Monday, April 18, 2016

Sweet’s syndrome and the Kidney

This is an interesting case which I have been managing over the last six months. A 50-year-old male, with no previous medical illnesses, presented with fatigue, weight loss and arthralgia for several weeks. Clinical examination was unremarkable. Investigations revealed a rise in Creatinine from a baseline of 86 to 120 µmol/l (eGFR= 70 down from 90). His urine dipstick revealed protein (1+) and blood (1+). He had a normal Chest X-ray, but his p-ANCA was positive with a high MPO titre. Renal imaging was normal and he underwent a kidney biopsy which showed non-specific findings i.e. some tubulointerstitial inflammation and glomerulosclerosis with mild features of thrombotic microangiopathy (TMA). There were NO crescents and both immunofluorescence and electron microscopy showed NO immune deposits. Putting it all together, a diagnosis of vasculitis was made and treatment with Steroids & Rituximab was initiated. ANCA titre started to fall and urine sediments disappeared. Unfortunately, he developed a steroid-induced psychosis and had a failed suicide attempt. Subsequently, corticosteroids were discontinued and he was commenced on Azathioprine.
Four months later he presented with fever, constitutional symptoms and skin rash in the form of reddish papules & nodules involving the trunk, neck & face. Lesions got progressively worse and coalesced to form plaques. A skin biopsy confirmed the presence of neutrophilic dermatosis and a diagnosis of Sweet’s syndrome was made. Interestingly there was no evidence of vasculitis in the skin biopsy. He was treated with high-dose systemic steroids and improved dramatically. This was done in a closely monitored environment in-hospital, given his history of steroid-induced psychosis. Currently, he is being thoroughly investigated for any possible underlying malignancies.
What is Sweet’s syndrome?
Sweet’s syndrome, also known as acute febrile neutrophilic dermatosis, is a reactive skin disorder characterized by the sudden onset of papules and nodules which are tender and reddish/purple in colour. These lesions coalesce later to form plaques. It mainly involves the upper extremities, face, or neck and is typically accompanied by pyrexia and peripheral neutrophilia.
It is more common in females and often occurs after a respiratory illness, which is usually mild. More severe disease often occurs with underlying malignancies, drugs or inflammatory conditions e.g. inflammatory bowel disease. Sometimes it could be the first manifestation of the underlying disorder, so whenever it is diagnosed it should prompt further investigation.
Sweet’s syndrome responds dramatically to systemic corticosteroids and may improve or resolve with treatment of the underlying condition. Without treatment, the syndrome may persist for weeks or months but eventually improves, in the majority of cases, without leaving any scars; rarely it may persist and never resolve completely. Recurrences are common.
The diagnosis of Sweet syndrome is based on both clinical and histopathologic findings. A characteristic that distinguishes the lesions of Sweet syndrome from other neutrophilic dermatosis is the absence of vasculitis. However, the presence of vasculitis should not exclude the diagnosis as this may represent an epiphenomenon instead of a primary disease. ANCA have been reported positive in Sweet syndrome and other neutrophilic dermatoses, but this finding is not consistent. This case raised a number of interesting questions:
1-      Was this case a Sweet’s syndrome from the outset rather than an ANCA vasculitis?
ANCAs have been reported to be positive in Sweet syndrome. The kidney biopsy findings, in this patient, were not convincing and the renal course of the disease was not typical of vasculitis. Moreover, it was previously reported that Sweet’s syndrome is associated with renal involvement manifesting most commonly as proteinuria, and less often as haematuria and membranoproliferative glomerulonephritis. Unfortunately, this disease is uncommon and there is a paucity of studies describing the association between Sweet's syndrome and kidney diseases.
2-      Was this case an ANCA vasculitis and the Sweet’s syndrome was a reactive process to the inflammation?
This is another possibility and the association between this syndrome and inflammatory conditions is well known.
3-      Is it a drug-induced Sweet’s syndrome secondary to Azathioprine?
There are several drugs that have been implicated as a cause of this syndrome. Examples are: Azathioprine, Frusemide, Hydralazine, Quinolones and many others.
4-      After complete recover from Sweet’s syndrome and exclusion of underlying malignancy, is it reasonable to continue treating a possible ANCA vasculitis or will it is more appropriate to attribute the positive ANCA and the non-specific renal findings to Sweet’s syndrome per se?
This is a difficult question to answer. The benefits of long-term immunosuppression should be weighed against the risk of infection, other serious adverse effects and the risk of missing an active vasculitis in a young patient.
In conclusion, Sweet’s syndrome is an uncommon disease which could be primary or secondary to an underlying inflammatory process or malignancy. It may cause a positive ANCA test in the absence of active vasculitis. Its association with kidney diseases is not well described and need to be explored.

