This analysis characterizes the degree of early organ involvement in a cohort of oligo-symptomati... more This analysis characterizes the degree of early organ involvement in a cohort of oligo-symptomatic untreated young patients with Fabry disease enrolled in an ongoing randomized, open-label, parallel-group, phase 3B clinical trial. Males aged 5-18 years with complete α-galactosidase A deficiency, without symptoms of major organ damage, were enrolled in a phase 3B trial evaluating two doses of agalsidase beta. Baseline disease characteristics of 31 eligible patients (median age 12 years) were studied, including cellular globotriaosylceramide (GL-3) accumulation in skin (n = 31) and kidney biopsy (n = 6; median age 15 years; range 13-17 years), renal function, and glycolipid levels (plasma, urine). Plasma and urinary GL-3 levels were abnormal in 25 of 30 and 31 of 31 patients, respectively. Plasma lyso-GL-3 was elevated in all patients. GL-3 accumulation was documented in superficial skin capillary endothelial cells (23/31 patients) and deep vessel endothelial cells (23/29 patients). T...
Background. The purpose of this study was to identify determinants of renal disease progression i... more Background. The purpose of this study was to identify determinants of renal disease progression in adults with Fabry disease during treatment with agalsidase beta. Methods. Renal function was evaluated in 151 men and 62 women from the Fabry Registry who received agalsidase beta at an average dose of 1 mg/kg/2 weeks for at least 2 years. Patients were categorized into quartiles based on slopes of estimated glomerular filtration rate (eGFR) during treatment. Multivariate logistic regression analyses were used to identify factors associated with renal disease progression. Results. Men within the first quartile had a mean eGFR slope of-0.1 mL/min/1.73m 2 /year, whereas men with the most rapid renal disease progression (Quartile 4) had a mean eGFR slope of-6.7 mL/min/1.73m 2 /year. The risk factor most strongly associated with renal disease progression was averaged urinary protein:creatinine ratio (UP/Cr) !1 g/g (odds ratio 112, 95% confidence interval (95% CI) 4-3109, P ¼ 0.0054). Longer time from symptom onset to treatment was also associated with renal disease progression (odds ratio 19, 95% CI 2-184, P ¼ 0.0098). Women in Quartile 4 had the highest averaged UP/Cr (mean 1.8 g/g) and the most rapid renal disease progression: (mean slope-4.4 mL/min/1.73m 2 /year). Conclusions. Adults with Fabry disease are at risk for progressive loss of eGFR despite enzyme replacement therapy, particularly if proteinuria is !1 g/g. Men with little urinary protein excretion and those who began receiving agalsidase beta sooner after the onset of symptoms had stable renal function. These findings suggest that early intervention may lead to optimal renal outcomes.
Introduction: To define the phenotypic spectrum of hematological and visceral disease in patients... more Introduction: To define the phenotypic spectrum of hematological and visceral disease in patients with type 3 Gaucher disease (GD3) and its response to alglucerase/imiglucerase therapy. Description/Results: All patients < 18 years of age who were enrolled in the International Collaborative Gaucher Group (ICGG) Gaucher Registry as of July 2010 with a diagnosis of GD3 were included in this analysis. Subsets of patients with baseline status of anemia, thrombocytopenia, splenomegaly, hepatomegaly, or height zscore ≤ −1 were identified. Outcomes of hemoglobin concentration, platelet count, and hepatic and splenic volumes and height Z-scores were assessed at baseline and up to 5 years following initiation of therapy using non-linear mixed effects models. A total of 334 GD3 patients were identified; the majority of patients were from the Middle East (34%), Europe (29%) and the USA (16%). Ninety percent of the patients were diagnosed at age <6 years and 81% of patients initiated therapy at age <6 years. GBA1 gene analysis revealed a preponderance of L444P mutations: L444P homozygotes (63%) and L444P compound heterozygotes (16%). Among the subset with height Z-score ≤ −1 at baseline (n = 159), the mean baseline height Z-score was −2.7. Improvement in height was seen after both 1 (mean height Z-score −2.5) and 5 years of treatment (mean height Z-score − 1.7). In the subset with anemia at baseline (n = 145), anemia was present in 42% within ≤1 year of treatment initiation, and declined to 29% after 5 years of treatment. For the subset with thrombocytopenia (platelet counts < 120 103/ mm3) at baseline (n = 131), thrombocytopenia was present in 57% within less than 1 year, and declined to 11% after 5 years of treatment. Liver and spleen volumes decreased over the 5 years of treatment. Conclusions: There is early onset of prominent visceral and hematologic disease in GD3 patients before the age of 6 years. Moreover, the patients exhibit striking growth failure. These effects are reversed by alglucerase/imiglucerase treatment within 5 years. This cohort represents the largest cohort of children with GD3 ever described to delineate the phenotypic spectrum and its response to alglucerase/imiglucerase therapy.
