CASE 4: MEDULLARY SPONGE KIDNEY

IMG_2303IMG_0827Medullary sponge kidney (MSK) is more spoken about than witnessed, and more witnessed than accurately diagnosed.

This patient adds to the 12 we have described in our publication, and adds also in having a very long and evolving history with one of us (FLC).

We write for a general audience yet hope to include a level of detail that satisfies physicians and scientists. Here, we may fail of clarity to the one audience or of a sufficiency to the other because the disease is complex. But withal, the evolution of diagnosis and care for this person so educates and the surgical anatomy and histopathology so instructs we have chosen to share the experience.

What is it we are sharing?

MSK is a Unique Disease

MSK is remarkably specific in its anatomy; nothing else is really like it. The terminal nephron segments are tremendously dilated and often filled with innumerable round tiny stone particles. The papillary shapes are distorted by these filled chambers so they become round instead of conical. The masses of tiny stone particles give a radiographic picture that can resemble large collections of stones or calcified papillae, but are neither. Renal tubular acidosis, or just ‘nephrocalcinosis’ come to mind and appear on radiology reports, but neither is the right answer.

The tissue itself is specific to an exactness. The massively dilated papillary collecting ducts are lined by multiple layers of cells, whereas all other people have tubules lined by a single layer of cells. The cells in the interstitium – the spaces between the tubules and vessels – look like those found in embryonic kidneys. The scale of the duct dilation is so great one loses perspective.

MSK has Few Unique Clinical Traits

But for all that, patients with MSK present to even the most discerning clinical eye almost no distinctive traits. They can look like any calcium phosphate stone former can look – papillary calcifications, perhaps multiple stones retained in the kidneys, and little else. When intravenous pyelograms (IVP) were popular, one could diagnose MSK if the contrast agent tracked into the dilated ducts and overlaid the stones there. But obstruction from a stone can create the same ‘pyelotubular backflow’, or can seem to, so diagnosis was fraught. Almost no one does IVPs anymore, because CT scans without contrast suffice for most patient care.

Renal tubular acidosis can come to mind: Masses of renal crystals seem to provoke the idea for physicians even when the blood is normal. ‘Incomplete’ renal tubular acidosis was a name coined to describe patients who formed calcium phosphate stones and had both normal blood and a more alkaline urine pH than 6.5 that did not always fall as much as one might expect with acid loads. In 1992 this patient was so named and treated by FLC who would never use the term today, and by his fellow at the time who is now a world famous kidney stone expert.

Perhaps the most reliable clue to MSK before surgery is done, one we only recently understood, is the combination of a kind of ‘nephrocalcinosis’ with calcium oxalate stones in the absence of remarkable hyperoxaluria.

Nephrocalcinosis is a worn out term, as vague in diagnosis as it is rich in associations. It can mean small calcifications that involve all or most of the papillae, or massive calcifications that fill whole calyces. Frequently one sees the latter, masses of crystal, with calcium phosphate stones, or uric acid or struvite stones. By contrast, calcium oxalate stones usually create the pattern of multiple, bright, small calcifications on individual papillae. It is marked hyperoxaluria that can produce masses of calcium oxalate crystals.

The reason we find massive calcified deposits associated with calcium oxalate stones in MSK is that the tiny proto stones are calcium oxalate yet can bundle in huge numbers within the dilated chambers of the terminal ducts. FLC and his now famous fellow missed the diagnosis despite masses of crystal by radiograph and calcium oxalate stones because neither knew what we know today. The marginal IVP changes of MSK were dismissed because they occurred on the obstructed side.

Pronouns

We are writing this, but separately. FLC is the physician so he writes as ‘I’. AE is the anatomist, and he writes his sections as ‘I’. ‘We’ is reserved for the amalgam of the clinical and anatomical.

The Initial Evaluation

I saw him about about 24 years ago when he was about 25 (real ages and personal details are blurred but accurate enough). He was healthy apart from a recent kidney stone passage, and had been referred to me by a friend. The stone was 65% CaOx and 35% calcium phosphate as hydroxyapatite – no brushite. Because the stone analysis lab used optical microscopy we learned that CaP formed the inner layers of the stone and CaOx grew over it.

