Hypomagnesemia in type 2 diabetic nephropathy: a novel predictor of end-stage renal disease

OBJECTIVE

There is now growing evidence that magnesium (Mg) deficiency is implicated in type 2 diabetes and its complications. However, it has not been fully elucidated whether hypomagnesemia is a predictor of end-stage renal disease (ESRD) in type 2 diabetic nephropathy.

RESEARCH DESIGN AND METHODS

This retrospective cohort study included 455 chronic kidney disease (CKD) patients (144 with type 2 diabetic nephropathy and 311 with nondiabetic CKD) who were hospitalized at Osaka General Medical Center for a CKD educational program between April 2001 and December 2007. The primary outcome was progression to renal replacement therapy. Participants were categorized based on serum Mg level into Low-Mg (serum Mg level ≤1.8 mg/dL) and High-Mg (serum Mg level >1.8 mg/dL) groups with the previously published normal lower limit chosen as the cutoff point.

RESULTS

Of the subjects with type 2 diabetic nephropathy, 102 progressed to ESRD during follow-up (median, 23 months). A multivariate Cox proportional hazards model showed that after adjustment for various demographic factors and laboratory data, the Low-Mg group had a 2.12-fold higher risk of ESRD than the High-Mg group (95% CI 1.28–3.51; P = 0.004). In contrast, 135 of the nondiabetic CKD subjects progressed to ESRD during follow-up (median, 44 months). No significant difference in outcome was found between the Low- and High-Mg groups of this population (adjusted hazard ratio, 1.15; 95% CI 0.70–1.90; P = 0.57).

CONCLUSIONS

Hypomagnesemia is a novel predictor of ESRD in patients with type 2 diabetic nephropathy.Magnesium (Mg) is the fourth most abundant cation in the human body and plays a key role in many fundamental biological processes, including energy metabolism and DNA synthesis. Mg deficiency has been shown to cause endothelial cell dysfunction, inflammation, and oxidative stress, which are major contributors to atherosclerosis (1–3). Some epidemiologic studies have reported associations between low Mg intake or serum Mg level and hypertension, coronary artery disease, and ischemic stroke (4–6).Mg and type 2 diabetes have a close relationship. Approximately one-third of patients with type 2 diabetes have hypomagnesemia, mainly caused by enhanced renal excretion (7). Mg deficiency is associated with poor glycemic control, and Mg supplementation improves insulin sensitivity (8). Moreover, there is substantial evidence of associations between hypomagnesemia and various complications of type 2 diabetes, including neuropathy, retinopathy, foot ulcers, and albuminuria (9–12). The relationship between Mg deficiency and advanced type 2 diabetic nephropathy, however, remains to be fully elucidated. Pham et al. (13) reported that serum Mg level was significantly associated with the slope of inverse serum creatinine (SCr) in type 2 diabetes with near-normal renal function. However, they failed to show a significant association between hypomagnesemia and hard renal outcome (doubling of SCr and initiation of renal replacement therapy [RRT]), probably due to low statistical power (14). Therefore, the aim of the current study was to determine whether hypomagnesemia is a predictor of end-stage renal disease (ESRD) in patients with advanced type 2 diabetic nephropathy. We also compared the impact of hypomagnesemia on renal outcome in type 2 diabetic nephropathy with that in nondiabetic chronic kidney disease (CKD).     

Effects of chromium and nitrogen content on the microstructures and mechanical properties of as-cast Co-Cr-Mo alloys for dental applications

