Size Matters

I don’t actually know how big my kidneys are. I do know that a normal adult kidney will be about 12cm long by 6cm wide and 4cm thick – that’s about the size of my hand clenched into a fist. A little maths gives a volume of around 160mls. Mine are most certainly larger. That’s not boasting but an unalterable fact of having ADPKD, as cysts replace the normal kidney tissue and expand year on year the kidneys grow larger, commonly to a volume around 900mls for each kidney, often even bigger.

So why don’t I know how large my kidneys are? Data from the CRISP studies suggest that it might be helpful to know for considering my prognosis.

Maybe I should begin this story with “Once upon a time…”, 1957 to be precise, when a Danish doctor, OZ Dalgaard, published a paper entitled “Bilateral polycystic disease of the kidneys: A follow-up of 284 patients and their families”. At that time nephrology as a medical specialty did not exist in its own right, subsumed by “The Department of Metabolism” with doctors who studied the maintenance of salt-water balance as pioneers of the field; Dalgaard was one of them. He summarised his findings with “End stage renal disease occurs in all patients within five years of the kidneys being detectable by physical examination.

This really was one of the first observations that the size of the kidneys was related in some way to the progression of the disease. That concept was ignored for decades, probably because there was no way to accurately ascertain the kidney volume. Renal function as measured by creatinine, and lately eGFR, became to default method of staging the illness. This of course can remain normal for 40 years or so while inside the kidneys are, not always quietly, continuing to grow with enlarging cysts and internal structural damage.

Renal cyst ultrasound 110316115548 1208010

Ultrasound of cystic kidney: cysts show as black holes

Ultrasound offered a tool in the mid 1960s but the limitations of 2D imaging and complexities of calculating volume with ellipsoid geometry meant that when it was used it was generally just for the initial diagnosis.

I had my first ultrasound in 1979, where, apart from noting that one cyst exceeded 5 cm, no other measurements were made.

The story jumps ahead some 3 decades to 1992 and a paper (Gabow et al, 1992) published in Kidney International (not one to be found in the dentist waiting room). “Factors affecting the progression of ADPKD” from a Colorado study concluded that “renal size as expressed by renal volume is independently associated with worse mean renal function at a given age” (The word “mean” is being used here for “average” – the study was using group data rather than individual). So 35 years after Dalgaard’s observation we come back to this same fact:

“size is important in prognosis”

MRI-Philips

MRI Scanner

The Consortium for Radiological Imaging Study of Polycystic Kidney Disease (CRISP) was established to determine whether MRI could be used accurately to detect renal volume changes over short periods of time and then to answer the specific question as to whether increase in cyst and renal volume is associated with loss of function. The studies began in 2001 and are ongoing. The project has developed innovative imaging techniques, has amassed reams of data and spawned numerous offshoot studies. The first results were published in 2001 and confirmed that Total Kidney Volume (TKV) could be accurately and reliably assessed with MRI. There is a PowerPoint presentation from a conference of 2014, using the CRISP data, with some interesting images, sadly all under copyright so I cannot reproduce them.

Having developed and standardised the imaging techniques, the subsequent studies looked at 241 patients in early stages of ADPKD, as defined by an eGFR above 70, and considered the question as to whether TKV correlated with deteriorating renal function in early disease. The strong points of the study are that it was prospective, as opposed to retrospective studies that review patient records looking backwards, and observational. Additionally they used what is known to be a gold standard method of measuring renal function – iothalamate clearance (that entails fasting, an IV injection and compared blood/urine measures of a period of several hours).

MRI of cystic kidneys in ADPKD (image radiopaedia.org)

MRI of cystic kidneys in ADPKD (image radiopaedia.org)

In 2006 their summary findings were:

  • the increase in kidney volume (TKV) is due to the increase in cyst (TCV) volume
  • the kidney volume increases in a continuous process
  • both kidneys grow at a similar rate
  • the steady growth rate is specific to an individual patient
  • the absolute (ml) and fractional (%) rates of renal enlargement are directly associated with absolute renal volume

Specifically they discovered that the size of the kidneys at the beginning of the study (baseline TKV) predicted the subsequent rate of increase, or, put another way, patients at a given age with the largest kidneys will have faster rates of renal enlargement. So young patients with high TKV may have a more difficult course.

The data showed that if you have a kidney volume of more than 1500mls (that is both kidneys, so each would be around 750mls) then you can expect your kidneys to grow on average a further 200 mL each year and your renal function to deteriorate by a fall in GFR of 4.3 mls per year.

That was CRISP I (Grantham et al, 2006).  Some 222 of those patients have continued into the CRISP II study which aimed to establish a useful marker of disease severity using TKV.  One of the offshoot papers was published in 2012 and used a refined measure of TKV, one that allows for the height of a patient, “Height-adjusted TKV”., This makes a lot of sense because obviously taller people will have larger kidneys. The conclusion from this was that if the htTKV was more than 600cc/m at baseline then the patient was highly likely to develop renal impairment at stage 3 level within 8 years. So they have shown definitively that htTKV is a prognostic marker that is sensitive (detects most patients) and specific (doesn’t get it wrong in many cases).

In case you are thinking that this is just one group of patients being studied, Switzerland (Kistler et al, 2008) have also demonstrated that TKV correlates with renal impairment and there is a huge Chinese study of over 500 patients that is coming up with comparable results, reported in a 2014 paper.

So now we have a tool that can, in the early stages of ADPKD, offer some prognostic leads.

But before you all rush to the cosy confines of an MRI scanner, there are some issues worth a thought:

  • TKV to date has been used to measure changes over short periods of time in clinical trials and not for individual patients in the clinical management of their condition
  • We do not have data for ethnic groups though there is some suggestion that African-American ADPKD patients may have smaller kidneys in general so the data we do have may not apply.
  • Does TKV measurement provide useful information in later stages of the disease once renal impairment is already monitored by GFR?

TKV has already been used in recent clinical trials, both in selecting appropriate trial patients and in monitoring therapeutic benefit.

TKV has also been linked to complications: TKV>600mls makes high blood pressure more likely, TKV >800 mL is linked to increasing chances of blood and protein in the urine. Those whose TKV is in excess of 1200ml are more likely than not to experience pain from the kidneys. Can this be utilised in management plans for the individual patient?

On a personal note, I am quite keen to undergo an MRI to assess my TKV, even if it does turn out that my somewhat chunky middle is primarily down to fat and not, as I might prefer to claim, due to my kidneys.

MRI ADPKD (image: radiopedia)

MRI ADPKD (image: radiopedia)

References:

Dalgaard OZ. Bilateral polycystic disease of the kidneys. Acta Med Scand 1957; 328: 1−255.

Gabow PA, Johnson AM, Kaehny WD et al. Factors affecting the progression of renal disease in autosomal-dominant polycystic kidney disease. Kidney Int 1992

Grantham JJ, Torres VE, Chapman AB et al. Volume progression in polycystic kidney disease. N Engl J Med 2006; 354: 2122–2130.

Kistler AD, Poster D, Krauer F et al. Increases in kidney volume in autosomal dominant polycystic kidney disease can be detected within 6 months. Kidney Int 2009; 75: 235–241

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