Post by Mohammed Kaballo

Sunday, April 17, 2016

Reminder: Attend the Origins of Renal Physiology Fellows Course 2016

National Course for Renal Fellows: Origins of Renal Physiology Applications are now open for this national renal fellows’ course, which runs from August 27 to September 3, 2016 at the Mount Desert Island Biological Laboratories, near Acadia National Park in Maine. Sponsored by ASN and supported by NIH NIDDK, the course offers a week long immersion in renal physiology research. Tuition, room and board are free of charge to trainees. Apply here

Note: I went to the first offering of this course in 2008 and it was AWESOME. Met Nate, got hooked on RFN and the rest is history. You would be a fool for missing this experience. Once in a lifetime chance to learn and network in a very unique environment.

It is FREE by the way. DO IT NOW.  SIGN UP!! Last day to apply is April 30, 2016

Thursday, April 14, 2016

A Fresh Approach to Understanding Clinical Hypertension

With advances in the field of nephrology broadening our knowledge of transplant medicine, glomerular disease, and the interventional aspects of access, I believe fellowship training in the traditional areas of the specialty such as hypertension have diminished.
And yet, apart antibiotics, anti-hypertensives are the single most important therapy contributing to rising life expectancies. Because while ESRD trials focus on endpoints such as PTH levels and the CKD literature uses outcomes such as a doubling of serum creatinine, hypertension studies utilize clinical endpoints such as all cause mortality.  Moreover, it’s a fascinating disease, our understanding of which is unrivaled by any other condition. What is the circadian rhythm of blood pressure? How does pulse pressure affect the risk of CAD? What is the relationship between basal heart rate and mortality? To understand hypertension is to appreciate human physiology, to apply evidence-based medicine, and to practice cost effective care. Moreover, despite the proliferation of national treatment guidelines, management is more nuanced than targeting similar blood pressure levels for all patients and prescribing the same handful of agents. The “art” of management hinges on understanding the difference between metoprolol and betaxolol, hydrochlorthiazide and indapamide, and losartan and azilsartan. As such, if there is one disease to know, and know well it’s hypertension.
To improve my own knowledge of the above, I’m currently undertaking an additional fellowship in hypertension under George Bakris at the hypertension center here at the University of Chicago. In order to share what I have learned, I’ve created a bi-weekly e-newsletter, “Concepts in Hypertension,” as a non-commercial medium to convey key aspects of the disease. Each issue is concise, summarizing one seminal paper and underscoring one key concept. The newsletter then ends with a “clinical perspective” that indicates how the selected paper informs the management of patients at our hypertension center.
Below are several recent issues. If you’d like to subscribe to this free, non-commercial publication, you can do so by visiting
Hillel Sternlicht
The University of Chicago

Monday, April 4, 2016

World repercussion of the NEJM desensitization article – A Brazilian perspective

The recently published paper in the NEJM entitled “Survival Benefit with Kidney Transplants from HLA-Incompatible LiveDonors” caused a huge impact on Brazil’s media. Our main broadcast TV devoted few minutes explaining it, suggesting as a real breakthrough. Patients and many members of our multidisciplinary team were questioning if compatibility could be forgotten as a barrier to transplantation.
         Moved by this repercussion, on our weekly meeting we debated the article. Three questions were posed:
       1. Does transplanting HLAi patients really improve quality of life (life expectancy was shown to be expanded), compared to waiting on the list for a deceased donor?
       2. Why 5-year life expectancy for live donor kidney recipients in the US is 86% (USRDS data), while in the UK, Australia and at our own service it is around 97%. Does anyone has any suggestion of why such a huge difference?
       3. What about the high costs of desensitization? 
The former question is far from our reality. In our center, we do not perform HLAi transplants despite our high volume of over 900 kidney transplants per year. Due to low reimbursement, complications that may arise from HLAi transplants such as re-hospitalizations, requirement for additional plasmapheresis and IVIG as well as biopsies may significantly affect the cost of post-transplant care and prevent appropriate treatment of complications.
This cautious approach to cost is immensely influenced by our political and economical scenario. After chaotic administration and corruption, our GPD is falling ~3%. State health insurance is paying less than the actual cost for a dialysis session. In some centers, this is forcing doctors do reduce the dialysis session by 30 minutes (from 240 minutes to 210 minutes/session). In this context, proposing a new and costly treatment (like desensitization) that should be reimbursed by our Public Health System would sound as an outrage to the state health managers. Clearly, it seems the media has been over optimistic with the article conclusions. Many centers in the USA are actually favoring kidney paired exchange to minimize the complications and costs of desensitization. What do physicians from developing countries think about this? Additional comments are appreciated. 

