Diuretic choice in decompensated liver disease

Spironolactone has long been favored in the setting of decompensated liver disease; the effective control of “secondary aldosteronism” is usually given as the reason for this in textbooks. However, this is like saying you should open a new bank account as you’ll receive a nice pen. There are more rational reasons for choosing this agent:

Less renal dysfunction: This complication of the management of edema in cirrhosis is frequently caused by over-aggressive diuresis, whereby ECF removed from the vascular space is not replaced from the interstitium quickly enough, resulting in renal ischemia.

The rate at which interstitial fluid may transfer to the vascular space is determined, in part, by the surface area of the local capillary network. As such, more than 3L of peripheral edema may be comfortably removed in a day (as in a typical dialysis session) whereas only ~0.5L of ascites can be safely removed (using diuretics) in 24 hours due to the sparse capillary monolayer of the abdominal wall available for fluid transfer. This explains why cirrhotic patients with both ascites and peripheral edema will often tolerate fairly aggressive diuresis up until the point that their peripheral edema has resolved, but quickly develop pre-renal failure thereafter.

Due to its distal site of action, spironolactone is the weakest diuretic. It is because of this that it has been the most successful choice in ascites, with most patients losing 0.5L/day on this agent, allowing systemic resorption of ascitic fluid to keep pace.


Less hypokalemia: Hypokalemia can precipitate hepatic encephalopathy. During hypokalemia, K moves out of proximal tubular cells into the extracellular fluid, in exchange for H+ to maintain electroneutrality. The increased intracellular pH stimulates the tubular production of ammonia from the amino acid glutamine, resulting in encephalopathy.

Inhibition of effective mineralocorticoid excess : Bile acids appear to contribute directly to sodium retention in cirrhosis by inhibiting 11 -hydroxy steroid dehydrogenase, allowing cortisol to activate mineralocorticoid receptors, much like in liquorice toxicity. Theorectically, spironolactone directly inhibits this process.

As a final aside, avoid acetazolamide (Diamox) in patients with cirrhosis. Renal ammonia excretion requires protonation of NH3 in the proximal tubule, an event that depends entirely upon bicarbonate resorption. Inhibition of this process with Diamox will also precipitate encephalopathy.

Nephron number, not glomerular filtration rate

Nephrologists for many years have been able to accurately measure kidney function, a measure termed the glomerular filtration rate or GFR. To this end we have been the envy of many other specialties. However the GFR can be a very misleading test when dealing with kidney pathology both acutely and chronically. The GFR is not the equivalent of Troponin-I for the heart, a factor released from injured cells of the heart. The reason for this is that as nephrons cease to function, the other nephrons have spare capacity and can take over the function of lost nephrons. Thus the GFR can and does remain normal even as nephrons are being lost. This compensation can be best seen following a nephrectomy. Rarely does GFR fall acutely by 50% as would be expected and within a few weeks GFR is often at or greater than 80% of the pre-nephrectomy GFR. Unfortunately, because the kidney cannot generate new nephrons, the existing nephrons hyperfilter, and as was so elegantly demonstrated by Brenner, Rennke and colleagues in the 70's to 80's, hyperfiltering nephrons eventually succumb to glomerular injury, proteinuria and sclerosis.

The point of this discussion may be clearly brought home by comparing the renal function of a female patient, age 36 with SLE (Creatinine 0.5mg/dL, eGFR >80ml/min) yet all three cores of a renal biopsy show the pathology in the figure above. The primary histological finding is of widespread glomerulosclerosis with tubular atrophy. While obviously not all nephrons can be obsolescent, the normal GFR obscure the fact that this patient may have fewer than 50% of nephrons intact.

I encourage my fellows strongly to intervene in active kidney pathology before there is a detectable decline in GFR. In my opinion, frequently, once the GFR declines, overwhelming kidney damage has already been done and even if the disease can be controlled, the recovery may at best be partial. Even the most minor of declines in GFR in patients with active kidney pathology may be an ominous sign and should be attended to urgently.
What we really need is a non-invasive measure of nephron number, or possibly GFR reserve. This was discussed at the Renal Grand Rounds recently and the eminent Dr. Barry Brenner suggested a large protein meal with GFR assessed before and after. This kind of test may not be practicable, but any ideas on this pressing question would be greatly welcomed.

To transplant or not to transplant (a pancreas)...

I recently saw a patient in clinic who has type I diabetes and received a kidney transplant from a sibling ~15 yrs ago. His allograft function remains excellent, but recently his diabetic control has been more difficult, despite the use of an insulin pump, and he has now been experiencing increasing number of hypoglycemic episodes. This brought me to wonder whether he would benefit from a pancreas transplant, i.e. pancreas after living donor kidney (PALK). [*Side note: he has a history of primary biliary cirrhosis precluding him from islet transplantation.]


