Anthony G.W. Norden

Remote Ischemic Preconditioning for Renal and Cardiac Protection during Endovascular Aneurysm Repair: A Randomized Controlled Trial

Purpose: To report a randomized clinical trial designed to determine if remote ischemic preconditioning (IP) has the ability to reduce renal and cardiac damage following endovascular aneurysm repair (EVAR). Methods: Forty patients (all men; mean age 76±7 years) with abdominal aortic aneurysms averaging 6.3±0.8 cm in diameter were enrolled in the trial from November 2006 to January 2008. Eighteen patients (mean age 74 years, range 72–81) were randomized to preconditioning and completed the full remote IP protocol; there were no withdrawals. Twenty-two patients (mean age 76 years, range 66–80) were assigned to the control group. Remote IP was induced using sequential lower limb ischemia. Serum and urinary markers of renal and cardiac injury were compared between the groups. Results: Urinary retinol binding protein (RBP) levels increased 10-fold from a median of 235 µmol/L to 2356 µmol/L at 24 hours (p=0.0001). There was a lower increase in the preconditioned group, from 167 µmol/L to 413 µmol/L at 24 hours (p=0.04). The median urinary albumin:creatinine ratio was significantly lower in the preconditioned group at 24 hours (5 versus 8.8, p=0.06). There were no differences in the rates of renal impairment or major adverse cardiac events. Conclusion: Remote preconditioning reduces urinary biomarkers of renal injury in patients undergoing elective EVAR. This small pilot trial was unable to detect an effect on clinical endpoints; further trials are warranted.

Detection and analysis of urinary peptides by on-line liquid chromatography and mass spectrometry: application to patients with renal Fanconi syndrome.

Urinary proteomics has become a topical and potentially valuable field of study in relation to normal and abnormal renal function. Filtered bioactive peptides present in high concentration in the nephron of patients with tubular proteinuria may have downstream effects on renal tubular function. In renal Fanconi syndromes, such as Dents disease, peptides implicated in altered tubular function or injury have recently been measured in urine by immunochemical methods. However, the limited availability of antibodies means that only certain peptides can be detected in this way. We have used nanoflow liquid chromatography and tandem mass spectrometry (nanoLC-MS/MS) as a complementary technique to analyse urinary peptides. Urine was desalted by solid-phase extraction (SPE) and its peptides were then separated from neutral and acidic compounds by strong cation-exchange chromatography (SCX), which was also used to fractionate the peptide mixture. Fractions from the SCX step were separated further by reversed-phase LC and analysed on-line by MS/MS. Extraction by SPE showed a good recovery of small peptides. We detected over 100 molecular species in urine samples from three individuals with Dents disease. In addition to plasma and known urinary proteins, we identified some novel proteins and potentially bioactive peptides in urine from these patients, which were not present in normal urine. These data show that nanoLC-MS/MS complements existing techniques for the identification of polypeptides in urine. This approach is a potentially powerful tool to discover new markers and/or causative factors in renal disease; in addition, its sensitivity may also make it applicable to the direct ultramicroanalysis of renal tubule fluid.

Remote Ischemic Preconditioning for Renal Protection During Elective Open Infrarenal Abdominal Aortic Aneurysm Repair: Randomized Controlled Trial

We aimed to determine whether remote ischemic preconditioning (IP) reduces renal damage following elective open infrarenal abdominal aortic aneurysm (AAA) repair. Sequential common iliac clamping was used to induce remote IP in randomized patients. Urinary retinol binding protein (RBP) and albumin-creatinine ratio (ACR) were measured following induction and 3, 24, and 48 hours postoperatively. In controls (n = 22), median urinary RBP increased from 112 µg/mL (interquartile range [IQR] 96-173 µg/mL) preoperatively to 5919 µg/mL (IQR 283-17 788 µg/mL) at 3 hours. Preoperative urinary RBP in preconditioned patients was 96 µg/mL (IQR 50 to 229 µg/mL) preoperatively, rising to 1243 µg/mL (IQR 540 to 15400 µg/mL) at 3 hours. Although control patients’ median urinary RBP level was 5 times greater at 3 hours, there were no statistically significant differences in renal outcome indices. This trial could not confirm that remote IP reduces renal injury following elective open aneurysm surgery.

Characterization of carrier females and affected males with X-linked recessive nephrolithiasis.

