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Kevin V Lemley

Publications and source records attributed to Kevin V Lemley.

12 recordsLinked to original sources
PubMed2006

Neonatal nephrotic presentation of a child with heterozygous NPHS1 mutation.

Congenital nephrotic syndrome of the Finnish type, due to homozygous mutation of NPHS1, is the most common form of congenital nephrotic syndrome. Angiotensin converting enzyme (ACE) and prostaglandin synthesis inhibition along with supportive albumin infusion therapy, with or without unilateral nephrectomy, has allowed management of the disease without dialysis until transplantation in some cases of congenital nephrotic syndrome. Reported here is a case of heterozygous NPHS1 mutation, with normal NPHS2 gene structure, presenting during prenatal screening and developing nephrotic syndrome within days of birth. The patient has responded well to very low doses of ACE inhibitors and indomethacin alone. This case illustrates the importance of an initial trial of conservative medical therapy in milder presentations of the congenital nephrotic syndrome, especially given the current limitations of diagnostic testing and our inadequate knowledge of the complete spectrum of disorders of podocyte proteins.

Adult↗
PubMed2005

Modeling GFR trajectories in diabetic nephropathy.

In an 8-year longitudinal study of Pima Indians with type 2 diabetes and nephropathy, we used statistical techniques that are novel and depend on minimal assumptions to compare longitudinal measurements of glomerular filtration rate (GFR). Individuals enrolled with new-onset microalbuminuria either progressed to macroalbuminuria (progressors, n = 13) or did not progress (nonprogressors, n = 13) during follow-up. Subjects with new-onset macroalbuminuria at screening were also followed (n = 22). Patients had their GFR determined serially by urinary iothalamate clearances (average 11 clearances; range 6-19). GFR courses of individuals were modeled using an adaptation of smoothing and regression cubic B-splines. Group comparisons were based on five-component vectors of fitted GFR values using a permutation approach to a Hotelling's T(2) statistic. GFR profiles of initially microalbuminuric progressors differed significantly from those of nonprogressors (P = 0.003). There were no significant baseline differences between progressors and nonprogressors with respect to any measured clinical parameters. The course of GFR in the first 4 yr following progression to macroalbuminuria in initially microalbuminuric subjects did not differ from that in newly screened macroalbuinuric subjects (P = 0.27). Without imposing simplifying models on the data, the statistical techniques used demonstrate that the courses of decline of GFR in definable subgroups of initially microalbuminuric diabetic Pima Indians, although generally progressive, follow distinct trajectories that are related to the extent of glomerular barrier dysfunction, as reflected by the evolution from microalbuminuria to macroalbuminuria.

Adult↗
PubMed2003

Gene expression in the normal adult human kidney assessed by complementary DNA microarray.

The kidney is a highly specialized organ with a complex, stereotyped architecture and a great diversity of functions and cell types. Because the microscopic organization of the nephron, the functional unit of the kidney, has a consistent relationship to the macroscopic anatomy of the kidney, knowledge of the characteristic patterns of gene expression in different compartments of the kidney could provide insight into the functions and functional organization of the normal nephron. We studied gene expression in dissected renal lobes of five adult human kidneys using cDNA microarrays representing approximately 30,000 different human genes. Total RNA was isolated from sections of the inner and outer cortex, inner and outer medulla, papillary tips, and renal pelvis and from glomeruli isolated by sieving. The results revealed unique and highly distinctive patterns of gene expression for glomeruli, cortex, medulla, papillary tips, and pelvic samples. Immunohistochemical staining using selected antisera confirmed differential expression of several cognate proteins and provided histological localization of expression within the nephron. The distinctive patterns of gene expression in discrete portions of the kidney may serve as a resource for further understanding of renal physiology and the molecular and cellular organization of the nephron.

Adult↗
PubMed2003

The effect of dopamine on glomerular filtration rate in normotensive, oliguric premature neonates.

We examined the effect of dopamine on glomerular filtration rate (GFR) at infusion rates of 0.5, 2.5, and 7.5 micro g/kg per min in 15 premature neonates. Study infants (mean gestational age 34+/-2 weeks, mean birth weight 2.43+/-0.6 kg) had respiratory distress, were normotensive, and had a low urine output (0.9+/-0.1 ml/kg per hour). GFR was determined by the plasma clearance of inulin after a single bolus injection (200 mg/kg). Four hours after inulin administration, dopamine infusion was begun and continued over 6 h. GFR was estimated before and after beginning the dopamine infusions from the slope of the log of plasma inulin concentration versus time. Gestational age, weight, and baseline GFR were similar in all three groups. With a dopamine infusion rate of 0.5 micro g/kg per min there were no changes in GFR, urine output, heart rate, or blood pressure. At an infusion rate of 7.5 micro g/kg per min there was no change in GFR, although urine output, heart rate, and blood pressure all increased. At 2.5 micro g/kg per min there were significant increases in GFR and urine output, with no changes in blood pressure or heart rate. In oliguric, non-hypotensive neonates, GFR increased significantly at 2.5 micro g/kg per min of dopamine. This probably reflects the effects of afferent vasodilatation and may be important clinically when enhancement of GFR is the major treatment objective.

