Current Status of Novel Biomarkers for the Diagnosis of Acute Kidney Injury: A Historical Perspective.

Acute kidney injury (AKI) is a common and serious medical condition associated with significant increases in morbidity, mortality, and cost of care. Because of the high incidence and poor outcomes associated with AKI, there has been significant interest in the development of new therapies for the prevention and treatment of the disease. A lack of efficacy in drug trials led to the concern that AKI was not being diagnosed early enough for an effective intervention and that a rise in serum creatinine itself is not a sensitive-enough marker. Researchers have been searching for novel biomarkers that can not only assess a decline in kidney function but also demonstrate structural damage to the kidney and at time points earlier than increases in serum creatinine measurements allow. Over the past 10 years, there have been 3300 new publications and hundreds of new biomarkers investigated, yet concern still remains regarding AKI biomarker performance. The AKI biomarkers are yet to be widely utilized in clinical practice, leading some to question whether AKI biomarkers will ever reach their initial promise. However, we believe that biomarkers are an important part of current and future AKI research and clinical management. In this review, we compare the historical contexts of acute myocardial ischemia and AKI biomarker development to illustrate the progress that has been made within AKI biomarker research in a relatively short period of time and also to point out key differences between the disease processes that have been barriers to widespread AKI biomarker adoption. Finally, we discuss potential paths by which biomarkers can lead to appropriate AKI treatment responses that lower morbidity and mortality.

Usefulness of basic renal function tests in decision-making in children with loss of renal parenchyma and/or dilation of the urinary tract. / Utilidad de las pruebas básicas de estudio de la función renal en la toma de decisiones en niños con pérdida de parénquima renal o dilatación de la vía urinaria.

Basic renal function tests such as maximum urine osmolality and urinary elimination of albumin and N-acetyl-glucosaminidase often reveal abnormalities in clinical cases involving hyperpressure in the urinary tract or loss of renal parenchyma. However, in all the available algorithms dedicated to the study of children with urinary tract infection or dilation, the benefit of using these functional parameters is not mentioned. In this review, we provide information about the practical usefulness of assessing the basic renal function parameters. From these data, we propose an algorithm that combines morphological and functional parameters to make a reasoned case for voiding cystourethrography.

Resolving an 80-yr-old controversy: the beginning of the modern era of renal physiology.

Marcello Malpighi discovered the glomerulus that bears his name in the 17th century, but it was not until the middle of the 19th century, in 1842, that William Bowman in London published his studies of the histological structure of the glomerulus and proposed that urine formation begins with glomerular secretion. At nearly the same time in Marburg, Carl Ludwig, unaware of Bowman's findings, proposed that urine formation begins with glomerular filtration followed by tubule reabsorption. The controversy lasted 80 yr. Prominent investigators weighed in on both sides. Rudolph Heidenhain's findings in 1874 swung the pendulum toward Bowman's theory until Arthur Cushny published his book, The Secretion of Urine, in 1917, in which he found the evidence insufficient to prove either theory. In 1921, a young physician, Joseph Wearn, began his postresidency training in the laboratory of Alfred N. Richards. He read Cushny's book and learned how to expose the glomerulus of a living frog. Richards proposed that Wearn use that experimental preparation to inject epinephrine into the glomerulus. Wearn proposed a different experiment: instead of using injection, collect fluid from the glomerulus and analyze it. Richards agreed, and the landmark results of that experiment, published in 1924, settled the controversy. The modern era of renal physiology was born.

The Cockroft and Gault formula for estimation of creatinine clearance: a friendly deconstruction.

AIMS: To review the derivation of the Cockroft and Gault formula for estimating creatinine clearance from serum creatinine in a historical context. METHOD: The derivation described by Cockroft and Gault was reviewed, and an alternative formula was sought using the data reported in the paper. RESULTS: Cockroft and Gault used 24 hour urine creatinine data expressed as mg/kg body weight and mathematical manipulation of a linear regression equation which introduced body weight as an independent variable into the formula. This involved a circular logic and may have been mathematically invalid. A more logical equation not containing body weight was derived from the data. CONCLUSION: The Cockcroft and Gault formula has been validated by long usage but the derivation appears logically insecure. Nevertheless, its role in estimating renal function at the bedside is established.

