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Dawn S Milliner

Publications and source records attributed to Dawn S Milliner.

14 recordsLinked to original sources
PubMed2006

Glyoxylate reductase activity in blood mononuclear cells and the diagnosis of primary hyperoxaluria type 2.

BACKGROUND: Primary hyperoxaluria type 2 (PH2) is a rare monogenic disorder characterized by an elevated urinary excretion of oxalate. Increased oxalate excretion in PH2 patients can cause nephrolithiasis and nephrocalcinosis, and can, in some cases, result in renal failure and systemic oxalate deposition. The disease is due to a deficiency of glyoxylate reductase/hydroxypyruvate reductase (GRHPR) activity. A definitive diagnosis of PH2 is currently made by the analysis of GR activity in a liver biopsy. GRHPR is expressed in virtually every tissue in the body, suggesting that utilization of more readily available cells could be used to determine GRHPR deficiency. In this study, we have evaluated the potential of determining GR and d-glycerate dehydrogenase (DGDH) activity in blood mononuclear cells (BMC) as a diagnostic indicator of PH2. METHODS: Blood samples were obtained from 10 male and 10 female normal subjects, median age 31, range 21-63, at the Wake Forest University Medical Center and from primary hyperoxaluria patients at the Mayo Clinic. The BMC were isolated and GR and DGDH activities measured in cell lysates. RESULTS: An assay of 20 normal individuals indicated that BMC contained a DGDH and GR activity of 0.97+/-0.20 (range 0.62-1.45), and 10.6+/-3.3 (range 8.3-16.6) nmol/min/mg protein, respectively. The intra-assay coefficient of variation for DGDH and GR activity was 8.2 and 11.5%, respectively. The BMC lysates from normal adult subjects and patients with PH1 showed similar GR and DGDH activities. This was confirmed by the presence of immunoreactive GRHPR protein by western blot analysis. In contrast, PH2 BMC lysates did not exhibit DGDH or GR activity, and showed no immunoreactive GRHPR by western blot analysis. CONCLUSION: These results suggest that the assay of DGDH or GR activity in BMC could be used as a minimally invasive diagnostic test for PH2.

Adult↗
PubMed2006

Stones, bones, and heredity.

Genetic disorders of mineral metabolism cause urolithiasis, renal disease, and osteodystrophy. Most are rare, such that the full spectrum of clinical expression is difficult to appreciate. Diagnosis is further complicated by overlap of clinical features. Dent's disease and primary hyperoxaluria, inherited causes of calcium urolithiasis, are both associated with nephrocalcinosis and urolithiasis in early childhood and renal failure that can occur at any age but is seen more often in adulthood. Bone disease is an inconsistent feature of each. Dent's disease is caused by mutations of the CLCN-5 gene with impaired kidney-specific CLC-5 chloride channel expression in the proximal tubule, thick ascending limb of Henle, and the collecting ducts. Resulting hypercalciuria and proximal tubule dysfunction, including phosphate wasting, are primarily responsible for the clinical manifestations. Low-molecular-weight proteinuria is characteristic. Definitive diagnosis is made by DNA mutation analysis. Primary hyperoxaluria, type I, is due to mutations of the AGXT gene leading to deficient hepatic alanine-glyoxylate aminotransferase activity. Marked overproduction of oxalate by hepatic cells results in the hyperoxaluria responsible for clinical features. Definitive diagnosis is by liver biopsy with measurement of enzyme activity, with DNA mutation analysis used increasingly as mutations and their frequency are defined. These disorders of calcium urolithiasis illustrate the value of molecular medicine for diagnosis and the promise it provides for innovative and more effective future treatments.

Adult↗
PubMed2005

Enteric hyperoxaluria, nephrolithiasis, and oxalate nephropathy: potentially serious and unappreciated complications of Roux-en-Y gastric bypass.

