/- 7 nmol/l, p < 0.001), but uremic patients had lower levels in red cells than in plasma (101 +/- 24 vs. 141 +/- 51 nmol/l, p < 0.05). Slight or moderate hemolysis induced by mechanical stress increased plasma xanthopterin levels by 35%, the effect being more pronounced when hemolysis was severe. We conclude that xanthopterin is increased and its binding to protein is decreased in chronic renal failure. The altered ratio of red cell/plasma xanthopterin levels may reflect an abnormality of the red cell membrane in uremia. We are conducting further studies to amplify our preliminary findings that xanthopterin inhibits cellular growth in vitro.

Nonamyloidotic fibrillar glomerulopathy and recurrent gestational anasarca.

Congo-red-negative microfibrils have been described in various glomerular diseases, some of which have no known etiology. We report the unusual case of a young woman who, over a period of 17 years, developed recurrent gestational anasarca but was asymptomatic between pregnancies except for proteinuria. Her blood pressure and renal function have remained normal over the years. A renal biopsy done 5 years after her third pregnancy showed diffuse mesangial expansion and irregular thickening of the glomerular basement membrane, both caused by the deposition of nonamyloidotic microfibrils. We discuss the differential diagnosis of this case and review the pertinent literature.

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.