----start----- medsurg2 9.24.98 Dr B has arrived, it is presently twelve minutes past the hour... *ahem* Renal consequences of hypercalcemia: 1. renal arterial vasoconstriction: Ca++ gets into smooth muscle cells and increases tone. this is happening all over the body but is most pronounced at the kidney. BP is not affected 2. inreased renal vascular resistance 3. decreased RBF and GFR 4. renal autoregulation is maintained 5. altered tubular reabsorption - decreased calcium, sodium, H2O 6. concentrating defect- high serum calcium interferes with ADH binding in distal tubule, creating appearance of DI. also there is increasead flow to medulla causing medullary washout, along with reduced flow to cortex 7. azotemia 8. tubular degeneration note: cause of hypercalcemia is usually paraneoplastic syndrome but there are other causes This progresses on for 5-20 days, and then you have an animal in classic ARF episode. slide: chart here shows that a control animal will have increasing RBF with increasing renal arteril pressure. but a hypercalcemic animal will not show the increase - RBF is cut by about half. This occurs when calcium is over about 13mg/dl. As it gets higher, renal vasoconstriction gets more severe. most important component - free ionized calcium. If you want to know how dramatic the calcium effect is - measure ionized calcium, not total calcium. Again - as renal vascular resistance increases, RBF decreases. Polyuria due to hypercalcemia: causes: malignancy, hyperparathyroidism, iatrogenic (vit D excess) MDs tell us about 35 tumor types that can cause hypercalcemia. vets lists is short - mainly lymphoma in dog and cow, not in cat. Etiology is htat tumor makes a pseudoparathyroid hormone. In dogs, perineal adenoma also does this. Removing the tumor will correct the situation but there may already be permanent renal damage. True hyperparathyroidism is very uncommon in all domestic animals. The iatrogenic cause is not rare - often owners decide to supplement their animals with vitamin D for some unknown reason. malignancy cases have Ca++ 15-20 so can parathyroid cases iatrogenic cases usually more like 13-15 we're concerned when it is over 13 and up to 20. at about 18-20 you see ARF. serum phosphorous will be normal or reduced, until ARF occurs, and then they get hyperphosphatemia. they present with incredible polyuria. presence of azotemia is variable. some animals do ok with calcium of 15 or 16, with normal GFR. Others will have ARF with calcium of15. so some animals are more sensitive. factors in hypocalcemic hyposthenuria: -medullary washout due to redistribution of blood flow -antagonism to ADH -decreased cortical/medullary osmotic gradient -change in urea and sodium transport across the LOH due to Ca++ Vascular casts are shown - normal and from animal w/vit d toxicosis and hypercalcemia. The sick dog had much less blood flow to cortex, and much more to medulla. renal pathology due to hypercalcemia: calcium damages proximal tubular cells within a few hours= -mitochondrial granules form within hours -tubular cells slough within days -BM of tubule gets dense -tubular casts form -tubular atrophy occurs -intratubular and interstitial calcification occurs. the interstitial fibrosis and calcification is permanent. slide: sloughing tubule with thick BM. three weeks later you would see large ca+= deposits in the interstitium near that tubule. slide: severity of tubular damage associated with increases in serum calcium. signs are seen at 13, 14 - tubular damage at 16, then tubular damage increases massively as calcium rises from thatpoint. if calcium hits 26, 60% of tubules are damaged. questions about ARF or hypercalcemia? no. ok. CHRONIC RENAL FAILURE: CRF this is the silent disease, present mos/yrs without detection high frequency in dog/cat no real age distribution in domestic animals. Old pathology literature which is completely false says that all older animals have CRF b/c they have some renal fibrosis, but that is untrue. Age forces renal function to decrease by about 10%. that's not failure. most cases of CRF are NONprotein losing diseases - that's run of the mill CRF. there are also cases of protein losing nephropathy, but that is a totally different thingn, is more noisy, easier to detect. incidence of CRF by species: 10,039 diagnoses - 80% dogs, 20% cats 1.2% of dogs presented here had CRF 7.2% of cats presented here had CRF we think incidence in cats is 2-3x that in dogs, and cats may tend to have more as they age. we see rates are relatively constant until you get out to about 16, 17 - when there is more in the cat (dogs don't usually live that long). the cases at age one are the ones due to congenital dysplasias. also in cats, at age 6 - probably due to inherited polycystic disease. etiology: -recurrent ARF -renal dysplasia -pyelonephritis -amyloidosis -partial urinary obstruction -tubulo-interstitial nephritis - most common in dog and probably cat. immune mediated. we know nothing about it. also common in man. -glomerulonephritis (protein losing