BACKGROUND: Neither the presence nor prevalence of enteric hyperoxaluria has been recognized after Roux-en-Y gastric bypass (RYGBP). We have noted a high rate of oxalate nephrolithiasis and even 2 patients with oxalate nephropathy in this patient population postoperatively. Our aim was to determine the frequency of the occurrence and effects of enteric hyperoxaluria after RYGBP. METHODS: Retrospective review of all patients at our institution diagnosed with calcium oxalate nephrolithiasis or oxalate nephropathy after standard (n = 14) or distal (n = 9) RYGBP. The mean postoperative follow-up was 55 months. RESULTS: A total of 23 patients (14 men and 9 women; mean age 45 years; mean preoperative body mass index 55 kg/m(2)) developed enteric hyperoxaluria after RYGBP, defined by the presence of oxalate nephropathy (n = 2) or calcium oxalate nephrolithiasis (n = 21) and increased 24-hour excretion of urinary oxalate and/or calcium oxalate supersaturation. Enteric hyperoxaluria was recognized after a mean weight loss of 46 kg at 29 months (range 2-85) after RYGBP. Two patients developed renal failure and required chronic hemodialysis. Of the 21 patients with nephrolithiasis, 14 had no history of nephrolithiasis preoperatively, and 19 of 21 required lithotripsy or other intervention. Of the 23 patients, 20 tested had increased oxalate excretion, and 14 of 15 tested had high urine calcium oxalate supersaturation. CONCLUSION: Enteric hyperoxaluria, nephrolithiasis, and oxalate nephropathy must be considered with the other risks of RYGBP. Efforts should be made to identify factors that predispose patients to developing hyperoxaluria.

Adult↗
PubMed2005

International registry for primary hyperoxaluria.

BACKGROUND/AIMS: Primary hyperoxaluria (PH) is an inherited disorder that causes calcium urolithiasis and renal failure. Due to its rarity, experience at most centers with this disease is limited. METHODS: A secure, web-based, institutional review board/ethics committee and American Health Insurance Portability and Accountability Act (HIPAA)-compliant registry was developed to facilitate international contributions to a data base. To date 95 PH patients have been entered. RESULTS: PH type was confirmed in 84/95 (PH1 79%, PH2 9%). Mean age +/- SD at symptom onset was 9.5 +/- 10.2 (median 5.5) years whereas age at diagnosis was 15.0 +/- 15.2 (median 10.0) years. Urolithiasis was present at diagnosis in 90% (mean 7, median 1, stones prior to diagnosis) and nephrocalcinosis in 48%. Surprisingly 15% of the patients were asymptomatic at the time of diagnosis. Nineteen of the 95 patients were first recognized to have PH after they had reached end-stage renal disease, with the diagnosis made only after kidney transplantation in 7 patients. Patients were followed for 12.1 +/- 10.6 (median 9.4) years. Thirty-four of 95 progressed to end-stage renal failure, before (19 patients) or after (15 patients) diagnosis. In the PH1 cohort actuarial renal survival was 64% at 30 years of age, 47% at 40 years, and 29% at 50 years. CONCLUSION: We have developed a PH registry, and demonstrated the feasibility of this secure, web-based approach for data entry. By facilitating accumulation of an increasing cohort of patients, this registry should allow more complete characterization of clinical expression of PH, an appreciation of geographic variability, and identification of treatment outcomes.

Adolescent↗
PubMed2005

The primary hyperoxalurias: an algorithm for diagnosis.

