Tuesday, 22 November 2016

A Spoiler of Two RCTs on Extracorporeal FLCs Removal (Eulite and MYRE)

At the time of Multiple myeloma (MM) diagnosis, severe AKI secondary to Myeloma Cast Nephrpathy is a common complication. Recovery of renal function is a key prognostic factor. Two RCTs have recently investigated the use of extracorporeal dialysis strategies to rapidly remove circulating monoclonal free light chains (FLC).
Waiting for final results publication, this is a spoiler of available data:
-          Eulite Study90 patients with severe de novo dialysis-dependent AKI secondary to biopsy–proven Myeloma cast nephropathy were randomised to receive either standard high-flux dialysis (n=47) or free light chain (FLC) removal haemodialysis using a HCO dialyzer (n=43).  Dialysis sessions in HCO group were longer (6 hours on day 0, then 8 hours on days 2, 3, 5–7, 9+10. After day 12, participants received 8 hours of haemodialysis on alternate days. After day 21, if patients still required renal support the dialysis schedule was reduced to 6 hours three times per week) and more frequent than the conventional dialysis received by the control arm (4h x3/wk). All patients received standardised chemotherapy (bortezomib based regime). The primary endpoint of the study I, i.e. independence of dialysis at 3 months from enrolment, was achieved in 55.8% of patients in HCO group and 51.6% in standard HF-HD group (p=0.65). An increase in mortality was reported in the treatment group mainly due to delay in chemotherapy and infection.
-          MYRE Study. Patients with severe de novo dialysis-dependent AKI secondary to biopsy–proven Myeloma cast nephropathy received 21-day courses of Bortezomib and dexamethasone (BD), reinforced by cyclophosphamide after 3 cycles in the absence of haematological response (HR). Patients were randomized to receive  conventional high-flux dialysis or  intensive HD (8 sessionsof 5 hours over the first 10 days, then thrice weekly) using a HCO dialyzer. Baseline characteristics in the control arm (n=48) and HCO arm (n=46) were close, including similarly high serum FLC levels (median 6,015mg/L).  HD independence was achieved in 33% and 43% (p= 0.31) at 3 and in 37.5% and 60 % (p=0.03) at 6 months, in the control and HCO arms, respectively. HR rate at 3 months based on FLC was 48% in control and 59% in HCO groups (p=0.29). At 12 months, 17 pts have died (10 vs 7).  


Differences in clinical outcomes could be theoretically justified by the more intensive treatment regimen adopted in Eulite Study. 

Tuesday, 1 November 2016

Cryoglobulinemic Syndrome: the essentials (My first ebook)

My first e-book, Cryoglobulinemic Syndrome: the essentials, is now freely available for Download

I hope you will enjoy it.

Monday, 3 October 2016

A Lecture on CKD-MBD

If you are interested in my last presentation on CKD-MBD please follow this link:

CKD-MBD

Comments are welcome.

Monday, 27 June 2016

The Original Water Deprivation Test from 1963

Risultati immagini per assetato

In the 1940s, in order to distinguish between primary polydipsia and diabetes insipidus a number iof dehydration tests were proposed  However, it was only in 1963 that Dashe et al published in JAMA a standardized water deprivation test, solving the problem of differential diagnosis of polyuric syndromes.



How to Perform a Water Deprivation Test according to the original Dashe's protocol: 

1.      On the morning of the test day, the patient is allowed to drink fluids ad lib until 8:30 am, and to eat breakfast prior to that time, but coffee, tea, and smoking are interdicted.
2.      For 7 hours after 8:30 am, the subjects are allowed no food or fluids.
3.      Serum and urine specimens are obtained for determination of osmolality
4.       Body weight is measured at the beginning and end of the experiment
5.      The subject voids urine at 8:30 am, and urine is subsequently collected by voiding at 9:30 and 11:30 am, and 12:30, 2:30 and 3:30 pm.
6.      Serum osmolality and serum sodium levels are to be measured at 9:00 am, 12 noon, and 3:00 pm

Dashe et al. compared changes in in the ratio Uosm-to-Sosm in several groups:

1)      Group A: Normal subjects. There weren’t significant changes in serum osmolality (285->286 mOsm/Kg). All normal subjects were able to excrete a highly concentrated urine (range of final-hour urine concentration, 756 to 1,496 mOsm/kg). The ratio of urine to serum osmolality ( urine-to-serum ) for the last hour of the test was 3.8 ± 0.9, with a range from 1.9 to 5.2
2)      Group B: patients with known diabetes insipidus. Six of the 13 patients had initial serum osmolalities within or below the normal range; however, all subjects developed a serum osmolality of 300 mOsm/kg or greater by the end of the test. The final osmolar concentration of the serum exceeded the initial level by an average of 12.0 mOsm/kg; the greatest change was +47 and the least was + 1.  Not surprisingly, patients with diabetes insipidus excreted urine which was less concentrated. The mean urine-to-serum ratio was  0.93 ± 0.45.
3)      Group C: Primary polydipsia. There was no change in serum osmolality during the test. The urine-to-serum ratio was comparable to group 1 ( > 2).


