BEDSIDE URINARY MICROSCOPY
GIOVANNI BATTISTA FOGAZZI LECTURES SERIES
URINARY SEDIMENT: Part 3: Particles II
G.B. Fogazzi, Milan, Italy
Dr G.B Fogazzi
Research Laboratory on Urine, Unità Operativa di Nefrologia
Fondazione IRCCS, Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena
Now casts. I will not speak about the whole spectrum of casts we can find but only the most important ones. Casts are elements, which form in the distal tubules and collecting ducts of the kidney. They have a matrix, which is Tamm-Horsfall glycoprotein, which is produced by the thick ascending segment of the loop of Henle. There are different types of casts with different clinical meanings.
What about the clinical meaning of casts? One cause that I think is important, whatever particle is contained in the cast, this particle comes from the kidneys.
Thus if we have an erythrocyte cast, we must know, we must remember that this means that the red cells come from the kidneys. With a sensitivity however, which seems to be low.
Several investigators have looked for erythrocyte casts in patients with various types of glomerulonephritis and you see here the percentage of patients which have been found is rather low from 22 to 38% even though a more recent paper published by the group of Doctor Köhler has shown that if they are found in a very extensive way, the percentage goes up to 86%. I will tell you later on what is our experience in 100 patients with glomerulonephritis.
Leukocyte casts. Again they tell us that the leukocytes come from the kidney which may happen both in patients with glomerulonephritis and in patients with for instance renal infection, pyelonephritis.
Epithelial casts, which contain tubular cells these casts are typically seen in patients with acute tubular necrosis but they are also seen in patients with glomerular nephritis and again I’ll show you later on our findings.
Bacterial casts, extremely rare but again these tell us that the bacteria comes from the kidney.
We can even have yeast casts but in this case this is a candial cast, again infection comes from the kidneys.
Now the big chapter of urinary crystals. We can very arbitrarily distinguish 3 groups of crystals, the so-called common crystals, the pathological crystals and crystals due to drugs.
Common crystals first, uric acid crystals, which we always find in acidic urine.
Calciumoxylate monohydrated which is found in this range of urinary pH,
and calcium oxalate dehydrated.
Calcium phosphate crystals, alkaline pH
and triple phosphate crystals, alkaline pH.
What is the clinical meaning of these common crystals? In most instances, 99.99% of cases, uric acid calcium oxalate and calcium phosphate crystals are simply due to a transient super saturation of the urine which is caused by foods, dehydration or changes of urine pH and/or temperature upon stenting. However, especially when they are persistent in the same patient they may be associated with a metabolic disorder such as hypercalcuria, hyperoxaluria or hyperuricosuria.
So they suggest that there is a metabolic disorder in these cases and very rarely they can be associated with acute renal failure due to intrarenal precipitation of crystals, which happens in 2 very well-known clinical situations which are acute urate nephropathy which is associated with an intratubular precipitation of uric acid crystals and the other situation is the poisoning entrained by ethylene glycol ingestion which is associated with intratubular precipitation of calcium oxalate crystals, which then appear in the urine.
What about pathological crystals? We have cholesterol crystals; we have already seen them, cysteine crystals, urocine, tyrosine and 2, 8 dihydroxy adenine crystals. We speak about cholesterol, cysteine and this one not about these ones very rare.
Cholesterol again as you can see it is a marker of heavy proteinuria.
Cysteine crystals they are a typical marker of patients with cysteinuria. The more the urine is acidic, the higher is the possibility to find these crystals in the urine.
Now 2,8 dihydroxy adenine crystals. These crystals are similar, maybe similar to uric acid crystals at least for their colour, which is an amber colour, brownish, yellowish colour. They have spherical particles with irradiations which have origin in the centre of the crystal and then spread towards the edge of the crystals.
These are crystals seen by phase, by bright-field microscopy and under polarised light they appear as maltese crosses very similar to lipid particles.
We know that there are 2 types of APRT deficiency, which is a condition, which is inherited in an autosomal recessive manner. Type 1 which is seen in Caucasian people is associated with a virtually absent enzyme activity while type 2 APRT deficiency is seen in Japanese and is associated with a low but however, some activity of the enzyme.
From the clinical point of view this condition has been well studied in Iceland where the condition is endemic and you see here that any age can be affected by the disease with a ratio male-female which is 1:1 and 65% of patients may have recurrent radiolucent stone disease which is often confused with uric acid stone disease. There will be 26% of patients with acute renal failure due to intratubular precipitation of the substance, 17% of patients with chronic renal failure probably due to chronic interstitial nephritis and 96% of patients may have crystalluria.
This is an example of acute renal failure due to the intratubular precipitation of 2, 8 ATHA which occurred in Rome at the Policlinico and Gemelli. It was a patient in which after biopsy it was found that there was a precipitation of crystals in the tubules, which were then identified as 2, 8-dehydroxy adenine. This is a PAH pen and this is a phase polarised light.
