Transplantation of HIV+ organs: from ban to HOPE

Organ donation from HIV positive patients has been prohibited in the USA since 1988. Pre-transplant screening for HIV is mandatory using nuclear amplification test (NAT), though false negative results during “window period” are a potential concern in donor selection.

Elmi Muller spoke at our Transplant Grand Rounds yesterday and told us about the challenge she faces in South Africa, where HIV infection affects more than 15% of the population, HIV patients frequently develop HIV-associated nephropathy (HIVAN) and progress to ESRD. Moreover, the availability of renal replacement therapy (hemodialysis) is limited.

In the early 90's, there were a number of uncertainties related to transplanting HIV positive patients including the worrisome concern about introducing a donor-derived virus that could lead to out of control HIV infection (resistant strain?); the effect on the immune system of HIV infection in combination with immunosuppression (worse immunodeficiency?); and the financial burden of expanding the services of transplantation to HIV+ patients in a country with limited health budget.

Against all the odds, Elmi performed four cases of HIV positive kidney donors to HIV positive recipients in South Africa in 2008. No IRB approval... Elmi reported having some intuition that it would work and she was in touch with other physicians around the world who shared her view. In her side, HIV resistance rate is very low in South Africa.

After performing those transplant, her colleagues and the hospital prosecuted her and banned her from performing surgery for more than 1 year. This past week, the HIV Organ Policy Equity (HOPE) Act was approved by the US Congress, permitting donation from HIV-positive organs to HIV-positive recipients. It took time but she is now recognized as a pioneer in the field and her courage to perform those surgeries were remarkable. The law that passed will help expand the availability of organ donors to HIV positive patients and will help with organ shortage.

Some challenges though still remain. HIV resistance is much higher in the States (~19%) and HIV+ transplant recipients experience a higher rate of rejection and significant difficulties with drug-drug interactions (P450 inhibitors). Details about a recent trial can be reviewed on this prior blog. In contrary to the idea of over-immunosuppression, recent paper suggests that ATG may be a better induction therapy choice for these patients. Closely monitoring of these patients will be essential as we learn more about HIV and transplantation. By bending rules, Elmi changed a transplant policy and made history.

Naoka Murakami
Leo Riella

Renal disease and HIV

Perhaps the most renowned renal disease associated with HIV infection is the collapsing variant of FSGS. This typically presents with the nephrotic syndrome and has been associated with relatively advanced HIV infection, with low CD4 counts and higher viral loads. HIV infection of tubular cells may play a direct role in the pathogenesis, with some supporting evidence from animals studies in which transgenic mice were created with HIV constructs in their genome – they developed proteinuria and similar histological findings of collapsing glomerular tufts and interstitial disease. Hypertension appears to be less common, possibly due to an association with salt wasting.

In addition there are many other renal diseases that can be associated with HIV infection, its treatment or associated conditions. An interesting review can be found here.

Below are some of the differentials on that long list:

Many of the anti-retrovirals have been associated with nephrotoxicity in various forms. Further information can be found on previous posts.

Similarly, various antibiotics and other anti-microbials used to treat or prophylaxis this population must be kept in mind (e.g. Bactrim, amphotericin, pentamidine etc.). Another potential problem over the longer term is the diabetogenic potential from various protease inhibitors.

Co-infection with other diseases, particularly HBV and HCV should be investigated. This opens a whole other list of differentials in terms of renal disease – e.g. membranous associated with HBV and syphilis; cryoglogulin and membranoproliferative disease associated with HCV. An immune complex mediated disease with predominance of IgA has also been described, as have various forms of lupus like clinical cases.

One other rare consideration is thrombotic thrombocytopaenic purpura, which may result from HIV induced endothelial injury.

Just some of the differentials to keep in mind when asked to see a patient with kidney disease and HIV infection.

Evolution of kidney transplantation in the HIV-positive recipient

The presence of HIV has in the past been viewed as a relative contraindication to transplantation. This stance stemmed from concerns that immunosuppression would exacerbate an already immunocompromised patient and accelerate the disease process of AIDs. Additionally, there was an ethical concern in terms of giving a precious, limited resource to a group with what was in the past considered limited life expectancy.