BACKGROUND/AIMS: The primary hyperoxalurias (PHs) are inborn errors of metabolism resulting in increased urinary excretion of oxalate. Nephrolithiasis, nephrocalcinosis, and renal failure result. Renal failure can occur as early as infancy or as late as the sixth decade of life, and if not addressed promptly, results in severe morbidity and mortality related to systemic oxalate deposition (oxalosis). Clinicians are likely to encounter few PH patients during a practicing lifetime. Definitive diagnosis requires special studies performed in only a small number of laboratories worldwide. Accordingly, delays in diagnosis are common. METHODS: An evidence-based guideline for diagnosis was developed. RESULTS: Patients with stones or nephrocalcinosis in childhood, recurrent calcium oxalate stones in adulthood, or renal insufficiency associated with stones or nephrocalcinosis should be evaluated for PH. A systematic approach to measurement of urine oxalate, glycolate and glycerate, and plasma oxalate is provided. Age-related variation in urine oxalate requires attention to normal ranges. Molecular analysis for mutations of the AGXT gene (PH, type I) or GRHPR gene (PH, type II) is definitive in some patients, while liver enzyme analysis is required for confirmation of the diagnosis in the remainder. CONCLUSION: An evidence-based algorithm will facilitate recognition and diagnosis of patients with the PHs, permitting earlier treatment.

Algorithms↗
PubMed2005

Implications of genotype and enzyme phenotype in pyridoxine response of patients with type I primary hyperoxaluria.

BACKGROUND: Marked hyperoxaluria due to liver-specific deficiency of alanine:glyoxylate aminotransferase activity (AGT) characterizes type I primary hyperoxaluria (PHI). Approximately half of PHI patients experience improvement in the degree of hyperoxaluria following pyridoxine (VB6) treatment. Recently, we showed an association between VB6 response and the commonest PHI mutation G170R, with patients possessing one or two copies showing 50% reduction or complete to near complete normalization of oxaluria, respectively. Two patients showed responses varying from this pattern. To further clarify the molecular basis of VB6 response in PHI, we performed additional genotyping. METHODS: 23 PHI patients diagnosed via hepatic enzyme analysis, hyperoxaluria and hyperglycolic aciduria or homozygosity for a known mutation, availability of pre- and post-VB6 24-hour urine oxalate and GFR >40 ml/min/1.73 m2 were included. Data was retrieved retrospectively, oxalate measured by oxalate oxidase, and genotyping performed by PCR-based methods. RESULTS: VB6 response was associated with the G170R and F152I mutations. Eight new sequence changes were detected. CONCLUSIONS: In PHI, two mutations resulting in AGT mistargeting are associated with VB6 response. Whether this favorable effect is specific to the peroxisomal-to-mitochondrial mistargeting caused by these changes or due to another mechanism remains to be determined.

Cohort Studies↗
PubMed2005

Pyridoxine effect in type I primary hyperoxaluria is associated with the most common mutant allele.

BACKGROUND: Pyridoxine (VB6) response in type I primary hyperoxaluria (PHI) is variable, with nearly equal numbers of patients showing partial to complete reductions in oxaluria, and resistance. Because high urine oxalate concentrations cause stones and renal injury, reduction in urine oxalate excretion is deemed favorable. Mechanisms of VB6 action on hepatic alanine:glyoxylate aminotransferase (AGT), the deficient enzyme in PHI, and VB6 dose response have not been well-characterized. METHODS: Sequencing or restriction site-generating polymerase chain reaction (PCR) was used for c.508 genotyping in 23 PHI patients. Pre- and post-VB6 24-hour urine oxalate excretion and VB6 dose were ascertained by retrospective chart review. RESULTS: There were six c.508 G>A homozygotes (AA), eight heterozygotes (GA), and nine patients lacking this change (GG). Pre-VB6 urine oxalate excretion was 152 +/- 39, 203 +/- 68 and 206 +/- 74 mg/1.73 m(2)/24 hours, respectively, and did not differ [AA vs. GA (P= 0.07); AA vs. GG (P= 0.07); GA vs. GG, (P= 0.47)]. Post-VB6 urine oxalate excretion was normal in AA (pre- vs. post-VB6) (P < 0.001), partially reduced in GA (P < 0.001), and unchanged in GG (P= 0.06). Urine oxalate excretion attenuation was similar for VB6 doses (mg/kg/day) of 1 to 4.9, 5 to 9.9, and 10 to 14.9 in AA (P= 0.41, P= 0.28, and P= 0.11, respectively) and GA (P= 0.42, P= 0.39, and P= 0.30, respectively) during follow-up. CONCLUSION: Presence of the c.508 G>A allele confers VB6 response in PHI and VB6 doses of 5 mg/kg/day appear sufficient. c.508 genotyping can be used to predict VB6 response and guide treatment in PHI. [c represents cDNA sequence where nucleotide position +1 corresponds to the adenine (A) of the translation start codon ATG. Equivalent positions based on 5' UTR nucleotide numbering are as follows: c.508 G>A = G630A (Gly170Arg), c.32 C>T = C154T (Pro11Leu), and c.454 T>A = T576A (Phe152Ile)], yields highest residual AGT activity. To test whether VB6 response might be attributable to this allele, we performed c.508 genotyping.