Thiago Reis, MD
Hospital do Rim, UNIFESP, São Paulo, Brazil 

Sunday, March 20, 2016

Mesenchymal Stem Cells In the NIT: Hopeful to Make #NephMadness '17. #TransplantRegion

#NephMadness season is here! The #TransplantRegion has very interesting matchups, but one player that was left out of this contest because is relatively new in the game and relatively unknown, is Mesenchymal Stem Cells (MSCs). In the last few years the transplantation field has struggled to find how to prolong graft survival by inducing tolerance, minimize immunosuppression, inhibit fibrosis and treat rejection episodes. A candidate with all these characteristics are MSCs. MSCs are mesoderm-derived multipotent stromal cells that have high self-renewal and multi-lineage differentiation potential, anti-inflammatory properties, effects in the innate and adaptive immunity and the ability to repair damaged tissue.

 But what exactly makes MSCs attractive to transplantation? First of all, their effectiveness has been reported in the treatment of graft-versus-host-disease (GVHD). MSCs are found in fat, bone, cartilage, umbilical cord, cord blood, synovium, synovial fluid, muscle, skin and pulp and they can also be isolated from those organs, including the kidneys, which could be of major interest due to its repairing properties. MSCs inhibit T cell proliferation via several mechanisms including indoleamine 2,3 -dioxygenase (IDO) activity, production of prostaglandin E2 and transforming growth factor (TGF-β), expression of low levels of major histocompatibility complex (MHC) class II and costimulatory molecules including B7-1 (CD80), B7-2 (CD86) and CD40. They also inhibit macrophages, NK cell proliferation by reducing IFN-γ and dendritic cells (DCs) activity. In experiments, MSCs affect the ability of DCs to prime T cells in vivo. They also have direct effects on the endothelium by enhancing angiogenesis via expression of vascular endothelial growth factor (VEGF) and angiopoietins. The available data on B cells has not been studied extensively but some experiments report that MSCs increase CD4+, CD25+ and FoxP3+ regulatory T cell function (Treg) which may cause arrest of B lymphocytes in the Go-G1 phase of the cell cycle. In addition, MSCs by mediating T cells, inhibit the maturation, migration, proliferation and antibody production of B cells.  Remember that FoxP3+ expression has an important role on Tregs. You can check details here in the #NephMadness Transplant Nephrology Science Region (#TransplantRegion). Although all these properties are exciting there are more questions than answers.

In mouse models of GVHD, MSCs were administered at 3, 8 or 20 days after bone marrow transplantation and other reports have suggested that a better immune suppression can be achieved when they are administered before transplantation, so clearly, there is no evidence for timing of administration. In regards to dosing and frequency, the MSCs proposed dose is 0.4 - 10 x 106 cells per kilogram of body weight in humans but using a high dose has also been reported. The frequency of administration has not been determined.

There are no reports on adverse events related to the infusion itself and long-term effects are not available, however in vitro and in vivo studies have shown that MSCs have the potential to differentiate into neoplastic cells and may promote growth of tumor cells.
In this report with autologous MSCs as induction therapy into living-related kidney transplant recipients, 159 patients were randomized to receive MSCs induction therapy with standard calcineurin inhibitor (CNI), MSCs induction with low-dose CNI or interleukin-2 (IL-2) receptor blocker. The authors reported reduced opportunistic infections in comparison to controls (HR, 0.42; 95% CI, 0.20-0.85; P = .02 ). Rejection episodes with MSCs induction were 8%, compared to 21% in the IL-2 receptor blocker group.

As of today (March, 2016), to my knowledge, there are 13 registered trials of MSCs in kidney transplantation that are currently recruiting patients or have been completed on the website. Other areas of interest in which MSCs are being used are acute kidney injury, chronic kidney disease and polycystic kidney disease. Most studies have used autologous MSCs since they seem to be more potent than allogeneic MSCs but it requires a long process and time can be an issue if recipients are in need of treatment for rejection. One advantage of allogeneic MSCs is that they can be available rapidly.

In conclusion, I think Tregs would have been a strong competitor in this year’s #NephMadness if MSCs would have qualified. Maybe next year or in the next few years they will be in better shape to compete in #NephMadness. MSCs may have a very important role in kidney transplantation given their immunosuppressive, reparative properties and potential to induce tolerance, however there are several technical aspects that are complex such as isolation, culture, amplification and cost, plus long-term outcomes are unclear at the moment and large clinical trials are needed.

