Dent’s Disease and Renal Tubular Acidosis
The important contributions of Professor Sir Charles Enrique Dent and Professor Oliver Murray Wrong to defining and understanding Dent’s (now known as Dent-1 and Dent-2) disease and Renal Tubular Acidosis (RTA).
by Robert Unwin (2023)
These two leading British medical figures of their day made seminal contributions to the description and defining characteristics of Dent’s disease and RTA, and both are inextricably linked in what they achieved with the help and support of national and international scientists, and many practising clinicians of their time.
Charles Dent was the senior of the two and was also one of Oliver Wrong’s most influential mentors, which is why the inherited disease and syndrome known originally as Dent’s disease bears his name as a tribute from Oliver Wrong to his mentor.
CE Dent
Professor Sir Charles Enrique Dent FRS (1911 – 1976) was a distinguished British Professor of Human Metabolism at University College London (UCL).
Born in Burgos, Spain, he eventually followed in the footsteps of his father, Franklin Dent, who had earned a PhD in chemistry. Charles Dent left school at the age of 16 to become a bank clerk, but soon decided to study chemistry like his father. He obtained a post as a laboratory technician and took evening classes at the Regent Street Polytechnic, now the University of Westminster in London. He gained a place at Imperial College and was soon awarded a first-class degree, followed quickly by a PhD. He then obtained a place as a medical student at UCL. His progress was interrupted by distinguished war service which included his evacuation from Dunkirk and a period in the War Office as an expert chemist working in intelligence, and also where he met his future wife. It is perhaps less well known that in 1945 at the end of WWII, because of his protein chemistry and amino acid expertise, Charles Dent was asked to help in the development of ‘protein hydrolysates’ for treating the starving population of the Netherlands and returning prisoners of war, but which were soon also needed to treat concentration camp survivors, particularly at Belsen.
The group developing ‘protein hydrolysates’ 1944 – CE Dent is on the right.
Dent graduated in 1944 and became house physician to Sir Thomas Lewis[1] , and gained his MRCP a year later when he was appointed assistant to the Medical Unit at University College Hospital (UCH) under Professor (Sir) Harry Himsworth[2] (who had research interests in diabetes and liver disease, and who was one of the first to differentiate between ‘insulin-sensitive’ and ‘insulin-insensitive’ diabetes mellitus).
Charles Dent was soon active in clinical research, particularly in the field of amino acid metabolism, when he became interested in the value and possibilities of partition chromatography, a new technique at the time, and he applied it to the study of biological fluids in metabolic disorders. He became a recognised authority on inborn errors of amino acid metabolism, including renal tubular Fanconi-like and intestinal epithelial disorders associated with neurological manifestations such as Hartnup disease (Baron et al., 1956) (an autosomal recessive disorder affecting neutral amino acid transport), arginosuccinic aciduria (Allan et al., 1958) (an autosomal recessive disorder causing systemic accumulation of ammonia) and homocystinuria (Carson et al., 1963) (an autosomal recessive disorder of methionine metabolism resulting in increased plasma levels of homocysteine). These early ground-breaking studies laid the foundation for subsequent advances in diagnosing and treating metabolic disorders.
The kidney-related findings he made as a result of these metabolic studies stimulated his interest in clinical disorders of calcium and phosphorus metabolism, and vitamin D deficiency. He went on to classify what had originally been described by Fuller Albright and colleagues in 1935 as ‘vitamin D resistant rickets with a renal tubular defect’, as different forms of what he called ‘tubular rickets’ (Dent, 1952) . He recognised 6 subtypes, I-VI, all with a high clearance of phosphate, but differing in their additional tubular defects:
Table from Dent 1952
Types I-IV were believed to be inherited disorders, whereas Types V and VI were thought to be acquired. Interestingly, he comments in this earlier paper (in 1952) that Types V and VI, which overlap somewhat, are ‘almost identical’ in children to the descriptions of ‘renal acidosis’ by Lightwood (“British Paediatric Association,” 1935) and Butler (Butler et al., 1936)[3]. These early examples of what is now known as Renal Tubular Acidosis (RTA) (and possibly describing what we now refer to as proximal and distal forms of RTA respectively) became a focus of Oliver Wrong’s clinical research for much of his working life, but more on that later.
