Henrik Birn

Comparison of Bone and Renal Effects In HIV-infected Adults Switching to Abacavir or Tenofovir Based Therapy in a Randomized Trial

Introduction Our objective was to compare the bone and renal effects among HIV-infected patients randomized to abacavir or tenofovir-based combination anti-retroviral therapy. Methods In an open-label randomized trial, HIV-infected patients were randomized to switch from zidovudine/lamivudine (AZT/3TC) to abacavir/lamivudine (ABC/3TC) or tenofovir/emtricitabine (TDF/FTC). We measured bone mass density (BMD) and bone turnover biomarkers (osteocalcin, osteocalcin, procollagen type 1 N-terminal propeptide (P1NP), alkaline phosphatase, type I collagen cross-linked C-telopeptide (CTx), and osteoprotegerin). We assessed renal function by estimated creatinine clearance, plasma cystatin C, and urinary levels of creatinine, albumin, cystatin C, and neutrophil gelatinase-associated lipocalin (NGAL). The changes from baseline in BMD and renal and bone biomarkers were compared across study arms. Results Of 40 included patients, 35 completed 48 weeks of randomized therapy and follow up. BMD was measured in 33, 26, and 27 patients at baseline, week 24, and week 48, respectively. In TDF/FTC-treated patients we observed significant reductions from baseline in hip and lumbar spine BMD at week 24 (−1.8% and −2.5%) and week 48 (−2.1% and −2.1%), whereas BMD was stable in patients in the ABC/3TC arm. The changes from baseline in BMD were significantly different between study arms. All bone turnover biomarkers except osteoprotegerin increased in the TDF/FTC arm compared with the ABC/3TC arm, but early changes did not predict subsequent loss of BMD. Renal function parameters were similar between study arms although a small increase in NGAL was detected among TDF-treated patients. Conclusion Switching to TDF/FTC-based therapy led to decreases in BMD and increases in bone turnover markers compared with ABC/3TC-based treatment. No major difference in renal function was observed. Trial registration Clinicaltrials.gov NCT00647244

Improved GFR and renal plasma perfusion following remote ischaemic conditioning in a porcine kidney transplantation model

Delayed graft function (DGF) complicates approximately 25% of kidney allografts donated after brain death (DBD). Remote ischaemic conditioning (rIC) involves brief, repetitive, ischaemia in a distant tissue in connection with ischaemia/reperfusion in the target organ. rIC has been shown to induce systemic protection against ischaemic injuries. Using a porcine kidney transplantation model with donor (63u2003kg) recipient (15u2003kg) size mismatch, we investigated the effects of recipient rIC on early renal plasma perfusion and GFR. Brain death was induced in donor pigs (nu2003=u20038) and kidneys were removed and kept in cold storage until transplantation. Nephrectomized recipient pigs were randomized to rIC (nu2003=u20038) or non‐rIC (nu2003=u20038) with one kidney from the same donor in each group. rIC consisted of 4u2003×u20035u2003min clamping of the abdominal aorta. GFR was significantly higher in the rIC group compared with non‐rIC (7.2u2003ml/min vs. 3.4u2003ml/min; ΔGFRu2003=u20033.7u2003ml/min, 95%‐CI: 0.3–7.2u2003ml/min, Pu2003=u20030.038). Renal plasma perfusion in both cortex and medulla measured by dynamic contrast‐enhanced magnetic resonance imaging (MRI) was significantly higher over time in the rIC group compared with non‐rIC. This experimental study demonstrated a positive effect of rIC on early graft perfusion and function in a large animal transplantation model.

4-Ethylphenyl-Cobalamin Impairs Tissue Uptake of Vitamin B12 and Causes Vitamin B12 Deficiency in Mice

Coβ-4-ethylphenyl-cob(III) alamin (EtPhCbl) is an organometallic analogue of vitamin B12 (CNCbl) which binds to transcobalamin (TC), a plasma protein that facilitates the cellular uptake of cobalamin (Cbl). In vitro assays with key enzymes do not convert EtPhCbl to the active coenzyme forms of Cbl suggesting that administration of EtPhCbl may cause cellular Cbl deficiency. Here, we investigate the in vivo effect of EtPhCbl in mice and its ability, if any, to induce Cbl deficiency. We show that EtPhCbl binds to mouse TC and we examined mice that received 3.5 nmol/24h EtPhCbl (n=6), 3.5 nmol/24h CNCbl (n=7) or NaCl (control group) (n=5) through osmotic mini-pumps for four weeks. We analyzed plasma, urine, liver, spleen, submaxillary glands and spinal cord for Cbl and markers of Cbl deficiency including methylmalonic acid (MMA) and homocysteine (tHcy). Plasma MMA (mean±SEM) was elevated in animals treated with EtPhCbl (1.01±0.12 µmol/L) compared to controls (0.30±0.02 µmol/L) and CNCbl (0.29±0.01 µmol/L) treated animals. The same pattern was observed for tHcy. Plasma total Cbl concentration was higher in animals treated with EtPhCbl (128.82±1.87 nmol/L) than in CNCbl treated animals (87.64±0.93 nmol/L). However, the organ levels of total Cbl were significantly lower in animals treated with EtPhCbl compared to CNCbl treated animals or controls, notably in the liver (157.07±8.56 pmol/g vs. 603.85±20.02 pmol/g, and 443.09±12.32 pmol/g, respectively). Differences between the three groups was analysed using one-way ANOVA and, Bonferroni post-hoc test. EtPhCbl was present in all tissues, except the spinal cord, accounting for 35-90% of total Cbl. In conclusion, treatment with EtPhCbl induces biochemical evidence of Cbl deficiency. This may in part be caused by a compromised tissue accumulation of Cbl.