First, the value of a pancreas after kidney transplant (PAK) in terms of survival benefit has been controversial. Venstrom et al. reported an overall relative risk of 1.42 (95% CI, 1.03-1.94; p=0.03) for PAK transplant compared with conventional therapy alone. 1- and 4-yr survival rates were 95.3% and 84.5% for PAK transplant compared to 97.1% and 88.1% for patients who received a kidney transplant and were on the waitlist for a pancreas. In contrast, Gruessner et. al showed that the overall mortality between PAK and those on the waitlist was not increased after transplantation. But besides the debate regarding survival benefit, there are also theoretical concerns that further antigenic challenge can lead to increased rates of rejection in both the existing kidney allograft as well as the newly placed pancreas. Higher immunosuppression increases the risk of infection/cancer and nephrotoxicity in the case of CNI use. On the other hand, pancreas transplantation restores euglycemia even after 10 yrs and, in doing so, can prevent diabetic nephropathy within the allograft and even partially reverse diabetic complications such as retinopathy, neuropathy and most notably atherosclerosis.


So the question is, would patients who have received a prior living donor kidney benefit from a subsequent pancreas transplant? A recent study by Sampaio et al. sought to address this. They analyzed OPTN/UNOS data to assess the impact of mortality and graft survival in type I diabetic patients receiving a pancreas after living donor kidney, compared to recipients of a living donor kidney transplant alone who were listed on the pancreas transplant waitlist but had yet to receive one. From 1997-2007, 4649 T1DM ESRD patients received a living donor kidney transplant and were placed on the pancreas transplantation list. Of these, 1026 subsequently received a PALK (75% of them received it within the first 2 yrs after their kidney transplant). These patients had superior patient and graft survival compared to those who did not receive a subsequent pancreas transplant at the 8yr follow-up (patient survival was 85% vs 75%, and overall graft survival was 75% vs 62%). However, because this was a retrospective, observational study, there was an inherent selection bias in choosing recipients for a subsequent pancreas transplant. For example, in order to receive a PALK, patients had to demonstrate acceptable kidney function and peri-operative risk assessment may have favoured transplanting those with less comorbidities.Indeed, the PALK group were younger, had a shorter pre-transplant dialysis time, and showed less “immunological risk” (fewer African Americans and lower PRA levels). These patients also had fewer episodes of DGF and acute rejection episodes.


So it appears that, at least based on this data, PALK does confer a longterm survival benefit in type I diabetics.

Posted by Melissa Yeung M.D.

Lithium-induced nephrotoxicity

I recently saw a patient in my outpatient clinic who was referred for management of chronic kidney disease presumed to be caused by chronic lithium-induced nephrotoxicity. The patient presented with a serum creatinine ranging from 1.4-1.5 mg/dL over the past year (baseline was 1.0 mg/dL ten years ago), minimal proteinuria, a history of polyuria and diabetes insipidus, and a non-anion gap metabolic acidosis (serum bicarbonate 15-18 mEq/L). She had been taking lithium as prescribed by her psychiatrist for 20+ years and was now questioning whether she should continue the medication given her renal insufficiency. I thought I'd use this opportunity to briefly discuss the principal forms of nephrotoxicity that are observed with chronic lithium administration. For those fellows who are beginning to think about the boards, this is a commonly covered topic.

Lithium is freely filtered by the glomerulus and up to 80% of the filtered load is reabsorbed. While the proximal tubule reabsorbs most of the filtered lithium, a small portion is reabsorbed in the distal nephron by the epithelial sodium channel (ENaC).

1. Nephrogenic diabetes insipidus (NDI). This is the most common adverse effect of lithium, occurring in up to 40% of patients. Chronic lithium ingestion can lead to ADH resistance and cause polyuria and polydipsia. Lithium enters the principal cells of the collecting duct via ENaC and accumulates intracellularly, interfering with the ability of ADH to increase water permeability. While the mechanisms are incompletely understood, they may involve downregulation of and decreased trafficking of aquaporin 2 channels from the cytosol to the luminal membrane. Cessation of lithium therapy can reverse this defect; however, NDI can persist permanently even after withdrawal of the medication. The use of amiloride has been shown to help improve the NDI (Bedford et al. Clin J Am Soc Nephrol 2008), as it competes with lithium for entry into the collecting duct cells via ENaC and prevents intracellular lithium accumulation.

2. Metabolic acidosis. Patients may also develop a hyperchloremic non-anion gap metabolic acidosis, thought to be secondary to impaired proton secretion in the collecting duct or excessive back-diffusion of acid equivalents.

3. Chronic tubulointerstitial nephropathy. This is the most common form of chronic kidney disease associated with chronic lithium administration. Renal biopsies in patients with lithium-induced CKD classically demonstrate interstitial fibrosis and thickened tubular basement membranes, often associated with focal segmental glomerulosclerosis, and renal cysts originating primarily from the distal tubule. Duration of lithium treatment and cumulative dose seem to be the main risk factors for the development of nephrotoxicity. CKD induced by lithium typically occurs in patients who have been treated with lithium for >10-20 years. In one study, 21% of patients treated with lithium for a mean of 16.8 years had a serum creatinine of 133 umol/L or higher on two consecutive occasions (Lepkifker et al. J Clin Psychiatry 2004). Renal impairment is usually mild, and the development and progression of renal insufficiency is generally insidious, although there have been a reported cases of patients progressing to ESRD (15-30% progress to ESRD within an average of 20 years in one series). Patients are normotensive, proteinuria is absent or minimal, and urine sediments are typically bland.