Progressive renal failure often complicates Fabry's disease. However, the pathogenesis of Fabry n... more Progressive renal failure often complicates Fabry's disease. However, the pathogenesis of Fabry nephropathy is not well understood. We applied unbiased stereological methods to the study of the electron microscopic changes of Fabry nephropathy and the relationship between glomerular structural parameters and renal function in young Fabry patients. Renal biopsies from 14 (M/ F=8/6) enzyme replacement therapy (ERT)-naive Fabry patients (median age 12 years; range 4-19 years) and 9 (M/F=6/3) normal living kidney donor control subjects were studied. Podocyte GL-3 inclusion volume density [Vv(Inc/PC)] increased progressively with age, while there was no significant relationship between age and endothelial [Vv(Inc/Endo)] or mesangial [Vv(Inc/Mes)] inclusion volume densities. Foot process width which was greater in male Fabry patients vs. controls also progressively increased with age, and correlated directly with proteinuria. Endothelial fenestration was reduced in Fabry patients vs. controls. These studies are the first to show relationships between quantitative glomerular structural parameters of Fabry nephropathy and urinary protein excretion. The parallel progression with increasing age in podocyte GL-3 accumulation, foot process widening and proteinuria, strongly suggest that podocyte injury may play a pivotal role in the development and progression of Fabry nephropathy.
Journal of the American Society of Nephrology, 2006
Diabetic nephropathy (DN) is a growing cause of ESRD despite widely known recommendations for imp... more Diabetic nephropathy (DN) is a growing cause of ESRD despite widely known recommendations for improved glycemic and BP control. Perhaps earlier identification of patients who have diabetes and are at high risk for DN could reverse these epidemiologic trends. Albumin excretion rate (AER), the mainstay of early detection of DN, is not a sufficiently precise predictor of DN risk. Careful family history, smoking history, consideration of absolute versus categorical AER values, more frequent AER measures, ambulatory BP monitoring, precise GFR measurements, diabetic retinopathy assessments, and plasma lipid levels all can add to predictive accuracy for DN. Thus, although further research in DN biomarkers and predictors is greatly needed, a careful integrated evaluation of currently available parameters can improve our ability to predict DN risk in individual patients.
Background-Animal models provide insights into the diabetic nephropathy pathogenesis, however, av... more Background-Animal models provide insights into the diabetic nephropathy pathogenesis, however, available rodent models do not mirror the heterogeneity of lesions in type 2 diabetic (T2DM) patients, and do not progress to end stage renal disease. Previous studies showed that spontaneously obese T2DM rhesus monkeys develop many of the features of human diabetic glomerulopathy, and may progress to ESRD. Here, in order to further characterize diabetic glomerulopathy in this model, we used electron microscopic stereology.. Methods-Renal biopsies from 17 diabetic, 17 pre-diabetes/metabolic syndrome (preDM/MS) and 11 non-diabetic monkeys were studied. Fractional volumes of mesangium [Vv(Mes/glom)], mesangial matrix [Vv(MM/glom)] and mesangial cells [Vv(MC/glom)], glomerular basement membrane (GBM) width and peripheral GBM surface density per glomerulus [Sv(PGBM/glom)] were estimated. Glomerular filtration (GFR) and albumin excretion rates (AER) were measured in a limited number of animals. Glomerular structural and biochemical/metabolic data were compared among the groups. Results-Diabetic monkeys showed classical diabetic nephropathy changes, including GBM thickening (p=0.001), increased Vv(Mes/glom) (p=0.02), and reduced Sv(PGBM/glom) (p=0.03) compared to non-diabetic monkeys. Increased Vv(Mes/glom) was primarily due to increased Vv(MM/glom) (p=0.03). Glomerular structural parameters interrelationships in diabetic monkeys mirrored those of human diabetic glomerulopathy. AER was greater (p=0.03) in diabetic vs. nondiabetic monkeys. There was evidence for a positive relationship between AER and Vv(Mes/ glom). Conclusions-These studies indicate that this primate model shares many features of human diabetic glomerulopathy. Mesangial expansion in this model, similar to human diabetic nephropathy and different from available rodent models of the disease, is primarily due to increased mesangial matrix.
The remnant kidney model, usually involving sudden removal or ablation of 1- 1 / (2) to 1-5 / (6)... more The remnant kidney model, usually involving sudden removal or ablation of 1- 1 / (2) to 1-5 / (6) of renal mass, results in compensatory hypertrophy followed by hypertension, proteinuria and declining glomerular filtration rate (GFR) associated with focal (FSG) and then global glomerulosclerosis (GS) and tubulointerstitial injury (TI). Since most renal diseases involve much more gradual injury, we asked whether slow ablation (SA) produced a different natural history than fast ablation (FA). Male Münich-Wistar rats underwent heminephrectomy, 3 weeks later a second, and 3 weeks later a third heminephrectomy (SA). They were compared to littermates undergoing simultaneous removal of 1- 1 / (2) kidneys (FA) and sham operated controls (C). Three weeks after the second heminephrectomy, the SA rats had no FSG and glomerular volume (GV) was similar to that of FA rat renal tissue removed at that time. Eight weeks following the final surgical procedure (FSP), the SA and FA groups had similar b...