 Don’t forget to fill out your brackets!

Image from: Mesenchymal stromal cells in renal transplantation: opportunities and challenges. Nature, Feb 2016. 

Sunday, March 13, 2016

False-positive AKI and the perfectly imperfect biomarker

E:\Renal Fellow Network\false AKI.png
A small absolute change in serum creatinine level, 0.3 mg/dl, is used by Acute Kidney Injury Network (AKIN) and Kidney Disease Improving Global Outcomes (KDIGO) guidelines to define the presence of Acute Kidney Injury (AKI). The base of this definition was formed by several studies findings of strong association between adverse outcomes and minor changes in serum creatinine level. Subsequently, evidence emerged suggesting that this may not be true to the same extent in people with pre-existing CKD, because variations in serum creatinine concentration are common in these individuals.

As with all other laboratory tests, serum creatinine measurements are affected by within- and between-sample coefficients of variation, intra-individual variation and biologic variation. Biological variation may result from variations in diet, muscle mass and breakdown, tubular secretion, variability in volume homeostasis and from medications uses. The variation in measured serum creatinine level could be as high as 9%. Because only a small increase in serum creatinine is needed to meet AKI criteria, random variation in creatinine level may be a significant contributor to AKI diagnosis in the absence of a true reduction in GFR. This is called a false-positive AKI. It has been shown that high variation in serum creatinine in the period, of days, preceding the development of AKI was not associated with the anticipated inpatient mortality or dialysis. This observation supports the existence of false-positive AKI.

Lin et al demonstrated, using the KDIGO definition, an 8% overall false-positive rate for AKI diagnosis. This rate was much higher, 31%, for the subgroup of CKD patients with serum creatinine ≥1.5 mg/dl. Therefore, an absolute change in serum creatinine of 0.3 mg/dl may represent a relative inconsequential change in GFR in CKD patients rather than a superimposed acute injury.

In my opinion, false-positive AKI could largely explain why most randomized trials for early intervention in AKI have been unsuccessful in improving outcomes. AKI is misclassified under frameworks that do not reflect true GFR reduction. Consequently, patients with false-positive AKI are included in AKI studies and dilute observed effect sizes. This potentially leads to false-conclusions that certain interventions are ineffective and do not improve outcomes. The underlying severe disease is quite likely the actual mediator of adverse outcomes seen in AKI. Therefore, small changes in serum creatinine may be nothing more than a reflection of the severity of the underlying disease process. This point remains a topic of hot debate. Moreover, AKI definition using small increments in serum creatinine level has not been validated among patients with CKD.
It is obvious now that serum creatinine is an imperfect AKI biomarker; especially that it is being used on the basis of a relative change in value of a continuous variable instead of the crossing of a particular threshold. The ideal biomarker would accurately detect true reduction in GFR, be detectable early in the course of renal dysfunction to allow for timely intervention, and predict outcomes. It is likely that current AKI criteria will eventually be modified at least in part by sensitive and specific biomarkers of kidney injury. The use of such biomarkers will help in the development of a new paradigm for classifying AKI that is not only dependent upon serum creatinine. Meanwhile, the awareness about false-positive AKI should be highlighted and the limitations of serum creatinine, as an AKI biomarker, should be re-emphasized.

Authored by Mohammed A. Kaballo, Nephrology Fellow, Ireland

Friday, March 11, 2016

#NephMadness 2016: Ecstasy and Kidney Injury #NSMC

NSMC intern and Pulm Critical Care Attending Kamran Boka produced a great info graphic on the pathophysiology of ecstacy induced kidney injury which has a first round matchup against cocaine toxicity in NephMadness 2016. Check out the entire scouting report for the Recreational Drugs and the Kidney Region.

#NephMadness 16: Let’s win it for the Fellows

NephMadness 2016

It’s finally arrived, the fourth annual NephMadness has dropped with 32 new Nephrology concepts battling it out for the month of March to see who will be crowned champion. Fully referenced blog posts on each of the topics are available at AJKD Blog and an explanation of the event can be found here for our new participants. Essentially, it involves reading up on the content provided and deciding which Nephrology concepts win in head to head, knockout match-play. You may fill out your bracket (pick your winners) using our online tournament page until March 23rd.

I’m hoping this year the winning participant will be a fellow/resident (or SpR/SHO) or better still a group of trainees. Last year there was a trend towards fellowship programs coming together, debating the topics and matchups and making their picks as a team. This is a fantastic way to extend the free online medical content to real-world flipped classroom teaching sessions at your institution. I’d also love to see this extend outside of the US to SpR training programs in Europe, Asia and beyond. So I propose you enter the contest individually but also with your colleagues as a group. Eternal glory awaits!

