Deceased Donor Kidney Allocation 2014

In the USA in June 2013 the OPTN/UNOS Board of Directors approved amendments to the OPTN policy for deceased donor kidney allocation. These ideas have been discussed for the last 9 years and Nate wrote about some of these ideas here and posted a poll here. The central premise for the changes were outlined in a press release on the OPTN website here. The exact dates for nation wide implementation are not currently available.

Longevity-matching

This is the main and most interesting part of the new system.

Priority will be given to transplant recipients most likely to live the longest post transplant. Each recipient is given an EPTS (estimated post-transplant survival) score ranging from 1 to 100%. This score is calculated from recipient characteristics; Age, years on dialysis, presence of diabetes and prior solid organ transplant.

Here is the OPTN online EPTS calculator

Remember the EPTS score needs to be updated daily.

·      The lower percentage EPTS score the longer estimated survival.

Recipients in the top 20^th percentile will be prioritized for the best kidneys, that is kidneys with a KDPI (Kidney Donor Profile Index) of less than 20%. The KDPI is a re-working of the Kidney Donor Risk Index, which is a risk quantification score defined in a study published by Rao et al in 2009. The KDRI expresses the relative risk of kidney graft failure for a given donor compared to the median kidney donor from the previous year. Values greater than 1 have higher risk of failure. A KDPI of 80% means that the donor kidney has a greater chance of graft failure than 80% of all kidneys retrieved in the previous year.

The KDPI is calculated using 10 donor characteristics; donor age, height, weight, ethnicity, history of hypertension and diabetes, cause of death, serum creatinine, hepatitis C status, and donation after circulatory death status.

The equation is complicated but here is the OPTN online KDPI calculator.

·      The lower the KDPI the better the kidney.

These two concepts will replace the current categories of SCD and ECD.

SCD will be the equivalent of KDPI of 85% or less. ECD will be equivalent to greater than 85%.

Waiting time calculation

With the new rules the waiting time will be calculated from when the recipient reached a GFR of 20ml/min or less or when they started on RRT even if they were listed after this. Thus, waiting times will be backdated. Waiting time points will be score as fractions of a year, number of days divided by 365.

The current system assigns the wait time when the candidate is listed.

Access for highly sensitized recipients

The new system includes additional priority for recipients that are highly sensitized. This is a sliding scale points system based in calculated PRA starting at a CPRA of 20%. Points on this scale are weighted significantly in favour of those with CPRA over 98%. 

The new system will also facilitate the offer of kidneys from certain blood type A donors (A2 and A2B) to type B recipients in an effort to reduce the wait time for these recipients.

CPRA (%)	Points
0–19	0
20–29	0.08
30–39	0.21
40–49	0.34
50–59	0.48
60–69	0.81
70–74	1.09
75–79	1.58
80–84	2.46
85–89	4.05
90–94	6.71
95	10.82
96	12.17
97	17.3
98	24.4
99	50.09
100	202.1

Wider sharing

The ‘payback’ rule will be removed. If a local service receives a well-matched kidney from another donation service they will no longer ‘owe’ a kidney.

Priority point system for new kidney allocation

This scoring system is used to rank recipients in four quartiles of KDPI.

KDPI <20%; 21 – 34%; 35 – 85%;  >85%

Within each quartile there is also a kidney allocation classification system based on location/OPO, ABDR mismatch, CPRA and blood group.

It is my understanding that EPTS determines which quartile a recipient is ranked in.

Factor	Points Awarded
For qualified time spent waiting	1 per year (as (1/365 per day)
Degree of sensitization (CPRA)	0–202
Prior living organ donor	4
Pediatric candidate if donor KDPI 35%	1
Pediatric candidate (age 0–10 yr at time of match) when offered a zero antigen mismatch	4
Pediatric candidate (age 11–17 yr at time of match) when offered a zero antigen mismatch	3
Share a single HLA-DR mismatch with donor	1
Share a zero HLA-DR mismatch with donor	2

This new system seems fair and is an effort to get the most out of each kidney transplanted. It also attempts to get more use out of poorer quality kidneys by more inter OPO sharing.

The full UNOS policy 3.5 statement can be found here.

Bedside Urinalysis - Blood

All to often now doctors in well-resourced hospitals rely on high tech, expensive and sometimes invasive tests to make a diagnosis. One of the most basic and cheapest tools we have at our disposal is the bedside urine ‘dipstick’ test. What can we learn from such an easy to perform test? 