Blood Pressure↗
PubMed2003

Urinary excretion of viable podocytes in health and renal disease.

The loss of glomerular visceral epithelial cells (podocytes) has been associated with the development of glomerular sclerosis and loss of renal function. Viability of podocytes recovered from urine of subjects with glomerular disease and of healthy controls was investigated by propidium iodide exclusion and TUNEL staining. Podocyte loss was quantified by cytospin. The growth behavior in culture of urinary cells and their expression of specific markers were examined. The majority of urinary podocytes are viable, although apoptosis occurs in about one-half of the cells. Patients with active glomerular disease excreted up to 388 podocytes/mg creatinine, whereas healthy controls and patients with quiescent disease generally excreted <0.5 podocytes/mg creatinine. The identity of cultured cells was confirmed by their morphology, growth behavior, and expression of podocyte-specific markers. The difference in growth behavior between healthy controls and subjects with active glomerular disease suggests that in active disease viable podocytes detach from the glomerular tuft due to local environmental factors rather than defects in the podocytes per se, whereas in healthy individuals mostly senescent podocytes are shed.

Adolescent↗
PubMed2003

Determinants of glomerular hypofiltration in aging humans.

BACKGROUND: The purpose of the present study was to confirm the extent to which glomerular filtration rate (GFR) is depressed in healthy, aging subjects and to elucidate the mechanism of such hypofiltration. METHODS: Healthy volunteers aged 18 to 88 years (N = 159) underwent a determination of GFR, renal plasma flow (RPF), afferent oncotic pressure, and arterial pressure. Glomeruli in renal biopsies of healthy kidney transplant donors aged 23 to 69 years (N = 33) were subjected to a morphometric analysis, so as to determine glomerular hydraulic permeability and filtration surface area. The aforementioned GFR determinants were then subjected to mathematical modeling to compute the glomerular ultrafiltration coefficient (Kf) for two kidneys and individual glomeruli. RESULTS: GFR was significantly depressed (P < 0.0001) by 22% in aging (>or=55 years old) compared to youthful subjects (<or=40 years old). Corresponding reductions of the following GFR determinants in the aging vs. youthful subsets were RPF by 28% (P < 0.0001), two-kidney Kf by 21% to 53% (P < 0.005), glomerular hydraulic permeability by 14% (P = 0.03), and the single-nephron Kf (SNKf) by 30% (P = 0.09). There were no significant differences between aging and youthful subsets for afferent oncotic pressure and filtration surface area per glomerulus. CONCLUSION: We conclude that a reduction in overall, two-kidney Kf contributes to GFR depression in aging subjects. We infer that this is due in part to structural changes that lower SNKf, and in part to the reduction in the actual number of functioning glomeruli that has been demonstrated by others at autopsy.

Adult↗
PubMed2003

A basis for accelerated progression of diabetic nephropathy in Pima Indians.

The Pima Indians of Arizona not only have a much higher incidence of nephropathy due to type 2 diabetes than Caucasians, but they also lose their renal function at an accelerated rate after they develop diabetic nephropathy. This rapid loss of renal function occurs despite a younger age of onset of nephropathy and lower blood pressures and lipid levels, all of which would seem to predict a slower rate of progression of nephropathy. These findings suggest that other factors contribute to the rapid progression of renal disease in this population. In particular, glomerulomegaly in this population may contribute to the high rate of glomerular filtration rate (GFR) loss during the terminal, clinically manifest phase of nephropathy, because of the greater incremental loss of single-nephron GFR (SNGFR) with each nephron lost to sclerosis. In nine Pima Indians with type 2 diabetic nephropathy who underwent renal biopsy followed by serial iothalamate clearances for up to ten years, we examined the relationship between glomerular tuft volume at initial biopsy and the rate of GFR loss during the terminal phase. By multivariate analysis, significant independent effects of both glomerular volume (P=0.006) and podocyte density (P=0.043) were evident in these individuals. The effect of glomerular volume may result from a greater loss of intrinsic filtration capacity with each glomerulus lost, while the effect of podocyte density may reflect the destabilizing influence of "podocyte insufficiency" on the glomerular tuft. Similar factors may play a role in the rapid loss of GFR associated with progressive glomerular diseases in other indigenous populations in whom glomerulomegaly and glomerulopenia coexist.

Arizona↗
PubMed2003

National Kidney Foundation's Kidney Disease Outcomes Quality Initiative clinical practice guidelines for chronic kidney disease in children and adolescents: evaluation, classification, and stratification.