Wednesday, March 9, 2016

The evolving role of PET imaging in Nephrology

Positron emission tomography (PET) is a nuclear imaging modality that provides functional imaging of structures based on their ability to metabolize glucose and concentrate specific molecules that have been labeled with a positron-emitting radionuclide. Metabolically active cells (e.g, malignant or inflammatory) utilize and import more glucose than other tissues and, thus, take up 18F-fluorodeoxyglucose (18F-FDG) more avidly. Integrated PET/CT is preferred, because it allows for more exact anatomic localization of isotope uptake and more accurate staging of cancers. PET is escaping oncology however and starting to find a role in nephrology.

In post-transplant lymphproliferative disorders, integrated PET/CT is used as a measure of disease activity. It has also been reported to differentiate fat-poor angiomyolipomas from renal cell carcinoma with 94% sensitivity and 98% specificity. Integrated PET/CT scanning may also be of utility in differentiating benign versus malignant fractures and highlighting impending ones in patients with multiple myeloma.

What about APKD? Cyst infection is common and may be difficult to diagnose in the presence of sterile urine. Bobot et al compared PET-CT to CT and MRI for a diagnosis of cyst infection. Cyst wall hypermetabolism was considered as a positive PET-CT result. A diagnosis of cyst infection was made in 18 of 32 cases: 14 with positive PET-CT findings, and 4 false negatives. There were no false positives and no hypermetabolism of cyst walls in 9 ADPKD control patients. PET-CT had a sensitivity of 77%, a specificity of 100%, and a negative predictive value of 77% compared to CT alone which had a sensitivity of 7% and a negative predictive value of 35%. Radiation doses were comparable and injection of nephrotoxic contrast was avoided in the former.

Similarly PET-CT may be useful the detection of vasculitis in the large arteries with 29/35 patients with known giant cell arthritis showing active arterial inflammation (sensitivity >80%) . Patients suffering from granulomatosis polyangiitis (GPA) show marked aortic FDG uptake although it is unclear whether this is indicative of atherosclerosis or large vessel involvement. If it is indeed the latter this calls into question the traditional classification of vasculitis. FDG-PET/CT accurately identified organ localizations in 16 patients with GPA, other than in nervous system, eye and skin, but may not bring additional benefit to the usual organ screening.
Retroperitoneal fibrosis is a rare fibro-inflammatory disorder that is most commonly idiopathic (>75%) and part of the IgG4-disease related spectrum. PET-CT has emerged as a useful tool for the assessment of disease activity and also detects any post-treatment residual disease. It may lead to early diagnosis of relapses and may also detect diseased sites other than the peri-aortoiliac tissue.

Could PET imaging have a role in the detection of occult malignancy, inflammation or infection in secondary glomerulonephritis? If we extrapolate from studies involving venous thromboembolism (VTE), a prospective cohort of 99 patients with a first episode of VTE reported occult cancer identified by PET/CT in 23% of cases with a sensitivity and negative predictive value of 77% and 97% respectively. However this sensitivity is still too low to justify its use as a widespread screening tool in this capacity as nearly 1/4 cancers may be missed.

Patients with ESRD undergoing maintenance hemodialysis are highly susceptible to infections. Of 104 study patients, 73 (70.2%) had positive 18F-FDG PET/CT findings, and a total of 95 major infection foci were identified. 7 (53.8%) of the 13 patients with primary vascular access-related infections had concurrent metastatic foci. 28 patients (26.9%) had their treatments modified by PET/CT results. In this population, positive PET/CT findings led to a significant change in clinical management and independently predicted mortality.

PET/CT may also help non-invasively prevent avoidable transplant biopsies in kidney transplant recipients with suspected antibody-mediated rejection. In 31 transplant recipients, PET/CT was performed in those who underwent biopsy with a positive correlation between mean SUV and acute composite Banff score (r2 =0.49). The area under the receiver operating characteristic curve was 0.93, with 100% sensitivity and 50% specificity using a mean SUV threshold of 1.6.

But are there any side-effects or limitations to use of PET-CT in our patients? For example, use of IV contrast may be precluded in certain cases of renal impairment and this may impair the optimal detection of small lung and liver lesions. IV contrast increases lesion conspicuity, which is of particular importance in the evaluation of lesions that do not always accumulate FDG. However use of PET-CT without IV contrast has become more widespread and differentiation of benign from malignant lesions is less relevant in Nephrology. The whole-body FDG distribution in patients on hemodialysis may be different from those with normal renal function, because they lack urinary FDG excretion and remain in a constant volume overload. There may be significantly higher physiological FDG uptake in the soft tissues, spleen and blood pool.

