From the Nate Hellman Unpublished Archive: Xanthogranulomatous Pyelonephritis

Image from Radiology Picture of the Day
http://www.radpod.org/2007/06/19/xanthogranulomatous-pyelonephritis/

Xanthogranulomatous pyelonephritis (XGP) is a rare but severe complication of chronic UTIs. I think of it (in simplistic terms) as a pyelonephritis so severe that it results in loss of renal function of the affected kidney as well as being a severe intra-abdominal abscess which can spread to other tissues. In fact, the disease is sometimes referred to as a "pseudotumor" in that it has the ability to "metastasize" to other tissues and often has the radiographic appearance of a renal cell carcinoma on imaging studies. Treatment involves iv antibiotics and very often requires urgent nephrectomy, meaning that a Urology consult should be on-board as early on as possible. Most cases of XGP are unilateral and thought to be secondary to chronic urinary tract infection, often associated with staghorn calculi and chronic obstruction. The most common organisms causing XGP are E. coli, Proteus, and Pseudomonas. Histologically, XGP demonstrates lipid-laden foamy macrophages on a background of diffuse renal parenchymal necrosis.

Emphysematous Pyelonephritis

I was asked to see 74 year old man with an acute on chronic kidney injury.  He had 2 days of generalised lower abdominal pain and vomiting but no urinary symptoms or fever.  His past history included advanced CKD, benign prostatic hypertrophy and a slow growing renal cell tumour under radiological surveillance.  His vital signs were normal and he had mildly raised inflammatory markers.  I ordered a CT KUB to exclude obstruction (it was a weekend and was no ultrasound service in the hospital).  To my surprise this came back as showing emphysematous pyelitis.  Interestingly there had been a hiss of air as he was catheterised for fluid balance monitoring – a fact I had dismissed at the time!


Emphysematous UTIs are gas forming infections of the urinary tract and can manifest as cystitis (gas within the bladder wall), pyelitis (gas within the collecting system) or pyelonephritis (gas within renal parenchyma or perinephric tissues).  It is a relatively rare condition and there is a dearth of literature describing incidence.  Diabetes and urinary tract obstruction are major risk factors, present in around 80% and 20% of patients respectively. Causative organisms are most commonly E. Coli and Klebsiella pneumoniae, with Candida being involved less frequently. Presentation is usually similar to acute severe pyelonephritis with fever, flank pain and vomiting. 50% of patients have an associated bacteraemia. Diagnosis is usually made by CT which shows the extent of gas within the urinary tract and any obstruction.
Treatment depends on the extent of infection.  It ranges from parenteral antibiotics alone for patients where gas is limited to the collecting system with no obstruction, to percutaneous drainage of purulent material and antibiotics if there is abscess formation or extension of gas into the perinephric space, to nephrectomy in patients with diffuse gas and extensive renal destruction.

In the above case, the urine sample was initially reported as ‘no significant bacteriuria’ but subsequently grew a resistant E. Coli >1,000 - <10,000 cfu/ml.  Urology felt that surgical intervention was not required as the renal parenchyma was not involved and he had no abscess formation.  The patient completed 2 weeks of ertapenem and his renal function returned to baseline.

I took several learning points away from this case:

• As someone who spends a lot of time signing off patients’ results, I realise that ‘no significant bacteriuria’ is not the same as ‘no growth’, and in this case the difference was substantial.  The wording of how we report things and how we interpret that is crucial.
• A high index of suspicion is required to diagnose emphysematous UTIs and the most appropriate imaging modality should be considered.  Ultrasound is generally the first line investigation for urinary obstruction in patients with acute kidney injury or febrile urinary tract infection due to high sensitivity for hydronephrosis, lack of ionising radiation and lower cost than CT. Ultrasound appearances in emphysematous UTIs can be difficult to interpret however: gas, calculi and calcifications are hard to distinguish and there is often variability in how they are reported. CT is able to precisely localise the presence of gas within the urinary tract and determine whether there is involvement of the renal parenchyma and perinephric tissues.  It can also identify any concomitant pathology or alternate diagnosis e.g. renal calculi.  CT is therefore preferable for diagnosis and subsequent severity staging.
• Pneumaturia has been described as a presenting feature of emphysematous UTI.  Other causes include vesicovaginal or vesicoenteric fistulae, renal tumour infarction and recent instrumentation.  The unexpected air hiss when catheterising this gentleman was a warning of a more serious pathology and should prompt further investigation.

While the outcome of emphysematous pyelitis is better than that of pyelonephritis (which has a mortality of 18-70% depending on extent of involvement), it is still not a condition to be taken lightly. 

Post by Ailish Nimmo, Royal Infirmary of Edinburgh

Beyond the kidney

Mostly I think about the bladder, in a professional sense, as a possible site for obstruction to be ruled out. Occasionally, when I’m personally reminded about it, I wonder how much urine it can hold. (Pearl from residency: never start a procedure on an empty stomach or with a full bladder) Recently, I had a chance to learn about the bladder while researching an article and discovered several fun facts:


- urine empties into the bladder every 10-15 seconds
- the bladder can hold comfortably between 350-550 cc (12-18 oz) of urine for several hours;
- the urge to urinate usually starts when it has anywhere between 150-300 cc or urine; it can be overridden voluntarily to volumes of 600-800 cc
- speaking of causes of bladder outlet obstruction, the largest bladder stone ever removed (per Guinness world records, 2007 edition) weighed 1.9 kg and measured 17.9 by 12.7 by 9.6 cm


The bladder is able to stretch to accommodate such swings in urine volume thanks to two properties of its epithelium. The first one is a folded apical membrane, which unfolds as the bladder is filling, changing the shape of the top layer of urothelial cells – also called umbrella cells -- from a rounded one to a more flat, squamous one. The second feature is a collection of membrane vesicles, tethered close to the apical surface by cytoskeletal fibrils. As the cell stretches and becomes flatter, the vesicles fuse with the apical membrane, increasing its surface.