Interestingly, in spite of the established association between lithium and renal impairment, monitoring of renal function in patients taking chronic lithium has been surprisingly insufficient in some countries. Currently, the American Psychiatric Association recommends that serum creatinine be measured every 2-3 months for the first 6 months of lithium treatment and then every year afterwards.

4. Hypercalcemia. While lithium-induced hypercalcemia was first documented in 1973, its association with hyperparathyroidism was not noted until 1978. Up to 25-30% of patients treated with lithium can develop hypercalcemia, and the prevalence of hyperparathyroidism may be as high as 10-15% of patients treated for >10 years. Many of these patients have parathyroid hyperplasia, and discontinuation of lithium does not always lead to rapid correction of serum calcium levels.

Since lithium is such an effective medication at controlling symptoms of bipolar disorder, many patients are reluctant to switch to another medication (e.g. valproate, lamotrigine, and olanzapine) which may not have as predictable of a therapeutic effect. The decision to withdraw lithium in a patient with nephrotoxicity is often a difficult one and should be jointly made by the patient, the patient's psychiatrist, and the patient's nephrologist.

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How low can we go for blood pressure control?

The much awaited results from the ACCORD-BP trial were recently presented at the ACC scientific session in Atlanta and published online in the NEJM on March 14th. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) was a major initiative (estimated cost of $300 million) funded by the NIH to answer important questions about the "intensive" management of glycemic control (HgbA1c less than 6 vs. 7-7.9) blood pressure control (SBP less than 120 vs. less than 140) and dyslipidemia (statin + fibrate vs. statin alone) in high risk patients with type 2 diabetes. The NIH stopped the intensive blood sugar lowering strategy on February 6, 2008, due to safety concerns. The results were published in the NEJM on June 12, 2008 and actually showed an INCREASE in mortality and no decrease in cardiovascular events in the intensive glycemic arm (A1c less than 6) compared to the standard glycemic (A1c 7-7.9). The blood pressure and lipid treatment trials continued until the planned end of the study in June 2009. The results of were published online in the NEJM on March 11th. The BP arm study examined the well-established epidemiological data that lower BP is associated with lower cardiovascular events.

Can you achieve more cardiovascular protection by reaching an even lower blood pressure target (less than 120/80)? Unfortunately, this trial compared this to a SBP of less than 140/80, which was the current guideline for BP control when ACCORD began.

Participants
• 4733 high-risk patients with DM2 (mean age, 62; 48% women)
• HgbA1c >7.5%
• >40 y/o with established CVD or
• >55 y/o with evidence of atherosclerosis, albuminuria, LVH or at least 2 additional risk factors for CVD (dyslipidemia, HTN, smoking or obesity).
• SBP between 130 -180 mmHg taking three or fewer meds for HTN

Exclusion criteria
• BMI >45, Creatinine >1.5 mg/dL, and other serious illness.

Study
• Patients were assigned to intensive BP control (target SBP less than 120) or standard BP control (target SBP less than 140)
• Mean follow-up was 4.7 years.
• Any FDA approved antihypertensive agent could be used to achieve targets
• Primary outcome was the first occurrence of a major cardiovascular event, which was defined as the composite of nonfatal MI, nonfatal stroke, or cardiovascular death.

Results
• Mean SBP and DBP at baseline were 139 and 76 mmHg in both groups.
• At 1 year, average SBP levels were 119 vs 134 mmHg (Intensive vs. Standard). This was achieved by prescribing more meds in the intensive group (at 1 yr 3.4 vs 2.1 meds).
• At 5 years, the rate of adverse cardiovascular events was 1.9% /yr vs. 2.1% /yr (HR, 0.88; P=0.2).
• Death rates were similar in the two groups.
• No secondary analysis was strongly positive, except that stroke incidence was significantly lower in the intensive-care group than in the standard-care group (0.32% vs. 0.53%).
• The intensive group had a higher rate of adverse events (3.3% vs. 1.3%), with more decrements in renal function and more episodes of syncope, bradycardia, hyperkalemia, and hypotension.