You see here these are the lumina of the tubules they are completely obstructed by precipitated crystals while here crystals are probably within the cytoplasm of cells. It is important to recognise this condition because after the renal biopsy the patient at the time was on dialysis, after the identification of the crystals allopurinol had been given and the patient was able to recover from acute renal failure.
The diagnosis of the deficiency of APRT. We can measure the level of the residual enzyme activity in erythrocyte lisate. We can measure the urine to dehydroxy adenine by high performance liquid chromatography, we can perform ultraviolet and infrared spectrophotometry of stones and we can finally examine the urine sediment.
What is the role of urine sediment examination in this condition? It is well written here, this statement of Doctor Alderperson an expert of this condition, skilful and let me add motivated urinary microscopy is the single most important diagnostic procedure because urinary 2 8-dehydroxy-adenine crystals are usually abundant in untreated patients. So with a simple test we can do very important clinical things.
Now the main types of crystals due to drugs. A number of drugs can cause crystalluria. For instance sulphadiazine and acyclovir, the antiretroviral agent indinavir, piridoxylate which is used in some European countries as a coronary dilator.
Primidone, which is a barbiturate. Naftidrofuryl oxalate, which is used again as a vasodilator, vitamin C, amoxycillin all these drugs can cause crystalluria.
This is an example of sulphadiazine under polarised light,
an example of amoxycillin under bright-field microscopy,
the nature of which here was confirmed by spectroscopy which was performed in Paris by our colleague and friend Professor Daudon in indinavir crystal and in acyclovir crystals.
What are the factors, which favour the precipitation of drugs in kidneys? First of all is a drug overdose, dehydration, hypoalbuminemia which causes the presence of a high percentage, proportion of unbound drug in the blood and urine pH, some drugs precipitate at acidic pH for instance, amoxycillin while neutral pH or alkaline pH is necessary for the precipitation of ciprofloxacin crystals.
What are the clinical manifestations of drug crystalluria? One is isolated and asymptomatic crystalluria, the most frequent one then they can cause hematuria, microscopic or gross hematuria with or without leucocyturia. Crystals are very frequently associated with stones, which can cause obstructive uropathy and they can even cause acute renal failure due to intratubular precipitation of crystals with the same mechanisms I’ve just described for 2,8 dihdyroxiadenine.
General rules to follow when we think that there is a crystalluria due to drugs in the urine. First think of a drug whenever you come across crystals with unusual appearance. Second, if you have this feeling, this impression ask the patient if and which drugs she/he is taking, then check the renal function because acute renal failure may be a consequence of crystalluria and then hydrate the patient and reduce and discontinuate the drug to prevent acute renal failure.
Microorganisms. We know here everybody knows that in the urine we can find bacteria, yeast protozoa and parasites. Bacteria can be present in the urine as a marker of infection or of contamination of the urine. Candida most of the time comes from contamination from the genital secretion as well as Trichomonas vaginalis. Enterobius vermicularis is very rare and it can be seen as a result of the contamination of the urine from faeces especially in children. A true infection is always caused by schistosoma haematobium. Urinary sediment plays an important role in the diagnosis of schistosoma haematobium. Urinary schistosomiasis may not be a problem in our countries, in Europe, in the United States but is a very important clinical problem in a number of developing countries.
The urine sediment shows in patients with urinary schistosomiasis the presence of the eggs of the schistosoma hematobium which are very easily recognised because they are very big first of all 120-50 micrometers, a typical shape and this spine which is a terminal spine which allows us to differentiate schistosoma haematobium from schistosoma mansoni which has a spine which is lateral but which is not found in the urine but is found in faeces.
Urinary schistosomiasis as I told you is endemic in many geographic areas, look here in many areas of Africa going from areas North of the Sahara and in many sub Saharan Africa, it is also present in the Middle East and here you see this is Iraq. This is responsible for a recurrent bouts of gross hematuria, which are recurrent and cyclic, and in many areas of sub-Saharan rural Africa it is also known as the agent causative of "male menstruation". It can cause obstructive uropathy, bladder carcinoma and glomerulonephritis.
What is the role of urinary sediment? The diagnosis of urinary schistosomiasis is largely based on the examination of the urinary sediment, which shows first of all the eggs. To increase the egg yield and then sensitivity, the urinary sediment is examined after a physical effort for example, a run and between 10 A.M. and 2 P.M. and then the quantification of the eggs is usually used to estimate the severity of the infection.
This is the experience we measured in a hospital of Republic of Benin, which is a small country of West Africa. We found over the years 50 subjects with urinary schistosomiasis and besides the eggs we found erythrocytes in 100% of cases, glucocytes in 92% of cases, transitional uroepithelial cells in 28% of cases and moderate to severe albuminuria in 14% of cases. You see from this data that we can arrive to define a urine profile in urinary schistosomiasis.
THE FOURTH PART WILL BE PUBLISHED ON NOVEMBER 23RD