Maximal Load of the Vitamin B12 Transport System: A Study on Mice Treated for Four Weeks with High-Dose Vitamin B12 or Cobinamide

Several studies suggest that the vitamin B12 (B12) transport system can be used for the cellular delivery of B12-conjugated drugs, also in long-term treatment Whether this strategy will affect the endogenous metabolism of B12 is not known. To study the effect of treatment with excess B12 or an inert derivative, we established a mouse model using implanted osmotic minipumps to deliver saline, cobinamide (Cbi) (4.25 nmol/h), or B12 (1.75 nmol/h) for 27 days (nu200a=u200a7 in each group). B12 content and markers of B12 metabolism were analysed in plasma, urine, kidney, liver, and salivary glands. Both Cbi and B12 treatment saturated the transcobalamin protein in mouse plasma. Cbi decreased the content of B12 in tissues to 33–50% of the level in control animals but did not influence any of the markers examined. B12 treatment increased the tissue B12 level up to 350%. In addition, the transcript levels for methylenetetrahydrofolate reductase in kidneys and for transcobalamin and transcobalamin receptor in the salivary glands were reduced. Our study confirms the feasibility of delivering drugs through the B12 transport system but emphasises that B12 status should be monitored because there is a risk of decreasing the transport of endogenous B12. This risk may lead to B12 deficiency during prolonged treatment.

Vitamin B12 dependent changes in mouse spinal cord expression of vitamin B12 related proteins and the epidermal growth factor system

Chronic vitamin B12 (cobalamin) deficiency in the mammalian central nervous system causes degenerative damage, especially in the spinal cord. Previous studies have shown that cobalamin status alters spinal cord expression of epidermal growth factor (EGF) and its receptor in rats. Employing a mouse model of cobalamin-depletion and loading, we have explored the influence of Cbl status on spinal cord expression of cobalamin related proteins, as well as all four known EGF receptors and their activating ligands. Following four weeks of osmotic minipump infusion (n=7 in each group) with cobinamide (4.25nmol/h), saline or cobalamin (1.75nmol/h) the spinal cords were analyzed for cobalamin and for the mRNA levels of cobalamin related proteins and members of the EGF system using quantitative reverse transcription PCR. The median spinal cord cobalamin content was 17, 32, and 52pmol/gr of tissues in cobinamide, saline, and cobalamin treated animals, respectively. Both cobinamide and cobalamin induced a significant decrease in the expression of the lysosomal membrane cobalamin transporter. All four EGF receptors and their activating ligands, except for EGF, were expressed in the spinal cord. Notably, the expression of one of the EGF receptors, HER3, and the ligands heparin-binding EGF-like growth factor, transforming growth factor-α, and neuregulins 1α was increased in cobalamin treated mice. Our studies show that four weeks treatment of mice with cobinamide induces spinal cord cobalamin depletion and that cobalamin loading induces an altered expression pattern of the EGF system thus confirming a spinal cord cross talk between Cbl and the EGF system.

Long-term risk of renal and urinary tract diseases in childhood cancer survivors: A population-based cohort study

BACKGROUNDnChildhood cancer has been associated with long-term risk of urinary tract diseases, but risk patterns remain to be comprehensively investigated. We analysed the lifetime risk of urinary tract diseases in survivors of childhood cancer in the Nordic countries.nnnMETHODSnWe identified 32,519 one-year survivors of childhood cancer diagnosed since the 1940s and 1950s in the five Nordic cancer registries and selected 211,156 population comparisons of a corresponding age, sex, and country of residence from the national population registries. To obtain information on all first-time hospitalizations for a urinary tract disease, we linked all study subjects to the national hospital registry of each country. Relative risks (RRs) and absolute excess risks (AERs) and associated 95% confidence intervals (CIs) for urinary tract diseases among cancer survivors were calculated with the appropriate morbidity rates among comparisons as reference.nnnRESULTSnWe observed 1645 childhood cancer survivors ever hospitalized for urinary tract disease yielding an RR of 2.5 (95% CI 2.4-2.7) and an AER of 229 (95% CI 210-248) per 100,000 person-years. The cumulative risk at age 60 was 22% in cancer survivors and 10% in comparisons. Infections of the urinary system and chronic kidney disease showed the highest excess risks, whereas survivors of neuroblastoma, hepatic and renal tumours experienced the highest RRs.nnnCONCLUSIONnSurvivors of childhood cancer had an excess risk of urinary tract diseases and for most diseases the risk remained elevated throughout life. The highest risks occurred following therapy of childhood abdominal tumours.

