Discussion board


Prof. J.Balasubramaniam, M.D.,D.M

Kidney Care Center.


El Nov 16, 2001 6:28 pm, Dr.V.T.Rajesh.MD (Pediatrics) dijo:

Dear sir,
When I was using oral Nimusulid for infants after vaccination I found that the urine out-put was less.
What is it due to?
Is it safe to use Nimusulide to infants and for children for fever and pain?

El Nov 18, 2001 7:27 pm, J.Balasubramaniam dijo:

Dear Dr.Rajesh,
COX 2 inhibitors were received with great enthusiasm when introduced. The scientific basis for its claimed safety was sound and the need for such a drug in day to say practice was great. Nimesulide was the first to be introduced and so naturally we have more data indicating nephrotoxicity for this drug. Though initially we were surprised by the failure of this drug to be safe as claimed, in the light of new knowledge, now we know that prostaglandins via COX 2 has definite role in maintaining GFR especially in Na depleted states and in nephrogenesis. So it is clear to us now that COX 2 inhibitors after all cannot be as safe as thought earlier. So your observations and apprehensions about Nimesulide are very valid.
As a pediatrician you should be all the more careful using these drugs. Please note that nephrogenesis goes on beyond birht during the early neonatal period. So COX 2 inhibiton during that period can cause permanant renal damage.
I am sad that Nimesulide is being promoted as an antipyretic in India and the pediatricians have developed a fancy for this drug. During infection and fevers there is bound to be dehydration making these children susceptible for renal dysfunction by COX 2 inhibitors. Hence I would advise my pediatric collegues to be vary of using ths group of drug.

El Nov 25, 2001 8:03 am, somasundaram dijo:

I am asking this question to my GURU of nephrology.
We have seen that prostoglandin analogues are used to ameloriate the gastric side effects of NSAIDs . Likewise whether early interventional theraphy with prostaglandin anologues will help reduce the nephrotoxic effects of COXII inhibitors.If so what anologue should be used?
Also it is clear that AII promotes prostaglandin production. So whether ACE inhitors in early childhood promotes nephon damage?

El Nov 25, 2001 8:03 am, somasundaram dijo:

I am asking this question to my GURU of nephrology.
We have seen that prostoglandin analogues are used to ameloriate the gastric side effects of NSAIDs . Likewise whether early interventional theraphy with prostaglandin anologues will help reduce the nephrotoxic effects of COXII inhibitors.If so what anologue should be used?
Also it is clear that AII promotes prostaglandin production. So whether ACE inhitors in early childhood promotes nephon damage?

El Nov 27, 2001 7:59 pm, J.Balasubramaniam dijo:

Dear Dr.Somasundaram,
Regarding prostaglandin analogues:
Going by renal physiology and the mechanism of NSAID action, it is quite reasonable and appropriate to think of Prostaglandin analogues in NSAID induced nephrotoxicity. In fact, many have tried Misoprostal in NSAID induced nephrotoxicity, hepatorenal syndrome and ischemic renal injuries, since early nineties. Though encouraging results were reported in prevention of nephrotoxicity, nothing dramatic evolved ultimately. The advent of COX 2 inhibitors, which promised remedy for this downside of NSAIDS, has probably stalled much development in this line. Now with COX 2 inhibitors too failing to meet our expectations, I think our interest in prostaglandin analogues, can very well be rekindled!
Regarding ACEI neonatal renal failure:
It is true that ACEI can also cause neonatal renal failure. Last trimester ACEI usage has been associated with renal tubulopathy besides many other problems. In fact, I know of a case report (presented at the annual congress of the Southern chapter Indian Society of Nephrology) of maternal ingestion of ACEI in the last trimester causing renal failure in the neonate. It was a reversible renal failure, though.
With best wishes.

Discussion on-line

[21:43] *** bala (cin2001@ has joined #cin

[22:04] (bala> hello

[22:14] (gtorres> good night

[22:14] (bala> Welcome Dr.Torres

[22:15] (bala> How does my summary reach here?

[22:17] (MJesus> yes

[22:17] (MJesus> I have it

[22:18] (bala> I am glad you are a pathologist

[22:18] (bala> Did you go through the neonatal slide

[22:19] (bala> of my neonatal renal failure

[22:20] (MJesus> I d'ont understand

[22:22] (bala> I am refering to the case report of neonatal
renal failure caused by maternal ingestion of nimesulide

[22:22] (bala> which came in Lancet

[22:23] (MJesus> in Lancet ?

[22:23] (MJesus> this month Dr, Bala ?

