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NEPHROLOGY IN THE NEXT MILLENNIUMA V Mulay*, A L Kirpalani**
*Sr. Resident; **Prof. and Head, Dept. of Medicine, Bombay Hospital Institute of Medical Sciences, Mumbai 20.
In reality 1st Jan 2000 will be no different from 31st Dec. 1999. The sun will rise in the same way and set in the same place. Each inhabitant of this earth will do exactly the same things that he did on the previous day. And yet, it is the day eagerly looked forward to by each of us. Each one of us will have his own reflections of the millennium that was, his own regrets at failures and his own vision of expectations in the millennium and yet hardly a handful of us will really even see the second half of the next century. In penning this article we will try to recount the major successes and achievements of our own speciality i.e. nephrology, and by making a mental graph, extrapolate with a dotted line into the future in order to predict what may soon be possible. There is a little bit of HG Wells in each one of us. At the beginning of this century, he was thought of by most to be an unrealistic dreamer whose head was filled with flying saucers, submarines and unimaginable achievements. But it was because of daring day dreamers like him who aired their ridiculous and unrealistic dreams that many of those dreams became reality. By projecting our unrealistic dreams in the next few paragraph, we do hope that a hundred years from now, some nephorologist will say the same about us. So here goes!
CRF Today and in Future
Until the 1960s, there had been little modification of Richard Bright’s description of glomerular diseases. This was the lament of many textbooks of nephrology. The speciality of nephrology, came to exist only because dialysis, i.e. haemodialysis and peritoneal dialysis started to develop after the second world war. To William Kolff we bow our head in reverence for giving birth to this speciality of nephrology. Without him, we would not have been able to call ourselves nephrologist. Until dialysis was developed, renal diseases were looked after by general physicians. Next only to cardiology, nephrology is the speciality that has through dialysis and transplantation brought about a tremendous improvement in the quality of life of the patients with renal disease. Renal transplant recipients have their own Olympic games and one renal transplant recipient has actually participated in the real Olympics. The immunologists, of course, must claim the lion’s share of the credit for this, as they have developed newer immuno suppressants like cyclosporin, mycophenolate, FK 506 and rapamycin, each of which makes the results of the transplant patients better day by day. The nephrologist however deserve their fair share of plaudit for maintaining the patients alive and well on MHD and CAPD while the CRF patients await a new kidney, specially in those countries where cadaver transplantation is well developed. While waiting for the kidney, the patient on MHD and CAPD gets an artificial prolongation of his life with increasing improvements in quality ensured by biocompatible dialysis membranes, erythropoietin, vitamin D analogues and superior antibiotics to fight infections.
The Indian scenario cannot boast of comparable improvements in quality of life, mostly due to prohibitive cost. There is hardly any manufacture of dialysis material in India and with the decreasing value of the rupee everyday, the imports are increasingly dearer. Part of the blame for the sad state of affairs must be on the advanced countries where research towards reducing costs of RRT takes a backseat, because almost everyone hasgovernment or insurance funding. But even the advanced countries with new case rate of 30-40 per lakh requiring RRT yearly, are beginning to feel the pinch, financially, what with the US spending 14 billion dollars spending annually on CRF! Our greatest dream of the next millennium is to see the development of newer modalities of RRT, perhaps a pill or set of pills taken once or twice a day to neutralize uraemic toxins, completely eliminating RRT. Until that happens, we hope that RRT will become cheaper, i.e. disposable materials for dialysis, fluids and tubings for CAPD and the cost of drugs like cyclosporin, mycophenolate, calcitriol and erythropoietin. We can also hope, that in our own country, the next 30 years will see the development of cadaver transplant programme, mainly due to improvements in trauma care. Road accident cases in remote areas will be picked up within moments of happening, taken in helicopters and superfast ambulances running on 8-lane highways, with each paramedic carrying an iridium phone linking by satellite the victim to well equipped hospitals. The hospitals will have ventilators, monitors, defibrillators and operation theatres, reachable within 5-10 minutes from any point in the country. We also dream of government/NGO, employer and insurance funding, so that the average CRF patient is not reduced to the status of a sophisticated beggar, constantly seeking charity, as it is in India today. With the development of xenotransplantation and newer drugs to overcome the strong immunological barrier that exists today for this activity, we look forward to the day when there will be pig and baboon farms in every suburb of the metropolis where the recipient will be able to find suitable transgenic pig donor. We also look forward to the day when dialysis machines will come in a size of a wristwatch worn over the radial artery and vein permanently connected to the patient who periodically visits the toilet to empty out from the devise the ‘urine-equivalent’ produced. Of course, with the advent of cloning, which is already a laboratory reality, the day is not far when organs will be produced specifically from patient’s own tissue for replacement as spare parts. Nephrology may soon be named as ‘spare parts industry’!
Progress in Clinical Nephrology
One of the major lacunae in renal medicine is the inability to pick up early renal dysfunction due to limitations in serum creatinine and blood urea as biochemical markers to reflect early fall of GFR from 100 to 50%. By the time the SMA sheets reflect an increased creatinine, the GFR is already reduced by 50%. Although creatinine clearance approximates inulin clearance in health as marker of GFR, there are serious limitations to its application. Nuclear methods of B12 and iothalamate clearance also have serious limitations. Inulin clearance is purely a laboratory test for research and has no clinical applications. Recently new markers such as B2 microglobulin and cystatin-C have appeared, and of these cystatin-C may soon find clinical application in the form of serum cystatin-C levels and cystatin-C clearance to detect early renal disease particularly in children, s. creatinine being a very poor indicator in this population. In the future perhaps another substance whose serum levels had a linear correlation with GFR may be found.
