M. V. Pahl

Renal magnesium wasting associated with amphotericin B therapy

The effect of amphotericin B on magnesium metabolism was studied in 10 patients (aged 30 to 68 years) with systemic fungal infections. Renal magnesium wasting resulting in mild to moderate hypomagnesemia was demonstrated by the second week of therapy following relatively small cumulative dosages of amphotericin B (208 +/- 40 mg). The lowest serum levels and largest fractional excretions of magnesium were observed by the fourth week of therapy after cumulative dosages of 510 +/- 118 mg. A plateauing of the renal magnesium wasting is suggested, as there were no further increases or reductions in fractional magnesium excretion and serum magnesium level, respectively, despite continued amphotericin B administration. Reversibility of the magnesium wasting is indicated by data in three of the patients approximately one year following discontinuation of amphotericin B therapy, in whom the serum magnesium level and fractional magnesium excretion had returned to pretreatment baseline values. Although the available data do not allow precise localization of this defect, increased urinary excretion of magnesium despite its reduced filtered load suggests a tubular defect in magnesium reabsorption. Therefore, routine monitoring of the serum magnesium level during treatment with amphotericin B is recommended.

Effects of end-stage renal disease and haemodialysis on dendritic cell subsets and basal and LPS-stimulated cytokine production

BACKGROUND Although bacterial infections have dramatically declined as a cause of death in the general population, they remain a major cause of mortality in patients with end-stage renal disease (ESRD). Moreover, the response to vaccination is profoundly impaired in this population. Dendritic cells (DC) are the major antigen-presenting cells that bridge the innate and adaptive immune responses. Activation of DC by pathogens results in secretion of inflammatory cytokines and up-regulation of co-stimulatory molecules. The activated DC prime naïve T and B cells to the captured antigens. METHODS Using flow cytometry, the number and phenotype of circulating DC [myeloid DC (mDC) and plasmacytoid DC (pDC)] were quantified in pre- and post-dialysis blood samples from 20 ESRD patients maintained on haemodialysis. Ten normal individuals served as controls. In addition, the level of DC activation and their response to lipopolysaccharide (LPS) stimulation were determined by assessing expression of co-stimulatory molecule, CD86, and antigen-presenting molecule, HLA-DR, as well as production of TNFalpha, IFNalpha and IL-6. RESULTS Compared to the control group, the circulating dendritic cell count was significantly reduced in the ESRD patients before dialysis and declined further after dialysis. The reduction in pDC numbers was more striking than mDC. The magnitude of the LPS-induced up-regulation of CD86 was comparable among the study groups as well as pre- and post-dialysis samples. However, LPS-induced TNFalpha production was significantly reduced in the post-dialysis samples with no significant difference in IL-6 and IFNalpha productions among the study groups and in pre- and post-dialysis samples. CONCLUSIONS ESRD results in significant DC depletion which is largely due to diminished plasmacytoid DC subset. Haemodialysis procedure intensifies DC depletion and impairs LPS-induced TNFalpha production.

Genomewide Linkage Scan for Diabetic Renal Failure and Albuminuria: The FIND Study

Background: Diabetic nephropathy (DN) is a leading cause of mortality and morbidity in patients with type 1 and type 2 diabetes. The multicenter FIND consortium aims to identify genes for DN and its associated quantitative traits, e.g. the urine albumin:creatinine ratio (ACR). Herein, the results of whole-genome linkage analysis and a sparse association scan for ACR and a dichotomous DN phenotype are reported in diabetic individuals. Methods: A genomewide scan comprising more than 5,500 autosomal single nucleotide polymorphism markers (average spacing of 0.6 cM) was performed on 1,235 nuclear and extended pedigrees (3,972 diabetic participants) ascertained for DN from African-American (AA), American-Indian (AI), European-American (EA) and Mexican-American (MA) populations. Results: Strong evidence for linkage to DN was detected on chromosome 6p (p = 8.0 × 10–5, LOD = 3.09) in EA families as well as suggestive evidence for linkage to chromosome 7p in AI families. Regions on chromosomes 3p in AA, 7q in EA, 16q in AA and 22q in MA displayed suggestive evidence of linkage for urine ACR. The linkage peak on chromosome 22q overlaps the MYH9/APOL1 gene region, previously implicated in AA diabetic and nondiabetic nephropathies. Conclusion: These results strengthen the evidence for previously identified genomic regions and implicate several novel loci potentially involved in the pathogenesis of DN.

