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Biomedical subjects

J I Scheinman

Publications and source records attributed to J I Scheinman.

At least 19 recordsLinked to original sources
PubMed1994

Primary hyperoxaluria.

Primary hyperoxaluria (PH) is a rare inborn error of amino acid metabolism, now genetically defined, that results in excessive production and urinary excretion of oxalate. It serves as a model of severe nephrolithiasis that requires management of urinary supersaturation to prevent the common outcome of renal failure, which can be the presenting finding: the continued oxalate excess than causes progressive systemic oxalosis (deposition). Routine kidney transplantation almost invariably fails, but a (live donor) protocol that reduces danger of the accumulated load of oxalate can reduce the risk of recurrence. The attractive (and curative) option of combined kidney/liver transplant has considerably greater risk of mortality (in the US), although the European experience is considerably better, often employed earlier in the course. Key to appropriate decisions are early recognition, certain diagnosis, testing for vitamin B6 response, and immediate planning for definitive therapy when renal function is failing. PH provides one example of the absolute need for workup of the metabolic causes of stone disease.

Europe↗
PubMed1993

Enzymological and mutational analysis of a complex primary hyperoxaluria type 1 phenotype involving alanine:glyoxylate aminotransferase peroxisome-to-mitochondrion mistargeting and intraperoxisomal aggregation.

Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disease caused by a deficiency of the liver-specific peroxisomal enzyme alanine:glyoxylate aminotransferase (AGT). Three unrelated PH1 patients, who possess a novel complex phenotype, are described. At the enzymological level, this phenotype is characterized by a complete, or nearly complete, absence of AGT catalytic activity and reduced AGT immunoreactivity. Unlike normal individuals in whom the AGT is confined to the peroxisomal matrix, the immunoreactive AGT in these three patients was distributed approximately equally between the peroxisomes and mitochondria. The peroxisomal AGT appeared to be aggregated into amorphous core-like structures in which no other peroxisomal enzymes could be identified. Mutational analysis of the AGT gene showed that two of the three patients were compound heterozygotes for two previously unrecognized point mutations which caused Gly41-->Arg and Phe152-->Iso amino acid substitutions. The third patient was shown to be a compound heterozygote for the Gly41-->Arg mutation and a previously recognized Gly170-->Arg mutation. All three patients were homozygous for the Pro11-->Leu polymorphism that had been found previously with a high allelic frequency in normal populations. It is suggested that the Phe152-->Iso and Gly170-->Arg substitutions, which are only eighteen residues apart and located in the same highly conserved internal region of 58 amino acids, might be involved in the inhibition of peroxisomal targeting and/or import of AGT and, in combination with the Pro11-->Leu polymorphism, be responsible for its aberrant mitochondrial compartmentalization. On the other hand, the Gly41-->Arg substitution, either in combination with the Pro11-->Leu polymorphism or by itself, is predicted to be responsible for the intraperoxisomal aggregation of the AGT protein.

Adult↗
PubMed1992

Success of kidney transplantation in oxalosis is unrelated to residual hepatic enzyme activity.

We evaluated hepatic alanine glyoxylate aminotransferase (AGT) activity in percutaneous hepatic biopsy material obtained from four children with long-term renal allograft function following transplantation for primary hyperoxaluria type 1 (PH 1). The study was performed to determine whether these successes had occurred because relatively high residual levels of AGT activity had introduced a selection bias. The children ranged from seven months to eight years at transplant and are currently well 7 to 11 years later, with no oxalate deposition on repeated allograft biopsies and creatinine clearances of 80 to 128 ml/min/1.73 m2. AGT activity ranged from 0 to 13.8%, and in two of three patients with detectable levels the AGT was in mitochondria rather than peroxisomes. These results indicate that long-term renal allograft success can occur in spite of severe AGT deficiency. Thus, the therapeutic choice of kidney alone versus combined kidney-liver transplant cannot currently be made by measuring residual hepatic AGT in PH 1. Kidney transplant alone remains a reasonable initial therapeutic alternative for patients with recent onset of renal insufficiency due to PH 1.

Adolescent↗
PubMed1992

Specialized collagen mRNA and secreted collagens in human glomerular epithelial, mesangial, and tubular cells.