However, the widespread introduction of HAART in the mid-90s has resulted in a marked decrease in morbidity and mortality in patients with HIV. As a result, people infected with HIV are living longer and dying less often from opportunistic infections and progression to AIDS, and more often from complications of traditional comorbidities such as coronary disease, diabetes, and chronic kidney disease. The incidence of ESRD continues to rise in those infected with HIV, and it is estimated that 1% of patients with ESRD are infected with HIV. In the United States, HIV nephropathy is the third most common cause of ESRD among blacks who are between the ages of 20 and 64.

As a result of this increasing incidence of disease and the improvement in management of HIV, many transplant centers have now eliminated HIV as a contraindication for transplantation. Several small studies have shown promising results, but there is really a lack of quality evidence in this field and it remains a controversial topic amongst nephrologists.

A recent publication in the NEJM has provided some stronger, encouraging data demonstrating that transplanting an HIV-positive recipient is feasible and offers good outcomes.

This study was a multicenter, non-randomized, prospective trial that was conducted at 19 U.S. transplant centers, which was designed to examine the safety and efficacy of kidney transplantation in ESRD patients who were also infected with HIV. The authors followed prospectively 150 HIV-positive recipients for up to 3 years after transplantation. Inclusion criteria were a CD4 count greater than 200 and undetectable viral load in the serum in the 16 weeks prior to transplantation. Patients were excluded if they had a history of PML, CNS lymphoma, or visceral kaposi’s sarcoma. They also were excluded if they did not meet center-specific transplant criteria. Primary outcomes were patient and allograft survival, and secondary outcomes were opportunistic complications, changes in CD4 counts, and detectable plasma HIV RNA levels. Refer to the paper for further details on their methods and post-transplant care.

The authors looked at patient and graft survival rates at years 1 and 3, and compared them to both the survival rates reported by the scientific registry of transplant recipients (SRTR) for all kidney transplant recipients, as well those older than 65. They conclude that patient survival rates in their population were similar to that of the general population, and that allograft survival rates were somewhere between that of the general population and the high risk elderly population. Significant opportunistic infections were minimal and there was no evidence of HIV progression during their follow period. Neoplasm rates were comparable to the general population, and there were no cases of PTLD. Interestingly, as has been previously described, they found their patients to have a very high rate of acute rejection which is much higher than the general population.

While this study does have its limitations, it provides some convincing evidence supporting kidney transplantation in HIV-infected patients. In a carefully selected population of HIV-infected patients with ESRD, it shows that kidney transplantation is a safe and feasible management option.

Justin Westervelt, MD

Nephrotoxic HIV Drugs

I've done a post on renal-relevant HIV drugs previously, but I just heard an interesting case of tenofovir-induced renal failure at our Renal Grand Rounds and thought I'd mention a few interesting tidbits from the presentation.

1. HIV-Associated Nephropathy (a.k.a. "HIVAN"), which refers to the rapidly progressive GN characterized by a collapsing FSGS pathology on biopsy, is becoming less common with improved HAART therapy. Furthermore, HIVAN occurs almost exclusively in individuals with African ancestry, so it can usually be left off the differential diagnosis of non-African heritage patients with HIV and renal failure. Drug toxicities are accounting for a higher percentage of HIV-associated renal problems.

2. The mechanism of tenofovir toxicity is unclear but appears to have the most toxicity at the level of the proximal tubule, as affected individuals will usually exhibit a Fanconi's syndrome (with attendant phosphaturia, glucosuria, aminoaciduria, etc.) in addition to AKI. One thought is that tenofovir causes mitochondrial toxicity within proximal tubule cells specifically because the drug tends to concentrate there as tubular secretion is an important aspect of the drug's metabolism. Thus, patients with any degree of CKD should either avoid the drug altogether or get a dose adjustment; this can often be missed clinically as tenofovir is often given as a "combo pill" with other HAART medications (e.g., Truvada = tenofovir + emtricitabine; Atripla = tenofovir + emtricitabine + efavirenz).