In conclusion, I believe that combined PET-CT imaging has the potential to be a very useful and versatile tool for Nephrologists. Whether we are dealing with metastatic infections, occult malignancy, suspicious GN or vasculitic relapses, it may be a revealing diagnostic test at times when our concern exceeds the objective evidence that we have to hand. That said, it is not without cost or risk, and therefore should only be employed judiciously when likely to change clinical management.

Post by Dearbhla Kelly,
NSMC Intern

Friday, March 4, 2016

Web Episode #005 - Renal Pathology Teaching Series

Another great episode of the Wash U Renal Pathology Teaching Series from Timothy Yao.

Monday, February 29, 2016

Pregnancy and Kidney Transplantation: Frequently Asked Questions

During my nephrology fellowship, I was asked by a renal transplant recipient at her 9-month post transplant clinic visit “Doctor, can I become pregnant?  Will I have a live healthy baby? Will my kidney function get affected?” I did not have clear answers then and read extensively on the subject.

**below, I will summarize what I have learned about pregnancy in kidney transplantation, please consult your nephrologist before you consider pregnancy if you have a kidney transplant**

The first successful pregnancy in kidney transplant recipient occurred in 1958 to the 23 year old Edith Helm who had received a kidney from her identical twin sister Wanda Foster. Thus, this occurred not long after the first kidney transplant in 1954. She delivered a healthy full term boy of 3300 grams by cesarean section 2 years after her transplant. Interestingly, even her donor and twin sister Wanda Foster gave birth four times successfully after kidney donation.

Chronic kidney disease is associated with disruption of hypothalamic gonadal axis primarily causing hyperprolactinemia and anovulation due to absence of the luteinizing hormone surge.

Pregnancy is rare in women with ESRD with the incidence of conception ranging from 0.9 to 7%. Kidney transplantation is associated with normalization of the reproductive hormones and restoration of fertility as soon as 6 months after transplantation and gives us an apparent large window of opportunity to help women of childbearing age who want to have babies. On the other hand, deteriorating allograft function may narrow this window unpredictably. In addition, pregnancy in kidney transplant recipients is challenging due to the side effects of immunosuppressive medications, and higher risk of adverse maternal and fetal complications. Therefore, It becomes important as physicians to counsel and medically optimize kidney transplant recipients who wish to become pregnant.
I have put below common questions that are frequently asked by women with history of kidney transplant.
Question: Is pregnancy possible after a kidney transplant?
Answer: Yes, pregnancy is possible in kidney transplant recipients. However, there are several important things that one must consider before you decide to conceive like timing of conception, risk and changes in immunosuppression that we have discussed below. It is extremely important that you talk to your transplant nephrologist about this beforehand.

Question: What is the likelihood of maternal complications if I do decide to get pregnant?
Answer: There is a 6 fold higher likelihood of preeclampsia in women who have a kidney transplant and a reported incidence of 15-25%. There is a also 5 fold higher risk of needing a cesarean section. However, there is no increased risk of maternal mortality.

Question: Will I have a live healthy baby?

Answer: Likely Yes, having had a kidney transplant does not increase fetal mortality, especially if the timing is right and adequate precautions are taken (see below). However there is a 12 fold high likelihood of preterm and low birth weight babies; and a 3 fold higher likelihood of having small for gestational age babies.

Question: What are the risk factors associated with poor maternal and fetal outcomes?

Question: What is the optimal time to conceive?

Answer: The optimal time to conceive is after 6 months and within 2 years of getting the transplant. It is known that if time to conception is more than 2 years of getting a transplant, it reduced the likelihood of viable fetal outcomes.

Question: Will pregnancy affect my allograft function?

Answer: Likely No, the kidney allograft is able to adapt normally to physiological changes of hyperfiltration in pregnancy. An uncomplicated pregnancy does not increase the risk of kidney loss. However it may affect graft function if you have risk factors like higher pre-pregnancy creatinine (or lower kidney function) or develop hypertension during pregnancy.

Question: What are the changes in immunosuppression that are made if I wish to become pregnant?

Answer: Mycophenolic acid (cellcept) and sirolimus are teratogenic, and must be stopped 6 weeks prior to conception. Cellcept has shown to be associated with limb and facial anomalies tacrolimus/cyclosporine (class C), azathioprine (class D) and low dose maintenance prednisone (< 20 mg/day) (class B)  are safe to be used during pregnancy. Even though azathioprine is listed as class D, it is to safe to be used during pregnancy because the fetal liver lacks the enzyme inosinate pyrophosphorylase that converts it to active metabolite 6 mercaptopurine; and fetus is protected from its adverse effect.