enteropathy) -nephrosclerosis - scarring in glomeruli, mainly in cat, etiology unknown -hypercalcemia -unknown other factors "chronic interstitial nephritis" is a wastebasket term. when you make a dx of CRF the first thing to ask yourself is is it worth trying to find a cause. usually it isn't. We do some tests, because if the cause is reversible you should know that and then reverse it. that would be active pyelonephritis, or urinary obstruction. also glomerulonephritis is importantif there is protein loss. hypercalcemia is reversible, too. but for the other causes, which are the majority, the damage has been done, the disease is in late stages and may not even be active anymore, the kidney is really full of fibrous CT and you can't do anything about it. the culprit, as it were, is long gone - hidden by fibrosis. so we don't launch any further investigation from there, we simply treat. ok, now,the next topic to gointo for the next ten minutes is the functional response to nephron loss. CRF comes on slowly, and the nephrons that are not affected can make major changes and undergo hypertrophy and hyperplasia, trying to take over role of affected nephrons. this happens gradually and leads to big changes in morphology and function of surviving nephrons. slide: four nephrons from a dog with naturally occuring renal dz. one is normal. the other three are survivors from a dog with renal failure. the dog only had small number of nephrons left. these survivors are weird looking. glomeruli are bigger than normal in all the survivors. b/w 50-200% larger than normal. All the microscopic features of the glomeruli are enlarged and the function is increased. The proximal tubule is clearly longer, wider, more convoluted. the LOH is also bigger than normal with wider diameter, parts dilated and parts a bit constricted. These are like "supernephrons". this led to a concept of functional response paralleling the morphological response. they studied these nephrons to look into this. classic work was done here at penn - put pipettes into the glomeruli to measure function. after about 35 years of study, they found that the surviving supernephrons handle solute so it can be put into 3 categories - in CRF we talk about % loss of GFR. this chart shows an animal who lost 75% of GFR and was operating at 25% GFR. some solutes are in group A - these have no regulation at all as renal function is lost. A solutes rise in plasma as GFR goes down. these are solutes with no major tubular transport processes, that are handled mainly by filtration. Urea, creatinine are group A solutes. As we lose GFR, urea and creatinine rise. category B is partially regulated by tubules - evn though there is a big loss of renal mass, plasma concentration is normal. but when you lose 75% of function, concentration rises. B solutes are phosphate,mainly. Phosphate is regulated well until you lose about 75% of GFR, by increases in tubular transport. group C solutes are normally regulated the whle time - sodium and potassium - b/c there is a very efficient tubular adjustment system for them. this categorization is only for CRF though. w/ARF there isn't time to make these adjustments. it takes a lot of time to go through the adjustments to maintain these things normally. it's a great adaptation but it confounds our diagnosis. ---break--- whooops, i walked in a tad late here. he's talking about hypercalcemia --- you can remove the PTH gland or 7/8s of it if you need to, or stop giving the vit D, but you need to lower serum calcium faster than it goes down on its own. Diuretic which inhibits reabsorption of Na and Ca -- furosemide. that with volume expansion to vasodilate the animal which increases urine output since renal function is still reasonably ok is a good thing to do. make sure animal isnt dehydrated. you load with fluid, give diuretics, and serum calcium falls over a few days. in the tumor cases where you do not have a positive effect, the old fashioned tx was to give steroids to suppress production of paraneoplastic stuff, and that works well to knock down calcium within 24-48 hr. this only works a few weeks though. then tumor makes a different form of stuff or something. but by then, you can hopefully have animal on chemo. volume expansion and diuretics - tx for hypercalcemic renal failure. OK, back to this. a solute with no tubular regulation - BUN or creatinine- if animal presents with dehydration AND CRF you have to replace volume deficit, to take away prerenal component which may equal 30-50% of the existing azotemia. Then wait a few days, then repeat BUN and creat.They may be lower.If animal is NOT dehydrated, and creat is 3.6, and animal isn't sick, then this is fine. if the animal is dehydrated you have to rehydrate then repeat. that's category A stuff. category B - changes in tubular phosphate reabsorption as GFR falls. the kidney i set up to absorb 90% of filtered phosphate - controlled by PTH. as GFR falls, % reabsorption of phosphate starts to fall. this is due to increased PTH. animals with CRF have secondary hyperPTHism. this