Several limitations of the ACCORD BP trial
1. Trial had an open-label design
2. The rate of cardiovascular events was lower than the expected rate in the standard group which reduced the statistical power calculation.
3. Patients <40>79 y/o were not included
4. SBP goal of less than 140 was used and not less than 130 which is currently recommended by JNC7

The ACCORD trial represents an important effort to understand the limit of cardiovascular risk modification in patients with type 2 diabetes. Is it pushing the limit of the J-shaped curve or is it possible that a larger trial or one in a higher-risk population might have shown a significant benefit? A beneficial effect was seen for the secondary end point of total stroke. Although the number of stroke events during the trial were quite small (36 vs. 64). It is also possible that 5 years of followup is not enough time to see a beneficial effect and following these patients over 10 to 20 years this effect will become evident. Lowering systolic blood pressure to levels below 120 mmHg is not without risk as seen by the more frequent hypokalemia, hypotension and syncope in the intensive group. This study implies that pushing blood pressure control to levels lower than a systolic blood pressure of 120 mmHg should not be used in high-risk patients with type 2 diabetes. However, the findings do not answer the question as to what the optimal blood pressure target is for these patients. Furthermore, this trial excluded patients with significant kidney disease. A comforting fact from the trial is that the overall cardiovascular event rate was low in both groups, showing what can be achieved with good treatment strategies. For now, we can continue to aggressively treat blood pressure to less than 130/80 in patients with type 2 diabetes, but pushing this to less than 120/80 does not provide added benefits.

The dialysis patient with a hidden inflammatory state: a quick clinical assessment.

When caring for dialysis patients, we all use the well described KDOQI and KDIGO guidelines and ensure that the published goals are reached (please remember that the necessary government forms must also be completed!). We all pay special attention to the urea reduction ratio, the Kt/V, the PTH level and continuously test ourselves with the optimal management of “the uncontrolled hyperphosphatemic state". In addition to these markers and a physical examination (sometimes a forgotten cheap and valuable tool), I use a handful of specific laboratory tests which have helped me promptly determine the possible presence of a coexistent but hidden inflammatory state.

A reduced BUN/Creatinine ratio, an elevated total C02, a low uric acid level, a low Hb (specially if associated with a high ferritin level and a low reticulocyte count), a low cholesterol, a low phosphorus and a low albumin level are the ones which I have found to be most useful. In many outcome studies, several of these abnormalities have been found to be associated with increased mortality.

A low BUN/Creatinine ratio (i.e. characterized by a ratio ≤ 10-15/1) usually implies a low urea generation rate as a result of protein-calorie malnutrition, suboptimal dialysis and/or liver disease.
An elevated or inappropriately normal predialysis bicarbonate level as well as a low uric acid usually denotes the presence of decreased net acid generation as a result of malnutrition.
Low phosphorus, low cholesterol and/or low albumin levels are also seen as the result of malnutrition.
Resistance to the action of erythropoietic stimulating agents is usually suspected in the setting of an unresponsive anemia in conjunction with a hypo-proliferative bone marrow response (i.e. low reticulocyte index). This phenomenon can be the consequence of underdialysis, iron deficiency (as a result of decreased intake-administration, impaired utilization and/or increased losses) and endocrine dysfunction (e.g. hypothyroidism, uncontrolled secondary hyperparathyroidism).

In addition to the etiologies mentioned above, we should also consider (“think outside the box”) that any of them may also be caused by a common denominator – an inflammatory process. In addition to searching for an occult infection (particularly in patients with dialysis catheters), an ischemic skin ulceration, neoplasia, a clotting disorder, etc., we should also think of the retained clotted arteriovenous graft and/or the failed renal allograft as sources of malady! Clarification of their pathogenic role may not be easy as no clinical evidence of a problem (e.g. fever, renal allograft tenderness, hematuria, clotted AV graft warmth-erythema) may be noticeable (specially when patients returning to dialysis with a failed renal transplant are kept on “low dose prednisone”). Markers of inflammation such as an elevated ESR or CRP are useful but not specific. Nuclear studies using radiolabeled WBC’s and/or renal allograft biopsies are not only expensive-invasive but have not always being helpful. Therefore, we must always maintain a high index of suspicion and, if nothing else is found, we should remember that our friendly surgical colleague is just a phone call away!

Posted by Mario Rubin MD

Are ACE inhibitors good for the peritoneal membrane?

While it has long been postulated that ACE inhibition may help PD patients preserve their residual renal function, there may be another benefit to angiotensin blockade: preservation of peritoneal membrane transport . Last year, a group from the Netherlands analyzed a cohort of incident PD patients in the Netherlands Cooperative Study on Adequacy of Dialysis, and found that the D/P creatinine ratio in patients on ACE inhibitors increased at a significantly slower rate than those not on ACEIs. An increase in small solute transport is thought to represent an increase in membrane neoangiogenesis, likely mediated by TGF-beta and VEGF, which have also been shown to promote peritoneal fibrosis. The study’s authors postulate that ACE inhibitor-mediated downregulation of TGF beta and VEGF explains the slower rate of membrane transport alteration. While no difference in mortality or residual renal function was noted, there did appear to be a beneficial effect on technique survival, one which might have reached statistical significance if the study had continued beyond its 2-4 year duration. Ultrafiltration efficacy was not analyzed, but one might expect increased UF difficulty with increased membrane transport. 



Patients on PD have a number of reasons to be on ACE inhibitors, including their high rates of cardiovascular disease and hypertension, as well as desire to preserve residual renal function. Membrane preservation may be yet another reason to add to the list.