3. The World Health Organization recently announced that tenofovir-based regimens be considered preferred, first-line treatment for HIV in developing countries. Apparently the authors of this report factored into account all the various HAART drug toxicities in their recommendations (the previously-recommended stavudine-based regimens also have significant toxicity in the form of lipodystrophy, lactic acidosis, and peripheral neuropathy), but the idea of using a drug known to cause AKI in countries where serum creatinine monitoring and dialysis is not routinely available could be troubling. This is obviously a complex topic, though, where a thorough risk/benefit analysis will be key.

4. Other drugs commonly used in the HIV population which may cause renal side effects include valacyclovir (associated with TMA), foscarnet (hypocalcemia, AKI), Bactrim (AIN, hyperkalemia), and crixivan (protease inhibitor which can cause nephrolithiasis).

Recent Urine NGAL Biomarkers Studies

Two recent articles in JASN--one by Siew et al and the other by Paragas et al--provide further support to the idea of using urinary NGAL as a biomarker for acute kidney injury. An accompanying editorial by Lynda Szczech, entitled, "The Development of Urinary Biomarkers for Kidney Disease Is the Search for Our Renal Troponin", provides a thoughtful analogy for thinking about how best to use these tests. The author emphasizes that biomarkers will not necessarily replace creatinine and urine output as a means of assessing AKI--but rather it will supplement these more traditional tests, much like troponin is now used in conjunction with older methods (e.g., EKG analysis) is diagnosing myocardial injury. A marker such as urinary NGAL may be a better marker for injury, as serum creatinine is really a marker of kidney function, and becomes elevated far after the kidney insult.

In the study by Siew et al, over 400 critically ill patients underwent urinary NGAL measurement within 24 hours of admission to an ICU; these patients were then followed prospectively and assessed for AKI, as defined by an increase in serum creatinine of greater than 0.3mg/dL or a greater than 50% increase in the baseline creatinine. The investigators found that elevated urinary NGAL levels was moderately successful in predicting AKI.

In the second study by Paragas et al, investigators looked at the ability of urinary NGAL to distinguish between HIV patients with a collapsing FSGS pathology (e.g., "HIVAN") compared to HIV patients that had either normal kidney function or CKD from another cause. Importantly, patients with HIVAN had 11-fold higher urinary NGAL levels compared to HIV-positive controls without a reduced GFR, and still 5.5-fold higher urinary NGAL levels compared to HIV-positive controls with CKD due to a cause other than HIVAN. These findings may prove useful in terms of diagnosing patients with HIV and rapidly declining renal function with HIVAN in a non-invasive manner (e.g., no biopsy). While biopsy should still likely remain the gold standard until these findings can be confirmed with a larger n, it could potentially be useful information in patients where biopsy is deemed too risky to proceed--a situation in which HIVAN patients may commonly find themselves.

Race & Risk for ESRD

See if you can answer this True or False question:  The increased risk of ESRD in African-Americans is due to the increased risk of hypertension and diabetes seen in this population.  

I think the prevailing view in the past was that this statement is true.  However, according to newer data as described in this month's NephSAP on CKD, the current view is likely FALSE!  

How so?  For one, a 2007 JASN-published longitudinal study looking at the development of ESRD in a cohort of Medicare beneficiaries by Xue et al.  Overall, African-Americans had about 1.5 times the risk of whites of developing ESRD.  However, the subgroup in which there was the GREATEST increased risk of developing ESRD in African-Americans compared to whites was the group in which there was no diagnosis of diabetes nor hypertension (about 3.5 times as likely to develop ESRD).  Thus while hypertension & diabetes are still the leading causes of ESRD overall, these two diseases do not account for all the racial proclivities for developing ESRD.

 

The NephSAP summary describes other phenomena which may account for such racial dfiferences.  For instance, living in a neighborhood with a high poverty rate has been shown to increase the risk of ESRD; it is speculated that this may account for some of the increased risk of ESRD in African-Americans.   Recent work identifying polymorphisms in the MYH9 gene may provide a genetic explanation for the increased ESRD risk.  Finally, although not a leading cause of ESRD, HIV Nephropathy often pursues a much more aggressive course of African-American patients compared to their white counterparts.  