The Journal of clinical endocrinology and metabolism, Jan 14, 2015
Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD) in the USA. The ... more Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD) in the USA. The aim of this study was to determine whether there were skin fibroblast (SF) gene expression differences between subjects with type 1 diabetes (T1D) with or without DN. Cross-sectional Setting: This study was conducted in the University of Minnesota. Study volunteers were 100 Genetics of Kidneys in Diabetes (GoKinD) former participants: 40 were diabetic nephropathy (DN) Controls, normoalbuminuric after ≥ 15 years of T1D; and 60 were DN Cases, 25 with proteinuria and 35 with ESRD. SF were grown in high glucose (HG) for 5 passages (approximately 6 weeks). SF gene expression was assessed by transcriptome sequencing using the Illumina HiSeq 2000 platform. Pathway analyses tested directionally consistent group differences within the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Eight pathways, all related to cell cycle and repair, were up-regulated in the DN Controls versus the DN Ca...
Fabry disease is an X-linked-galactosidase A deficiency, resulting in accumulation of glycosphing... more Fabry disease is an X-linked-galactosidase A deficiency, resulting in accumulation of glycosphingolipids, especially globotriaosylceramide, in cells in different organs in the body. Renal failure is a serious complication of this disease. Fabry nephropathy lesions are present and progress in childhood while the disease commonly remains silent by routine clinical measures. Early and timely diagnosis of Fabry nephropathy is crucial since late initiation of enzyme replacement therapy may not halt progressive renal dysfunction. This may be challenging due to difficulties in diagnosis of Fabry disease in children and absence of a sensitive non-invasive biomarker of early Fabry nephropathy. Accurate measurement of glomerular filtration rate and regular assessment for proteinuria and microalbuminuria are useful, though not sensitive enough to detect early lesions in the kidney. Recent studies support the value of renal biopsy in providing histological information relevant to kidney function and prognosis and renal biopsy could potentially be used to guide treatment decisions in young Fabry patients. This review aims to provide an update of the current understanding, challenges and needs to better approach renal complications of Fabry disease in children.
Nephropathy and retinopathy remain important complications of type 1 diabetes. It is unclear whet... more Nephropathy and retinopathy remain important complications of type 1 diabetes. It is unclear whether their progression is slowed by early administration of drugs that block the renin–angiotensin system. Methods We conducted a multicenter, controlled trial involving 285 normotensive patients with type 1 diabetes and normoalbuminuria and who were randomly assigned to receive losartan (100 mg daily), enalapril (20 mg daily), or placebo and followed for 5 years. The primary end point was a change in the fraction of glomerular volume occupied by mesangium in kidney-biopsy specimens. The retinopathy end point was a progression on a retinopathy severity scale of two steps or more. Intention-to-treat analysis was performed with the use of linear regression and logistic-regression models. Results A total of 90 % and 82 % of patients had complete renal-biopsy and retinopathy data, respectively. Change in mesangial fractional volume per glomerulus over the 5-year
Higher serum uric acid (SUA) is associated with diabetic kidney disease (DKD). Preventing Early R... more Higher serum uric acid (SUA) is associated with diabetic kidney disease (DKD). Preventing Early Renal Loss in Diabetes (PERL) evaluates whether lowering SUA with allopurinol slows glomerular filtration rate (GFR) loss in people with type 1 diabetes (T1D) and mild to moderate DKD. We present the PERL rationale, design, and baseline characteristics. RESEARCH DESIGN AND METHODS This double-blind, placebo-controlled, multicenter trial randomized 530 participants with T1D, estimated GFR (eGFR) of 40-99.9 mL/min/1.73 m 2 , SUA ‡4.5 m/dL, and micro-to macroalbuminuric DKD or normoalbuminuria with declining kidney function (NDKF) (defined as historical eGFR decline ‡3 mL/min/1.73 m 2 /year) to allopurinol or placebo. The primary outcome is baseline-adjusted iohexol GFR (iGFR) after 3 years of treatment plus a 2-month washout period. RESULTS Participants are 66% male and 84% white. At baseline, median age was 52 years and diabetes duration was 35 years, 93% of participants had hypertension, and 90% were treated with renin-angiotensin system inhibitors (median blood pressure 127/ 71 mmHg). Median HbA 1c was 8%, SUA 5.9 mg/dL, iGFR 68 mL/min/1.73 m 2 , and historical eGFR slope 23.5 mL/min/1.73 m 2 /year. Compared with participants with albuminuria (n = 419), those with NDKF (n = 94) were significantly older (56 vs. 52 years), had lower HbA 1c (7.7 vs. 8.1%) and SUA (5.4 vs. 6.0 mg/dL), and had higher eGFR (82 vs. 74 mL/min/1.73 m 2) and historical eGFR loss (24.7 vs. 22.5 mL/min/ 1.73 m 2 /year). These differences persisted when comparing groups with similar rates of historical eGFR loss.