[22:23] (bala> hello somu

[22:23] (somu> hello

[22:23] (somu> sir

[22:23] (bala> No, a yr ago

[22:24] (somu> what was the article about in the lancet

[22:25] *** palani (cin2001@~ has joined #cin

[22:25] (bala> Hello Palani

[22:25] (somu> hello palani sir

[22:25] (MJesus> welcome palani !

[22:25] (MJesus> where are you from ?

[22:25] (palani> Hello bala

[22:26] (palani> India

[22:26] (somu> which part of india sir

[22:26] (VICTOR> thank

[22:26] (somu> i am also from India palani sir

[22:26] (palani> south most

[22:26] (somu> oh me too

[22:27] (palani> pleased to know

[22:27] (gtorres>Is the spaeaker here?

[22:28] (bala> Yes I am as bala

[22:28] (palani> Prof.Bala

[22:28] (bala> Shall change my nick

[22:28] (palani> okey

[22:28] (somu> ya that seems good

[22:30] (palani> What is the topic

[22:30] (bala> COX 2 inhibitor and nephrotoxicity

[22:30] (speaker> Prof. J.Balasubramaniam, M.D.,D.M.

[22:30] (speaker> Kidney Care Center. Tirunelveli, Tamilnadu, India

[22:30] (speaker> 'COX 2 inhibitors and nephrotoxicity'

[22:31] (speaker> There has been lot of new thoughts in the recent past, on the role of prostaglandins in renal physiology . This has thrown more light on how NSAIDs affect renal physiology.

[22:31] (speaker> NSAIDs, inspite of their known renal toxicity, are wonderful drugs serving as sheet anchor of treatment for many painful diseases.

[22:31] (speaker> The various inflammatory mediators, esp. prostaglandins are derived from the cell membrane phospholipids via the cyclo-oxygenase pathway.

[22:31] (speaker> NSAIDs, as a group, derive their anti-inflammatory capability by inhibiting the cyclo-oxygenase (COX) and hence the synthesis of prostaglandins.

[22:31] (speaker> Many physiological actions other than inflammation such as maintenance of gastric mucosal integrity and modulation of renal microvascular hemodynamics, renin release, and tubular salt and water reabsorption are also mediated by the prostaglandins.

[22:31] (speaker> Positive role of prostaglandins in maintaining the GFR in the face of adverse circumstances has been known to us for sometime. Hence, nephrotoxicity due to NSAIDs is rather inevitable.

[22:31] (speaker> In the 1990s, it was recognized that there were two enzymes COX 1 and COX 2 involved in the cyclo-oxygenase pathway and there arose the possibility of dissociating the good from the bad effects of NSAIDs. COX-1 is expressed in most tissues,

[22:31] (speaker> 'constitutively', but variably, is described as a "housekeeping" enzyme, regulating normal cellular processes. COX-2 is usually undetectable in most tissues; its expression is increased only during states of inflammation and is hence 'inducible'.

[22:31] (speaker> Thus selective COX 2 inhibitors evolved, giving us hopes of NSAIDs free of nephrotoxicity.

[22:32] (speaker> But reports of renal failureinduced by COX 2 inhibitors are increasingly seen, in the case of nimesulide, celecoxib and rofecoxib.

[22:32] (speaker> This has been predominantly witnessed in special situations like salt depletion, old age, mild renal failure, nephrotic syndrome, CCF, cirrhosis, etc. implying a role for COX 2 receptors.

[22:32] (speaker> Prostaglandins(PG) as paracrine mediators, are believed to be important factors that can alter rennin secretion and hence AII and GFR, esp in salt depleted states.

[22:32] (speaker> The macula densa mechanism for the control of renin release has been well established and direct evidence exists for prostaglandins responsible for low Nacl- stimulation of renin secretion.

[22:32] (speaker> It has been recently shown that AII augments the expression of COX 2 in the vascular smooth muscle cells. The converse relation, namely, PG stimulating A II release is also true.

[22:32] (speaker> The demonstration of COX 2 in the macula densa and the Thick Ascending Limb (TAL),

[22:32] (speaker> by Harris et al35 is a breakthrough finding, since it immediately suggests a pathway along which the PG's produced in the Nacl sensing epithelium through COX 2 could interact with the renin producing granular cells.

[22:32] (speaker> More disturbing are reports of evidence of disturbed nephrogenesis and renal irreversible failure in the newborn exposed to COX 2 inhibitors. It has been now clearly shown that during kidney development,

[22:33] (speaker> immunoreactive COX-2 is first observed in mid-gestation embryonic stages, notably in cells undergoing induction and/or morphogenesis and for the duration of nephrogenesis, through postnatal week 2.