Reticular Inclusions in HIVAN

The histology of HIVAN (HIV-Associated Nephropathy), at the light microscopy level, is indistinguishable from that of collapsing FSGS: the glomerular capillary loops are collapsed. Furthermore, both entities demonstrate foot process effacement (as in all forms of nephrotic syndrome) on electron microscopy.

However, one distinguishing feature between HIVAN and collapsing FSGS is the presence of tubular reticular inclusions (see photo) within endothelial cells commonly seen in HIVAN, but not collapsing FSGS. This finding is not 100% sensitive for HIVAN, nor is it 100% specific: the current thought is that these inclusions form in response to high circulating interferon-alpha levels, which may also be present in inflammatory conditions such as lupus.

Differential Diagnosis for Large Kidneys

The differential diagnosis for large kidneys (often demonstrated on renal ultrasound) is interesting, as there are a few conditions which are especially associated with this finding. Of course, with any type of chronic damage, the kidneys tend to scar down and atrophy.

1. HIV Nephropathy.
2. multiple myeloma.
3. the early stages of diabetic nephropathy.
4. any type of infiltrative process--classically amyloidosis or sarcoidosis of the kidney.
5. autosomal dominant polycystic kidney disease.
6. pyelonephritis.
7. any type of very acute nephritis (e.g., RPGN).

Renal Side Effects of HIV Medications

The treatment of HIV infection has been radically changed with the development of HAART--highly active antiretroviral therapy. Fortunately for nephrologists, these medications are relatively safe from a renal standpoint.

There are two notable exceptions to be aware of.

The most relevant is the medication tenofovir, a NRTI which has been reported to cause renal failure which can lead to dialysis-dependence. The mechanism is unclear but there is some degree of tubular toxicity e.g. ATN. Other tubular pathologies have been reported with this medication including Fanconi's syndrome and nephrogenic diabetes insipidus. The trade name of tenofovir is Viread, and is tenofovir is sometimes given as part of a "combined" pill (Truvada or Atripla) containing tenofovir and 1-2 other antivirals as part of a cocktail.

The other relevant HAART drug nephrologists should be aware of is indinavir (Crixivan), a protease inhibitors. It has been shown to precipitate and result in nephrolithiasis in some patients, and therefore these individuals are instructed to increase their water intake.

Collapsing Variant of FSGS

The collapsing form of FSGS is a histologic variant which is characterized by mesangial hypercellularity and resultant collapse of the glomerular capillaries, as illustrated in the photo to the left. Its identification is important for prognostic reasons as it is known to progress much more rapidly than garden-variety FSGS (average time to progression to ESRD 13 months from diagnosis as compared to only 65 months). Not surprisingly these patients often have profound proteinuria.

The differential diagnosis of collapsing glomerulopathy is limited, but should include HIV ("HIV Nephropathy"), parvovirus B19 infection, hepatitis C infection, therapy with the bisphophonate pamidronate, lymphoproliferative disease, and certain autoimmune disease (e.g., lupus, Still's disease, etc). The Collapsing FSGS also occur in an idiopathic form, which is interestingly much, much more common in blacks than in whites.

Diffuse Infiltrative Lymphocytosis Syndrome

The differential diagnosis of renal disease in an HIV patient is fairly long. Perhaps the most well-known amongst the list is HIV-associated nephropathy (HIVAN), which involves massive protein wasting, collapsing FSGS, and rapidly-progressive renal failure.

Another entity on the list of HIV-associated renal diseases which I just recently learned about, however, is diffuse infiltrative lymphocytosis syndrome (DILS). The disease is due to an infiltration of CD8+ T-cells within the renal interstitium leading to an interstitial nephritis, enlarged kidneys, and declining renal function. The condition may involve other organs as well, typically the salivary glands (where the patient may demonstrate bilateral parotid gland enlargement or sicca symptoms) or the lungs (where it causes "lymphocytic interstitial pneumonitis").