Adolescent↗
PubMed2005

Early subclinical coronary artery calcification in young adults who were pediatric kidney transplant recipients.

Coronary artery disease (CAD) is the leading cause of death in adults after successful kidney transplantation. Children who have undergone successful kidney transplantation are entering young adulthood; however, the prevalence and extent of CAD in this population is unknown. We conducted a pilot study in young adults with stable allograft function, who received kidney transplants as children to measure coronary artery calcification (CAC), a marker of coronary artery atherosclerosis and CAD. We evaluated 19 young adults after successful pediatric kidney transplantation for known CAD risk factors; these patients underwent noninvasive imaging with electron-beam computed tomography (EBCT) for measurement of CAC. Prevalence and quantity of CAC were then compared to asymptomatic individuals from the community. All patients had multiple risk factors for CAD. Mean age at evaluation was 32 years (range: 21-48 years). CAC is uncommon in individuals in the community in this age range; however, nearly half of our patients had CAC detected with the quantity of CAC comparable to asymptomatic individuals from the community 10-40 years older. These data suggest young adults who received pediatric kidney transplants are at increased risk for developing early CAC and need close monitoring to detect early CAD so as to prevent premature cardiac morbidity and mortality.

Adult↗
PubMed2004

Outcomes and complications of pregnancy in women with primary hyperoxaluria.

BACKGROUND: Information about pregnancy in females with primary hyperoxaluria types I and II (PH-I, PH-II) is limited to isolated case reports. This study sought to determine the number and outcomes of pregnancies in a series of women with PH-I and PH-II, to assess the incidence of complications during pregnancy, and to characterize infant outcomes. METHODS: From a database of patients with PH followed at the Mayo Clinic, we identified 16 females who had been pregnant. A retrospective medical record review and telephone survey were performed. RESULTS: Forty pregnancies occurring between 1961 and 1998 were identified: 26 pregnancies in 11 patients with PH-I and 14 pregnancies in 5 patients with PH-II. Thirty (75%) of the pregnancies were carried to term, and 33 infants were born. Four miscarriages, 4 preterm births, and 2 elective abortions occurred. No maternal complications were reported in half of the pregnancies. In the remaining pregnancies, the most common complications were hypertension, urinary tract infection, and urolithiasis-associated symptoms. One PH-I patient developed pre-eclampsia resulting in a stillborn infant, and another PH-1 patient developed hyperemesis gravidarum with a decline in renal function. Approximately 75% of the infants had no perinatal problems. All of the PH-I patients eventually required initiation of renal replacement therapy at a mean of 17.5 years following their first pregnancy. No PH-II patients have required renal replacement therapy. CONCLUSION: Overall, pregnancy appeared to be well tolerated in this series of women with primary hyperoxaluria, with 1 of 16 women experiencing loss of renal function during 1 of 40 pregnancies.

Female↗
PubMed2004

Hand-assisted laparoscopic donor nephrectomy for pediatric kidney allograft recipients.