Confusing Sign

Everyone has a certain diagnosis in Nephrology that is just hard to understand. For me, it has been the diagnosis of MPGN (membranoproliferative glomerulonephritis). After extensive reading, I have developed a couple of pearls and interesting points that I would like to share with you.

First: you can add MPGN to any differential diagnosis of kidney disease you have, since the presentation can range from nephritic syndrome, isolated proteinuria, isolated hematuria to nephrotic syndrome.

Second: In order to develop MPGN, you have to have damage to the endothelium of the glomeruli in one of the following ways:

- Chronic subendothelial immunecomplex deposition from persistent antigenemia, like in HCV, HBC or bacterial endocarditis. Or persistent deposition of immunecomplexes in autoimmune diseases like SLE;

- Chronic thrombotic microangiopathy like in TTP/HUS or antiphospholipid syndrome

- Monoclonal immunoglobulin deposition disease like in multiple myeloma.

Third: there is usually consumption of complements (low C4 and C3)

Fourth: the term MPGN is only helpful in defining the pattern of injury characterized by the thickened GBM and the hypercellularity. Think about potential causes of damage to the endothelium when approaching your differential.

Fifth: it has been recently demonstrated that the mesangial cells are not responsible for the ‘tram-track’ appearance as you may find in numerous books. The additional basement membrane is formed by the endothelium, displaced by the presence of subendothelial immune deposits and cell projections derived from endothelium cells and infiltrating macrophages.

Lastly, nephrologists decided to name a completely different disease type II MPGN – also called dense deposit disease. Different because its etiology involves abnormal activation of the alternative complement pathway usually in kids, C3 is low while C4 is normal (postStrep GN also) and diagnosis requires EM (electro-dense material).

Depression in ESRD

This blog post focuses on some of the lesser-discussed aspects of ESRD: depression and psychosocial issues related to ESRD. Studying depression in the ESRD population is an important issue because it is likely the most prevalent psychiatric disease among ESRD patients and there is growing evidence that depression is associated with impaired quality of life and mortality. However, it is often times overlooked in the traditional care of patients with ESRD. What are some of the methodological challenges to studying depression in ESRD patients?

First, there is the difficulty in measuring depression, which has resulted in varying reports on the prevalence of depression in ESRD patients. There have been inconsistent results from multiple studies, and as Hedayati summarized, this lack of consistency likely reflects different disease severity, populations assessed at different time points since starting dialysis, and different depression measures. Kimmel placed the prevalence between 5-10%. In the large Dialysis Outcomes and Practice Patterns Study (DOPPS), the prevalence of physician-diagnosed depression was 14% and probable depression was 43%.

Which instrument is used to assess depression? The DSM-IV is considered the appropriate tool for a clinical diagnosis of depression and is administered by a trained interviewer, rather than being filled out by a patient. While other instruments have been used, Hedayati et al. found that a clinical DSM IV-based diagnosis of depression is a stronger predictor of outcomes compared with self-report scales.

Compounding these challenges is the difficulty in distinguishing between depression and physical symptoms of ESRD and uremia. Other methodologic issues: applying the instruments to varying demographic populations across time (at the initiation of dialysis versus several years later), race, and geography.

Ultimately, what is needed are well-designed, longitudinal, large studies to determine the association between depression and mortality and whether intervention and treatment of depression, whether through greater screening efforts, treatment with anti-depressants, or cognitive behavioral therapy approaches, will impact outcomes such as lowering mortality in patients with ESRD.

Posted by Julie Paik M.D.

Technology wins again???

The interest in machine perfusion for preservation of kidney transplants has been revived. Were we serious when we decided to put the organ in ice??? A recent NEJM prospective, controlled trial randomizing 336 consecutive deceased donors to either machine prefusion or static cold storage preservation showed the advantage of technology!!!

The incidence of delayed graft function (DGF) was less in the machine perfusion group compared to cold storage (20.8% vs 26.5% respectively, P = 0.01) but if DGF developed, it was 3 days shorter with machine perfusion (10 days vs 13 days, P = 0.04). The most interesting result of this study was that the 1-year kidney graft survival rate was significantly greater in the machine perfusion group (94% vs 90%, P = 0.04). The superiority of the machine perfusion technology was shown regardless of deceased donor category. No differences were noted in patient survival, length of hospital stay, acute rejection, or calcineurin inhibitor toxicity between the 2 groups. Seriously, Ice????

INF2, actin polymerization and FSGS

Focal segmental glomerulosclerosis (FSGS) is a clinicopathologic syndrome manifesting with proteinuria, usually of nephrotic range. Early in the disease process, there is a pattern of glomerular sclerosis that is focal, involving a subset of glomeruli, and segmental, involving a portion of the glomerular tuft. As the disease progresses, a more diffuse and global pattern of sclerosis evolves. Alterations of the podocyte constitute the major ultrastructural findings.