The original paper that led eventually to the characterisation and identification of Dent’s disease as an X-linked genetic disorder with a causative gene defect affecting an intracellular chloride ion channel was published by Dent & Friedman in 1964 in the Archives of Diseases of Childhood (Dent & Friedman, 1964). The paper entitled ‘Hypercalciuric rickets associated with renal tubular damage’ describes two unrelated young boys with hypophosphataemia, hyperphosphaturia, hypercalciuria, tubular proteinuria (a2– and b-globulins) and aminoaciduria with rickets. Bone healing was seen with modest doses of vitamin D, but both patients had growth retardation. However, in the absence of a family history the condition was thought to be acquired, rather than inherited. In light of the later classification of Dent’s disease into Dent-1 and Dent-2, it is perhaps of interest that one of the boys was noted to have ‘mental retardation’, which is more commonly observed in cases of Dent-2 that is the result of a different gene abnormality giving rise to an almost identical clinical phenotype (see later). Oliver Wrong followed these index patients and their families, and 30 years later he reported that they had developed nephrolithiasis and renal failure, and coined the eponym ‘Dent’s disease’ (O. M. Wrong et al., 1994).
Charles Dent made a visit to Fuller Albright’s department at the Massachusetts General Hospital in Boston[4]. When Dent returned from this visit, he successfully persuaded UCH to set up a metabolic ward that Oliver Wrong eventually joined.
Charles Dent made significant contributions to medicine by defining various inborn errors of metabolism. His work on amino acid metabolism and related fields greatly enhanced our understanding of these crucial physiological processes. His research paved the way for progress in diagnosing and treating metabolic disorders[5].
(An interesting aside is that Charles Dent was also a great supporter of academic medicine and of a better clinical academic career structure. He wrote a short article for the BMJ in 1975 criticising the view that there should be close equalisation at each stage of academic and NHS salaries, meaning that a professor = a consultant and a lecturer = a senior registrar. He believed this perpetuated the false belief that the work of a clinical academic is essentially the same as that of an NHS doctor, but he thought that the role of an academic should be primarily to teach and carry out research, without additional and often unrelated clinical duties. He objected that promotion to a personal chair was often used as a means of saving money by not supplementing fairly the salary that should accompany such a promotion. Indeed, he also objected to the then merit award system for clinical academics arguing that it would be unnecessary if academics were reasonably paid and not so disadvantaged compared with their NHS counterparts – ‘all generals and no privates’ as he put it!)
OM Wrong
Professor Oliver Murray Wrong (1925 – 2012) was also a distinguished British physician and Professor of Medicine at UCL.
Oliver Wrong was born at Magdalen College Oxford where his Canadian father was a fellow who taught modern history and became College Vice-President and Junior Proctor. Oliver Wrong’s maternal grandfather was also a senior Oxford figure, a Master of Balliol College, and Oliver grew up exposed to many leading writers, politicians, university academics and scientists of the day. His father, who was treated by Sir William Osler (a close family friend and also originally from Canada), died at the early age of 38 of cardiac failure as a result of earlier bouts of ‘rheumatic fever’ when Oliver was only three (he wrote a personal account of the relationship between Sir William Osler and his father in 2003 entitled simply ‘Osler and my father’ (O. Wrong, 2003). His father’s early death had a major financial impact on the family during the Great Depression and Oliver was sent with two of his young siblings to live with his grandparents in Canada. He returned to Britain having gained a place at the Edinburgh Academy followed at the age of seventeen in 1942 by a scholarship to Magdalen College to study medicine . This was during WWII, when all clinical teaching was then in Oxford itself and not at one of the London medical schools, as was the norm for most Oxford and Cambridge medical students. He qualified in 1947, spent a year of National Service in the RAMC in Malaya, an experience that resulted in later examining and teaching links, and which eventually led much later to the beginnings of a discovery of a genetic form of RTA. Oliver returned briefly to Oxford for more clinical training and then spent several years of academic training overseas in Toronto and Harvard, returning to Britain in 1954, first to Manchester, and then in 1959 to join the Medical Unit and metabolic ward at UCH where he began working with Charles Dent. He moved for a short time to the Royal Postgraduate Medical School and Hammersmith Hospital to take up a new post as a ‘nephrologist’, a then emerging clinical specialty in its own right, followed by a brief appointment as Professor of Medicine at Dundee University, before returning to UCL and UCH as Professor of Medicine in 1972 to succeed Charles Dent and where he remained until and beyond his retirement. In fact, some of his major discoveries were in made in retirement and he was still writing on the subject of RTA while in hospital shortly before his death.