allows filtered phosphorous to be lost into urine and not absorbed. the serum phosphorous concentration remains normal! eventually, there isn't enough renal function to respond to PTH, and plasma concentration of phosphorous starts to rise. category C- situation wherethere is complete regulation - sodium. serum sodium concentration stays normal the whole time. what happens is there are increased natriuretic factors, which decrease sodium secretion - eventually animals are allowing 10-15% of filtered sodium to stay in the urine, keeping plasma sodium normal. remember normally 99.9% of filtered sodium is reabsorbed. now, with this sodium loss into the urine there is increased urine volume - dilute, high volume urine, getting worse with more severe, chronic renal failure. there are three paragraphs on the bottom of this handout - "intact nephron hypothesis" from some guy in the 60s. The functional capacity of the residual nephrons is independent of the etiology of the disease. it matters not if the cause is UO, amyloidosis, recurrent ARF, whatever. the changes in the surviving nephrons is limited and the nephron will undergo the changes independent of whatever the insult was. the result has nothing to do with how nephrons were lost, it has to do with what changes occured in the surviving nephrons to allow them to take over for the lost ones. this guy studied many dogs, over 20 yrs. he proved this. there are, in the diseased kidneys, a group of nephrons that look sick, worn out and tired, and they probably do not contribute much to any renal function. the only populaton that is relatively healthy is the hypertrophied supernephrons. then there are also atrophied remnants. How do animals regulate the solutes? Trade off hypothesis if you are going to have the advantage of hypertrophy/hyperplasia to keep feelig better during loss of renal mass, this will come at a price - the adjustment process itself has negative effects - mainly the phosphate adjustment - it is wonderful and precise, but leads to hyperPTH state which has other associated problems. Stages of CRF: there are four 1. initial stage: no signs, but there is decreased GFR 2. renal insufficiency: mild azotemia, reduced urine concentration, polyuria, intermittent anorexia, some tiredness. you can see these animals, test them. you will see them in practice, and in this group the dz process MAY still be active, and you might be able to intervene. can't tx unless you find anything specific though. there is really nothign else you can do to help. 3. renal failure: moderate to severe azotemia, hyperphosphatemia (indicating loss of 75% of renal function), isosthenuria (SG about 1.010 and fixed), anemia, anorexia, wt loss, "tired and sick." Some animals, though DO NOT act sick, even though they are in renal failure. they can adjust to the azotemia and not feel sick. owners will not believe you that animal is in failure. but some animals are very stoic! 4. end stage failure: progression of all of above. severe depression, weakness, vomiting, stupor, seizures. lab values off the chart, creat and phos over 15-20. No useful tx, recommend euthanasia. it sounds harsh, but there isn't anything you can do to help. slide: representation of survival rate in patients with CRF over a period of weeks or mos. chart shows 7 mos. some animals deteriorate rapidly within a few weeks - others go more slowly and gradually - others are stable for along time, then deteriorate rapidly - and yet others are stable for a really long time. but, when an animal presents with creat 6-10, it is generally not going to live over a year. cats, however, can remain stable for years with CRF - they are tougher about it than dogs. appetites are finicky and they are difficult to tx and medicate, but they do tend to handle CRF better than dogs do. People are more like cats. Dogs are more sensitive to CRF and don't do as well. Dogs are sissies about it, he says. cats are tough. Lab values- what do you see in these patients? age can be anything, no sex predisposition.typical hx pu/pd x few weeks. maybe some wt loss and depression, but that's +/- lab values: creat 3.6, BUN 95 - this is moderate azotemia. this dog is in stage 3, early failure. CBC WNL except nonresponsive anemia due to loss of erythropoietin. WBC WNL unless there is infection present; diff also normal. Na, K, Ca normal; phosphorous slightly elevated. BG 185 - it's common for animals in CRF to have moderate hyperglycemia and hyperinsulinemia due to moderate peripheral insulin resistance. just ignore this. U/A WNL except SG fixed at 1.012, protein 1+ (usually none) now, originally when disease was active, theremight have been something in urine sediment, but usually you do not find anything. UREMIC SYNDROME: a constellation of metabolic abnormalities, only fully developed in CRF. can potentially include all these things: -uremic toxins: you're lucky not to have to battle this one. the story of these toxins goes back 250 yrs with fascinating history and confusion. there was a fuss over what killed patients