An IVP showed ‘bilateral nephrocalcinosis’, but the left side was the more prominent. That side showed marginal evidence of medullary sponge kidney but, being obstructed by the passing stone, prominence of the terminal collecting ducts could have been secondary to the obstruction.

His family members had no stones. He worked at a high intensity job in the entertainment industry with little time to eat or drink. Accordingly there was no breakfast, fast food for lunch, but a reasonable supper with his wife. His physical examination was normal.

Three fasting serums taken between 7 and 9 am showed normal results (not shown) including serum chloride and total CO2. Serum potassium was 4.3.

Here is my table of his lab results.

The first three rows up from the bottom (1992) were done before any treatment. Dates are partly cut off for privacy.

Urine creatinine values (Cr24) were all about the same, so the collections seem reliable.

Main urine risk factors: Volume (vol24) and citrate (Cit24) were low enough and oxalate (Ox24) high enough to confer risk. His urine calcium (Ca24) varied with urine sodium (Na24) as expected but at even the highest sodium urine calcium posed little risk. Urine uric acid, potassium, phosphate, magnesium and sulfate (UA, K, Ph, Mg and Sul, respectively) were not abnormal. We did not measure urine ammonia (NH4) or urea nitrogen (UUN) at that time.

Technically, for those who are interested, the molarity of citrate (Citmol) was far below that of calcium (Camol), so more calcium was available for crystallization, and less citrate for inhibition. Urine pH (upH) was variable and thought a bit high.

His urine creatinine was high per kg body weight (CrKg) signifying low body fat – expected for a young active man. SS for CaP was higher than usual among normal people, that for CaOx was also impressive. SS for uric acid was below 1 because the urine pH was relatively alkaline.

So, long ago, I cared for a man with a calcium oxalate / calcium phosphate stone and nephrocalcinosis whose laboratory studies showed mainly low urine volume, low urine citrate, and modestly increased urine oxalate, and whose IVP showed what might have been MSK or simply the effects of obstruction from a stone passing.

I, and my renal fellow – now a distinguished professor and director of a program – decided that the low urine citrate along with modestly high urine pH arose from renal tubular acidosis (RTA) – despite normal blood findings, and also that MSK might be the cause of RTA. We treated him accordingly, with potassium citrate 25 mEq twice daily, and fluids, and planned a follow up shortly to see if citrate would rise and CaP SS not rise overly. Likewise we hoped for a new IVP after the obstruction resolved so as to see if the ‘MSK’ was real or merely an artifact.

Looking back, I see higher urine oxalate excretion rates that I would have liked to treat, and suspect it was due to a low calcium diet. Today I would never have accepted the idea of RTA.

First Follow up Visit

In 1993, his urine volume remained low (look back at the two lab tables), citrate had not risen, but urine potassium was higher and serum potassium was 5.07 so he took the medication. Supersaturations with respect to CaOx and CaP were not at all improved. I increased the potassium citrate to 25 mEq 3 times a day and insisted on a new serum potassium a few weeks later – which was unchanged.

Laboratory Follow up Measurements

In 1994 (lab tables above) his serum potassium was 4.5, urine potassium was higher at 136 mEq/d, and urine citrate and volume higher. SS for CaOx and CaP had fallen by half or more, and I felt satisfied. There were no reported new stones since 1992.

In 1995 his serum potassium was 4.4, urine citrate and potassium had fallen, and I realized he had stopped the medication. I strongly suggested he continue it and get a new kidney radiograph to follow any changes.

I heard no more from him for ten years.

Second Follow up Visit

In 2005 I got word he was passing many more stones, and referred him to my urological colleague for management. Serum values were unchanged, urine volume was low; urine citrate and potassium were back to levels seen in 1993 even though he was not taking the potassium citrate. Urine pH was no longer noticeably high. SS with respect to CaOx was very high as was that for CaP – though this latter was below his peak in 1992 and 1993.

I saw him clinically in 2006 after the 10 year hiatus, and he explained he had stopped all treatment in 1995 as I had guessed. He had many stones in his possession and planned to send them to me for analysis. I re-instituted the potassium citrate and more fluids. My records do not indicate if he saw a urologist or what may have happened.