One urinalysis reagent strip or ‘dipstick’ costs about 14cents (Pinnacle 10SG Urinalysis).

Finnian wrote two excellent blog posts on urine specific gravity and osmolality and on urine albumin and protein measurements using the ‘dipstick’ test. Here’s what else this bedside test can help you with.

Urine dipstick ‘Blood’ test

Heme acts as a pseudoperoxidase and when exposed to the peroxide and a chromagen on the test pad a colour change takes place.

The urine dipstick is a highly sensitive test for the presence of heme in the urine and detects as few as 1 to 2 RBCs per high power field.

The presence of urinary ascorbic acid is one circumstance where false negative tests for hematuria occur. Some manufactures make test strips that can oxidize ascorbic acid to reduce false negative tests.

Semen in the urine can cause a false positive test.

Of course the ‘blood’ panel turns positive due to the heme in free urinary hemoglobin or myoglobin.

Thus the presence of RBCs in the urine needs to be confirmed by microscopic analysis of the urine.

What disorders can we assess with the ‘dipstick’ test for blood/heme?

           

Rhabdomyolysis

Myoglobin is released from damaged muscle along with CK. 

Myoglobin is not avidly bound to protein and is thus rapidly excreted in the urine and has a half-life of about 2 hours. It is also rapidly metabolized to bilirubin so serum levels return to normal within 8 hours.

Thus, a diagnosis of rhabdomyolysis is not ruled out by negative urinary myoglobin.

On must also be aware that there may also be heme or RBCs present in the urine for other reasons during rhabdomyolysis.

Myoglobin appears in the urine when serum levels are above 1.5mg/dl but visible changes in urine colour only occur when serum levels are above 100mg/dl. A clear urinary supernatant usually helps to distinguish myoglobinuria from hemoglobinuria (red supernatant) after centrifugation.

Myoglobin can be detected by the urine (orthotolidine) dipstick at concentrations of only 0.5 to 1 mg/dL.

Mean peak serum Creatinine Kinase (CK) levels in a large study of rhabdomyolysis was 10,000 to 25,000. 46% of this cohort had AKI. In another study that included only patients with a CK over 5000 AKI was present in 51%.

A good history and physical exam helps makes the diagnosis.

Hemolysis

Again this diagnosis is easy with a good history and physical exam and some basic ‘hemolysis’ lab tests. What can you do while waiting for the lab results?

The urine dipstick will be positive for heme in the urine. In theory there will be no RBCs in the urine and the supernatant will be red without a red cell pellet. However, there are caveats to this, an old urine sample and rarely a very dilute urine sample (low specific gravity – see Finnians post) may cause red cells present in the urine to hemolyze. Urine microscopy should be done to look for presence or absence of RBCs.

Red urine supernatant but negative dipstick ‘blood/heme’?

Rifampin, phenytoin, food dyes, beets (beeturia), rhubarb, senna or Acute intermittent porphyria.

Renal or urological bleeding.

In either of these circumstances urine dipstick tests will be positive for blood.

Hematuria present with proteinuria is suggestive of a glomerular cause. Hematuria with proteinuria greater than 1+ is almost never due to extra glomerular bleeding even when gross hematuria is present. However, massive bleeding can cause proteinuria. Massive bleeding is more likely to occur due to extra glomerular bleeding and the presence of clots and very red or pink urine as opposed to Coca-Cola coloured urine indicates extra glomerular bleeding.

SGLT-2 and the genesis of hyperfiltration

Over at eAJKD, Swapnil Hiremath has a nice post about the potential for SGLT-2 inhibitors to prevent diabetic nephropathy based on a review article published on the topic in AJKD. Essentially the theory is that increased serum glucose levels leads to an increase in the filtered load of glucose. This is reabsorbed in the proximal tubule along with sodium and chloride. This leads to a reduction in the load of NaCl delivered to the macula densa. The kidney senses this as a low effective circulating volume state leading to afferent renal vasodilation and an increase in GFR.