Question: My friend wants to donate a kidney. Will donating a kidney affect her future pregnancy?

Answer: Likely No, donating a kidney does not affect the chances of her becoming pregnant. Post-donation, however, there is a 2.5 fold higher risk of preeclampsia and gestational hypertension in living donors, without any associated fetal complications.
Question: I am currently on dialysis. Should I try to become pregnant now or wait till I get a kidney transplant?

Answer: The incidence of conception on dialysis patients is very low ranging from 1-7%. Even when women with ESRD are able to conceive, the incidence of live birth is 20-40%. Women should be advised to wait till they get a transplant. However if the wait list for transplant is long due to high PRA or they are getting older, they may be advised to try to conceive while on dialysis. How Intensification of dialysis to >36 hours per week is associated with improved fetal outcomes with a live birth rate of 85%.

For a review of Pregnancy in Kidney Transplant review its entry in NephMadness ‘15.

Post by Silvi Shah, NSMC Intern

Wednesday, February 24, 2016

What can high nephron abundance teach us about CKD?

If you are fortunate, you’ll start life with somewhere in the neighborhood of two million nephrons at birth, and for most, that’s enough to journey through life without a hint of uremia. Even those who maintain good health experience a gradual loss of renal function through life.

But what about those who have and maintain really fantastic renal function? 

Do possessors of “elite kidneys” have something to teach us for the benefit of those with failing kidneys? 

The concept that low nephron endowment is associated with the development of renal disease, has been around since at least 1988, with the work of Brenner and colleagues. Despite the technical difficulties in estimating glomerular number from biopsies and autopsy samples, low nephron number has been reproducibly associated with hypertension and chronic kidney disease in human populations and experimental models. This is particularly true of disadvantaged populations such as Aboriginal Australians. And an association between low nephron number and hypertension has been demonstrated at autopsy after accidental death in patients and matched controls.

It’s fair to say the converse - high nephron endowment - is little studied. 

Interestingly, when studies from a variety of populations (totalling 182 subjects) are taken together, the number of glomeruli per kidney averages ≈850,000 with an enormous 8.6 fold range (≈230,000 - ≈1,960,000).

So, what of these well endowed people with nearly 2 million glomeruli per kidney? Do they resist an age associated decline in renal function? Do they weather pathologic insults better? Do they develop hypertension less readily? Would they be amongst the best transplant donors?

  • Experimental models of high nephron endowment have examined murine models with altered TGF-β family signalling. Mice expressing a dominant negative truncated type II activin receptor (tActRII) have a 1.8x increase in glomerular number compared to wild type mice. Despite this, creatinine clearance and blood urea nitrogen did not significantly differ.
  • Another experimental study from 2012 examined tgfb2+/- heterozygous mice, which constitutionally bear 30% greater nephron number [6]. Compared to their wild type counterparts, there was no difference in terms of blood pressure or creatinine clearance. However when challenged with a chronic high salt diet, moving from 0.9%, to 4%, then 8% saline, tgfb2+/- mice proved resistant to the hypertensive effects. 
In terms of translating this to humans, the weight of evidence supports a model in which a wide range of nephron number is determined principally by birth weight, and higher nephron number might prove protective against the development of hypertension and CKD. It is certainly tempting to speculate that a very high filtration area would provide robust renal reserve in the face of aging, or overt renal insults. Further studies of the effects of nephron number are hampered by the lack of non-invasive measures. Use of MRI in the measurement of glomerular number and size in perfused kidney has been described, but this is not yet ready for use in vivo.

Nephron endowment is a purely structural measure. In looking for “elite kidneys”, functional measures may be much more valuable. The concept of renal functional reserve (RFR) reflects the idea that stressing a physiological system reveals its dynamic range to a greater extent than a static measure (e.g GFR). Renal function reserve is therefore the capacity of the kidney to increase glomerular filtration rate in response to a physiological stimulus (e.g. amino acid load, pregnancy, increased renal perfusion pressure), or a pathological stimulus. In the diseased state the maximal GFR that can be achieved by residual nephrons should be a better measure of renal function than average GFR, which may be near normal early on. It appears that renal functional reserve (measured by assessing the rise in GFR after vasodilator stimuli) does decline even with healthy aging. But this only tells us young kidneys are functionally better than old ones. We knew that anyway. Amongst healthy children there is a surprising range of RFR. In a study of 89 children challenged with a protein meal, 46% were able to raise their GFR to ≥20% baseline, with a quarter struggling to increase beyond 10% [10]. Unfortunately, we don’t know what happened to the owners of these high performance kidneys in adulthood.