Renal imaging
Renal imaging has gone up leaps and bounds in usefulness, sonography being the mainstay in assessing renal size. Nuclear scanning still has limitations which can be overcome by 2D or 3D MRI imaging using phase contrast or time of flight principles. Similar progress is being made in 3D-CT angiography which defines vascular and other anatomical features precisely.
Renal physiology
Various channels are now being described in tubules which are linked with transport of substances and their detection has led to the
Name of the channel Disease associated due to mutation 1. E N C (epithelial sodium channel) Gain in function - Liddle’s syndrome
Loss of function - Pseudohypoaldosteronism Type 12. Na K 2Cl cotransporter (frusemide sensitive) Bartter’s syndrome Type 1 3. ROMKI (Potassium channel) Bartter’s syndrome Type 2 4. CCl ka (chloride channel) Bartter’s syndrome Type 3 5. Na Cl cotransporter (Thiazide sensitive) Gitleman’s syndrome 6. CCl 5 (Chloride channel) Dent’s disease/hereditary hypercalciuric nephrolithiasis 7. Aquaporin 2 (Water channel) Autosomal recessive nephrogenic diabetes insipidus 8. Ca R (Calcium sensor) Decreased sensitivity-Familial hypocalciuric hypercalcaemia.
Increased sensitivity - Hereditary Hypoparathyroidismunderstanding of various disorders due to defects in these channels. The list of channels and diseases associated is given above.
The day is not far that gene therapy instituted at proper time will prevent or cure these illnesses.
Primary Glomerular and Tubular disease
There has been tremendous progress in understanding of pathogenesis of renal injury both in tubules and glomeruli. The role of various new mediators, cytokines, adhesion molecules etc., once clearly understood, will help produce solutions of curing difficult illnesses like ATN. Already in this disease, various substances like atrial natriuretic factor, IGF-1 and growth hormone have been tried to facilitate recovery from ATN; success is so far limited. Adhesion molecules called Integrins are responsible for producing tubular injury and adhesion of dead cells causing tubular obstruction. Anti integrin substances called R-G-D block the integrins and prevent the cell clumping leaving the tubules free. We can expect soon the development of a cocktail of substances including such anti integrins, anaritide (ANP), IGF or EGF, growth hormone etc. to be administered when a patient has impending prerenal azotaemia so that ATN does not develop. Similarly we may expect dopamine and dobutamine to be replaced by another amines that cause renal vasodilatation.
Similar progress has been made in glomerular disease and one can expect similar antidotes to be developed against immune mediated injury either due to circulating antibodies or immune complexes.
Secondary glomerular disease
The last 20 years have seen a major focus on diabetic nephrology, particularly in early detection (microalbuminuria) and prevention (control of blood glucose, ACE inhibitors). Drugs like aldose reductase inhibitors which block the sorbitol-myoinsitol pathway and prevent the deposition of basement membrane are under trial. Somatostatin is also under trial for the same. Drugs like sulodexide-a proteoglycan combination of heparan and dermatan sulphate replenishes the glomerular polyanion and restores the negative charge to basement membrane and reduce proteinuria. We can expect that diabetics will soon be receiving such drugs over and above insulin and oral hypoglycaemic agents in order to prevent all the complications of diabetic retinal-renal syndrome.
Diseases which were earlier called idiopathic are rapidly being labeled as secondary glomerular diseases as their mechanisms are unravelled. One such example is ANCA associated vasculitis. Progress in lab diagnosis may soon make the concept of ‘primary’ illness disappear as the aetiology of each disease is known. Almost all cases of cryoglobulinaemia which were initially thought to be idiopathic are now known to be due to hepatitis-C, and with treatment of hepatitis-C being possiblewith drugs like interferon, a cure may be possible in such incurable diseases. Moreover, thanks to the increasing applications of plasmapheresis, such patients can have alleviation of symptoms temporarily with plasmapheresis.
Kidney care in the ICU
The major limitations of ordinary haemodialysis and peritoneal dialysis in patients suffering from multiorgan failure are being overcome effectively with the use of CRRT which is rapidly innovative to obtain effective replacement of renal function without producing haemodynamic instability. In the past, ordinary dialysis membranes like cuprophone and cellulose acetate would contribute to increased morbidity and mortality in MOF by inciting cytokine activation. With the development of biocompatible membranes such as polysulphone and polyacrylonitrile, which do not activate the complement cascade and incite the cytokine production, CRRT has been rendered safe to patients with sepsis.
Space constrains prevent us from listing more of the tremendous achievements that the science of nephrology has made in the last 20-30 years and the aspirations for next century, if not next millennium. Fancy ideas and wild dreams must be looked at with the realistic perspective, particularly in the Indian context. Our greatest hope for Indian nephrology and the immediate goals are to achieve a level of sophistication in dialysis and transplant that are prevalent in the west today. In the next few decades, that constitute our lifetime and the lifetime of our children and grandchildren, if we can achieve the same patients survival and the same quality of life on maintenance haemodialysis, CAPD, and renal transplantation, as it is possible in the west today, we will have achieved plenty. It is not that the know-how, the technical expertise and the innovative intelligence do not exist in this country - quite the contrary. We have kept patients alive in the face of severe economic constrains that the average Indian faces. We have achieved plenty to be proud of. For example, reuse of dialysers and tubings specially marketed as ‘Only for Single Use’, developed in our country long before being adopted elsewhere. But the fact is, the person reusing dialysers, is never going to achieve the same quality and longevity of life as the person doing single use. Therein lies the genesis of the dictum! ‘The survival of the CRF patient is directly proportional to the size of his bank balance’. Therefore the most important aspiration in the next millennium will be to see an economically strong India which can afford nephrology facilities of the highest quality for everyone from banker to beggar.
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