Toxicity with Intravenous Injection of Crude Marijuana Extract

Intravenous injection of crude marijuana extract led to development of an acute illness with multisystem involvement. Gastrointestinal manifestations consisted of severe vomiting, diarrhea, and crampy abdominal pain. Hypotension, tachycardia, and peripheral vasodilation constituted the main cardiovascular manifestations of the disease. Moderate azotemia and oliguria, presumed to be of prerenal origin, were present and rapidly resolved with administration of intravenous fluids. Hematologic manifestations consisted of leukocytosis with a left shift, thrombocytopenia, prolonged partial thromboplastin time, increased fibrin degradation products, and positive protamine sulfate test. The observed coagulation abnormalities may suggest intravascular coagulation. C3, C4, and total hemolytic complement were reduced, suggesting possible activation of the complement system. Hyperventilation, hypoxemia, pulmonary edema, obstructive, and restrictive pulmonary function abnormalities and bilateral pleural effusions highlighted the pulmonary manifestations of the disease. Rhadbomyolysis and mild hepatic function abnormalities were also present. All observed abnormalities reversed in a few days with no significant sequelae.

A Genome-Wide Search for Linkage of Estimated Glomerular Filtration Rate (eGFR) in the Family Investigation of Nephropathy and Diabetes (FIND)

Objective Estimated glomerular filtration rate (eGFR), a measure of kidney function, is heritable, suggesting that genes influence renal function. Genes that influence eGFR have been identified through genome-wide association studies. However, family-based linkage approaches may identify loci that explain a larger proportion of the heritability. This study used genome-wide linkage and association scans to identify quantitative trait loci (QTL) that influence eGFR. Methods Genome-wide linkage and sparse association scans of eGFR were performed in families ascertained by probands with advanced diabetic nephropathy (DN) from the multi-ethnic Family Investigation of Nephropathy and Diabetes (FIND) study. This study included 954 African Americans (AA), 781 American Indians (AI), 614 European Americans (EA) and 1,611 Mexican Americans (MA). A total of 3,960 FIND participants were genotyped for 6,000 single nucleotide polymorphisms (SNPs) using the Illumina Linkage IVb panel. GFR was estimated by the Modification of Diet in Renal Disease (MDRD) formula. Results The non-parametric linkage analysis, accounting for the effects of diabetes duration and BMI, identified the strongest evidence for linkage of eGFR on chromosome 20q11 (log of the odds [LOD] = 3.34; P = 4.4×10−5) in MA and chromosome 15q12 (LOD = 2.84; P = 1.5×10−4) in EA. In all subjects, the strongest linkage signal for eGFR was detected on chromosome 10p12 (P = 5.5×10−4) at 44 cM near marker rs1339048. A subsequent association scan in both ancestry-specific groups and the entire population identified several SNPs significantly associated with eGFR across the genome. Conclusion The present study describes the localization of QTL influencing eGFR on 20q11 in MA, 15q21 in EA and 10p12 in the combined ethnic groups participating in the FIND study. Identification of causal genes/variants influencing eGFR, within these linkage and association loci, will open new avenues for functional analyses and development of novel diagnostic markers for DN.

Association of beta hydroxybutyric acidosis with isoniazid intoxication.

Acute metabolic acidosis associated with accumulation of lactate has been previously reported in isoniazid (INH) intoxication. To our knowledge, association of INH toxicity with beta-hydroxybutyric acidosis has not been demonstrated previously. The present report documents the occurrence of beta-hydroxybutyric acidosis in patients with INH intoxication. The reason for the lack of previous reports of this association is not clear, although failure to measure plasma beta-hydroxybutyrate levels in previous studies is a likely possibility. Our patients received intravenous sodium bicarbonate, anticonvulsants and dialysis which resulted in complete reversal of metabolic acidosis and other manifestations of INH toxicity.