Laparoscopic donor nephrectomy (LDN) is the method of choice for procuring kidneys from living donors at many transplant centers. The aim of this study was to assess the feasibility as well as outcome of LDN in pediatric recipients. Twenty-two pediatric patients, 18-yr old or younger received kidneys procured by a hand-assisted LDN technique. The mean operative time was no different (p = 0.9) and the mean length of stay was more than 1 day shorter in the LDN group (p = 0.0001) compared with the 13 pediatric patients who received kidneys by standard open nephrectomy. Body mass index (BMI), number of donor kidney vessels, or laterality of the kidney did not impact the donor operation or outcome. Actuarial 1-yr patient survival was 100% and allograft survival was 95%, which are equivalent to registry data. There were no donor mortalities and there were five morbidities. None required hospitalization. There were no conversions from LDN to open nephrectomy. One kidney was lost because of overwhelming infection necessitating withdrawal of immunosuppression. In conclusion, hand-assisted LDN is a safe method of procuring kidneys from potential donors with no significant negative outcomes to the pediatric recipients.

Adolescent↗
PubMed2002

The gene mutated in autosomal recessive polycystic kidney disease encodes a large, receptor-like protein.

Autosomal recessive polycystic kidney disease (ARPKD) is characterized by dilation of collecting ducts and by biliary dysgenesis and is an important cause of renal- and liver-related morbidity and mortality. Genetic analysis of a rat with recessive polycystic kidney disease revealed an orthologous relationship between the rat locus and the ARPKD region in humans; a candidate gene was identified. A mutation was characterized in the rat and screening the 66 coding exons of the human ortholog (PKHD1) in 14 probands with ARPKD revealed 6 truncating and 12 missense mutations; 8 of the affected individuals were compound heterozygotes. The PKHD1 transcript, approximately 16 kb long, is expressed in adult and fetal kidney, liver and pancreas and is predicted to encode a large novel protein, fibrocystin, with multiple copies of a domain shared with plexins and transcription factors. Fibrocystin may be a receptor protein that acts in collecting-duct and biliary differentiation.

Adult↗
PubMed2002

Potential mechanisms of marked hyperoxaluria not due to primary hyperoxaluria I or II.

BACKGROUND: Hyperoxaluria may be idiopathic, secondary, or due to primary hyperoxaluria (PH). Hepatic alanine:glyoxylate aminotransferase (AGT) or glyoxylate/hydroxypyruvate reductase (GR/HPR) deficiency causes PHI or PHII, respectively. Hepatic glycolate oxidase (GO) is a candidate enzyme for a third form of inherited hyperoxaluria. METHODS: Six children were identified with marked hyperoxaluria, urolithiasis, and normal hepatic AGT (N = 5) and GR/HPR (N = 4). HPR was below normal and GR not measured in one. Of an affected sibling pair, only one underwent biopsy. GO mutation screening was performed, and dietary oxalate (Diet(ox)), enteric oxalate absorption (EOA) measured using [13C2] oxalate, renal clearance (GFR), fractional oxalate excretion (FE(ox)) in the children, and urine oxalate in first-degree relatives (FDR) to understand the etiology of the hyperoxaluria. RESULTS: Mean presenting age was 19.2 months and urine oxalate 1.3 +/- 0.5 mmol/1.73 m2/24 h (mean +/- SD). Two GO sequence changes (T754C, IVS3 - 49 C>G) were detected which were not linked to the hyperoxaluria. Diet(ox) was 42 +/- 31 mg/day. EOA was 9.4 +/- 3.6%, compared with 7.6 +/- 1.2% in age-matched controls (P = 0.33). GFR was 90 +/- 19 mL/min/1.73 m2 and FE(ox) 4.2 +/- 1.4. Aside from the two brothers, hyperoxaluria was not found in FDR. CONCLUSIONS: These patients illustrate a novel form of hyperoxaluria and urolithiasis, without excess Diet(ox), enteric hyper-absorption, or hepatic AGT, GR/HPR deficiency. Alterations in pathways of oxalate synthesis, in liver or kidney, or in renal tubular oxalate handling are possible explanations. The affected sibling pair suggests an inherited basis.

Alcohol Oxidoreductases↗