The advent of SGLT2 inhibitors has allowed us to test this theory in both animal models and humans. Recently, a small physiologic study was published in Circulation which tested the effect of SGLT2 inhibition in individuals with type 1 DM stratified by the presence or absence of hyperfiltration at baseline. GFR was measured using inulin clearance. The figure above is taken from the paper and shows the putative mechanism for hyperfiltration and the role of SGLT2 inhibitors. In this paper. empaglifozin treatment for 8 weeks lead to a significant decrease in weight, BMI, daily insulin dose and carbohydrate intake in both groups. In the normofiltration group, it had no effect on renal hemodynamics. However, in the hyperfiltration group, there was a significant reduction in GFR (-33ml/min), renal plasma flow, renal blood flow and an increase in renal vascular resistance. These results are remarkable but to me it does beg a question.Why is there such a dramatic effect in the hyperfiltration patients and what makes them different in the first place. Based on the evidence of this study, most of the hyperfiltration is indeed related to increased TGF. Looking at table 1 gives a hint of what might be the correct answer.

The baseline BMI and insulin doses were similar in both groups. However, the HbA1c was marginally higher in the hyperfiltration group as was the baseline carbohydrate intake. 24 hour glucose excretion was identical in the two groups. Following treatment, the daily carbohydrate intake increased significantly in both groups but to approximately the same extent. However, the increase in 24 hour urine glucose was substantially higher in the hyperfiltration group. What this suggests to me is that the hyperfiltration may be driven by higher overall carbohydrate intake despite relatively similar HbA1c levels. Because the 24 hour glucose excretion was the same in both groups prior to treatment, this suggests that the majority of the filtered glucose was being reabsorbed. Because the hyperfiltration group were taking in more carbohydrate, this would lead to an increase in the delivered load of glucose to the proximal tubule with a consequent increase in NaCl reabsorption. Treatment with empaglifozin prevented the kidneys from reabsorbing this excess glucose and this is reflected in the fact that the 24 hour urine glucose increased more in the hyperfiltration group than the normofiltration group.

I should point out that this is my theory alone based on the reading of this paper and that many of these between group differences were not statistically significant because of the low numbers of patients involved. Still, this paper at least provides elegant proof of the role of proximal glucose reabsorption on the maintenance of hyperfiltration.

The use of IVIg in Kidney Disease

It’s time for a quick nephro-centric summary of immune globulin use. Immune globulin, usually administered intravenously (IVIg), is made from pooled human plasma and used for a wide variety of human disease. It contains mostly IgG with various IgA concentrations depending on the preparation and different stabilizers (see sucrose nephropathy below). IVIg has various anti-infections and anti-inflammatory effects via mechanisms that are still incompletely understood. The sphere of renal transplantation is where most nephrologists will see it being administered.

HLA Desensitization

IVIg is incorporated into various desensitization protocols which may decrease preformed anti-HLA antibodies and render a previous positive crossmatch negative. Two broad regimes are (a) high dose IVIg at 2g/kg single dose or monthly and (b) plasmapheresis with low dose IVIg 100mg/kg after each session. The latter regime is likely more beneficial when an appreciable level of sensitization is present and rituximab may be also be added. The immunomodulatory mechanisms at play may include neutralizing donor-reactive antibodies, reducing anti-HLA antibody formation and the inhibition of complement-dependent endothelial injury.

Antibody-Mediated Rejection (AMR)

IVIg is generally incorporated into a multi-targeted regimen for AMR, usually at least 1g/kg given after plasmapheresis. My own experience is with 2g/kg at the end of the final plasmapheresis sessions. It must be noted that IVIg may interfere with anti-HLA titers, causing false-positive results so it is important to send levels before administering IVIg.

Transplant Infectious Disease

BK Polyoma virus nephropathy (PVN): IVIg may have a role in the treatment of (PVN), particularly in cases where acute rejection co-exists or is suspected. IVIg presumably contains anti-BK antibodies, as the virus is ubiquitous in the general population. However, whether these antibodies are neutralizing or not is unknown. As the cornerstone of PVN treatment is immunosuppression reduction, coexistent acute rejection presents a difficult scenario with IVIg being attractive due to its anti-infective and immunomodulatory properties. Other post-transplant infectious complications where IVIg may be useful include Parvovirus B19 (which may cause severe anemia or an FSGS renal lesion) and possibly resistant CMV infection. The use of IVIg in these settings is usually in conjunction with a decrease in the burden of immunosuppression.

Glomerular disease

IVIg has been used without much convincing evidence for a variety of glomerular pathologies. These include an uncontrolled series of 11 patients with severe IgA Nephropathy given monthly doses of 2g/kg. A decrease in proteinuria and stabilization of GFR was observed. Other unconvincing reports for IVIg use in glomerular disease include a small study in idiopathic membranous nephropathy as well as in lupus nephritis and ANCA associated vasculitis (ref).