I heard no more from him for 10 more years. The stones were never sent, never analysed.

Third and Fourth Follow up Visits

Third Visit

In the spring of 2016 he came back because of more stones. During the 10 year interval he had passed no stones – which hiatus he ascribed to more fluids – but recently had begun to pass them again.

First there was a new stone, then up to 10 or 12 more. Several of these were analysed. One was 100% CaOx the other 88% CaOx, 12% HA. His serum bicarbonate and chloride were normal, as was potassium (not shown). Urine (lab table is above) showed high volume, and the best citrate ever; the low urine calcium and high oxalate were ascribed bristol-upper-pole-posteriorto excess vitamin C and high oxalate diet along with a rather low calcium intake; SS with respect to CaOx bristol-upper-pole-stoneswas much lower at 4.5 and for CaP was below 1 mainly from the high urine volume.

Urine ammonium (NH424) and sulfate (SUL24) both in 2005 and 2016 were unremarkable. In ‘incomplete’ RTA the former is thought to be higher than normal in relation to net acid load – the sulfate. I did not comment about this in my records as the idea of RTA was no longer one I would consider.

I suggested a lower diet oxalate, continued fluids, and left out the citrate given the history of no stones for 10 years without it. I ordered a new CT.

I believed after this visit that perhaps his new spate of stones was provoked by vitamin C loading – from ‘Airborne‘ and 1000 additional units of vitamin C daily. The Airborne products contain about 1000 units of vitamin C in each pill, so with his supplement the amounts could have been quite large.

Fourth Visit

I saw him again after the CT was available.

Calcifications were only left sided but involved both the upper and lower poles. The deposits were large, and I could not tell if they were stones, calcifications in kidney tissue, or both.

Transverse views confirmed the disease limited to the left side.

Review of my drawings from 1992 showed calcifications on both sides, which was puzzling. The actual radiographs are no bristol-cross-sectionlonger available.

I was puzzled, and still am, about the conflict between my old drawing and the obvious unilateral stones, but had become convinced the present stones needed to be removed. They seemed large enough and so positioned as to obstruct flow out of calyces and gradually cause injury. Obviously they would never pass.

Lithotripsy was not a consideration nor ureteroscopy – too large. This left percutaneous nephrolithotomy (PERC) that has the advantage of offering – in potential at least – a stone free kidney, and I chose that course assuming my surgical colleague would agree.

As for his stones, I now suspected they arose from a hectic and complex work life with poor hydration and high urine oxalate. His urine oxalate had been hefty all along and there was the recent vitamin C loading. Even so, my notes expressed considerable doubt about the why of it. Of interest he made clear at this visit that he had renal pain that had been present for years and always left sided. My notes had never before recorded this fact. As for RTA the idea was foreign and unacceptable to my mind.

Diagnosis

krp395-lt-upper-poles-b-croppedSurgery

At PERC he had the characteristic papillary changes of MSK. The papillae in the upper pole of the left kidney contained many cavernous spaces filled with stones.

At the left of the panel to the left of this text a stone peers out from inside a dilated duct, and a larger one, in the middle of the panel, reaches out of its duct, one side of it a jagged glittering blue white.

The tissue itself is diaphanous and layered, seen well in the partition between the stones in the left and middle ducts in the image. Beneath the surface lies a maze of dilated ducts filled with stones; the openings to two of them are at about noon and 1 pm in the picture.

krp395-lt-upper-pole-new-c-cropped

Imagine a family come to farm the land above the hollow shafts and tunnels of an unsuspected cave. As with time minerals in the sluggish waters consolidate into crystals and the crystals into myriad strange shapes unseen, tubule fluid in these dilated ducts – we believe –  fills with innumerable stones that appear enormous in the magnifying lens but are to the eye unaided tiny.

Seen in another papillum, at right, is the opening of such a duct and to its immediate left, facing toward the leftmost light colored stone in the tunnel – as though it were a mirror, a bulge below the shiny covering of the papilla marks another tunnel not yet opened and filled with stones.

We have shown MSK in another article, and detailed there the laciness and tunneling, and even in a movie the unroofing of some tunnels so one can peer down into them from above. Likewise we have already spoken about how ductal dilation comes about in the development of the kidney which goes awry.