X-linked recessive nephrolithiasis (XRN) was described in a large kindred in which nephrolithiasis; proximal tubular dysfunction, proteinuria, nephrocalcinosis, and renal failure occur only in males. Carrier females are asymptomatic, but formal studies of them have not been done. The gene for XRN has been mapped to the pericentromeric region of the X chromosome, close to the loci for several eye disease genes. We studied six affected males, 13 carrier females, and 25 normal members of this family including 7 females whose genetic haplotype predicted them to be carriers. Studies were done in the Clinical Research Unit on a diet containing 400 mg of calcium and 2 g of sodium, and by an additional outpatient urine collection was obtained on a 1-g calcium intake. Hypercalciuria occurred in five of six affected males, 4 of 12 carrier females, and three of seven predicted carriers. Significant proteinuria was present in all affected males and in no other subjects. Low-molecular-weight proteinuria was present in all affected males: the excretion of alpha 1-microglobulin exceeded normal by 3- to 14-fold, of beta 2-microglobulin exceeded normal by 100- to 400-fold, and of retinol-binding protein exceeded normal by 1,000- to 3,000-fold. The excretion of these proteins was less strikingly elevated in carrier females, but the excretion of alpha 1-microglobulin was abnormal in 9 of 15 carriers, beta 2-microglobulin was abnormal in 12 of 15, and retinolbinding protein in was abnormal 12 of 13, and this pattern was similar in predicted carriers. The urinary concentrating ability was abnormal in four affected males with renal insufficiency but normal in all other subjects. Urinary wasting of potassium, phosphorous, and glucose occurred infrequently, and no subject was hypouricemic. Formal ophthalmologic studies were normal in five affected males. Thus, the most consistent urinary abnormalities in XRN are hypercalciuria and low-molecular-weight proteinuria, the latter of which appears to be a marker for the carrier state.

Does N-acetylcysteine prevent contrast-induced nephropathy during endovascular AAA repair? A randomized controlled pilot study.

Purpose: To examine if N-acetylcysteine (NAC) reduces the incidence of contrast nephropathy during endovascular abdominal aortic aneurysm repair (EVAR) as evidenced by changes in markers of renal function. Methods: Twenty consecutive men (mean age 72 years, range 65–79) undergoing EVAR were randomized to receive standard intravenous fluid hydration or standard fluid hydration and NAC (600 mg BID orally, 4 doses). Venous blood and urine were collected prior to the procedure and for 5 postoperative days and analyzed blindly for serum creatinine, urinary retinol-binding protein (RBP), and albumin/creatinine ratio (ACR). Results: There were no significant differences in baseline demographics between the groups. No patient developed acute renal failure. In both groups, urinary RBP rose significantly from baseline (median 15 μg/mmol to peak 699 μg/mmol in controls versus 17 to 648 μg/mmol in the treatment group, p<0.003). There were similar significant rises in ACR (p<0.02). There was, however, no significant difference in the postoperative RBP or ACR between the groups at any time point. Conclusion: EVAR causes significant acute renal injury in most patients. This was not attenuated by N-acetylcysteine. The causes of renal injury are probably multifactorial, the long-term clinical significance of which is unclear.

A pivotal role of the human kidney in catabolism of HDL protein components apolipoprotein A-I and A-IV but not of A-II.

Renal handling of major HDL components was studied by analyzing urine from patients with Fanconi syndrome, a rare renal proximal tubular reabsorption failure, including dysfunction of the kidney HDL receptor, cubilin. A high urinary excretion of apolipoprotein A-I and A-IV corresponding to a major part of the metabolism of these proteins was measured. In contrast, no urinary excretion of apolipoprotein A-II which is more hydrophobic and tighter bound to HDL was found. Control urines displayed absence of the three apolipoproteins. Urinary excretion of phospholipids, triglycerides, cholesterol and cholesterol esters in patients was as low as in controls. In conclusion, these data indicate that the human kidney is a major site for filtered nascent apolipoprotein A-I and A-IV but not for HDL particles.

Does oral N-acetylcysteine reduce contrast-induced renal injury in patients with peripheral arterial disease undergoing peripheral angiography? A randomized-controlled study.

The nephroprotective role of N-acetylcysteine (NAC) against contrast-induced nephropathy (CIN) in patients undergoing peripheral arterial angiography remains unclear. A total of 40 patients undergoing peripheral arterial angiography were randomized to receive intravenous (iv) hydration only (group 1) or oral NAC in addition to iv hydration (group 2; ISRCTN: 35882618). Primary outcome was reduction in the elevation of urinary retinol binding protein (RBP), albumin—creatinine ratio (ACR), and serum creatinine (serC). Groups 1 and 2 had equivocal percentage reduction in RBP and ACR levels from baseline (P = .80 and .30). A significant reduction in serC was, however, observed with NAC by third postprocedure day (P = .04). One patient in the treatment arm developed CIN compared with 3 patients in the control group (P = .33). Equivocal changes in RBP and ACR levels by both treatments seem to indicate that either is equally effective in affording renal protection.

X-linked recessive nephrolithiasis: Presentation and diagnosis in children☆☆☆★★★

We report a new X-linked recessive nephrolithiasis kindred. X-linked recessive nephrolithiasis is a recently described disease characterized by recurrent nephrolithiasis, nephrocalcinosis, and progressive renal failure, associated with mutations in a renal chloride channel gene, chloride channel number 5. Screening individuals at risk with renal ultrasonography and measurement of urinary excretion of low molecular weight proteins and calcium will exclude boys without X-linked recessive nephrolithiasis kindred and identify boys likely to have the disease.