OBJECTIVES: A series of new guidelines has been developed by the National Kidney Foundation's Kidney Disease Outcomes Quality Initiative to improve the detection and management of chronic kidney disease (CKD). In most instances of CKD, the earliest manifestations of the disorder may be identified by relatively simple tests. Unfortunately, CKD is often "underdiagnosed," in part because of the absence of a common definition of CKD and a classification of the stages in its progression. The Kidney Disease Outcomes Quality Initiative clinical practice guidelines for CKD evaluation, classification, and stratification provide a basis to remedy these deficits. The specific goals of the guidelines described in this review are to provide: 1) an overview of the clinical practice guidelines as they pertain to children and adolescents, 2) a simple classification of the stages of CKD, and 3) a practical approach to the laboratory assessment of kidney disease in children and adolescents. METHODS: The guidelines were developed as part of an evidence-based evaluation of CKD and its consequences in patients of all ages. The data that were used to generate the guidelines in this article were extracted from a structured analysis of articles that reported on children with CKD. RESULTS AND CONCLUSIONS: This review presents the definition and 5-stage classification system of CKD developed by the work group assigned to develop the guidelines, and summarizes the major recommendations regarding the early detection of CKD. Major emphasis is placed on the identification of children and adolescents with CKD by measuring the protein-to-creatinine ratio in spot urine specimens and by estimating the glomerular filtration rate from serum creatinine using prediction equations.

Adolescent↗
PubMed2002

Podocytes, parietal cells, and glomerular pathology: the role of cell cycle proteins.

Podocytes are highly differentiated cells that play a central role in glomerular function. Cell cycle quiescence sustained by the tight regulation of cell cycle molecules seems to be the basis of podocyte differentiation, as reflected in reciprocal expression of cyclins and cyclin kinase inhibitors (CKIs) during glomerulogenesis, concurrent with the expression of podocyte-specific markers. In addition, cell cycle re-entry by podocytes, accompanied by down-regulation of CKIs, leads to either nuclear division without cytokinesis or to marked cell proliferation, both of which result in heavy proteinuria and progressive glomerulosclerosis. These observations suggest that proper cell cycle regulation in podocytes is pivotal for their role in glomerular function and that dysregulation of this system plays a role in glomerular pathology. This review discusses the role of cell cycle molecules in the differentiation, function, and pathology of podocytes.

Cell Cycle↗
PubMed2002

Podocytopenia and disease severity in IgA nephropathy.

BACKGROUND: IgA nephropathy is a common form of progressive glomerular disease, associated with proliferation of mesangial cells and mesangial deposition of IgA. The present study was designed to investigate functional and morphological covariates of disease severity in patients with IgA nephropathy. METHODS: Glomerular hemodynamics, permselectivity and ultrastructure were studied in 17 adult patients with IgA nephropathy using inulin, para-aminohippuric acid (PAH) and 3H-Ficoll clearances and morphometric methods. A mathematical model of macromolecule permeation through a heteroporous membrane was used to characterize glomerular permselectivity. Controls consisted of 14 healthy living kidney donors and 12 healthy volunteers. RESULTS: The patients were heterogeneous in their disease severity, but as a group had a decreased glomerular filtration rate (GFR) and increased urinary protein excretion compared to controls [63 +/- 29 SD vs. 104 +/- 23 mL/min/1.73 m2, P < 0.001, and (median) 1.34 vs. 0.11 g/day, P < 0.0001, respectively). A multivariate analysis of structural and functional relationships revealed GFR depression to be most strongly correlated with the prevalence of global glomerular sclerosis (t = -4.073, P = 0.002). Those patients with the most severe glomerular dysfunction had a reduced number of glomerular visceral epithelial cells (podocytes) per glomerulus. The degree of podocytopenia was related to the extent of glomerular sclerosis and of impairment of permselectivity and GFR, with worsening injury below an apparent threshold podocyte number of about 250 cells per glomerulus. There were no corresponding correlations between these indices of injury and the number of mesangial and endothelial cells. CONCLUSIONS: Our findings show that podocyte loss is a concomitant of increasing disease severity in IgA nephropathy. This suggests that podocyte loss may either cause or contribute to the progressive proteinuria, glomerular sclerosis and filtration failure seen in this disorder.

Adult↗
PubMed2000

Glomerular permselectivity at the onset of nephropathy in type 2 diabetes mellitus.

The development of microalbuminuria in individuals with type 2 diabetes mellitus is associated with a 10-fold increase in the risk of progression to overt nephropathy and eventual end-stage renal failure. The present study reports long-term (up to 8 yr) follow-up of 43 Pima Indians with type 2 diabetes detected on screening to have microalbuminuria. The natural history of albuminuria in these individuals included progression to overt proteinuria (urinary albumin excretion > or = 300 mg/d) in half of the participants by 7 yr of follow-up. The size selectivity of the glomerular barrier was also investigated using dextran sieving and pore theory. Whereas a comparison group of macroalbuminuric Pima Indians had an excess of large pores that served as a macromolecular "shunt," individuals with microalbuminuria had a shunt size no different from long-term diabetic, normoalbuminuric control subjects. An abrupt transition from little or no relationship to a highly significant and positive relationship between increasing albuminuria and shunt size occurred at an albumin-to-creatinine ratio of approximately 3000 mg/g. Shunt size in macroalbuminuric individuals correlated with the extent of foot process broadening. Podocyte foot processes in microalbuminuric participants were not different from those in control subjects. In conclusion, although microalbuminuria in type 2 diabetic Pima Indians often heralds progressive glomerular injury, it is not the result of defects in the size permselectivity of the glomerular barrier but rather of changes in either glomerular charge selectivity or tubular handling of filtered proteins or of a combination of these two factors.

Adolescent↗