Isolated glomeruli and cultured cells were examined under nonmitogenic conditions by Northern hybridization of steady-state mRNA levels for procollagens alpha 1(I), alpha 1(III), alpha 1(IV), alpha 2(IV), beta-actin, and fibronectin. Procollagens concurrently secreted from these cells were characterized after limited pepsin digestion. Poly(A)-mRNA from freshly isolated whole porcine glomeruli was primarily type IV. For cultured glomerular and tubular epithelial cells, the collagen mRNA species were almost exclusively alpha 1(IV) and alpha 2(IV). Correspondingly, the secreted collagen was almost entirely type IV. The mRNA signals for collagens in glomerular mesangial cells included alpha 1(I), alpha 1(IV), alpha 2(IV), and less alpha 1(III). The secreted collagens were also types I and IV, with less types III and V. There were similar patterns of mRNA signal levels for the two type IV collagens and similar patterns of expression of alpha 1(I) and alpha 1(III). In situ hybridization showed the fibroblast and epithelial cell populations homogeneous in expressing the same mRNA signals seen by Northern hybridization. These findings establish the correlation of collagen mRNA and protein expression of collagens in differentiated glomerular cells in culture, under resting nonmitotic conditions.

Animals↗
PubMed1991

Hyperglycaemia associated with lactic acidaemia in a renal allograft recipient with type I glycogen storage disease.

Renal disease is a frequent and serious complication of type I glycogen storage disease. A type I glycogen storage disease patient with focal segmental glomerulosclerosis and progressive renal insufficiency underwent a renal allograft transplantation. Despite the same cornstarch therapy, the post-transplantation course was complicated by worsening of the metabolic control manifested by exacerbated lactic acidaemia and hyperlipidaemia. This lactic acidaemia was remarkable for its association with hyperglycaemia. Hyperglycaemia accompanied by lactic acidaemia is strikingly unusual in type I glycogen storage disease, since this is a disease characterized by hypoglycaemia and an inverse relationship between blood glucose concentration and lactate levels. Both fasting insulin and C-peptide levels in the patient were greater than similar age-matched type I glycogen storage disease controls, indicating hyperinsulinaemia. The most likely mechanism responsible for the combined hyperglycaemia and lactic acidaemia was insulin resistance due to glucocorticoid treatment, instituted for immunosuppression. The hyperglycaemia associated with the lactic acidaemia was transient and resolved with steroid tapering. The exacerbated hyperlipidaemia, however, persisted after renal transplantation. Type I glycogen storage disease patients may be prone to glucocorticoid-induced insulin resistance, since the cellular metabolism in these patients may already be compromised with ineffective insulin action and/or reduced insulin output.

Acidosis, Lactic↗
PubMed1988

Renal disease in type I glycogen storage disease.

Although kidney enlargement occurs in Type I glycogen storage disease, renal disease has not been considered a major problem. Death from renal failure in three patients known to us prompted a study of renal function in this disorder. Of the 38 patients with Type I glycogen storage disease under our care, the 18 children under 10 years old had normal renal function. Fourteen of the 20 older patients (13 to 47 years) had disturbed renal function, manifested by persistent proteinuria; many also had hypertension, hematuria, or altered creatinine clearance. Progressive renal insufficiency developed in 6 of these 14 patients, leading to three deaths from renal failure. At the onset of proteinuria, creatinine clearance was increased in seven patients (3.05 +/- 0.68 ml per second per 1.73 m2 of body-surface area; range, 2.47 to 4.13 [normal range, 1.33 to 2.33 ml per second per 1.73 m2]). Renal biopsies were performed in three patients after an average of 10 years of proteinuria. All three biopsies demonstrated focal segmental glomerulosclerosis in various stages of progression. Our data suggest that chronic renal disease is a frequent and potentially serious complication of Type I glycogen storage disease. In addition to treating hypoglycemia vigorously, physicians should monitor renal function carefully in patients with this disorder.

Adolescent↗
PubMed1986

Immunochemistry of urinary calcium oxalate crystal growth inhibitor (CGI).