Adverse Renal Events

It should be noted that IVIg preparations may uncommonly cause AKI (<1% of infusions). This almost always happens with use of high sucrose-content preparations. IV Sucrose was used in the mid-20^th century for treatment of various edematous states and was associated with AKI, via an osmotic effect causing proximal tubular cell swelling and vacuolization (see JAMA paper from 1942!). IVIg may also cause hyponatremia, as discussed by Nate previously.

Endothelin Antagonism for Diabetic Nephropathy: Nephrology Twitter Journal Club

The next Nephrology Twitter Journal Club (@NephJC) will discuss a study in JASN describing the use of Atrasentan, a selective Endothelin-A receptor blocker, in diabetic kidney disease. This is the latest attempt to resurrect this class of agents in CKD. Within the last year, the big diabetic nephropathy stories have been the Bardoxolone saga and the VA Nephron D study so it’s about time we had some good news. We can perhaps be cautiously optimistic after this Endothelin (ET) antagonist study.

There are many ETs with ET-1 being the predominant isoform. They are produced by many cells in the kidney and have a wide variety of biologic actions including the regulation of vascular resistance, fluid and electrolyte transport and cell proliferation (including the development of fibrosis). ET acts through the activation of G–coupled receptors, with 2 main subtypes. Activation of ET-A receptors cause vasoconstriction and cell proliferation, whereas activation of ET-B causes natriuresis and the release of nitric oxide and prostacyclin, mediating vasodilation. Selective antagonism of the ET-A receptor is therefore an attractive target with combined blockade, perhaps unsurprisingly, appearing to have no beneficial effects. A previous large multicenter RCT of 1392 participants was performed in patients with Type 2 diabetes and CKD 3-4 using Avosentan with RAAS blockers. The study was halted after a median 4 months for cardiovascular safety concerns. Avosentan significantly reduced proteinuria compared to placebo but at the expense of excess fluid overload and congestive cardiac failure. It should be noted that Avosentan is a less ET-A selective antagonist than Atrasentan, the agent in the current JASN study.

The current study was a placebo-controlled RCT involving 211 patients with diabetic nephropathy, overt proteinuria and eGFR 30-75mls/min. The mean age was 65 years and 70-80% were male. Two doses of Atrasentan were studied, 0.75mg/day and 1.25mg/day. There was a significant improvement seen in albuminuria with albumin/creatinine ratios decreasing by a mean of 35% and 38% in the 2 Atrasentan groups respectively. There was no change in renal function or office BP but 24-hour BP, LDL cholesterol and triglycerides decreased significantly in both treatment groups. More patients in the high dose group discontinued due to adverse events and as expected, there was an increase in weight in the Atrasentan group. However, the rates of peripheral edema or congestive heart failure did not differ between groups. The weight gain was presumed to be fluid-related as reflected by small but significant decreases in hemoglobin and hematocrit.

There are two simultaneous basic science publications examining the disparate effects of ET-A & ET-B receptors which I will briefly mention. A KI paper reported on pigs with unilateral renovascular disease treated with either ET-A or ET-B antagonists. Renal blood flow and GFR were significantly improved after ET-A but not ET-B blockade. Moreover, only ET-A blockade therapy reversed renal microvascular rarefaction and was accompanied by markedly decreased renal inflammation and fibrosis. Another study in JASN investigated ET effects in podocytes during experimental diabetic nephropathy. Mice with a podocyte-specific double deletion of ET-AR and ET-BR manifested less albuminuria and were protected from podocyte loss and diabetic nephropathy. Interestingly, this study also provides evidence that dual blockade of the ET-AR and ET-BR may be necessary to achieve maximal benefit in diabetic nephropathy; challenging the belief that ET-B antagonism is detrimental.

So, is it time for ET antagonists to enter the mainstream? These agents have been around for quite some time but the adverse events reported with previous agents looked like it had buried these drugs for good. This study is welcome and obviously encouraging. However, the short follow-up and lack of hard endpoints mean further data is needed and longer studies warranted. Also, it is obvious that we have much still to learn regarding the ET system and how to manipulate it for gain in our CKD patients. The Nephrology community is well used to false dawns, particularly in diabetic nephropathy. Will ET antagonists prove to be the first clinically useful agents since the introduction ACE inhibitors/ARBs? We would like to hear what you think. Please follow the live Twitter journal club on May 13^th at 9pm Eastern time and feel free to comment using #NephJC.