Oliver Wrong’s research was clinically based and concerned human physiology, especially as it applied to the kidney and intestine. He was particularly interested in their respective roles in acid-base balance. He was a self-experimenter and designed bags containing cellulose tubing filled with a colloidal solution that could be swallowed and when passed used to analyse the electrolyte content of the bowel lumen.
Swallowed dialysis bags, compacted, full length and ‘before and after’ used for intestinal electrolyte studies
On this topic he commented that the ’stool is the Cinderella of electrolyte studies’. He even wrote a small monograph on the large intestine and its role in ‘nutrition and homeostasis’ with CJ Edmonds and VS Chadwick.
However, Oliver Wrong is probably best known for his ‘citation classic’ paper published in 1959 while still in Manchester (he moved shortly thereafter to UCH) with co-author Howard Davies[6] in the Quarterly Journal of Medicine (Wrong & Davies, 1959) entitled ‘The excretion of acid in renal disease’[7]. This unusually lengthy paper (by today’s standards) describes a series of clinical cases providing examples of defects in urinary acidification and the first detailed description and application of what is now known as the ‘short ammonium chloride test’. They used the test to illustrate the relationship between phosphate and creatinine with urine pH and their contributions to titratable acid, and the inverse relationship between ammonium excretion and urine pH, and how the latter differed in patients with chronic kidney disease, where the relationship is preserved, and in (distal) RTA where it is not.
The paper includes a series of individual graphs for the response to an acute oral ammonium chloride acid load comparing normal participants with patients.
Graphs of urinary pH (top left), ammonium excretion (bottom left), titratable acid excretion (top right) and net acid excretion (bottom tight) in response to a short ammonium chloride test – red lines indicate the normal range of responses for each (Wrong & Davies 1959)
‘Complete’ RTA ‘Incomplete’ RTA
This illustrates nicely the difference between what Oliver described as ‘complete’ RTA and ‘incomplete’ RTA; the latter had a blood bicarbonate level within the normal range, unlike the cases of complete RTA, but who still showed an impaired urinary ammonium increase in response to the acid load, although just sufficient to maintain a near normal blood bicarbonate level. These patients were easy to miss, but often had a low-normal blood potassium level, a characteristic feature of patients with ‘classical’ distal RTA. The decrease in ammonium excretion in RTA was not thought to result from a decreased GFR, but from the effect of impaired acid excretion itself, although there is a comment in the paper that in the Fanconi syndrome, and what would be considered proximal RTA, there may be a defect in ammonium excretion; subsequent work has suggested that this may be due to reduced ammoniagenesis in the proximal tubule in this disorder. The paper also alludes to the familial nature of RTA, suggesting a dominant mode of inheritance and close association with nephrocalcinosis and kidney stones[8]. Oliver wrote more about this in a paper in the Lancet in 1972 entitled ‘Dominant inheritance in a family with familial renal tubular acidosis’ with Peter Richards (later Dean of St Mary’s Hospital Medical School).
Other eminent British ‘metabolic’ physicians, MD Milne [disorders of amino acid transport] and SW Stanbury [bone and mineral metabolism] had also described cases of ‘hyperchloraemic acidosis’ [1952] in examples of the Fanconi syndrome and like Dent before them [1947] noted the alkaline urine pH, which they attributed to impaired bicarbonate reabsorption, and also concluded there was unlikely to be a primary defect in ‘ammonia secretion’.
Over the years as a practising clinician, Oliver collected patients with unusual chronic electrolyte problems and received referrals from all over the UK. In later years working closely with his colleague Terry Feest (later nephrologist in Exeter and then Bristol) he described what he believed was an autoimmune condition seen in older women presenting with hypokalaemia and which may be part of a spectrum of disease from isolated hypokalaemia to hypokalaemia with RTA, both the result of an autoimmune process causing interstitial nephritis and proximal and distal tubular damage; tubular or low molecular weight proteinuria being a common feature. In a 1993 paper he termed this IRPLIN – Immune-Related Potassium-Losing Interstitial Nephritis.
