What is High-Efficiency and what is High-Flux ?

Unusually Low or High Endogenous Creatinine

NKF K/DOQI recommended target ranges

Serum phosphorus 3.5 mg/dL–5.5 mg/dL
Serum calcium 8.4 mg/dL–9.5 mg/dL
Ca X P product <55 mg2/dL2
Intact PTH 150 pg/mL–300 pg/mL
Serum total CO3 >22 mmol/L

these are the targets for Bone Metabolism

Summary of Treatment Recommendations for IgAN

All summarised ....

IgAN latest

Management of IgA nephropathy


ACE-inhibitors, ARBs and ACEI/ARB combinations - beneficial

Steroids
Pozzi et al (vs placebo) - better renal survival with steroids
Katafuchi et al (vs placebo) - similar renal survival
A recent metaanalysis also support use of steroids : reduce proteinuria, prevent progression to ESRD

Oral CYC
Ballardie et al. better 5-year renal survival

Fish Oil - conflicting results
Donadio et al. Mayo Clinic. NEJM 1994 (fish oil better)
Pettersson et al (no benefit, in fact worse)
Hogg et al (no benefit)

MMF - no evidence in IgAN

Membranous nephropathy

Management of membranous nephropathy

Chlorambucil } both proven effective by Ponticelli et al
cyclophospamide }

Cyclosporin A (Cattran et al.KI 2001)
CSA + low dose steroids vs steroids only (n=51)
CSA + low dose steroids - more CR/PR (21/28 vs 5/23)

MMF (only uncontrolled trials)
Choi et al. reduced proteinuria
Miller et al. reduced proteinuria

Rituximab (also uncontrolled trials)
Ruggenenti et al. reduced proteinuria up to 1 year.

FSGS latest update

Management of FSGS

Steroid-resistant FSGS
Cyclosporin A vs placebo (Cattran et al. KI 1999)
CR/PR : 70% vs 4% (CSA much better)

MMF : Choi et al (n=18) but not controlled. New NIH multicenter RCT ongoing
Sirolimus : no evidence

PD Guidelines : Quick Summary

European Best Practice Guidelines

UF > 1L/day
Kt/V > 1.7 per week

UK Renal Guidelines

CCr 50L/week
Kt/V > 1.7 per week

KDOQI Guidelines

CCr 50-60L/week
Kt/V > 2.0 per week

Strategies to Expand Living Donor Pool

Due to the lack of living donors here, this is something we need to know :

What are the strategies available to expand Living Donor Pool?

1) Use of genetically unrelated donors such as a spouse, friend or acquaintance (emotionally related donors) or a stranger(altruistic or living nondirected donors [LNDs])

2) Paired-donor kidney exchanges, either direct (living-donor–living-donor) exchanges (kidney-paired donation) or indirect (living-donor–deceased-donor) exchanges (list-paired donation)

3) Integration of paired exchanges with LND donation, as either domino-paired donation (LND donation plus direct exchanges) or chain-paired donation (LND donation plus direct and indirect exchanges)

4) Transplantation across ABO or HLA barriers using desensitization techniques

5) Use of expanded-criteria living donors including hypertensive donors, obese donors and elderly donors

Lupus Nephritis Maintenance Trials (Revision)

OK, yesterday I posted on Induction trials. Now lets look at Maintenance of LN.

Remember the name ....
Contreras et al.
n=59
After induction with IV CYC (4-7 monthly doses),
split into 3 arms:
1) continue IV CYC (3-monthly doses)- 2 years
2) Azathioprine (1-3mg/kg/day)- 2 years
3) MMF (0.5-3gm/day) - 2 years

IV CYC arm : more reached end point (death/CRF) compared to Aza or MMF
Aza and MMF arms : more relapse-free survival
Mortality increased with IV CYC

Limitations : large % of Hispanics/Blacks

... Watch out for upcoming trial MAINTAIN Nephritis Trial (comparing aza to MMF as maintenance)

Lupus Nephritis Induction Trials (revision)

OK guys. Time for lupus revision. OK we all know that the NIH protocol for INDUCTION has both short-term and long-term adverse effects of Cyclophosphamide (CYC). What else is there?