[The classics of Italian nephrology. 'Functional semiology of the kidney' by Giovanni Gigli (1913-1988) and Sergio Giovannetti (1924-2000)]. / I Classici della Nefrologia Italiana. ''Semeiologia funzionale del rene'' di Giovanni Gigli (1913-1988) e Sergio Giovannetti (1924-2000).

The monograph Semeiologia funzionale del rene (Functional semiology of the kidney) by Giovanni Gigli (1913-1988) and Sergio Giovanetti (1924-2000), published in 1953, was the first systematic survey on the subject to appear in Italy. Besides the classical renal function tests (urinalysis, BUN measurement, urea clearance), the book recounts the many new techniques that were introduced into clinical practice in that period as a result of the great advances in the field of renal physiology (e.g., glomerular filtration rate, renal plasma and blood flow, tubular water reabsorption, maximum tubular excretion and reabsorption capacity, filtration fraction). In addition, it describes the utility and pitfalls of such tests in a wide spectrum of kidney diseases, but especially in different types of glomerulonephritis, of which the two authors had collected a personal cohort of 48 patients. Today, the monograph by Gigli and Giovannetti shows the difficulties and uncertainties encountered in the evaluation of kidney diseases in a period in which renal biopsy was yet to become the widely used technique it is today.

Odd E. Hanssen and the Hanssen method for measurement of single-nephron glomerular filtration rate.

In the middle of the twentieth century, the suspicion that deep and superficial nephrons might serve different functions created a demand for measurement of single-nephron glomerular filtration rate (SNGFR). Rather unexpectedly, the answer came from Odd E. Hanssen (1917-1964), a Norwegian physician working on his own in the Department of Pathological Anatomy, University of Oslo, with minimal support and no interaction with renal physiologists. In 1963, after nearly 10 years of work, he presented the ferrocyanide method, allowing simultaneous estimates of SNGFR in a large number of nephrons in all layers of the kidney. This review first describes his early visions of the method and the elaborate and extremely time-consuming studies in mice to verify the technique. As a byproduct came valuable information on the relationship between nephron size and SNGFR, glomerular intermittency, and the emptying of the tubules on filtration stop. Hanssen died from a cerebral hemorrhage in 1964, and for several years the method seemed entirely forgotten. Fortunately, Andrew Baines took up the use of ferrocyanide in 1963-1964 while working on his thesis in Toronto, but his first publication came in 1969 from Saclay, France, in collaboration with Christian de Rouffignac. Modifications allowing determination of absolute SNGFR were worked out by de Rouffignac and by Jaime Coehlo in New York. Thereafter, the "Hanssen method" spread rapidly, and in the early 1980s about 50 reports had been published from 17 laboratories in 9 countries. The distribution of SNGFR in mammals, birds, and fish was described, as well as the response to water and salt loads, vasoactive substances, hormones, varying perfusion pressure, blood loss, etc. Finally, after mentioning two recent methods inspired by the Hanssen technique but using other filtration markers, the review concludes that most of our present knowledge on SNGFR distribution and regulation has been obtained by the method developed by Hanssen 40 years ago.

[On the history of kidney disease]. / Zur Geschichte der Nierenkrankheiten.

Except for infections (pyelonephritis, abscess of the kidney), which cause symptoms such as pyuria, pain and fever, most diseases of the renal parenchyma were unknown in Greek and Roman antiquity. Even in the Renaissance they were not yet properly identified. Edema was generally thought to be related to liver disease. Proteinuria was discovered at the end of the 18th century. In 1827 Bright provided the first, almost complete clinical description of the various forms of acute and chronic glomerulonephritis and showed that they were accompanied by macroscopic changes in the kidneys. Between 1850 and 1885, Frerichs, Klebs and Langhans described the primary glomerular lesions. The amount of new knowledge acquired during the 20th century has been tremendous, and covers the mechanism of urine formation, the role of sodium retention in edematous states, the physiology and physiopathology of the renin-angiotensin-aldosterone system, the glomerular origin of the nephrotic syndrome, new methods of investigation, progress in histology and immunology, the discovery of many tubular syndromes, the introduction of antibiotics and antihypertensive drugs, and the development of dialysis and transplantation.