[22:33] (speaker> This expression pattern of COX-2 in the developing kidney is of interest because of the evidence that COX metabolites play important functional and developmental roles in the fetal kidney.

[22:33] (speaker> In summary,

[22:33] (speaker> * COX-2 mRNA and immunoreactive protein are 'constitutively' expressed at high levels in restricted locations in the mammalian kidney, the macula densa and surrounding TALH, and the medullary interstitial cells.

[22:33] (speaker> * Regulation of expression during development and in a variety of physiologic and pathophysiologic conditions indicates potentially important roles for COX-2 metabolites in glomerulogenesis,

[22:33] (speaker> regulation of renal hemodynamics, and the renin-angiotensin system.

[22:33] (speaker> * COX 2 inhibitors have been found to be nephrotoxic particularly during nephrogenesis

[22:33] (speaker> (during last part of pregnancy and early neonatal period) and in clinical settings (salt depleted state, diuretic use, CCF, cirrhosis, nephrotic syndrome and elderly )

[22:33] (speaker> of hyper-reninemia secondary to low Nacl delivery to TAL.

[22:34] (speaker> THE END
[22:34] (MJesus> plas plas plas plas plas plas plas
[22:34] (MJesus> plas plas plas plas plas plas plas
[22:34] (MJesus> plas plas plas plas plas plas plas
[22:34] (MJesus> plas plas plas plas plas plas plas
[22:34] (MJesus> plas plas plas plas plas plas plas

[22:35] (gtorres> plas plas plas plas plas plas plas

[22:35] (jczafra> plas plas plasplas plasplas plas

[22:35] (gtorres> questions?

[22:36] (bala> Before we start the discussion, Dear Friends, good evening to you all. It is a pleasure to be involved in this forum and I should thank the organizers of this congress for having given me this splendid opportunity

[22:36] (bala> Let me introduce myself to the forum. I am a Nephrologist practicing in the southern most part of India. I am in charge of Kidney Care Centre, a dedicated renal hospital, catering to predominantly a rural population of more than 4 million.

[22:36] (bala> This centre has facility to undertake all kinds of renal management including Renal Tx and CAPD.

[22:37] (MJesus> Dr. bala... Renal Tx= transplant kidney ?

[22:37] (bala> Yes

[22:37] (MJesus> (I'm d'ont know well the jerga )

[22:38] (MJesus> how many tx do you do every year ?

[22:38] (bala> 20

[22:39] (MJesus> very much !!

[22:39] (bala> This being rather a rural centre affordability is a big problem

[22:39] (bala> Actually the cases are much much more

[22:40] (gtorres> uptodate says that cox 2 is equal of nefrotoxic that NSAID. What do you think about?

[22:40] (MJesus> Dr. bala, do you know if COX2 inhibitor are also related with hereditary nephronoptise or Fanconi'syndrome ?

[22:41] (bala> The two cases I have seen presented with CRF.

[22:41] (somu> what were the cases

[22:42] (bala> But tubular dysfunction is very much possible.

[22:42] (somu> can u please brief me

[22:43] (bala> Actully the mothers were on Nimesulide during the last part of preg

[22:43] (bala> for various indications and the newborn had renal failure on birth

[22:44] (bala> Unlike NSAID induced problem in adults it was CRF here

[22:44] (bala> very sad indeed

[22:44] (somu> was a biopsy done for the se infants

[22:45] (bala> Yes. The slides are given in the article in the net

[22:46] (bala> It showed tubules in different stages of maturation arrest and fetal glomeruli

[22:47] (bala> Is nsaid used as a tocolytic in preg in your country?

[22:48] (bala> Tocolysis is to reduce uterine contraction and preserve preg

[22:49] (somu> i have asked you of role prostaglandin analogue in reversing NSAID induced damage

[22:50] (bala> PG analogues have been tried since early 90s

[22:50] (bala> At best it can prevent nsaid toxicity if used along with nsaid

[22:51] (bala> In established toxicity it may not have any role

[22:52] (bala> DR. Jesus have you come accross newbormn with similar history?

[22:53] (jczafra> no we haven't

[22:53] (MJesus> not newborn, but little child

[22:53] (bala> Gnerally people are careful using drugs during early part of preg

[22:53] (MJesus> and as you know that it is hereditary

[22:53] (bala> but somehow relax towards the end

[22:54] (bala> So we should keep this possibility in mind in all newborn rf>

[22:55] (somu> but in india it is horrible to note paediatricians using nimesulide for antipyretic action to infants

[22:56] (somu> what do u think Prof.bala

[22:56] (bala> That is sad.