Fabry disease is an inherited X-linked disorder that presents during childhood in male and female... more Fabry disease is an inherited X-linked disorder that presents during childhood in male and female patients. Young patients may initially experience pain, hypohidrosis, and gastrointestinal symptoms. Other manifestations of Fabry disease, such as renal and cardiac disease, manifest later in adolescence or adulthood. In the pediatric population, renal damage is typically subclinical and identifiable only through biopsy. Specialists from the United States with expertise in Fabry disease convened during 2013-2014 in order to develop these consensus guidelines about the management and treatment of children with Fabry disease. The presence of symptoms in boys and girls of any age is an indication to begin therapy. Early treatment before the onset of potentially irreversible vital organ pathology is ideal. Asymptomatic children with Fabry mutations should be followed closely for the development of renal, cardiac, neurological, or gastrointestinal signs, symptoms, or laboratory changes, whi...
Journal of the American Society of Nephrology, 2003
ABSTRACT. Glomerular structure has been studied in tissues derived from normal living and cadaver... more ABSTRACT. Glomerular structure has been studied in tissues derived from normal living and cadaver kidney donors. Values obtained in such subjects were considered interchangeable and have been used to define the normal parameters when evaluating the effects of various renal diseases. The present study evaluated glomerular structure by light and electron microscopy in 83 living and 53 cadaver kidney donors. Glomerular basement membrane (GBM) width (356 ± 52versus329 ± 45 nm), glomerular volume (1.64 ± 0.47versus1.33 ± 0.39 × 106μm3), and mesangial matrix volume per glomerulus (0.15 ± 0.05versus0.12 ± 0.04 × 106μm3) were significantly greater in cadaver compared with living kidney donors, respectively. It is hypothesized that glomerular and extracellular matrix swelling is associated with the cadaver kidney preservation process. This study suggests that the normal values for glomerular structure should be derived only from living kidney donor tissues. E-mail: [email protected]
American journal of physiology. Renal physiology, Jan 22, 2018
We examined the association of urine inositol pentakisphosphate 2-kinase (IPP2K) with the presenc... more We examined the association of urine inositol pentakisphosphate 2-kinase (IPP2K) with the presence and progression of diabetic kidney disease (DKD) lesions. Urine IPP2K was measured at baseline by quantitative liquid chromatography mass spectrometry in 215 participants from the Renin-Angiotensin System Study who had type 1 diabetes and were normoalbuminuric and normotensive with normal or increased glomerular filtration rate (GFR). Urine IPP2K was detectable in 166 participants. Participants with IPP2K below the limit of quantification (LOQ) were assigned concentrations of LOQ/√2. All concentrations were then standardized to urine creatinine concentration. Kidney morphometric data were available from biopsies at baseline and after 5 years. Relationships of IPP2K/Cr with morphometric variables were assessed by linear regression after adjustment for age, sex, diabetes duration, HbA1c, mean arterial pressure, treatment assignment and, for longitudinal analyses, baseline structure. Base...
Although estimated glomerular filtration rate and albuminuria are well-established biomarkers of ... more Although estimated glomerular filtration rate and albuminuria are well-established biomarkers of diabetic kidney disease (DKD), additional biomarkers are needed, especially for the early stages of the disease when both albuminuria and estimated glomerular filtration rate may still be in the normal range and are less helpful for identifying those at risk of progression. Traditional biomarker studies for early DKD are challenging because of a lack of good early clinical end points, and most rely on changes in existing imprecise biomarkers to assess the value of new biomarkers. There are well-characterized changes in kidney structure, however, that are highly correlated with kidney function, always precede the clinical findings of DKD and, at preclinical stages, predict DKD progression. These structural parameters may thus serve as clinically useful end points for identifying new biomarkers of early DKD. In addition, investigators are analyzing tissue transcriptomic data to identify pa...
Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the GLA gene leadi... more Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the GLA gene leading to deficient α-galactosidase A activity, glycosphingolipid accumulation, and life-threatening complications. Phenotypes vary from the "classic" phenotype, with pediatric onset and multi-organ involvement, to later-onset, a predominantly cardiac phenotype. Manifestations are diverse in female patients in part due to variations in residual enzyme activity and X chromosome inactivation patterns. Enzyme replacement therapy (ERT) and adjunctive treatments can provide significant clinical benefit. However, much of the current literature reports outcomes after late initiation of ERT, once substantial organ damage has already occurred. Updated monitoring and treatment guidelines for pediatric patients with Fabry disease have recently been published. Expert physician panels were convened to develop updated, specific guidelines for adult patients. Management of adult patients depends ...