Pathology

A biopsy from the papillum stained with Yasue stain shows no crystals. The linings of the large collecting ducts – enormously larger than normal – are not in a single layer of cells but three layers or more. These are two of the three diagnostic traits of MSK. The third diagnostic trait is the very cellular interstitium – this is easy to see at nine o’clock where the cells become lacy looking because they have the traits of embryonic cells with many extensions off the cell bodies.

Some idea of the tremendous enlargement of papillary collecting ducts can be obtained by looking at the four or five smaller round ducts down toward 6 o’clock and ringed about the upper surface of one of the huge ducts. These are also papillary collecting ducts and even though they are much smaller than the huge ones they are still somewhat larger than normal. Even these are lined by multiple layers of cells – this is hard to see at the magnification of the slide.

So, given the enlargement of the smaller round tubules, and that the dilated ducts are perhaps 10 times larger, the overall dilation of the large ducts is perhaps 15 to 20 times normal, an immense distortion.

Fifth Visit

Looking Back

After the surgery, and with the truth of things made evident, I thought about the years behind and that I had not taken very seriously the idea of MSK first raised by an IVP long ago. In his recent CT he had one sided massive radiographic nephrocalcinosis. This itself could have been the reflection of any number of conditions – calcium phosphate stones only on one side, for example. But his stones passed were mainly calcium oxalate, a fact more evident in his recent than his first visit. Medullary sponge kidneys more often have calcium oxalate than calcium phosphate stones.

There was also the slightness of his urine abnormalities compared to the extreme amount of renal mineral deposit. If indeed stones in MSK form as in a cave, from stagnation of tubule fluid in blind end dilated ducts, then even the most normal urine chemistries are sufficient because calcium oxalate supersaturation is near universal whereas calcium phosphate supersaturation is not. I could have been, perhaps, more prescient.

Treatment

Given that no trials have ever focused on this uncommon disease, and the formation of stones may well be simply spontaneous crystal formation from supersaturated tubule fluid stranded and stationary in dilated ducts, my tendencies would have been simply to lower supersaturation by any means possible. This would lead me to a 1,200 mg calcium, 1,500 – 2,300 mg sodium diet. Compared to present calcium and sodium intakes, the higher diet calcium will lower urine oxalate and the lower sodium intake will prevent a rise in urine calcium. Likewise the higher the fluid intake and urine flow the lower the supersaturation. And, given that refined sugars raise urine calcium abruptly in even normal people, I would prefer he avoid them. In other words, I would have wanted the kidney stone diet which is the modern healthy people diet for Americans. Finally I would have eschewed oxalate loading from any source.

I had at the beginning used potassium citrate for his treatment, based on a pattern of thought I would no longer be guided by. Yet he remembered it and that his stones seemed less when he used it. So at his request I added it back. He is due for a new low radiation dose CT in a while to see if his kidneys are really stone free, and I suggested he wait to use the drug until then.

This Case in Large Perspective

Our Prior Work

As against our other reported cases, this one would be as abnormal as any we have seen. The duct dilation, multilayered epithelium, and lacy aberrant interstitial cells are remarkable. Our surgeon had no difficulty in diagnosis during PERC because the dilated ducts and abnormal papillary shape were obvious.

Yet, an experienced clinician was surprised altogether, even being one of the authors of our paper.

You who practice, beware: MSK is as easily underdiagnosed as overdiagnosed, renal tubular acidosis likewise, and the lesson is clear. Radiographs are of minimal use. Only ureteroscopy can be definitive, as can PERC.

One takeaway is the combination of calcium oxalate stones and minimal urine stone risk abnormalities with massive nephrocalcinosis.

Because stones seem to form in stagnant chambers the lower the supersaturation the better. Likewise for higher urine citrate – as an inhibitor.

New Published Work

We have already commented in our paper about the probable cause of MSK as a developmental defect of the kidneys and urinary tract. But recent work since our paper suggests MSK can be associated with other genetic diseasesThis new paper reviews prior reports of linked genetic defects with MSK and adds to the list. Of 143 cases of MSK 6 – all men – had associated defects that involved the heart of brain or – on one case – was Marfan syndrome. In two cases relatives also had MSK. A prior paper from this group found an additional 7 patients with developmental disorders. This makes a total of 13 of 143 cases or nearly 10%.