Overall, this is a very open question. The best route to answering it likely lies in identifying young subjects with normal GFR, but a high renal functional reserve, perhaps with an associated high (non-invasively measured) nephron number. The key questions would be: what are the factors associated with supranormal function, and are there any modifiable factors which might be translatable to those with pathologically subnormal function?

Post by Benjamin Stewart, NSMC Intern

Wednesday, February 10, 2016

Kidney Transplantation in Identical Twins: Do They Need Immunosuppresion?

The first kidney transplant between two identical twins, the Merrick brothers, took place on Dec 23, 1956 in Boston, MA and its is very interesting to read the original article and how Dr. Merril and Dr. Murray concluded that they were identical. They performed a full-thickness skin graft on the recipient and 31 days later a histological examination of the skin graft indicated no rejection and these observations among other clinical findings lead the investigators to conclude that they were monozygous twins and rejection would be unlikely. No HLA typing existed at that time. Surgery was successful and Mr. Herrick lived for 9 years after the transplant without receiving any maintenance immunosuppression. He later died secondary to a myocardial infarction. The side effects of immunosuppression (IS) is a constant battle for nephrologists and finding a sweet spot on maintaining adequate IS to prolong graft survival and avoiding side effects is almost impossible to achieve.

A few days ago we took care of a 72 year-old female that underwent living donor kidney transplantation from her identical twin. Prior to surgery there was a discussion whether the recipient should get any induction and maintenance IS. She was a 0/6 HLA mismatch and genetic testing using PCR-based Short Tandem Repeats (STR) analysis indicated they were identical for the 16 different polymorphic gene loci that were evaluated and because she was elderly and highly functional she was at a low immunological risk. 

Monozygous twins come from a single ovum fertilized by one sperm, and recent studies have shown that monozygous twins are not genetically-related due to the phenomenon of somatic variation, which can arise from three different mechanisms: somatic mosaicism, chimerism and epigenetic drift. Somatic mosaicism occurs in early embryo development and results in tissues having varying genetic expression arising from a single zygote (think about the Rubik’s cube) through numerous mechanisms such as heteroplasmy (unequal division of mitochondrial DNA within the cellular cytoplasm) and uniparental disonomy (where both copies of a chromosome or genomic region are inherited from a single parent) Chimerism arises when new genetic material is introduced from an exogenous source such as maternal cells entering fetal circulation or between two embryos in multiple pregnancies. Epigenetic drift is the result of genetic alterations that have been accumulated throughout life as a result of the interaction of genes and environment (early in utero and lifestyle).

So, should monozygous twins receive any induction or maintenance IS? First of all, there are no randomized controlled trials addressing this question and there have been only a few reports where patients received minimal or no immunosuppression. In this article, the authors reported 194 probable identical twin transplants. Seventy percent of the cases received steroids as induction and 71% were discharged with some form of IS therapy. At one year post-transplant, 21% of recipients were receiving calcineurin inhibitors and 27% were on steroids. By one year post-transplant, 66% percent of recipients were not on any form of IS. Recipients off IS, tended to be younger, White, and had a cold ischemia time of less than 12 hours.

In regards to rejection rates in kidney transplantation in identical twins in the US and United Kingdom during 1988 and 2004, the authors reported 120 cases in the US and 12 cases in the UK and they concluded that there was no significant difference in graft survival between recipients that are received IS and those who did not. In addition, they also reported no differences on cases that had maintenance IS for possible recurrence disease in comparison to those recipients at low risk for recurrence disease. In another series of 5 cases in a single center between 1969 and 2013 in Spain of kidney transplantation between monozygotic twins, the investigators reported good outcomes at one and five years. Recipients received only a single dose of high dose steroids intraoperatively and no maintenance IS. Of this five cases, two recipients died (from cardiovascular disease and melanoma) after 16 and 22.5 years post-transplant, respectively. One patient was lost to follow up and the two remaining were still alive.

DAMPs (damage-associated molecular patterns), among other chemokines, are released during ischemia-reperfusion injury and cellular stress during organ recovery which may modify gene expression after transplant, so using high dose perioperative steroids as induction therapy to suppress this response is a good approach. The somatic variation phenomena described in monozygotic twins should also be considered since they are not strictly identical. In conclusion, once the immune system has been adequately suppressed after the initial inflammatory response related to kidney transplantation surgery, the next step would be to attempt reducing or withdrawing maintenance IS very cautiously considering postoperative course, primary disease and pathological graft findings. Our patient received only high dose steroids as induction IS.

Image from Bioinfoworld