This analysis characterizes the degree of early organ involvement in a cohort of oligo-symptomati... more This analysis characterizes the degree of early organ involvement in a cohort of oligo-symptomatic untreated young patients with Fabry disease enrolled in an ongoing randomized, open-label, parallel-group, phase 3B clinical trial. Males aged 5-18 years with complete α-galactosidase A deficiency, without symptoms of major organ damage, were enrolled in a phase 3B trial evaluating two doses of agalsidase beta. Baseline disease characteristics of 31 eligible patients (median age 12 years) were studied, including cellular globotriaosylceramide (GL-3) accumulation in skin (n = 31) and kidney biopsy (n = 6; median age 15 years; range 13-17 years), renal function, and glycolipid levels (plasma, urine). Plasma and urinary GL-3 levels were abnormal in 25 of 30 and 31 of 31 patients, respectively. Plasma lyso-GL-3 was elevated in all patients. GL-3 accumulation was documented in superficial skin capillary endothelial cells (23/31 patients) and deep vessel endothelial cells (23/29 patients). T...
Background. The purpose of this study was to identify determinants of renal disease progression i... more Background. The purpose of this study was to identify determinants of renal disease progression in adults with Fabry disease during treatment with agalsidase beta. Methods. Renal function was evaluated in 151 men and 62 women from the Fabry Registry who received agalsidase beta at an average dose of 1 mg/kg/2 weeks for at least 2 years. Patients were categorized into quartiles based on slopes of estimated glomerular filtration rate (eGFR) during treatment. Multivariate logistic regression analyses were used to identify factors associated with renal disease progression. Results. Men within the first quartile had a mean eGFR slope of-0.1 mL/min/1.73m 2 /year, whereas men with the most rapid renal disease progression (Quartile 4) had a mean eGFR slope of-6.7 mL/min/1.73m 2 /year. The risk factor most strongly associated with renal disease progression was averaged urinary protein:creatinine ratio (UP/Cr) !1 g/g (odds ratio 112, 95% confidence interval (95% CI) 4-3109, P ¼ 0.0054). Longer time from symptom onset to treatment was also associated with renal disease progression (odds ratio 19, 95% CI 2-184, P ¼ 0.0098). Women in Quartile 4 had the highest averaged UP/Cr (mean 1.8 g/g) and the most rapid renal disease progression: (mean slope-4.4 mL/min/1.73m 2 /year). Conclusions. Adults with Fabry disease are at risk for progressive loss of eGFR despite enzyme replacement therapy, particularly if proteinuria is !1 g/g. Men with little urinary protein excretion and those who began receiving agalsidase beta sooner after the onset of symptoms had stable renal function. These findings suggest that early intervention may lead to optimal renal outcomes.
Introduction: To define the phenotypic spectrum of hematological and visceral disease in patients... more Introduction: To define the phenotypic spectrum of hematological and visceral disease in patients with type 3 Gaucher disease (GD3) and its response to alglucerase/imiglucerase therapy. Description/Results: All patients < 18 years of age who were enrolled in the International Collaborative Gaucher Group (ICGG) Gaucher Registry as of July 2010 with a diagnosis of GD3 were included in this analysis. Subsets of patients with baseline status of anemia, thrombocytopenia, splenomegaly, hepatomegaly, or height zscore ≤ −1 were identified. Outcomes of hemoglobin concentration, platelet count, and hepatic and splenic volumes and height Z-scores were assessed at baseline and up to 5 years following initiation of therapy using non-linear mixed effects models. A total of 334 GD3 patients were identified; the majority of patients were from the Middle East (34%), Europe (29%) and the USA (16%). Ninety percent of the patients were diagnosed at age <6 years and 81% of patients initiated therapy at age <6 years. GBA1 gene analysis revealed a preponderance of L444P mutations: L444P homozygotes (63%) and L444P compound heterozygotes (16%). Among the subset with height Z-score ≤ −1 at baseline (n = 159), the mean baseline height Z-score was −2.7. Improvement in height was seen after both 1 (mean height Z-score −2.5) and 5 years of treatment (mean height Z-score − 1.7). In the subset with anemia at baseline (n = 145), anemia was present in 42% within ≤1 year of treatment initiation, and declined to 29% after 5 years of treatment. For the subset with thrombocytopenia (platelet counts < 120 103/ mm3) at baseline (n = 131), thrombocytopenia was present in 57% within less than 1 year, and declined to 11% after 5 years of treatment. Liver and spleen volumes decreased over the 5 years of treatment. Conclusions: There is early onset of prominent visceral and hematologic disease in GD3 patients before the age of 6 years. Moreover, the patients exhibit striking growth failure. These effects are reversed by alglucerase/imiglucerase treatment within 5 years. This cohort represents the largest cohort of children with GD3 ever described to delineate the phenotypic spectrum and its response to alglucerase/imiglucerase therapy.