Calcium oxalate crystal growth inhibitor (CGI) was isolated from human urine in monomeric form (14,000 daltons). Antibody was elicited and purified to monospecificity by affinity chromatography. Tamm-Horsfall protein was isolated from human urine and an antibody to Tamm-Horsfall protein compared to anti-CGI. The anti-CGI reacted with its antigen on immunodiffusion, by ELISA and by Western Blotting of polyacrylamide gel electrophoresis-separated antigen. Immunofluorescent localization of CGI was found in distal renal tubules. This was precisely the localization of Tamm-Horsfall protein. Isolated Tamm-Horsfall protein was found to bind CGI which could only be partially removed with EDTA. While anti-CGI is suitable to assay CGI in human urine by ELISA techniques, it will also detect CGI that is complexed to THP. While the CGI found in human urine possesses 90% of the urinary macromolecular crystal growth inhibitor activity, THP is without effect on crystal growth, in spite of bound CGI. The balance between free CGI and that bound to Tamm-Horsfall protein may be important in the overall balance of urinary macromolecules that affect calcium oxalate nephrolithiasis.

Calcium Oxalate↗
PubMed1986

Radiological aspects of primary hyperoxaluria.

Primary hyperoxaluria is a rare metabolic disorder characterized by excessive synthesis and urinary excretion of oxalate. Nephrocalcinosis with or without calcium oxalate nephrolithiasis leads to renal failure in infancy through young adulthood. Oxalosis is the condition in which the highly insoluble calcium oxalate crystals are deposited in extrarenal tissues including bone, blood vessels, heart, and the male urogenital system. The radiographic abnormalities in 14 patients with primary hyperoxaluria are described. These abnormalities include nephrolithiasis, nephrocalcinosis, dense vascular calcifications, abnormal bone density, and characteristic metaphyseal abnormalities. Changes of renal osteodystrophy and pathologic fractures are common. Radiographic bone abnormalities are dependent on the age of the patient when renal failure occurred and the degree of success of renal transplantation. Characteristic skeletal changes are present in six of seven patients who developed renal failure when less than 7 years of age.

Adolescent↗
PubMed1986

Acute cellular rejection and cyclosporine nephrotoxicity monitored by biopsy in a renal allograft recipient. The differentiation of drug nephrotoxicity from rejection by phenotyping of cellular infiltrates.

Serial allograft biopsies were performed on a renal transplant patient who experienced recurrent episodes of acute cellular rejection as well as cyclosporine nephrotoxicity. Five biopsies were performed after acute elevations of the serum creatinine level (15, 46, 155, 244, and 324 days after transplant). Each specimen was evaluated by routine histologic techniques as well as by immunofluorescence analysis and by monoclonal antibody labeling for determination of the cell phenotype of the mononuclear cell infiltrates within each specimen. The first and third specimens disclosed significant T-cell infiltrates with an equal number of T-cytotoxic-suppressor (Leu 2a) and T-helper-inducer (Leu 3a) cells in a diffuse cortical pattern, while the second biopsy showed a slightly milder infiltrate with a marked elevation (7:1) in the Leu 3a:Leu 2a ratio in the cortical-diffuse pattern. Clinically, the patient responded dramatically to cyclosporine dosage reduction following the second biopsy, and bolus steroid antirejection therapy following the first and third biopsies. These findings suggest that phenotypic cell marker analysis within the context of histologic pattern is a useful adjunct to the routine histologic evaluation of renal allograft biopsy specimens and may provide a means of differentiating rejection from cyclosporine nephrotoxicity.

Child, Preschool↗
PubMed1984

Successful strategies for renal transplantation in primary oxalosis.

Eleven patients, aged 6 months to 47 years, with renal failure due to primary oxalosis, received renal allografts and were followed for 1 to 9 years. A specialized strategy for medical management included intensive pre-transplant hemodialysis and post-transplant long-term diuresis, administration of neutral phosphate, Mg++, and pyridoxine. Seven of ten living-related (LRD) transplants have good renal function, six with no biopsy evidence of renal oxalate deposition at up to 7 years after transplant. Two LRD graft losses from recurrent oxalosis, accompanied by massive secondary oxalate deposits, occurred in patients following endstage renal failure for over 3 years. A third LRD graft loss occurred following long-term (6 month) peritoneal dialysis in an infant. One cadaver transplant recipient has survived with recurrent oxalosis and poor graft function for 9 years. It is possible to perform successful renal transplantation in small children and adults with primary oxalosis and to completely prevent the deposition of oxalate in the renal allograft. Renal transplantation, with a strict medical protocol, would appear to be the initial treatment of choice for renal failure due to primary oxalosis.

Adult↗
PubMed1984

Monoclonal antibody to type IV collagen with selective basement membrane localization.