[22:57] (pino> Do you think that there is a relationship between thrombosis and COX 2 inhibitors?

[23:00] (balas> So it is possible that COX 2 inhibitor will not prevent thrombosis

[23:01] (MJesus> iceman, this is a confrence, silent please

[23:01] (balas> Am I heard?

[23:01] (palani> prof. Bala, i read your letter in lancet sometime back about the story of a new born renal failure due to nimusulide can you explain the sequences

[23:02] (balas> This failure of COX 2 Inh to prevent thrombosis is negative feature

[23:03] (balas> Also ulcer healing may be delayed by COX 2 inh

[23:04] (pino> Could cox 2 inhibitors trespass to mother milk?

[23:04] (balas> Dr.Palani, it was neonatal rf and the mother had been taking Nimesulide for sinusitis pain

[23:04] (balas> I am not sure. I shold check it up

[23:04] (palani> How long sir

[23:05] (balas> It is a good thing to keep in mind regarding mothers milk

[23:05] (IceMaN> are you doctors?

[23:06] (balas> because nephro maturation goes on even beyond birth for sometime

[23:07] (balas> In the time to come we may here about COX 2 receptors in other organs also and so more problem of organogenesis

[23:08] (jczafra> Maturation arrest of the tubules and the presence of immature fetal glomeruli is recoverable?

[23:08] (balas> No. Both my patients had irreversible rf

[23:10] (pino> any more questions?

[23:10] (somu> is there any time duration after which NSAID induced damage occurs

[23:11] (balas> It is dose dependent often and also

[23:12] (balas> depends on the clinical setting

[23:12] (balas> and how much prostaglandin dependant is the GFR

[23:12] (palani1> so can we use a low dose therapy

[23:12] (somu> how long your patient was consuming nsaids

[23:13] (balas> The mothers were using it for more than 3 weeks

[23:13] (balas> So 1 or 2 tablets may not affect nephrogenesis

[23:14] (balas> but in adults with appropriate setting, say

[23:14] (balas> old age, salt depletion, ccf etc few doses may matter

[23:15] (palani1> the was taking the drug in which trimster

[23:15] (balas> Is nsaid used as tocolytic agent in your country Spain?

[23:16] (balas> Last trimester

[23:16] (pino> I think it is not

[23:17] (somu> whether consumption in infancy also leads to crf is it so?

[23:17] (balas> Is brufen a OTC product? pino

[23:17] (pino> what is OTC?

[23:18] (balas> Over the counter drug without prescription

[23:18] (balas> like paracetamaol

[23:18] (gtorres> what are the differencies between renal failure recoverable and non-recoverable one?

[23:18] (gtorres> in biopsy?

[23:18] (pino> no, here it is necessary to be prescribeb by a doctor

[23:19] (balas> Generally the rf due to nsaid in adults is dute to AIN which is reversible

[23:20] (balas> In newborn it is not AIN but immature and

[23:20] (balas> tubules without lumen

[23:20] (balas> which cannot recover

[23:21] (gtorres> is posible maturation?

[23:21] (gtorres> thats is a process dinamic

[23:21] (balas> Now we feel that COX 2 receptor is essential for maturation

[23:22] (balas> and they are not expressed beyond first month of life

[23:22] (balas> Please refer my article

[23:22] (balas> So later maturation may not be possible

[23:22] (gtorres> thanks dr bala

[23:23] (pino> thanks, Prof Bala
[23:23] (MJesus> clap clap clap clap clap clap clap clap clap
[23:23] (MJesus> clap clap clap clap clap clap clap clap clap
[23:23] (MJesus> clap clap clap clap clap clap clap clap clap

[23:23] (palani11> thanks prof bala

[23:23] (balas> I thank all the participants and the Organizers Dr.Torres, Dr.Pedro, Dr.Jesus for the wonderful session.

[23:23] (pino> it is interesting but to late for us

[23:23] (somu> thnks prof. bala>

[23:24] (gtorres> gracias dr bala

[23:24] (palani11> we too feel the same Dr. pino

[23:24] (MJesus> Thank you Prof. J.Balasubramaniam.. you are very kind !

[23:24] (balas> Thank you all. Good night

[23:24] (gtorres> good night

[23:24] (somu> ya it is 4 am in india

[23:25] (palani11> so good morning

[23:25] (gtorres> hasta mañana somu and all

[23:25] (somu> good morning palani sir and all indians

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