However, the two important discoveries he made and for which he is perhaps now best known were made in retirement and built on his long clinical experience and meticulous record keeping. As already mentioned, Oliver had been following Charles Dent’s original two patients with ‘hypercalciuric rickets’ and went on to identify other similar cases with a Fanconi syndrome, noting that males were more severely affected and initially concluding that inheritance was autosomal dominant. Coincidentally, Steve Scheinman at Syracuse University in the US had been part of a New England Journal publication (Frymoyer et al., 1991) that described a very similar familial and clinical phenotype, but which the authors had identified as being X-linked and described as ‘X-linked recessive nephrolithiasis with renal failure’ later recognised to be the same as so-called ‘X-linked recessive hypophosphataemic rickets’.Steve Scheinman contacted Oliver Wrong and together with mutual colleague Rajiv Thakker in Oxford they were able to identify the causative gene defect.[9] Thakker as an endocrinologist and clinical geneticist had an interest in bone and mineral metabolism and had already been involved in mapping the X chromosome and had the necessary markers to confirm the X-linked pattern of inheritance in these patients; he was able to identify a micro-deletion in one kindred that pointed to a potential chloride channel abnormality. This led to prompt contact with a known authority on chloride channels, the electrophysiologist Thomas Jentsch in Hamburg. The story rapidly evolved to confirm the causal gene defect, the chloride channel CLCN5 which aids acidification of intracellular endosomes involved in the uptake and degradation of small, filtered proteins reabsorbed by the proximal tubule (Lloyd et al., 1996). Also closely involved in the later clinical studies of Dent-1 and Dent -2 was Anthony Norden, a chemical pathologist and clinical biochemist in London and later in Cambridge, who was expert in ‘tubular proteinuria’, a feature of the Fanconi syndrome, of which Dent’s disease is an example.
It was agreed to name this new tubular disorder Dent’s disease in honour of Charles Dent. Shortly thereafter, from work led by Steve Scheinman, it became apparent that some cases of supposed Dent’s disease did not have a CLCN5 mutation. Interestingly some of these cases were associated with intellectual impairment and were eventually found to have mutations in the OCRL gene, the cause of X-linked Lowe syndrome, although without its other typical and often more severe clinical features. This finding also pointed to a role for the gene encoded enzyme PIP2 (a phosphatidylinositol 4,5-bisphosphate 5-phosphatase) in proximal tubular endosomal function. To distinguish these two forms of Dent’s disease, they are now known as Dent-1 and Dent-2.
While the work on Dent’s disease was going on, Oliver happened to share an office with Robert Unwin, a clinician who had recently moved to UCL from the Hammersmith Hospital and who had spent time in the Yale laboratory of renal physiologist Gerhard Giebisch. Robert Unwin’s background was as a physician and renal physiologist with an interest in epithelial transport mechanisms. Thus, they had a shared interest in clinical fluid and electrolyte problems, including in acid-base balance. Oliver, as the more experienced clinician, generously encouraged Robert Unwin to take care of many of the patients he had known and who were still attending the hospital outpatient clinic[10]. In the clinic were several families with what appeared to be an autosomal dominant pattern of distal RTA with nephrocalcinosis and stones. In discussion they wondered about the possible underlying transport abnormality that could account for the urinary acidification defect. Robert Unwin was already familiar with the current kidney cell models for acidification and the transporters thought to be involved: the primary active ATP-dependent hydrogen ion pump (H-ATPase) on the apical membrane of the collected duct intercalated cell and the chloride-bicarbonate exchanger (AE1) on the basolateral membrane. Their attention was focused on AE1 because of a clinical observation made by Oliver Wrong had made while examining in Malaysia in the 1970s. He had been shown a patient with ovalocytosis and anaemia with RTA. At the time he thought the conditions were coincidental but knowing now that Southeast Asian Ovalocytosis (SAO) is due to a defect in the Band 3 protein of the red cell, and that this protein is a chloride-bicarbonate exchanger, they developed the idea to look at the red cells of patients with familial RTA. With the help of Gordon Stewart, a local red cell transport expert, contact was made with the group in Bristol that had worked on SAO and was led by Michael Tanner, a biochemist, and his close associate Lesley Bruce. This collaboration eventually led to the finding published in 1997 in the Journal of Clinical Investigation (Bruce et al., 1997) that the red cells of affected RTA patients did indeed have impaired chloride transport. With the the help of Sue Povey, a geneticist at UCL, mutations in the chloride-bicarbonate exchanger AE1 were identified that affected the kidney form of the protein (which is truncated) more than the red cell form resulting in impaired acid excretion; mainly as a result of the protein being trapped inside the cell, rather than being misdirected to the apical cell membrane. This finding was soon confirmed by others and found to be the main cause of autosomal dominant RTA, in contrast to the H-ATPase mutations causing recessive distal RTA and presenting earlier in childhood (and later described by Fiona Karet in Cambridge and others).