Progressive renal failure often complicates Fabry's disease. However, the pathogenesis of Fabry n... more Progressive renal failure often complicates Fabry's disease. However, the pathogenesis of Fabry nephropathy is not well understood. We applied unbiased stereological methods to the study of the electron microscopic changes of Fabry nephropathy and the relationship between glomerular structural parameters and renal function in young Fabry patients. Renal biopsies from 14 (M/ F=8/6) enzyme replacement therapy (ERT)-naive Fabry patients (median age 12 years; range 4-19 years) and 9 (M/F=6/3) normal living kidney donor control subjects were studied. Podocyte GL-3 inclusion volume density [Vv(Inc/PC)] increased progressively with age, while there was no significant relationship between age and endothelial [Vv(Inc/Endo)] or mesangial [Vv(Inc/Mes)] inclusion volume densities. Foot process width which was greater in male Fabry patients vs. controls also progressively increased with age, and correlated directly with proteinuria. Endothelial fenestration was reduced in Fabry patients vs. controls. These studies are the first to show relationships between quantitative glomerular structural parameters of Fabry nephropathy and urinary protein excretion. The parallel progression with increasing age in podocyte GL-3 accumulation, foot process widening and proteinuria, strongly suggest that podocyte injury may play a pivotal role in the development and progression of Fabry nephropathy.
Journal of the American Society of Nephrology, 2006
Diabetic nephropathy (DN) is a growing cause of ESRD despite widely known recommendations for imp... more Diabetic nephropathy (DN) is a growing cause of ESRD despite widely known recommendations for improved glycemic and BP control. Perhaps earlier identification of patients who have diabetes and are at high risk for DN could reverse these epidemiologic trends. Albumin excretion rate (AER), the mainstay of early detection of DN, is not a sufficiently precise predictor of DN risk. Careful family history, smoking history, consideration of absolute versus categorical AER values, more frequent AER measures, ambulatory BP monitoring, precise GFR measurements, diabetic retinopathy assessments, and plasma lipid levels all can add to predictive accuracy for DN. Thus, although further research in DN biomarkers and predictors is greatly needed, a careful integrated evaluation of currently available parameters can improve our ability to predict DN risk in individual patients.
Background-Animal models provide insights into the diabetic nephropathy pathogenesis, however, av... more Background-Animal models provide insights into the diabetic nephropathy pathogenesis, however, available rodent models do not mirror the heterogeneity of lesions in type 2 diabetic (T2DM) patients, and do not progress to end stage renal disease. Previous studies showed that spontaneously obese T2DM rhesus monkeys develop many of the features of human diabetic glomerulopathy, and may progress to ESRD. Here, in order to further characterize diabetic glomerulopathy in this model, we used electron microscopic stereology.. Methods-Renal biopsies from 17 diabetic, 17 pre-diabetes/metabolic syndrome (preDM/MS) and 11 non-diabetic monkeys were studied. Fractional volumes of mesangium [Vv(Mes/glom)], mesangial matrix [Vv(MM/glom)] and mesangial cells [Vv(MC/glom)], glomerular basement membrane (GBM) width and peripheral GBM surface density per glomerulus [Sv(PGBM/glom)] were estimated. Glomerular filtration (GFR) and albumin excretion rates (AER) were measured in a limited number of animals. Glomerular structural and biochemical/metabolic data were compared among the groups. Results-Diabetic monkeys showed classical diabetic nephropathy changes, including GBM thickening (p=0.001), increased Vv(Mes/glom) (p=0.02), and reduced Sv(PGBM/glom) (p=0.03) compared to non-diabetic monkeys. Increased Vv(Mes/glom) was primarily due to increased Vv(MM/glom) (p=0.03). Glomerular structural parameters interrelationships in diabetic monkeys mirrored those of human diabetic glomerulopathy. AER was greater (p=0.03) in diabetic vs. nondiabetic monkeys. There was evidence for a positive relationship between AER and Vv(Mes/ glom). Conclusions-These studies indicate that this primate model shares many features of human diabetic glomerulopathy. Mesangial expansion in this model, similar to human diabetic nephropathy and different from available rodent models of the disease, is primarily due to increased mesangial matrix.
The remnant kidney model, usually involving sudden removal or ablation of 1- 1 / (2) to 1-5 / (6)... more The remnant kidney model, usually involving sudden removal or ablation of 1- 1 / (2) to 1-5 / (6) of renal mass, results in compensatory hypertrophy followed by hypertension, proteinuria and declining glomerular filtration rate (GFR) associated with focal (FSG) and then global glomerulosclerosis (GS) and tubulointerstitial injury (TI). Since most renal diseases involve much more gradual injury, we asked whether slow ablation (SA) produced a different natural history than fast ablation (FA). Male Münich-Wistar rats underwent heminephrectomy, 3 weeks later a second, and 3 weeks later a third heminephrectomy (SA). They were compared to littermates undergoing simultaneous removal of 1- 1 / (2) kidneys (FA) and sham operated controls (C). Three weeks after the second heminephrectomy, the SA rats had no FSG and glomerular volume (GV) was similar to that of FA rat renal tissue removed at that time. Eight weeks following the final surgical procedure (FSP), the SA and FA groups had similar b...