FSGS is a nonspecific histopathologic finding in several renal disorders characterized by proteinuria and progressive decline in renal function. Although it is often secondary to other disorders, including obesity, hypertension, diabetes mellitus and HIV infection, FSGS also appears as an isolated idiopathic condition. The genetic contribution to the etiology of idiopathic FSGS is indicated by reports of its occurrence in multiple members of families. Both autosomal dominant and recessive patterns of inheritance have been described.

Autosomal dominant FSGS can be caused by mutations in the gene encoding alpha-actinin-4 (ACTN4) and transient receptor potential cation channel subfamily c member 6 (TRPC6). Mutations in NPHS1 (Nephrin) cause the Finnish form of congenital nephrosis and mutations in the NPHS2(Podocin) cause steroid-resistant nephrotic syndrome. Both result in a clinical picture of congenital FSGS and are transmitted in recessive fashion. Other genes implicated in glomerulosclerosis with nephrotic range proteinuria include CD2-associated protein (CD2AP), Laminin Beta-2 (Lamb2), LIM Homeobox transcription factor 1 BETA (LMX1B) and WT1.

Martin Pollak and colleagues recently reported in Nature Genetics another gene causing adult-onset FSGS with autosomal dominant inheritance. They used two large families with several affected family members in three and four generations respectively. The phenotype was defined by biopsy-proven FSGS, ESRD without cause or macro-albuminuria > 250 mg per gm creatinine. Genome wide linkage analysis defined the gene locus on chromosome 14q32. Altogether 15 genes were screened which lead to identification of non-synonymous (amino acid changing) mutations in the INF2 (Inverted Formin 2) gene in all affected family members. The investigators sequenced 91 unrelated individuals with idiopathic FSGS and identified 9 more families with mutations in INF2 all segregating with disease. Over 600 control individuals were sequenced for INF2 mutations and were negative. Most mutations were identified in the highly conserved exon 4 which encodes for DID (diaphanous inhibiting domain) of INF2.

The phenotypes in families with INF2 mutations shared certain features. Affected individuals presented in early adolescence or adulthood, typically with moderate proteinuria. Although some family members had nephrotic-range proteinuria, none of the affected individuals showed the spectrum of clinical findings that constitutes nephrotic syndrome. Microscopic hematuria and hypertension were noted in some affected individuals. Disease and proteinuria appeared to be progressive and often lead to ESRD.

INF2 is a member of the formin family of actin-regulating proteins that accelerate both polymerization and depolymerization of actin in vitro. Most mutations in FSGS were identified in DID, an autoinhibitory domain. In the most extensively studied diaphanous formin, mDia1, the interaction of the N-terminal DID domain with the C-terminal diaphanous activating domain (DAD) inhibits mDia1 function.

INF2 is highly expressed in podocytes. Electron microscopy of kidney biopsy material from an individual with INF2 mutation showed irregular podocyte foot-process morphology and prominent actin bundles. In addition, transfection studies of overexpressed wild-type and FSGS-associated mutant forms of INF2 indicate differences in the subcellular localization of the mutant and wild-type proteins, as well as differences in the pattern of distribution of actin. The precise mechanism by which actin behavior is disrupted in the presence of INF2 alterations in vivo is unclear and has yet to be defined.

Image from Podocyte Injury in Glomerular Diseases - eJIFCC 20/01 2009 http://www.ifcc.org

INF2 article published in January 2010 in Nature Genetics:

The Nephrologist as Team Leader

Within the last 2 years dialysis facilities in the US have been adjusting to the now not-so-new Center for Medicare & Medicaid Services (CMS) Conditions of Coverage. CMS, as many of you know, funds the ESRD program to the tune of many billions of dollars and as such gets to set some of the rules, known as "Conditions of Coverage". These rules are designed to ensure quality of service from their perspective. Auditors acting on behalf of CMS periodically survey dialysis facilities in a rigorous fashion and may (and often do) issue citations and conditional warnings as result.
In order to prepare for the eventuality of one of these surveys, I received a memo this week with a reminder of my responsibilities as the Hemodialysis Unit Medical Director:
"By virtue of the Medical Director's leadership of the facility's Governing Body, his/her responsibilities extend beyond the primary focus on improving quality of care delivered in the facility and extends to the general management and operations of the facility. As such, all condition level citations are linked to /and are the responsibility of the Medical Director according to CMS".
It went on to append a summary of findings from recent audits, occurring in a particular geographical region, identifying some of the deficiencies which have been noted by the auditors as citable or worthy of a conditional warning. Here are a few of them:


Infection control standards not met due to: 

- Patients not washing and sanitizing their hands pre and post treatment 

- Staff members accessing computer terminals with gloves on after patient contact 

- Patients self holding needle access sites post treatment without gloves on 



Physical environment standards not met due to: 

- Unsanitary and non working sinks and faucets 

- Open boxes of needles and syringes not properly stored 



Documentation requirements not met due to: 

- Incomplete Interdisciplinary Team assessments 

- Medical records not stored properly 

- Peritoneal dialysis orders incompletely and improperly written. 