Is the Albumin Retrieval Hypothesis a Paradigm Shift for Nephrology

The albumin retrieval hypothesis is alive and well, if still controversial. Although emphasis on different aspects of this hypothesis has changed over the years, there are now several papers in the nephrology and clinical chemistry literature that seem to endorse it.[1][1],[2][2] In its original

In memoriam: Oliver M. Wrong.

Kidney International (2012) 82 121 Steven J. Scheinman1, John Feehally2*, Terry G. Feest3, Anthony G.W. Norden4, Rajesh V. Thakker5 and Robert J. Unwin6 1Department of Medicine, Upstate Medical University, Syracuse, New York, USA; 2The John Walls Renal Unit, University Hospitals of Leicester, Leicester, UK; 3University of Bristol, Bristol, UK; 4Department of Clinical Biochemistry, Addenbrooke’s Hospital, Cambridge, UK; 5Academic Endocrine Unit, University of Oxford, Nuffield Department of Clinical Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, UK; 6UCL Centre for Nephrology, University College London Medical School, Royal Free Campus and Hospital, London, UK *Professor Feehally is the President of the International Society of Nephrology Correspondence: Steven J. Scheinman, Department of Medicine, Upstate Medical University, 750 E. Adams Street, Syracuse, New York 13210, USA. E-mail: scheinms@upstate.edu O liver Murray Wrong, Emeritus Professor of Medicine at the University College Hospital in London, died on 24 February 2012, at age 87. During a distinguished career spanning nearly six decades, Professor Wrong contributed enormously to our understanding of renal tubular acidosis, the renal Fanconi’s syndrome, and inherited tubular disorders. He was a clinical scientist of broad intellectual scope, whose accomplishments reflected his great energy, devotion to his patients, talent for close observation, and deep understanding of electrolyte, mineral, and acid–base physiology. Professor Wrong was destined to be an academic by both his genome and his environment. He was born at Magdalen College, Oxford, where his Canadian father taught. Both parents were historians, and he was surrounded by brilliant, and in some cases idiosyncratic, relatives. His maternal grandfather was master of another Oxford college, Balliol, and other relatives included highly prominent writers, academicians, politicians, and scientists, both in Britain and in Canada, not the least of whom were two Nobel laureates, Dorothy Hodgkin and Alan Hodgkin. Oliver spent part of his childhood in Canada. He did his undergraduate medical studies at Magdalen College and trained at the Radcliffe Infirmary, Oxford, before his military service in the Royal Army Medical Corps in Singapore and Malaysia. His experiences and friendships in Southeast Asia remained with him and informed one of the important threads of his research interests. He became a senior intern in medicine at Toronto General Hospital and then a research fellow in medicine at the Massachusetts General Hospital. It was in Boston, working with Fuller Albright and Alex Leaf, that he developed what was to become a lifelong interest in salt and water metabolism. He pursued an academic career in Great Britain, starting in 1954 as university tutor in medicine at the Manchester Royal Infirmary. It was there that he did the work, with H.E.F. Davies, that led to the seminal paper on “The excretion of acid in renal disease,” which was published in 1959 and was to become a citation classic. He joined the Medical Unit at University College Hospital, where he worked with Charles Dent and Max Rosenheim. This was followed by appointment as a senior lecturer in the new clinical specialty of nephrology at the Royal Postgraduate Medical School at the Hammersmith Hospital, and then as the chair of medicine at Dundee University in Scotland. In 1972 he returned to University College Hospital in London as director of medicine, where he spent the remainder of his productive career. Oliver’s early work on acid excretion defined the standard protocol for the acid load test, and formed the background for his descriptions of both inherited and immune-related distal renal tubular acidosis. He was fascinated by the role of the gut in acid–base and electrolyte physiology and, in 1961, designed bags of cellulose tubing filled with a colloidal solution, which would be swallowed and, when they emerged, allow him to analyze the electrolyte content of the bowel lumen. Oliver felt that the importance of the gut in electrolyte physiology was underappreciated. He began his 1965 paper on “Electrolyte content of faeces” with the statement that “Stool is the Cinderella of electrolyte studies.” He wrote a book on the colon. For decades Oliver cared for and observed closely the many patients he had inherited from Charles Dent. This included the patients Dent and Friedman had reported in 1964 with hypercalciuric rickets and renal tubular damage; over time Oliver discovered that their condition was familial and associated also with kidney stones and renal failure. When 30 years later he reported these observations, with Anthony Norden and Terry Feest, the title of that paper represented a full summary of the phenotype of “Dent’s disease: a familial proximal renal tubular syndrome with low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, metabolic bone disease, progressive renal failure and a marked male predominance.” He did the world a great service in offering a simple and elegant name for the disease, a significant improvement on the alphabet soup of alternative names that others had proposed. In fact, In memoriam: Oliver M. Wrong