In-vivo and In-vitro hemodialysis studies of thiocyanate

Dialysis clearance of thiocyanate was studied using in-vivo and in-vitro systems. The in-vivo studies were performed in a patient with renal failure receiving sodium nitroprusside infusion for accelerated hypertension. In-vitro studies were carried out under experimental conditions similar to those of the in-vivo experiment. Plasma thiocyanate level consistently fell with single passage through the dialyzer. In-vivo dialysance of thiocyanate averaged 82.8 ml/min as compared to urea dialysance of 129.6 ml/min. The in-vitro studies revealed an average thiocyanate dialysance of 102.3 as compared to a urea dialysance of 138.6 ml/min. Removal of thiocyanate by hemodialysis was further verified by recovery of significant amounts of thiocyanate in the outgoing dialysate. The thiocyanate clearance calculated directly from the amount recovered in the dialysate and mean plasma concentration was 82.2 ml/min, a value closely approximating that obtained using the transdialyzer concentration gradient. We conclude that hemodialysis is effective in removing thiocyanate and can be used as adjunct in the treatment of thiocyanate toxicity particularly in the presence of renal failure in which thiocyanate excretion is impaired.

Clinicopathological Characteristics of Dialysis Patients with Spinal Cord Injury

Forty-three spinal cord injured patients with endstage renal disease (ESRD) maintained on hemodialysis were studied. The most prevalent renal lesions consisted of chronic pyelonephritis and amyloidosis while the main renal functional features included nephrotic range proteinuria, high urine output and relatively low serum creatinine for the degree of renal insufficiency. Normocytic, normochromic anemia with low reticulocyte response, low serum iron and iron binding capacity and high transfusion requirement and serum ferritin were noted. Various cardiovascular, pulmonary and gastrointestinal abnormalities were found with considerable frequencies. The incidence of amyloidosis was much higher than that reported previously. This is thought to be due to continued progression of amyloidosis occasioned by longer survival in the present series.

Iron indices and survival in maintenance hemodialysis patients with and without polycystic kidney disease

BACKGROUND Anemia is less prominent in patients with polycystic kidney disease (PKD). Such iron indices as ferritin and transferrin saturation (TSAT) values are used to guide management of anemia in individuals on maintenance hemodialysis (MHD). Optimal levels of correction of anemia and optimal levels of TSAT and ferritin are unclear in chronic kidney disease patients and have not been studied specifically in PKD. METHODS We studied 2969 MHD patients with and 128 054 patients without PKD from 580 outpatient hemodialysis facilities between July 2001 and June 2006. Using baseline, time-dependent and time-averaged values with unadjusted and multivariable adjusted analysis models, the survival predictabilities of TSAT and ferritin were studied. RESULTS PKD patients were 58 ± 13 years old and included 46% women, whereas non-PKD patients were 62 ± 15 years old and 45% women. In both PKD and non-PKD patients, a time-averaged TSAT between 30 and 40% was associated with the lowest mortality. Time-averaged ferritin between 100 and <800 ng/mL was associated with the lowest mortality in PKD patients, although this range was 500 to <800 ng/mL in non-PKD patients. CONCLUSIONS In MHD patients with and without PKD, there was a U-shaped relationship between the average TSAT and mortality, and a TSAT of 30-40% was associated with the best survival. However, an average ferritin of 100-800 ng/mL was associated with the best survival in PKD patients, whereas that of non-PKD patients was 500-800 ng/mL. Further studies in PKD and non-PKD patients are necessary to determine whether or not therapeutic attempts to keep TSAT and ferritin levels in these ranges will improve survival.

Intestinal transport of pyrodoxine in experimental renal failure

Renal failure (RF) has been shown to alter intestinal transport of a number of nutrients. We studied jejunal absorption of pyridoxine (B6) in rats rendered azotemic by subtotal nephrectomy (RF group) and compared the results with those obtained in normal rats subjected to sham operation (controls) and animals pair-fed (PF) with their RF counterparts. In vivo recirculating perfusion and in vitro everted sac techniques were employed. The in vitro experiments were repeated using sera from uremic and normal individuals to assess the possible effect of uremic chemical environment. The results showed significant reduction in B6 absorption in vivo in the RF group as compared to the control and PF groups. Paradoxically, the rate of in vitro B6 absorption determined for a wide range of concentrations was increased in the RF and PF groups as compared to the control group. The observed increase in B6 absorption in vitro suggests enhanced permeability in the RF and PF groups due probably to reduced nutrient intake which was common to both groups. The disparity between the in vivo and in vitro results is indicative of some inhibitory factor(s) present in the RF animals. Sacs containing uremic serum showed significantly suppressed B6 absorption in vitro as compared to those containing normal serum. These observations suggest that the uremic chemical environment may be, in part, responsible for the observed impairment of B6 transport in RF animals despite in vitro evidence of hyperpermeability.