The microstructure and mechanical properties of as-cast Co-(20-33)Cr-5Mo-N alloys were investigated to develop ductile Co-Cr-Mo alloys without Ni addition for dental applications that satisfy the requirements of the type 5 criteria in ISO 22674. The effects of the Cr and N contents on the microstructure and mechanical properties are discussed. The microstructures were evaluated using scanning electron microscopy with energy-dispersive X-ray spectroscopy (EDS), X-ray diffractometry (XRD), and electron back-scattered diffraction pattern analysis. The mechanical properties were evaluated using tensile testing. The proof strength and elongation of N-containing 33Cr satisfied the type 5 criteria in ISO 22674. ε-phase with striations was formed in the N-free (20-29)Cr alloys, while there was slight formation of ε-phase in the N-containing (20-29)Cr alloys, which disappeared in N-containing 33Cr. The lattice parameter of the γ-phase increased with increasing Cr content (i.e. N content) in the N-containing alloys, although the lattice parameter remained almost the same in the N-free alloys because of the small atomic radius difference between Co and Cr. Compositional analyses by EDS and XRD revealed that in the N-containing alloys Cr and Mo were concentrated in the cell boundary, which became enriched in N, stabilizing the γ-phase. The mechanical properties of the N-free alloys were independent of the Cr content and showed low strength and limited elongation. Strain-induced martensite was formed in all the N-free alloys after tensile testing. On the other hand, the proof strength, ultimate tensile strength, and elongation of the N-containing alloys increased with increasing Cr content (i.e. N content). Since formation of ε-phase after tensile testing was confirmed in the N-containing alloys the deformation mechanism may change from strain-induced martensite transformation to another form, such as twinning or dislocation slip, as the N content increases. Thus the N-containing 33Cr alloy with large elongation is promising for use in dentures with adjustable clasps through one piece casting.     

Pseudorenal failure due to intraperitoneal bladder rupture after blunt trauma: usefulness of examining ascitic fluid sediment

A 42-year-old man noted decreased urine output and visited our emergency department. He said that 3 days previously, he had gotten drunk and fallen down a set of stairs. Blood tests and abdominal contrast-enhanced computed tomography revealed no abnormalities. A serum creatinine level of 5.89 mg/dL led to a diagnosis of acute renal failure and his hospitalization. After admission, his ascitic fluid level gradually increased, suggesting urine leakage into the peritoneal cavity. Microscopic examination of his ascitic fluid sediment revealed the presence of hyaline casts enclosing renal tubular epithelial cells. Cystography demonstrated contrast medium leakage into the peritoneal cavity, which led to a diagnosis of bladder rupture. Examination of ascitic fluid sediment is simple and very useful for diagnosing bladder rupture.     

Dialysate purification after introduction of automated hot water disinfection system to central dialysis fluid delivery system

Most dialysis clinics in Japan have mainly adopted the central dialysis fluid delivery system (CDDS) to provide constant treatment to many patients. Chemical disinfection is the major maintenance method of the CDDS. Our clinic introduced an automated hot water disinfection system that used the heat conduction effect to disinfect a reverse osmosis (RO) device and dialysis fluid supply equipment. Endotoxin level and the amount of viable bacteria often showed abnormal values before introduction of this system. After its introduction, weekly disinfection resulted in endotoxin levels and the amount of viable bacteria lower than measurement sensitivity. In hot water disinfection, water heated to 90°C in the RO tank flows into the dialysis fluid supply equipment. The maximum temperature inside the tank of the supply equipment is 86.3°C. (We confirmed that the temperature was maintained at 80°C or more for 10 minutes or more during the monitoring.) Dialysate purification was maintained even after introduction of the automated hot water disinfection system and the dialysate could be supplied stably by the CDDS. Therefore, this disinfection system might be very useful in terms of both cost and safety, and can be used for dialysis treatment of multiple patients.     

Treatment of a mouse model of spinal cord injury by transplantation of human induced pluripotent stem cell-derived long-term self-renewing neuroepithelial-like stem cells

Because of their ability to self-renew, to differentiate into multiple lineages, and to migrate toward a damaged site, neural stem cells (NSCs), which can be derived from various sources such as fetal tissues and embryonic stem cells, are currently considered to be promising components of cell replacement strategies aimed at treating injuries of the central nervous system, including the spinal cord. Despite their efficiency in promoting functional recovery, these NSCs are not homogeneous and possess variable characteristics depending on their derivation protocols. The advent of induced pluripotent stem (iPS) cells has provided new prospects for regenerative medicine. We used a recently developed robust and stable protocol for the generation of long-term, self-renewing, neuroepithelial-like stem cells from human iPS cells (hiPS-lt-NES cells), which can provide a homogeneous and well-defined population of NSCs for standardized analysis. Here, we show that transplanted hiPS-lt-NES cells differentiate into neural lineages in the mouse model of spinal cord injury (SCI) and promote functional recovery of hind limb motor function. Furthermore, using two different neuronal tracers and ablation of the transplanted cells, we revealed that transplanted hiPS-lt-NES cell-derived neurons, together with the surviving endogenous neurons, contributed to restored motor function. Both types of neurons reconstructed the corticospinal tract by forming synaptic connections and integrating neuronal circuits. Our findings indicate that hiPS-lt-NES transplantation represents a promising avenue for effective cell-based treatment of SCI.     