Oliver Wrong’s last posthumous publication in the Quarterly Journal of Medicine (Khositseth et al., 2012) was almost ‘back to the future’ and like his 1959 paper on RTA, presented lengthy and comprehensive case studies. Summarising various red cell abnormalities and showing evidence of RTA, he compared those mutations found in occidental populations with those found in the tropical populations of Southeast Asia. The important conclusions were that the western mutations caused autosomal dominant distal RTA, whereas the tropical mutations could cause an autosomal recessive form and be associated with red cell abnormalities with a more severe clinical phenotype. The selective pressure for these mutations, given their geographical distribution, may have something to do with resistance to malaria, but this remains speculative.
Oliver Wrong played a pioneering role in unravelling the complexities of electrolyte and acid-base disorders and his influential work has advanced our understanding of several important kidney-related disorders.
A symposium was held in 2007 in honour of Oliver Wrong
From left to right: Adrian Woolf, Steve Scheinman, Stephen Powis, Raj Thakker, Guy Neild, Robert Unwin, Marilda Wrong (Oliver’s Italian wife), Oliver Wrong, Terry Feest, Thomas Jentsch, Robert Kleta, John Cunningham, Daniela Riccardi, Anthony Norden, Fiona Karet
Charles Dent and Oliver Wrong epitomise the clinical academic physician of yesteryear who was fortunate in having sufficient time to combine specialised clinical care and careful observation with rigorous laboratory-based research. Both were major figures in British medicine and examples of clinical applied physiologists par excellence!
Bibliography
Allan, J. D., Cusworth, D. C., Dent, C. E., & Wilson, V. K. (1958). A disease, probably hereditary, characterised by severe mental deficiency and a constant gross abnormality of aminoacid metabolism. The Lancet, 271(7013), 182–187. https://doi.org/10.1016/s0140-6736(58)90666-4
Baron, D. N., Dent, C. E., Harris, H., Hart, E. W., & Jepson, J. B. (1956). Hereditary pellagra-like skin rash with temporary cerebellar ataxia, constant renal amino-aciduria, and other bizarre biochemical features. The Lancet, 268(6940), 421–428. https://doi.org/10.1016/s0140-6736(56)91914-6
British Paediatric Association. (1935). Archives of Disease in Childhood, 10(57), 205. https://doi.org/10.1136/adc.10.57.205
Bruce, L. J., Cope, D. L., Jones, G. K., Schofield, A. E., Burley, M., Povey, S., Unwin, R. J., Wrong, O., & Tanner, M. J. (1997). Familial distal renal tubular acidosis is associated with mutations in the red cell anion exchanger (Band 3, AE1) gene. Journal of Clinical Investigation, 100(7), 1693–1707. https://doi.org/10.1172/jci119694
Butler, A. M., Wilson, J. L., & Farber, S. (1936). Dehydration and acidosis with calcification at renal tubules. The Journal of Pediatrics, 8(4), 489–499. https://doi.org/10.1016/s0022-3476(36)80111-5
Carson, N. A. J., Cusworth, D. C., Dent, C. E., Field, C. M. B., Neill, D. W., & Westall, R. G. (1963). Homocystinuria: A new inborn error of Metabolism associated with Mental Deficiency. Archives of Disease in Childhood, 38(201), 425. https://doi.org/10.1136/adc.38.201.425
Davies, H. E. F., & Wrong, O. (1957). Acidity of urine and excretion of ammonium in renal disease. The Lancet, 270(6996), 625. https://doi.org/10.1016/s0140-6736(57)91949-9
Dent, C. E. (1952). RICKETS AND OSTEOMALACIA FROM RENAL TUBULE DEFECTS. The Journal of Bone and Joint Surgery. British Volume, 34-B(2), 266–274. https://doi.org/10.1302/0301-620x.34b2.266