My personal concern with this work is how MSK was diagnosed. In the paper, and confirmed by private email correspondence with one of the principal investigators, it is clear that contrast radiographs were always used, so one can believe that dilated ducts were directly visualized. One hopes that as URS and PERC are needed for stone management the diagnosis will be confirmed more directly and those comparisons published. This is a very important cohort and the findings of linked genetic and developmental defects of long term interest.

78 Responses to “CASE 4: MEDULLARY SPONGE KIDNEY”

  1. Kimber

    Sorry Dr Coe, forgot to mention I live in Osoyoos BC Canada, on the Washington borderline. Also, I’ve noticed for years that usually every 3 months I cycle on overall health decline with alot of symptoms/flares, like it comes and goes in waves. I did a Lyme test submitted to CDC and results were negative. Lyme and CFS have same/similar symptoms. Certainly with all the antibiotics I have had, lots of symptoms have changed/lessened except for kidney issues, worse!! Also do Accupuncture, have used RX’d CBD oil 1:20 mg/ml that helps neuro. I’ve stopped all OTC supplements/vitamins as directed by Surgeon in 2018 due to the unknown . Any advice or info, I would be so greatful. Please feel free to email me at any time. Peace

    Reply
    • Fredric L Coe

      Hi Kimber, This information does not help me in thinking of what might benefit you. The problem of infection stones is as I said, and available treatments, as well. Best, Fred Coe

      Reply
  2. Kimber

    Thank you Dr Coe for your literature! I’m 50 yrs old and in search of putting puzzle pieces together and feel like ive been doing it forever. As a child, multiple ear infections(tubes in both ears at age 8), kidney/bladder infections, pain in left abdominal(below rib cage) during running/gym class/sports. As a teen bladder and urine frequency issues, car accident in 1989 resulting in extreme whiplash, led to Fibro myalgic diagnosis. Pregnancy in 1991, abruptio placenta at 7 months and bed ridden, induced brutal long delivery at 38weeks. Second child in 1994, no issues of complications. Then began heavy flow, painful menstrual issues and had 2 dnc’s. In 1998 kidney stone removal with stent. Then 2003 accidental head trauma(while putting up kids volleyball net, sledge hammer broke and hit me full force on head) Doctor said I was fine and take it easy. Nothing was easy, full out concusion, slept for 10 days in dark room in excruciating pain, walking, talking, thinking, all altered. Months later after having nervous breakdown returning to work, CT scan said all was normal and doc gave me meds for anxiety. Also told me to change job and lifestyle, owned and operated large family fruit farming business. Menstrual problems intensified, mentally/cognitive challenged daily. Increased marital/business/family stress. In 2010-2011 left marriage/business , had hystorectomy/bladder lift resulting in repeated surgical infection repairs and clean up, think 7. Final procedure calcium kidney stone removal left kidney(passed 2 stones 2015) 2012-2016 Educated/employed as pharmacy assistant, found non narcissistic life partner while battling bankruptcy and never ending divorce issues, rejuvinating an active zest for life! Noticing seasonal flu shots left me feeling unwell, hormone therapies unbalanced, increased brain fog/memory recall lose, right side head pain, change in eye sight, felt gassed or high. Left side lump in throat said to be sinusitis now waves when I’m tired or hungry. Did Ideal Protein Weight Lose Program to reboot, lost 20lbs but underneath felt like shit. Months later H-Pylori treatment, months later 1 of 3 HepB shot for travel and Dukeral, it’s like my body did a shift to downhill fast. Four months later (Mar2018) GP diagnosed me with ME/CFS/SEID with FM. Bedridden/housebound, standing long enuf to brush my teeth was impossible. Suffering from PEM from both minimal mental and physical exersion and POTS. Put on waiting list at CCDC in Van BC set for Aug +/-2020. Then June 2018 CT scan from left flank pain complaints discovered 2.5×1.5×1.6cm staghorn calculus in right kidney w/satellite stones upper right pole, multi left renal calcifications, lower left pole/interpolation region consistant with a baseline medullary nephrocalcinosis with attached calyceal stones. Surgical Urologist required a right kidney PN procedure, left kidney ureteroscopy/laser which possibly could leave residual as she has radiologic findings consistent with MN. Surgery was Oct 15 2018 PN procedure on right kidney completed, surgeon mentioned kidney had mass infection and his focus was cleaning it up. He opted not to do left kidney to avoid contamination. Antibiotic thereafter, sick and unwell, urine cultured enterococcus faecalis after complaints of UTI in Nov. Daily dose of long term Macrobid RX’d. Stone analysis indicate struvite with calcium. In March flare of hot flashes, chills,thirsty,uti, vaginosis, abdominal inflamation, left flank pain, energy level at 20%. Follow up CT scan another same size stone in right and left stones larger. Repeat surgery Jul 15 2019 on right kidney as well as left kidney w/stents. Experienced 14 hrs of kidney spazms when urinating, stopped when re inserted catheter, removed stents and cathader 2 weeks later. Oct 1 follow up CT scan reports growth of same size stones!!! Surgeon wants to repeat surgery in early Feb and I have declined until further investigation is done, finding root cause!!! Feels like nobody is doing anything other than surgery! Internist won’t see me because its Nephology/Urology. Infectious disease Dr says remove portion of kidney where tuff to remove stone/fragment are because of sponge kidney to elimited enterococcus. GP’s hands in the air. Seems everyone agrees all my tests are normal so they don’t know what’s going on. Now Macrobid has stopped working and on Amox/clav. I went over and above heads and have an appt with a Nephologist Jan 24 and have no clue where it will go, at first he wanted to see me after surgery until I said I’m refusing because of 10 weeks later I’ll need it again. Hello! Lots of emotions/frustrations. I just want my life back, I’m tired of struggling in survival mode. My trust and faith challenged. I’m sure I’ve left holes in this story but I’d certainly help to fill in blanks if needed. Please, she’d some light on me 😇