Should all adult patients with diarrhoea-associated HUS receive plasma exchange?

www.thelancet.com Vol 379 February 11, 2012 515 Submissions should be made via our electronic submission system at http://ees.elsevier.com/ thelancet/ complications, and should be compared with supportive therapy alone. We report the outcome in a series of four unselected adult patients admitted to centres in which plasma exchange was not standard treatment during the 2011 outbreak of diarrhoea-associated HUS in northern Europe. The patients (mean age 40·3 years [range 23–49]; two male, two female) were admitted with bloody diarrhoea and HUS. Stool cultures, identifying toxin-producing Escherichia coli O104:H4, were obtained in three patients; the fourth had visited Germany recently. Renal failure was identifi ed a mean of 8 days (range 7–9) after fi rst symptoms. Average minimum estimated glomerular fi ltration rate was 46 mL/min per 1·73 m2 (range 20–65). All patients recovered renal function after 1–7 days, and no patient developed the need for dialysis. Platelets normalised within a mean of 3·8 days (range 3–5). In conclusion, we report a benign outcome in unselected, adult patients not receiving plasma exchange. This fi nding should be taken into consideration when the positive outcome after plasma exchange is assessed. The outbreak in Germany resulted in the admission of patients at several centres and should allow for comparison of outcome between centres that routinely use plasma exchange and those, such as ours, that do not. Considering the absence of randomised controlled trials, we strongly encourage such a comparison before any conclusion about the potential benefi ts of plasma exchange is made.

Giardia lamblia infection after pancreas-kidney transplantation

Infection is a common complication of solid organ transplantation. It is associated with an increased risk of acute cellular rejection and loss of graft function. The most common infections are due to bacteria and viruses, including transmission of cytomegalovirus from donor to recipient. In the past years, an increasing number of parasitic infections have been documented in transplant recipients. We describe the first reported case of intestinal Giardia lamblia transmission following simultaneous pancreas and kidney transplantation.

A new method of modelling early plasma creatinine changes predicts 1-year graft function after kidney transplantation

Abstract Background: Delayed graft function after renal transplantation is associated with inferior long-term outcome. To evaluate the impact of slow onset graft function, we aimed to model and correlate early changes in plasma creatinine (p-cr) with long-term graft function. Materials: In a single centre observational study of 100 kidney transplants we identified all p-cr measurements from the time of transplantation until 30 days post-transplant or last post-transplant dialysis, and correlated this with estimated glomerular filtration rate (eGFR) 1 year after transplantation. The initial changes in p-cr were modelled for each patient using an exponential, logistic, or linear model, and the time to a 50% decrease in p-cr (tCr50) was estimated. Results: Linear regression analysis showed a negative correlation between tCr50 and eGFR 1 year post-transplant (nu2009=u200996, r = −0.369, β = −0.112, pu2009=u20090.0002). The correlation was maintained when corrected for the relevant recipient and donor characteristics. tCr50 correlated positively with the number of hospitalisation days, the number of graft ultrasound examinations, and the number of biopsies. Conclusions: A modelled time to a 50% decrease in p-cr predicts 1-year graft function. tCr50 may be a relevant surrogate endpoint in renal transplant studies aimed at improving long-term function by reducing the incidence of slow onset graft function.

A case report of hereditary apolipoprotein A-I amyloidosis associated with a novel APOA1 mutation and variable phenotype.

Apolipoprotein A-I (apo A-I) amyloidosis is a non-AL, non-AA, and non-transthyretin type of amyloidosis associated with mutations in the APOA1 gene inherited in an autosomal dominant fashion. It is a form of systemic amyloidosis, but at presentation, can also mimic localized amyloidosis. The renal presentation generally involves interstitial and medullary deposition of apo A-I amyloid protein. We describe the identification of apo A-I amyloidosis by mass spectrometry in a 52-year old male, with no family history of amyloidosis, presenting with nephrotic syndrome and associated with heterozygosity for a novel APOA1 mutation (c.220xa0Txa0>xa0A) which encodes the known amyloidogenic Trp50Arg variant. Renal amyloid deposits in this case were confined to the glomeruli alone, and the patient developed progressive renal impairment. One year after diagnosis, the patient had a successful kidney transplant from an unrelated donor. Pathogenic mutations in the APOA1 gene are generally associated with symptoms of amyloidosis. In this family however, genotyping of family members identified several unaffected carriers suggesting a variable disease penetrance, which has not been described before in this form of amyloidosis and has implications when counselling those with APOA1 mutations.