What does this all mean? At first glance these citations/conditions may seem to be out of the realm of the practicing clinician whose focus is elsewhere, but in actuality they are integral to the proper care of our patients and the infection control lapses certainly should raise a high level of concern. We all have a natural disinclination to being surveyed but maybe these surveys are useful if they encourage us to put into place processes which ensure these lapses do not occur and if we develop systems of self assessment and quality improvement within our domain of responsibility.

Which brings me to the point of this blog. It's all about the team, and as Physicians we assume a natural leadership role when we deliver care to our patients and some of us are eventually appointed to leadership positions as our career advances. The usual dialysis unit personnel resources include Nurses, Patient Care Technologists, Dieticians, Social Workers and Administrative Staff. CMS is telling us we are responsible for the performance of this team on multiple levels. Traditionally our training has not focused much attention on preparing us for such leadership. But, the ability to develop and lead a team in the delivery of care to a defined patient population such as an office practice or a dialysis facility may be as important as an extensive clinical knowledge base in terms of improving outcomes. Being able to function as a clinician and a team leader is a challenge and interestingly many of the leadership skills we eventually acquired are done so by osmosis and without direct teaching.

For those interested the Medicare and Medicaid Programs; Conditions for Coverage for End-Stage Renal Disease Facilities; Final Rule can be found in the Federal Register / Vol. 73, No. 73 / Tuesday, April 15, 2008 / Rules and Regulations. It is ~ 120 pages but is worth reviewing if you are planning career involving outpatient dialysis care.


Posted by David Steele M.D.

HCG in Kidney Disease

That cardiac biomarkers, including Troponin and BNP, can be elevated in CKD or ESKD without necessarily having clinical significance is familiar to most of us. Whether you believe that an elevated Troponin in ESKD is due to diminished clearance or some constant low-level myocardial damage of unclear significance, most would be comfortable dismissing borderline positive results without suggestive signs or symptoms.

Recently I was asked an interesting question pertaining to pregnancy testing in CKD and ESKD. A dialysis patient had a serum HCG level that was borderline positive. The patient and her physicians wanted to know whether this could be a false positive related to her kidney disease or whether she may in fact be in the first weeks of a pregnancy. After searching the literature and conferring with my OB colleagues, here is what I found:

Here is a case report and a nice review of the topic. Not surprisingly HCG levels can be falsely elevated in CKD, though for quite a variety of reasons. These include decreased clearance of HCG, increased levels of other gonadotropins that cross react with the HCG assay, including LH and FSH, as well as other cross-reacting substances including cold agglutinins and heterophile antibodies.

How to distinguish? The urine HCG assay does not cross-react with these substances, and so, if the patient still makes urine, confirmatory testing with urine HCG is a reasonable first step. In ESKD patients who no longer make urine, progesterone levels can be used as a next step especially when more immediate knowledge of pregnancy status is required. If progesterone is low, viable pregnancy is unlikely, though serial serum HCG levels should be monitored to rule out non-viable pregnancy (egs, ectopic). If there is no urgency to determining pregnancy status, follow-up serum HCG to see if doubling occurs at expected intervals should be performed. In my patient's case, her serum HCG level one week later was the same as that one week prior, and the serum HCG was deemed to be elevated due to decreased clearance in ESKD.

Don't forget to look for proteinuria!

At Renal Grand Rounds yesterday, we discussed the case of a previously healthy 50 year old man who presented with fulminant hepatic failure and AKI. He was initially thought to have AKI related to either SIRS/hypotension or Hepatorenal Syndrome (which should be a diagnosis of exclusion), but was astutely noted to have significant (about 6 gm/day) proteinuria. The patient was worked up further: his serum electrophoresis revealed a monoclonal immunoglobulin spike and urine Bence Jones protein was present. Serum free kappa light chains were high and the kappa to lambda light chain ratio was significantly elevated. Concomitant liver biopsy revealed AL amyloidosis, which was further confirmed and typed by fat pad and colon biopsies. Unfortunately, the patient succumbed to multi-organ failure.

The teaching point from this case is that the proteinuria was the key to making the correct diagnosis.

By way of quick review, amyloidosis is a group of diseases characterized by extracellular deposition of beta sheet fibrils which, in systemic forms, cause progressive organ dysfunction.

AL amyloidosis is characterized by fibrils that contain fragments of the variable portion of monoclonal light chains. This is the result of a clonal expansion of plasma cells, but interestingly, most patients with AL amyloidosis do not develop the manifestations of multiple myeloma, and most multiple myeloma patients do not have amyloid deposition. What both diseases have in common, however, is renal dysfunction which presents with significant proteinuria. Of note, given the pathophysiology of these diseases, the proteinuria is not related to albuminuria. Therefore, it is important to obtain a spot protein to creatinine ratio on all patients who may have otherwise unexplained or difficult to explain AKI, and subsequently pursue further work-up, including free serum light chain measurement.