For exam purposes ;

CYCLOPHOSPHAMIDE
Euro Lupus Nephritis Trial (Houssiau et al)
(n=90)class IV LN receive either high-dose (monthly pulses x 6 followed by quarterly pulses x 2) or low-dose (500 mg biweekly × 6 pulses) IV CYC induction followed by azathioprine (AZA) maintenance in a dose of 1 mg/kg/day
Result : No difference in remissions. No difference in flares. Less infections with low dose. Limitation : milder disease, almost all causasians (no blacks)

Cellcept / MMF
Chan et al. (n=42)DPLN receive 6 months of induction with MMF (2 g/day) or oral CYC (2.5 mg/kg/day), both with concurrent prednisolone.During the maintenance phase, those in the MMF arm continued the drug at a reduced dose (1 g/day)and those in the CYC arm switched to AZA (1.5 mg/kg/day)for 6 months.
Result: At 12 months, there were no differences in CR, PR or relapse.
.... they added another 22 patients, followed up 5 years.
Result: same, no difference as above. Fewer infections with MMF arm.

Hu et al. 6 months MMF vs conventional IV CYC. Result : MMF better

Ginzler et al. (n=140) majority Class IV. MMF vs standard IV CYC (6 months). Crossover allowed at 3 months.
Result: MMF better at 6 months(CR, PR, infection rate). At 3 years, no difference (death, flare, renal failure)

... watch out for Aspreva (IV CYC vs MMF 6 months) ... but after that MMF vs Aza (i think i can predict the result ... clear winner in MMF ... but imagine if there is no difference between MMF and aza .... hehehe.

Another basic problem ... Dialysis Cramps

Aetiology - unclear (likely volume depletion and tissue hypoxia) and usually due to requirement for large volume removal.

Management options :

1) administration of hypertonic fluid, most commonly 50% dextrose (50mls), in order to raise plasma osmolality.

2) Quinine 200-300mg before dialysis or at bedtime can be tried but is unproven

3) Oral agents such as clonazepam, vitamin E, carnitine, or anti-convulsants are sometimes used as prophylaxis.

4)Limitation of inter-dialytic weight gains, ensuring that post-dialysis dry weight is correct and the use of an appropriate dialysate sodium are the best means to prevent this problem. Remember that a higher dialysate sodium will reduce intra-dialytic symptoms at the expense of thirst and weight gains; the converse holds true for a lower dialysate sodium. Sodium profiling may again be of benefit.

5)Patients who experience cramps at night may benefit from muscle-stretching for a minute or two. Heat and massage for the camping muscle can help.

Personally, I haven't tried numbers 2) and 3), and 4) makes you spend a lot of time counselling patients (who still end up not following your advice!)but there are some good obedient patients... usually adjusting dry weight and IDWG helps .... and sodium profiling seems to be useful too. I usually advocate linear sodium profiling for such problematic patients (ie start Na 140 or 145 and end up with 135)and the patients have less problems - not sure if it is just psychological. I wonder if anyone else has encountered same experience with sodium profiling in this situation?

Intradialytic Hypotension (IDH) ... what can we do about it?

Hi team,

time for some basic dialysis stuff for revision. I'm revising on intradialytic complications now and one of the commonest complication is IDH (intradialytic hypotension).

Usually occurs for one of three broad reasons:

1) Patient is below dry weight (q.v.)
2) Fluid removal is faster than redistribution can occur (eg, too large weight gains, unstable circulation)
3) Some effect of dialysate/ membrane/ extracorporeal circuit on cardiac output and/or peripheral resistance

... and of course sometimes anti-hypertensive accidentally served in the morning!

What can we do?

1) Advise patient about fluid, salt, etc

2) Review dry weight

3) Consider longer, slower dialysis (unpopular with patients understandably)

4) Consider serial ultrafiltration followed by isovolaemic dialysis (lengthens dialysis again; can be used for a time to get nearer to dry weight)

5) Review haemoglobin (effect of anaemia possibly via cardiac oxygenation)

6) Consider providing oxygen during dialysis

7) Tricks with dialysate:
(a) cooling (causes increased peripheral resistance);
(b) sodium profiling, or ramping, in which the dialysate sodium is altered during dialysis. A higher dialysate Na reduces hypotension (probably by maintaining ECF osmolality) - but reduces Na removal. Start high Na, lower Na later helps (ie linear profiling). Ultrafiltration rate can also be profiled on some machines.

8)Avoid eating and drinking before/during dialysis (reduces peripheral resistance by causing splanchnic vasodilation)

9)Omit hypotensive agents on the morning (or evening) before dialysis

10) Oral midodrine, an a1 adrenergic agonist (I don't think it is available here though)

11) Consider haemofiltration or haemodiafiltration (different membranes, but in the case of haemofiltration, also usually a slower treatment - and possibly with more cooling of blood)

Physiological levels of Haemoglobin increase mortality in CKD?