A monoclonal antibody (MCA IV-1) has been developed to a determinant of the high molecular weight fractions of human placental collagen, present also in bovine lens capsule and glomerular basement membrane type IV collagens. This unique determinant is pepsin and collagenase resistant and is apparently distinct from the alpha 1(IV) and alpha 2(IV) helical peptides. As part of the high molecular weight molecules, the determinant is located in a region additively deformable by reduction and sodium dodecyl sulfate denaturation. However, when a 20-kilodalton, largely collageneous, fragment containing this determinant is separated from the larger fraction by 37 degrees C collagenase treatment, the determinant is insensitive to reduction or sodium dodecyl sulfate denaturation. Immunohistologic analysis and comparison with a polyclonal antibody to type IV collagen shows a marked selectivity of localization in the glomerular basement membrane. MCA IV-1 reacts in the inner aspect of the glomerular basement membrane but primarily in the mesangium, where it selectively expands in diabetic nephropathy. Tissue selectivity is also evident in lens and corneal basement membrane.

Animals↗
PubMed1983

Neoantigen of the polymerized ninth component of complement. Characterization of a monoclonal antibody and immunohistochemical localization in renal disease.

A monoclonal antibody to a neoantigen of the C9 portion of the membrane attack complex (MAC) of human complement has been developed and characterized. The distribution of this neoantigen was assessed by indirect immunofluorescence microscopy in nephritic and nonnephritic renal diseases. The antibody (Poly C9-MA) reacted on enzyme-linked immunosorbent assay (ELISA) with a determinant in complement-activated serum that was undetectable in normal human serum (NHS). Zymosan particles incubated in NHS had positive immunofluorescent staining with Poly C9-MA; however, binding of Poly C9-MA was not observed with zymosan particles incubated in sera deficient in individual complement components C3, C5, C6, C7, C8, or C9. Reconstitution of C9-deficient sera with purified C9 restored the fluorescence with Poly C9-MA. Poly C9-MA reacted positively by ELISA in a dose-dependent manner with purified MC5b-9 solubilized from membranes of antibody-coated sheep erythrocytes treated with NHS but not with intermediate complement complexes. Poly C9-MA also reacted in a dose-dependent manner on ELISA and in a radioimmunoassay with polymerized C9 (37 degrees C, 64 h) (poly C9) but not with monomeric C9. Increasing amounts of either unlabeled poly C9 or purified MC5b-9 inhibited the 125I-poly C9 RIA in an identical manner. These studies demonstrate that Poly C9-MA recognizes a neoantigen of C9 common to both the MAC and to poly C9. By immunofluorescence, Poly C9-MA reacted minimally with normal kidney tissue in juxtaglomerular loci, the mesangial stalk, and vessel walls. Poly C9-MA stained kidney tissue from patients with glomerulonephritis in a pattern similar to that seen with polyclonal anti-human C3. In tissue from patients with nonnephritic renal disease--diabetes, hypertension, and obstructive uropathy--Poly C9-MA was strongly reactive in the mesangial stalk and juxtaglomerular regions, tubular basement membranes, and vascular walls. Poly C9-MA binding was especially prominent in areas of advanced tissue injury. Poly C9-MA frequently stained loci where C3 was either minimally present or absent. These studies provide strong evidence for complement activation not only in nephritic but also in nonnephritic renal diseases.

Adult↗
PubMed1983

Polyantigenic expansion of basement membrane constituents in diabetic nephropathy.

The immunohistopathology of the intrinsic basement membrane-associated antigens were examined in diabetic nephropathy. In early and moderate stages of disease there was polyantigenic expansion of all the intrinsic components of mesangium, glomerular basement membrane (GBM), and tubular basement membrane (TBM) assessed by polyclonal antisera to collagen types IV and V, laminin, and by monoclonal antibodies to type IV collagen and fibronectin and to four other intrinsic components of normal renal extracellular matrices (MBM10, 11, 12, and 15). In the mesangium the first intrinsic antigens to increase were fibronectin and type V collagen. In late stages of disease, there was a diminution in the mesangium of all of these antigens with the exception of type V collagen, which persisted. Additionally, antigens appeared in the mesangium, recognized by MBM11 and MBM15, which are normally present in fetal but not adult mesangial regions. Similarly, in the GBM in late stages of disease, there was a decrease in all of the antigens, except for a persistence of the antigen recognized by MBM15. However, in TBM all of the antigens assessed increased in early, moderate, and severe disease. These studies document the complexity of polyantigenic alterations in the development of diabetic nephropathy.

Animals↗