The bladder is normally impermeable to the components of urine: molecules, such as urea, ammonia, and water, which usually freely travel through epithelial membranes. Aside from the presence of tight junctions between cells, this impermeability is a function of the composition of the lipid bilayer of the apical epithelial membrane, where the specific arrangement of lipid hydrocarbon tails impairs travel of these molecules across the bilayer. In addition, special proteins, called uroplakins, form aggregates called plaques. These plaques occupy 70-90% of the surface of each cell and help keep urea and water out. When uroplakin was knocked out in mice, their urothelium became permeable to urea, and, to a lesser extent, water.


Interestingly, the urothelium has amiloride-sensitive ENaC–type channels, present at very low levels in normal human bladders (and with different subunit stoichiometry in different mammals). Channel expression may increase in states of elevated bladder pressure, such as in bladder obstruction, an observation consistent with a recent report suggesting that the role of the ENaC -type channels appears to be more important in mechanosensation.


Some interesting reviews and relevant articles can be found here, here, here and here.


Posted by Marta Hristova, MD, PhD

The Uroplakins

We are taught that water is freely diffusable via cell membranes--even in the absence of aquaporin function, there are usually some water molecules which traverse the lipid bilayer.  However, there are tissues within the human body which must be extraordinarily tight:  two that come to mind are the thick ascending limb of the nephron, as well as the bladder epithelium.  How does the epithelium comprising these "water-tight" barriers obtain these characteristics?  

The epithelium lining the bladder (a.k.a. "the urothelium") is one of the tightest epithelia in the body:  the bladder must be capable of holding urine for long periods of time without leakage, and furthermore serves as an important barrier for toxic substances filtered by the kidney.  The urothelium's water-impermeable properties can be explained in large part by a family of proteins called the uroplakins.  The uroplakins form tiny, hexagonal arrays of particles--visualized best by electron microscopy (see figure taken from this excellent recent KI review by Wu et al)--which comprise structures called "urothelial plaques" that overlie the plasma membrane of superficial umbrella cells of the urothelium.  It is thought that these plaques are tethered to the lipid bilayer, limiting the movement of phospholipids and therefore limiting water permeability.  Interestingly, mice deficient in uroplakins show increased water permeability.  

The uroplakins also appear to play a role in urinary tract infections; the uroplakin Ia/Ib glycoprotein is the means by which some strains of E. coli adhere to the urothelium.  

Xanthogranulomatous pyelonephritis

Xanthogranulomatous pyelonephritis (XGP) is a rare but severe complication of chronic UTIs. I think of it (in simplistic terms) as a pyelonephritis so severe that it results in loss of renal function of the affected kidney as well as being a severe intra-abdominal abscess which can spread to other tissues. In fact, the disease is sometimes referred to as a "pseudotumor" in that it has the ability to "metastasize" to other tissues and often has the radiographic appearance of a renal cell carcinoma on imaging studies. Treatment involves iv antibiotics and very often requires urgent nephrectomy, meaning that a Urology consult should be on-board as early on as possible. Most cases of XGP are unilateral and thought to be secondary to chronic urinary tract infection, often associated with staghorn calculi and chronic obstruction. The most common organisms causing XGP are E. coli, Proteus, and Pseudomonas. Histologically, XGP demonstrates lipid-laden foamy macrophages on a background of diffuse renal parenchymal necrosis.

Tamm-Horsfall Protein

It took me until just recently to realize this, but the Tamm-Horsfall protein and uromodulin are two names for the same gene.  

As we all know, Tamm-Horsfall protein (discovered by Tamm and Horsfall in 1950) is the most abundant protein in normal urine and forms the transparent matrix of hyaline casts.  It is synthesized as a membrane protein which is attached to the apical membrane by a GPI-anchor facing the tubular lumen; when cleaved off it is excreted in the urine.  Casts only form in the distal tubule & collecting duct, not in the proximal tubule.  What is its function?

1.  Tamm-Horsfall protein acts as a constitutive inhibitor of calcium-based stone formation.   Mice deficient for Tamm-Horsfall protein show an increased tendency towards nephrolithiasis.

2.  Tamm-Horsfall protein acts to prevent urinary tract infection.  There is some data that certain strains of E. coli may be bound by Tamm-Horsfall protein; once cleaved this could represent a means of eliminating the organism from the urinary tract.

3.  Mutations in Tamm-Horsfall protein cause the autosomal dominant disorder medullary cystic kidney disease type 2 (MCDK2) as well as the disorder familial juvenile hyperuricemic nephropathy (FJHN) . This is a pediatric-onset disease characterized by hyperuricemia, gout, and progressive renal failure.  Interestingly it appears that the pathophysiologic mechanism here is that mutations in this gene lead to defects in protein folding and intracellular deposition of mutant Tamm-Horsfall protein.