Interestingly, whereas the test is currently stopped when body weight decreases by 3% from baseline, in the original study by Dashe et al. an average of 2.6% of body weight was lost by the patients with severe diabetes insipidus. Indeed, the authors used a fixed duration of 6.5 h

These are Dashe’s conclusions, reporting clinical results for each diagnosis

1)      Mildest degree of diabetes insipidus currently identifiable:  Stability of serum osmolality with subnormal urine-to-serum osmolal ratio
2)      Moderate diabetes insipidus: supernormal serum concentration or supernormal increment in serum osmolar concentration. The serum concentration, however, is not greater than 300 mOsm/kg at any time.
3)      Severe diabetes insipidus: a serum osmolality which is greater than 300 at the end of the experiment
4)      A urine-to-serum ratio above 1.0 excludes the diagnosis of diabetes insipidus. Although some patients with rather severe diabetes insipidus may achieve a urine-to-serum ratio greater than 1.0, they do so only at a time when serum osmolalities were greater than 300 mOsm/kg.


Values before and after a Water Deprivation Test according to Dashe et al.

Diagnosis
Initial Sosm
Post-test Uosm-to-Sosm ratio
Normal subjects
Normal
> 1
Diabetes Insipidus
High (or High Normal)
< 1
Primary polydipsia
Low (or Low Normal)
> 1

Reference: Dashe et al: A Water Deprivation Test for the Differential Diagnosis of Polyuria. JAMA Vol. 185, No 9. Aug 31, 1963.

Tuesday, 12 April 2016

A few notes on "Dent’s disease"

Inheritance:
X-linked recessive, with a wide range of severity of phenotype (the gene CLCN5.) Of patients with Dent’s disease but lacking mutation in CLCN5, OCRL1 is mutated in a proportion, though not all, of the remainder.

Pathogenesis:
Both CLC-5 and ORL1 are strictly related to endosomal membrane trafficking and function.

Clinical features:
Proximal tubular solute loss,
LMW proteinuria;
hypercalciuria;
nephrocalcinosis and kidney stones; and
progressive renal insufficiency.
(rickets)

LMW proteinuria is the most consistent finding in patients with Dent’s disease, and the degree of protein loss is extreme
From childhood, the degree of albuminuria ranges 1–2 grams per day, representing about half of the proteinuria in these patients..
Other clinical signs of proximal reabsorptive dysfunction, such as glycosuria, aminoaciduria, and hypophosphatemia,
are common but not universal. When hypophosphatemia and hypokalemia occur, they can be severe and may require replacement.
Kidney stones occur in only half of patients. Hypercalciuria is an early finding, almost universal. In young adults with Dent’s disease, it ranges from 4 to 6 mg/kg body Weight. Nephrocalcinosis develops in a majority of patients with
Dent’s disease
Serum levels of PTH are consistently below the mean of the normal range in patients with Dent’s disease, and often
frankly low. Conversely, levels of 1,25-dihydroxyvitamin D are often elevated.
Renal failure develops in two-thirds of patients, but variably, and some patients reach an advanced age with little or only modest renal impairment. The mechanism of the renal failure is unknown.
Patients with clinical bone disease have elevated serum levels of alkaline phosphatase, but those without clinical
rickets have normal alkaline phosphatase levels and normal bone density.
One remarkable feature of Dent’s disease is the absence of systemic acidosis, except in the presence of renal insufficiency or nephrocalcinosis.
Nocturia is often the first symptom in affected boys, and moderate polyuria in the range of 1–3 liters per day is common.

Therapy:
Patients with recurrent stones and hypercalciuria may benefit from treatment with a thiazide diuretic. In view of one report of a dramatic natriuretic and kaliuretic response to a large dose of hydrochlorothiazide, patients should be followed closely when starting the diuretic.
Dietary sodium restriction may reduce calcium excretion,.
Vitamin D should only be considered in patients with clinical bone disease.

Tuesday, 29 March 2016


I don't believe in...




This is a big match: "Personal experience vs. EBM". This is not against EBM, I am 100% in favour of an EBM approach, but I think personal experience should help us in our everyday practice.

So, here's a short list with a few things I don't believe in:

- I don't believe in D5W to correct hyperNa
Of course, it works, but I really find H2O is better and easier to use: no need to account for metabolic effects and possible changes in K levels. Effects on sodium levels are really more predictable. I'd like to see an head to head RCT.

- I don't believe in "Don't Use Furosemide in HyperCalcemia"
Most of these patients have high creatinine levels and, if there is not a very high Ca level (> 14 mg/dL),  you must be a very brave doctor to use pamidronate as a first line drug. Someone could say: "Creatinine is up because of hyperCa", that's true, but speaking clearly there are a number of circumstances in which you have no data about basal creatinine or precedent CKD history. If so, if you are not brave, you'll need to use large volume of saline in a patient whose heart function is a mystery. So, it would be prudent if you work in a busy ward to administer a little bit of furosemide. .

    .     Don't forget: this is a dumb comment!