    Reply
    • Fredric L Coe

      Hi Kimber, Struvite stones form because bacteria have found their way into your urinary system that can hydrolyze urea to ammonia and CO2. The resulting alkaline pH cause formation of magnesium ammonium phosphate – struvite crystals. The crystals are infected inside and out and their growth is driven by bacterial functioning. Your surgeons are coping with management of infected foreign bodies. Antibiotics are not very helpful unless the surgeons can remove all of the infected material. Possibly things are advanced enough in difficulty your physicians may wish to consider acetohydroxamic acid – a difficult to use inhibitor of the bacterial enzyme that hydrolyzes urea. I have used it in rare cases with success but side effects are legion. All I can say from here is that perhaps they may want to consider the possibility, but knowing nothing really about the details of your conditions please consider me as a mere outsider with nothing to offer but a slim suggestion for your physicians to ponder or not. Regards, Fred Coe

      Reply
  3. Pauline Verhaeghe

    Dr. Coe I have suffered from bilateral MSK for 27 years. The last few years are very debilitating. I have had multiple lithotripsy procedures, countless uteroscopies and a double PERC. I was going to lose my top left lobe because two stones over an inch a piece were blocking off the entire top lobe. Fortunately I have healed well enough to keep it. Last November they finally started listening to my complaints of constant pain, fatigue and nausea. I have extreme anxiety as I continue to form stones at a fast rate. I watch what I eat and have over a 3L/day output. All my levels appear good after multiple 24 hour collections.
    I am having what I believe to be arthritis and bone issues. My feet and hands become stuck my hands are wrists are weak. My wrists, shoulders, knees and ankles crack constantly.
    Do you have any advice for me or suggestions. I feel like I am fighting a battle without any Allies.
    Thank you for all you have done sir, I appreciate you and your efforts greatly.

    Reply
    • Fredric L Coe

      Hi Pauline, Is it really MSK or calcium phosphate stones with tubule plugging. You can tell from the stone type and what your physicians saw in during your URS procedures and PERC. You might ask your physicians about this as treatment and possible causes might be affected. Your stone disease does not – from this vast distance – seem like MSK. Regards, Fred Coe

      Reply

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