Dent, C. E., & Friedman, M. (1964). Hypercalcuric Rickets Associated with Renal Tubular Damage. Archives of Disease in Childhood, 39(205), 240. https://doi.org/10.1136/adc.39.205.240
Frymoyer, P. A., Scheinman, S. J., Dunham, P. B., Jones, D. B., Hueber, P., & Schroeder, E. T. (1991). X-Linked Recessive Nephrolithiasis with Renal Failure. The New England Journal of Medicine, 325(10), 681–686. https://doi.org/10.1056/nejm199109053251003
Khositseth, S., Bruce, L. J., Walsh, S. B., Bawazir, W. M., Ogle, G. D., Unwin, R. J., Thong, M. K., Sinha, R., Choo, K. E., Chartapisak, W., Kingwatanakul, P., Sumboonnanonda, A., Vasuvattakul, S., Yenchitsomanus, P., & Wrong, O. (2012). Tropical distal renal tubular acidosis: clinical and epidemiological studies in 78 patients. QJM, 105(9), 861–877. https://doi.org/10.1093/qjmed/hcs139
Lloyd, S. E., Pearce, S. H. S., Fisher, S. E., Steinmeyer, K., Schwappach, B., Scheinman, S. J., Harding, B., Bolino, A., Devoto, M., Goodyer, P., Rigden, S. P. A., Wrong, O., Jentsch, T. J., Craig, I. W., & Thakker, R. V. (1996). A common molecular basis for three inherited kidney stone diseases. Nature, 379(6564), 445–449. https://doi.org/10.1038/379445a0
Wrong, O. (2003). Osler and My Father. Journal of the Royal Society of Medicine, 96(9), 462–464. https://doi.org/10.1177/014107680309600914
Wrong, O., & Davies, H. E. (1959). The excretion of acid in renal disease. The Quarterly Journal of Medicine, 28(110), 259–313.
Wrong, O. M., Norden, A. G., & Feest, T. G. (1994). 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. QJM : Monthly Journal of the Association of Physicians, 87(8), 473–493.
[1] Thomas Lewis was an eminent cardiologist of the time, although he preferred to be known as a ‘cardiovascular disease specialist’, who had helped develop electrocardiography (ECG), especially for the detection of atrial fibrillation, and whose pioneering contribution to the ECG was acknowledged by the Nobel laureate Professor Willem Einthoven in 1925).
[2] Himsworth had research interests in diabetes and liver disease, and was one of the first to differentiate between ‘insulin-sensitive’ and ‘insulin-insensitive’ diabetes mellitus.
[3] Lightwood was a paediatrician based at St Mary’s Hospital Medical School and Great Ormond Street Hospital in London and Butler was a US paediatrician at Harvard Medical School.
[4] Albright was an endocrinologist, he had followed up on the reports of Lightwood and Butler to describe what he termed ‘renal hyperchloraemic acidosis’ due to ‘tubular insufficiency without glomerular insufficiency’. Albright had worked with Lord Rosenheim, a close associate of Charles Dent, and the successor to Sir Harold Himsworth as Professor of Medicine at UCL.
[6] Davies had considerable expertise in physiology, and later in membrane transport, who subsequently became a well-respected specialist in geriatric medicine in his native Wales.
[7] This detailed paper was preceded by an earlier brief description of use of the ammonium chloride acid-loading test in the Lancet in 1957 (Davies & Wrong, 1957)
[9] Thakker had worked previously at Middlesex Hospital Medical School under Dr JDH ‘Willie’ Slater, a renowned clinical physiologist (and editor of the popular textbook Clinical Physiology) who had wide interests spanning the effects of high altitude to various metabolic balance studies concerning endocrine control of fluid, electrolytes, mineral metabolism and blood pressure. Thakker went on to Hammersmith Hospital and soon to Oxford.
[10] Unwin also received help and support from Guy Neild who led the Department of Urology and Nephrology based at the Middlesex Hospital, by now part of UCL.
Last Updated on January 10, 2024 by John Feehally