Rapid clearance of supplemented tetrahydrobiopterin is driven by high-capacity transporters in the kidney

Tetrahydrobiopterin (BH(4)) is an essential cofactor of aromatic amino acid hydroxylases and NO synthase. Supplementation of BH(4) potentially targets cardiovascular dysfunction as well as inherited BH(4) deficiencies and BH(4)-responsive phenylketonuria. However, the high cost/effect ratio of the recommended daily dose of BH(4) supplementation acts against further popularization of this therapy. The aim of this study was to attenuate urinary excretion with the intention of improving efficacy of BH(4) supplementation. The rapid excretion of BH(4) in the urine was confirmed to be the major route of supplemented BH(4) loss. In addition to glomerular filtration into the urine, a dominant rapid exclusion by renal secretion was observed in rats (T((1/2))=16 min) when the plasma BH(4) was higher than about 1 nmol/mL (more than 10 times higher than normal), due to BH(4) supplementation. The rapidity of the process was slowed by prior administration of cyclosporin A, a representative anti-excretory drug, and the excretion decelerated to a moderate rate (T((1/2))=53 min). By the combined administration of BH(4) plus cyclosporin A, the blood BH(4) levels were dramatically elevated. It was hypothesized that the drug interfered with kidney excretion of BH(4) rather than by attenuating organ tissue distribution by inhibiting biopterin uptake from the plasma. Consistent with this hypothesis, biopterin levels after BH(4) administration were elevated in major organs in the presence of anti-excretory drugs without notable change in their BH(4) fraction which was consistently 95% or higher regardless of combined administration with the drugs. Targeting these putative transporters would be a promising approach for improving the efficiency of BH(4) supplementation therapy.     

Peutz–Jeghers syndrome-associated atypical mucinous proliferation of the uterine cervix: A case of minimal deviation adenocarcinoma (‘adenoma malignum’) in situ

We describe a case of a non-invasive precursor of minimal deviation adenocarcinoma (MDA) of the uterine cervix, associated with Peutz–Jeghers syndrome (PJS). A 27-year-old woman, who had been followed for PJS, was referred to the gynecology clinic. Colposcopic examination demonstrated a small polypoid lesion in the transformation zone. Microscopic examination of the biopsy specimen demonstrated papillary proliferation of the mucinous epithelium with bland nuclear morphology. Conization revealed lobular endocervical glandular hyperplasia (LEGH) with distinct nuclear anaplasia, as well as papillary proliferation of the mucinous epithelium with mild to moderate nuclear abnormalities. This case suggests that the incipient phase of PJS-associated MDA is related to atypical LEGH (“MDA in situ”), and indicates the importance of early screening and surveillance by gynecologists in cases of PJS to detect cervical adenocarcinomas.     

Anococcygeal raphe revisited: a histological study using mid-term human fetuses and elderly cadavers

Purpose

We recently demonstrated the morphology of the anococcygeal ligament. As the anococcygeal ligament and raphe are often confused, the concept of the anococcygeal raphe needs to be re-examined from the perspective of fetal development, as well as in terms of adult morphology.

Materials and Methods

We examined the horizontal sections of 15 fetuses as well as adult histology. From cadavers, we obtained an almost cubic tissue mass containing the dorsal wall of the anorectum, the coccyx and the covering skin. Most sections were stained with hematoxylin and eosin or Masson-trichrome solution.

Results

The adult ligament contained both smooth and striated muscle fibers. A similar band-like structure was seen in fetuses, containing: 1) smooth muscle fibers originating from the longitudinal muscle coat of the anal canal and 2) striated muscle fibers from the external anal sphincter (EAS). However, in fetuses, the levator ani muscle did not attach to either the band or the coccyx. Along and around the anococcygeal ligament, we did not find any aponeurotic tissue with transversely oriented fibers connecting bilateral levator ani slings. Instead, in adults, a fibrous tissue mass was located at a gap between bilateral levator ani slings; this site corresponded to the dorsal side of the ligament and the EAS in the immediately deep side of the natal skin cleft.

Conclusion

We hypothesize that a classically described raphe corresponds to the specific subcutaneous tissue on the superficial or dorsal side of the anococcygeal ligament.