The Journal of clinical endocrinology and metabolism, Jan 14, 2015
Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD) in the USA. The ... more Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD) in the USA. The aim of this study was to determine whether there were skin fibroblast (SF) gene expression differences between subjects with type 1 diabetes (T1D) with or without DN. Cross-sectional Setting: This study was conducted in the University of Minnesota. Study volunteers were 100 Genetics of Kidneys in Diabetes (GoKinD) former participants: 40 were diabetic nephropathy (DN) Controls, normoalbuminuric after ≥ 15 years of T1D; and 60 were DN Cases, 25 with proteinuria and 35 with ESRD. SF were grown in high glucose (HG) for 5 passages (approximately 6 weeks). SF gene expression was assessed by transcriptome sequencing using the Illumina HiSeq 2000 platform. Pathway analyses tested directionally consistent group differences within the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Eight pathways, all related to cell cycle and repair, were up-regulated in the DN Controls versus the DN Ca...
Fabry disease is an X-linked-galactosidase A deficiency, resulting in accumulation of glycosphing... more Fabry disease is an X-linked-galactosidase A deficiency, resulting in accumulation of glycosphingolipids, especially globotriaosylceramide, in cells in different organs in the body. Renal failure is a serious complication of this disease. Fabry nephropathy lesions are present and progress in childhood while the disease commonly remains silent by routine clinical measures. Early and timely diagnosis of Fabry nephropathy is crucial since late initiation of enzyme replacement therapy may not halt progressive renal dysfunction. This may be challenging due to difficulties in diagnosis of Fabry disease in children and absence of a sensitive non-invasive biomarker of early Fabry nephropathy. Accurate measurement of glomerular filtration rate and regular assessment for proteinuria and microalbuminuria are useful, though not sensitive enough to detect early lesions in the kidney. Recent studies support the value of renal biopsy in providing histological information relevant to kidney function and prognosis and renal biopsy could potentially be used to guide treatment decisions in young Fabry patients. This review aims to provide an update of the current understanding, challenges and needs to better approach renal complications of Fabry disease in children.
Nephropathy and retinopathy remain important complications of type 1 diabetes. It is unclear whet... more Nephropathy and retinopathy remain important complications of type 1 diabetes. It is unclear whether their progression is slowed by early administration of drugs that block the renin–angiotensin system. Methods We conducted a multicenter, controlled trial involving 285 normotensive patients with type 1 diabetes and normoalbuminuria and who were randomly assigned to receive losartan (100 mg daily), enalapril (20 mg daily), or placebo and followed for 5 years. The primary end point was a change in the fraction of glomerular volume occupied by mesangium in kidney-biopsy specimens. The retinopathy end point was a progression on a retinopathy severity scale of two steps or more. Intention-to-treat analysis was performed with the use of linear regression and logistic-regression models. Results A total of 90 % and 82 % of patients had complete renal-biopsy and retinopathy data, respectively. Change in mesangial fractional volume per glomerulus over the 5-year
Higher serum uric acid (SUA) is associated with diabetic kidney disease (DKD). Preventing Early R... more Higher serum uric acid (SUA) is associated with diabetic kidney disease (DKD). Preventing Early Renal Loss in Diabetes (PERL) evaluates whether lowering SUA with allopurinol slows glomerular filtration rate (GFR) loss in people with type 1 diabetes (T1D) and mild to moderate DKD. We present the PERL rationale, design, and baseline characteristics. RESEARCH DESIGN AND METHODS This double-blind, placebo-controlled, multicenter trial randomized 530 participants with T1D, estimated GFR (eGFR) of 40-99.9 mL/min/1.73 m 2 , SUA ‡4.5 m/dL, and micro-to macroalbuminuric DKD or normoalbuminuria with declining kidney function (NDKF) (defined as historical eGFR decline ‡3 mL/min/1.73 m 2 /year) to allopurinol or placebo. The primary outcome is baseline-adjusted iohexol GFR (iGFR) after 3 years of treatment plus a 2-month washout period. RESULTS Participants are 66% male and 84% white. At baseline, median age was 52 years and diabetes duration was 35 years, 93% of participants had hypertension, and 90% were treated with renin-angiotensin system inhibitors (median blood pressure 127/ 71 mmHg). Median HbA 1c was 8%, SUA 5.9 mg/dL, iGFR 68 mL/min/1.73 m 2 , and historical eGFR slope 23.5 mL/min/1.73 m 2 /year. Compared with participants with albuminuria (n = 419), those with NDKF (n = 94) were significantly older (56 vs. 52 years), had lower HbA 1c (7.7 vs. 8.1%) and SUA (5.4 vs. 6.0 mg/dL), and had higher eGFR (82 vs. 74 mL/min/1.73 m 2) and historical eGFR loss (24.7 vs. 22.5 mL/min/ 1.73 m 2 /year). These differences persisted when comparing groups with similar rates of historical eGFR loss.