Risk for all-cause mortality was significantly higher in patients with anemia caused by chronic kidney disease (CKD) who were treated with erythropoiesis-stimulating agents (ESAs) to higher rather than lower hemoglobin targets, according to a meta-analysis of 9 randomized controlled trials and more than 5000 patients.

The study, (published 3rd February 2007 in Lancet), also found that patients in the higher hemoglobin-target group were at increased risk for arteriovenous access thrombosis and poorly controlled hypertension.

"The most important of our findings is the significant increase in the risk of all-cause mortality seen when a target hemoglobin concentration of 120 to 160 g/L is achieved," despite this being within the normal physiologic range, the researchers from Monash University in Melbourne in Australia said.

The Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin Beta (CREATE) and the Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) also raised this issue.

Take note that there is another study coming up ....The Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT), which is investigating darbepoetin. This will provide further insight into optimal target levels.

So how do we apply this in clinical practice???

The editorialists conclude: "The question has been answered: higher hemoglobin-target concentrations increase mortality via cardiovascular end points. Partial, rather than complete correction of anemia is appropriate, although commercially less attractive, and it is time to move on."

Dr. Strippoli said: "Treat patients with CKD to a hemoglobin target of 100 to 120 g/L; if patients have severe cardiopathy, treat them to a hemoglobin target of 100 to 105 g/L."

"First, hemoglobin-target trials should be stopped, or their aims need to be strongly reassessed; second, a trial of different doses of erythropoietin is needed, because what is causing harm to the patients is probably that many of them do not respond to these drugs properly and higher doses are used."

DOPPS : European study

This was what they did .... 4 groups (total n=2165) from 5 european countries:

1) low flux HD
2) high flux HD
3) low efficiency HDF
4) high efficiency HDF

.... it turned out that high-efficiency HDF had 35% lower mortality rates than low flux HD (p=0.01). These observational results suggest that HDF may improve patient survival independently of its higher dialysis dose .... but more randomised controlled trials are needed before clinical recommendation. but looks like HDF is the way to go ....

This was published 26th April last year.

The gist of the HEMO study

HEMO Study was a randomized, controlled clinical trial that tested the role of high-flux membranes and high-efficiency dialysis on the morbidity and mortality of HD patients treated three times per week.

The results showed no major overall beneficial effects of an increase in dialysis dose above the currently recommended standard and no improvement in mortality with use of high-flux membranes in 1846 patients followed up to 6.5 years

Note, this study did not use convective systems which are present in HDF and theoretically large solute clearance not in consideration at all here .... a bit "kuno" lah in other words ....

What do you see in HPE for BK virus nephropathy?

the usual interstitial inflammation & tubules display diffuse degenerative changes and interspersed, enlarged, hyperchromatic (pleomorphic) nuclei with intranuclear viral inclusions typical of BK virus.

This diagnosis was subsequently confirmed by immunohistochemical staining for SV40.

Summary of what I read ... the salient points of BKVIN

1)Reactivation of BK virus is a cause of allograft dysfunction and can lead to allograft loss.

2) All renal transplant recipients should be screened for BK virus replication early in the transplant course or when allograft dysfunction is noted.

3) Definitive diagnosis of BKVIN requires allograft biopsy. Not urine, not serum.

4) If BKVIN and concurrent acute rejection is diagnosed, antirejection treatment should be considered, coupled with subsequently reducing immunosuppression.

5) Reduction of immunosuppression has been associated with clearance of viremia in asymptomatic patients.

6) Leflunomide may be associated with clearance of viremia and stabilization of renal function.

7) Cidofovir at low doses (0.25–0.33 mg/kg intravenously biweekly) without probenicid could be considered for refractory cases.

8) Retransplantation after renal allograft loss to BKVIN remains a treatment option for patients who have cleared viremia.

Antiviral treatment options in BKVIN

Well, what I read was that the following are options :

1) cidofovir
2)leflunomide

cidofovir is used & there have been several case reports using cidofovir at doses ranging from 0.25 to 1 mg/kg every 2–3 weeks showing clearance of viremia in many.

A bit about BK virus nephropathy screening

The recommendations of the 2003 consensus conference are that all renal transplant recipients should be screened for BK virus replication in the urine: (1) every 3 months during the first 2 years post-transplant; (2) when allograft dysfunction is noted; and (3) when allograft biopsy is performed. A positive screening result should be confirmed within 4 weeks and assessed by quantitative assays (e.g. BK viral load in plasma or urine).

Definitive diagnosis of BKVIN requires allograft biopsy. If BKVIN and concurrent acute rejection is diagnosed, antirejection treatment should be considered, followed by reduction in immunosuppression.