with kidney dz. from 1880 to 1970 people thought stuff in plasma acted as poisons "uremic toxins" and about 250 of them were studied. nothing important was found. no correlation b/w severity of renal dysfunction and concentration of toxin. bottom line - none of these correlate with severity of renal failure. some are elevated in groups, patterns, or individually, but no easy pattern. Urea and creatinine are not toxins. people think they are but they are NOT. urea will cause some nausea. creatinine, when metabolized in a peculiar way, is minor neurotoxin but that involves complex GI metabolism and really isn't important. Creatine isn't a toxin at all. Guanidinoacetic acid is a minor metabolite that causes some nervous abnormalities. Cyanate, AAs, pyruvate, lactate, volatile phenols, aromatic amines, and indoles were studied in the 1970s and none found to be toxic. organic acids - guanidineosuccinic acid, guanidine,and methylguanidine have CNS toxicity in man and not as much in dog. aliphatic amines, enzyme inhibitors also not important. "middle molecules" - 50-100 million bucks spent by NIH to find out about these small peptides that are raised in plasma and CNS of CRF patients - people thought for sure they were important, b/c hemodialysis must be removing something from people's blood right? so these were studied with great fanfare and nothing was found. you can't find any of this in veterinary literature, either. dogs were used in study though. oxalic acid not important. but...PTH is a toxin. -sodium and water balance: adaptation of sodium excretion after reduced GFR in dog - normal dog, GFR 50 ml/min vs CRF dog with GFR 10 ml/min. both have sodium intake 2100 ml/day, both have 146 meq/L in plasma. filtered load [remember filtered load is GFR * plasma concentration] is 7.3 in normal dog, 1.4 in CRF dog. excretion in normal dog is 0.036, in CRF dog is 0.112. fractional reabsorption in normal dog is 99.5%, and 92.0% in CRF dog. in CRF dog, tubular reabsorption is turned down. in CRF dog, per tubule excretion is higher. so the tubular adjustment system is working well. what allows this to happen is the natriuretic factors. in experimental animals with 50% nephrectomy and 85% nephrectomy we saw big increases in GFR - doubled in animal with 50% nephrectomy, then stayed a about the same in 85% nephrectomy animal. so there is really a limited capacity for hyperplasia and hypertrophy. generally they plateau somewhere. but the ability to excrete sodium - amount of sodium lost per surviving nephron is WAY higher in 85% nephrectomy animals than in 50% animals, and is way higher in 50% animals than in normals. so this is a necessary adjustment in all animals. factors leading to renal sodium los in uremia - major one is natriuretic hormone substances - ANP from endothelium of heart and vessels, and something from the brain. without these hormones the process doesn't work. also increased GFR per nephron increased tubular flow rate -acid/base balance -erythropoiesis -Ca/phos balance -GI absorption defect: variable pattern of severity; calcium malabsorption common, feeding into Ca/phos imbalance; other reabsorption defects for protein and electrolytes exist but aren't important. -CHO intolerance: a situation where there is some sort of blockade for receptor of insulin on cells, so insulin can't bind or act, and you have glucose transported into cells at slower rate, and modest hyperglycemia. this is a very important metabolic abnormality in man b/c it is coupled with a fat metabolism defect in man, but not in dog/cat. so the CHO intolerance is less important for us to worry about. MD students spend two hours learning it. you can skip it :) -neuromuscular alterations: there are multiple changes in neural function in CRF - most related to calcium deposition in nervous tissue - nerves, CNS. it's been studied in dogs and the peripheral NM abnormalities are minimal and hard to find clinically, but deposition of calcium in brain is important in dog/cat and may lead to some of the depression/anorexia in late stage CRF. this is permanent and irreversible, driven by PTH. -cardiopulmonary pathology: rare in dog/cat, unknown in farm aniamls, big deal in humans, we're skipping it. -endocrine abnormalities: several but not that important except hyperPTHism -hypertension: in CRF, hypertension is probably not important. it is minor hypertension, and to summarize 15 yrs of research, hypertension in dogs over time doesn't lead to renal damage. they are different from other spp. so primary hypertension or secondary hypertension as a result of CRF- neither is important to the animal. it cost the gov't 1.5 million bucks to find this out. Good news is the cash came here :). so don't worry about it - unless there is protein losing nephropathy. -infection/immunologic abnormalities: studied extensively in 70s and 80s. do animals with CRF have depressed immune systems? yes. but mild. no AIDS type thing or anything. They're ok. unless you violate them by putting in chronic urinary cath, they are ok. -----end----