Fabry disease is an inherited X-linked disorder that presents during childhood in male and female... more Fabry disease is an inherited X-linked disorder that presents during childhood in male and female patients. Young patients may initially experience pain, hypohidrosis, and gastrointestinal symptoms. Other manifestations of Fabry disease, such as renal and cardiac disease, manifest later in adolescence or adulthood. In the pediatric population, renal damage is typically subclinical and identifiable only through biopsy. Specialists from the United States with expertise in Fabry disease convened during 2013-2014 in order to develop these consensus guidelines about the management and treatment of children with Fabry disease. The presence of symptoms in boys and girls of any age is an indication to begin therapy. Early treatment before the onset of potentially irreversible vital organ pathology is ideal. Asymptomatic children with Fabry mutations should be followed closely for the development of renal, cardiac, neurological, or gastrointestinal signs, symptoms, or laboratory changes, whi...
Journal of the American Society of Nephrology, 2003
ABSTRACT. Glomerular structure has been studied in tissues derived from normal living and cadaver... more ABSTRACT. Glomerular structure has been studied in tissues derived from normal living and cadaver kidney donors. Values obtained in such subjects were considered interchangeable and have been used to define the normal parameters when evaluating the effects of various renal diseases. The present study evaluated glomerular structure by light and electron microscopy in 83 living and 53 cadaver kidney donors. Glomerular basement membrane (GBM) width (356 ± 52versus329 ± 45 nm), glomerular volume (1.64 ± 0.47versus1.33 ± 0.39 × 106μm3), and mesangial matrix volume per glomerulus (0.15 ± 0.05versus0.12 ± 0.04 × 106μm3) were significantly greater in cadaver compared with living kidney donors, respectively. It is hypothesized that glomerular and extracellular matrix swelling is associated with the cadaver kidney preservation process. This study suggests that the normal values for glomerular structure should be derived only from living kidney donor tissues. E-mail: [email protected]
American journal of physiology. Renal physiology, Jan 22, 2018
We examined the association of urine inositol pentakisphosphate 2-kinase (IPP2K) with the presenc... more We examined the association of urine inositol pentakisphosphate 2-kinase (IPP2K) with the presence and progression of diabetic kidney disease (DKD) lesions. Urine IPP2K was measured at baseline by quantitative liquid chromatography mass spectrometry in 215 participants from the Renin-Angiotensin System Study who had type 1 diabetes and were normoalbuminuric and normotensive with normal or increased glomerular filtration rate (GFR). Urine IPP2K was detectable in 166 participants. Participants with IPP2K below the limit of quantification (LOQ) were assigned concentrations of LOQ/√2. All concentrations were then standardized to urine creatinine concentration. Kidney morphometric data were available from biopsies at baseline and after 5 years. Relationships of IPP2K/Cr with morphometric variables were assessed by linear regression after adjustment for age, sex, diabetes duration, HbA1c, mean arterial pressure, treatment assignment and, for longitudinal analyses, baseline structure. Base...
Although estimated glomerular filtration rate and albuminuria are well-established biomarkers of ... more Although estimated glomerular filtration rate and albuminuria are well-established biomarkers of diabetic kidney disease (DKD), additional biomarkers are needed, especially for the early stages of the disease when both albuminuria and estimated glomerular filtration rate may still be in the normal range and are less helpful for identifying those at risk of progression. Traditional biomarker studies for early DKD are challenging because of a lack of good early clinical end points, and most rely on changes in existing imprecise biomarkers to assess the value of new biomarkers. There are well-characterized changes in kidney structure, however, that are highly correlated with kidney function, always precede the clinical findings of DKD and, at preclinical stages, predict DKD progression. These structural parameters may thus serve as clinically useful end points for identifying new biomarkers of early DKD. In addition, investigators are analyzing tissue transcriptomic data to identify pa...
Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the GLA gene leadi... more Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the GLA gene leading to deficient α-galactosidase A activity, glycosphingolipid accumulation, and life-threatening complications. Phenotypes vary from the "classic" phenotype, with pediatric onset and multi-organ involvement, to later-onset, a predominantly cardiac phenotype. Manifestations are diverse in female patients in part due to variations in residual enzyme activity and X chromosome inactivation patterns. Enzyme replacement therapy (ERT) and adjunctive treatments can provide significant clinical benefit. However, much of the current literature reports outcomes after late initiation of ERT, once substantial organ damage has already occurred. Updated monitoring and treatment guidelines for pediatric patients with Fabry disease have recently been published. Expert physician panels were convened to develop updated, specific guidelines for adult patients. Management of adult patients depends ...
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Papers by Michael Mauer