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.

29 Responses to “CASE 4: MEDULLARY SPONGE KIDNEY”

  1. Lori

    Hi Dr. Both my kidney’s are filled like case 4.I have had chronic flank pain and passing stones almost daily since 2006 .I started passing large up to 10 mm stones since 2/20016 I passed 22 stones in one day last may .My CT said innumerable non obstruction calculi through out my collecting systems forming a cast beyond the medullary pyramid. My left is worst but my pain is always right flank .One thing I believe causing increase in passing is medipose .I have passed over 100 stones since 2/2016 all some up to 10 mm.My Dr Euro whom I love wanted to do surgery right away to remove a 9.1 mm in length in my mid left collecting system that was just one Example my CT said. I have send your case study to My Uro. I have no life passing stones 24/7.I am very afraid of surgery again I had septic Shock after not my Dr but same hospital Dr stuck stents in with a known infection in 2012 I am only here by the grace of God.I have been infection free since 2013 now but every surgery I end up in hospital with infection my body also rejects stents.I would like you to email me so I can send you some pictures of my large very weird looking stones and my Ct you can read that.I am a good case study for you. My daughter has MSK had 3 stones at 4 years old I believe she got them in my whom because she dose not make them as I do but her infections scare me because of sepsis. I shared your study with other Msk people whom all have chronic pain like me . Thank you Lori

    Reply
    • Fredric Coe, MD

      Hi Lori, I suspect you do have MSK and you have obvious serious infection and pain problems. I do not understand why there is not more effort at prevention and perhaps some surgical management of the disease. Ideally you would get your care at a university medical center. Where do you live? What were your stones made of. Given the sizes of your stones, I am not sure the whole problem is MSK. Have you had 24 hour urine testing? Let me know. Regards, Fred Coe

      Reply
  2. Carolyn

    The information I have found on this website has been invaluable. I have been trying for years to find someone who will just listen to me. I live in Nashville, TN and have had absolutely no luck finding a doctor that will just listen and help me come up with a plan to help manage everything that accompanies my MSK diagnosis. Do you ever recommend doctors to patients? The best advice I have received is that I will most likely have to go out of state to find someone who can address my issues.
    Thank you for creating this website!
    All my best,
    Carolyn

    Reply
    • Fredric Coe, MD

      Hi Carolyn, Vanderbilt is in Nashville, and Ray Harris is a verys smart nephrology professor who I admire. I do not believe he personally does much kidney stone work but he will know the right person. Let me know, Regards, Fred Coe

      Reply
  3. Diane

    Hi Dr. Coe, I was recently diagnosed with MSK, and I am relieved to find your website. Thank you so much for it. I did not think to question my diagnosis but after reading your site, I want to make sure that the diagnosis is accurate. I had a CT scan w/wo contrast and the findings are as follows: “left kidney there is a punctuate calculus in the upper pole and a punctuate calculus in the lower pole. Right kidney there are multiple small and punctuate calculi in the mid and lower kidney. Largest inferiorly measuring up to 3mm. Calculi are seen mostly at the medullary pyramid tips. Urographic images demonstrate bilateral multifocal renal tubular ectasia. There is no hydronephrosis. There is no evidence of renal mass. The urinary bladder shows no focal finding. Impression: bilateral MSK with bilateral nephrocalcinosis.” My urologist also performed a cystoscopy which was negative. Should I have a second opinion or further testing to confirm the MSK diagnosis? Also, separately, the CT scan revealed a pericardial effusion, which led to an echocardiogram. The echo found my mitral and tricuspid vales to have mild regurgitation and trace regurgitation for the pulmonary valve. I was shocked and overwhelmed by all these findings at once and the link on your site to the NCBI PubMed gave me a much needed possible explanation. I’m 50 and have always led a very healthy lifestyle. Thank you.

    Reply
    • Fredric Coe, MD

      Hi Diane, I gather you had a CT with contrast and dilated terminal ducts could be seen. That is sufficient for diagnosis. Prevention is much the same as for all stone diseases and you should pursue it. I hope things go well with your cardiac issues. Regards, Fred Coe

      Reply
      • Diane

        Thank you so much for your answer. Yes the CT scan was with contrast. I don’t recall having a 24 hour urine test as is recommended on this site (however the doctor did send a urine sample to a lab). Is that something I should request from my doctor? My doctor told me to drink at least 2 1/2 liters of water each day, preferably with lemon, follow a low oxalate diet (I am eliminating the big offenders), and come back in one year. Thank you again and kind regards.

        Reply
        • Fredric Coe, MD

          Hi Diane, As much as I admire the diagnosis from an infusion CT I do not much believe in treatment without 24 hour testing – too random and often ineffective. The high fluids are always a good thing. The lemon is simply for taste as if one really needs the potassium and citrate lemons contain one would need a large amount of them and there are better ways to do this. Without a 24 hour urine how could you know if citrate matters at all. Regards, Fred Coe

          Reply
    • Gina

      I was diagnosed with MSK about a year ago however I’ve been dealing with kidney stones for about 8 yrs now. I’ve had several surgeries to remove stones that were too big to pass, my scans of my kidneys look like snow globes.

      Reply

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