In AL amyloidosis, response to therapy correlates with reduction in circulating light chains, so a hematologic response is the first marker in anticipation of renal function recovery or improvement. Interestingly, as well, the degree of baseline proteinuria on presentation correlates with response to treatment. Current treatment options include melphalan (an alkylating agent) plus steroids, Velcade (Bortezomib, a proteasome inhibitor) and rescue stem cell transplantation, which remains controversial.

Endocrine and thiazide-induced hyponatremia

We have all been taught that before making the diagnosis of SIADH, we have to ensure that the patient has normal adrenal and thyroid axes. Why is this so important and how do thyroid and adrenal dysfunction cause hyponatraemia?


The mechanism in hypothyroidism is incompletely understood, but felt to relate mainly to a reduction in cardiac output, increased activity of baroreceptors and subsequent non-osmotic release of ADH. Often, a reduction in GFR is noted in hypothyroid patients, thereby reducing the quantity of free water that reaches the distal nephron. Correction can be achieved by the administration of exogenous thyroid hormone.
In adrenal insufficiency, the reduction in cortisol may cause reduced cardiac output and blood pressure, again via a poorly understood mechanism. This can result in non-osmotic ADH release and tendency towards free water retention. Perhaps more importantly, ADH release from the posterior pituitary is under the control of CRH from the hypothalamus. CRH in turn is under negative feedback control from cortisol. So, in states of low cortisol, the negative feedback on CRH is lost and, in turn, ADH release is stimulated.


Why do thiazides cause more hyponatraemia than loop diuretics?
The efficacy of ADH depends on the generation of the medullary concentration gradient via NaCl reabsorption, without water, in the thick ascending limb of the loop of Henle. This creates a gradient for water reabsorption via aquaporin-2 insertion in the luminal membranes of the cortical and outer medullary collecting tubules.
With this in mind, it becomes clearer why thiazide diuretics are more likely to cause hyponatraemia than loop diuretics. Loop diuretics, by inhibiting the sodium reabsorption in the thick ascending limb of Henle’s loop, interfere with the generation of the hypertonic medullary interstitium; so, despite inducing a mild increase in ADH secondary to volume depletion, the ADH is less effective because there is a reduced concentration gradient for water reabsorption. Thiazide diuretics act on the distal tubule, having no effect on the medullary concentration gradient, thereby allowing ADH induced by volume depletion to promote water reabsorption unabated.


Posted by Finnian McCausland M.D.

VEGF inhibitors and proteinuria

I've recently had the privilege of caring for a patient undergoing chemotherapy for a metastatic malignancy using agents targeting the vascular endothelial growth factor (VEGF) pathway. This patient, having tolerated three cycles of avastin and ipilumimab without any complications, was found on routine screening by his oncologist to have >1g/day of proteinuria and was thus referred to us for further evaluation. He was seen in our clinic two weeks later, at which time he was feeling generally well and had no gross abnormalities on physical exam (normal volume status, normal cardiac and pulmonary exams, no peripheral edema). His serum BUN and creatinine were both normal, a urine protein to creatinine ratio revealed essentially no proteinuria, and his urine sediment was bland without any cellular casts. We were, of course, pleasantly surprised. On the basis of these findings, we decided that the most likely etiology of the transient proteinuria was the VEGF inhibitor, and that it was less likely that he had developed a de novo renal disease. We informed our patient and his oncologist that they could continue with the prescribed treatment regimen, and that we should continue to observe him closely for any subsequent development of renal abnormalities.

There is a documented association between VEGF inhibitors (e.g. bevacizumab, sunitinib, sorafenib, pazopanib, axitinib) and renal disease. While these agents are usually well tolerated, their toxic effects include proteinuria and hypertension. The incidence of proteinuria has been variable in different studies depending on patient characteristics, cancer type, and signals targeted, though a number of clinical studies report that treatment with bevacizumab (avastin) may be associated with increased proteinuria. For instance, bevacizumab has been associated with proteinuria in 23-38% of patients treated for colorectal cancer and in up to 64% of patients treated for renal cell carcinoma. One meta-analysis of RCTs with patients receiving bevacizumab reports a relative risk of 1.4 for proteinuria at a low dose (2.5 to 7.5 g/kg) and 1.6 for a high dose (10 to 15 mg/kg) of bevacizumab. Proteinuria appears to at least partly resolve with discontinuation of the VEGF inhibitor, though some patients are able to resume therapy without an increase in proteinuria. It is not clear at this time whether there is an association between duration of treatment and the development of proteinuria.

Renal biopsy may be indicated in patients with metastatic cancer and proteinuria with evidence of worsening kidney disease, unexplained acute kidney injury, or nephritic syndrome. Among patients who have undergone renal biopsy for proteinuria associated with VEGF inhibitors, the most common pathological finding is thrombotic microangiopathy, though other conditions including:

• Collapsing glomerulopathy
• Cryoglobulinemic glomerlonephritis
• Immune complex-associated focal proliferative GN
• Sorafenib-induced acute interstitial nephritis

Currently, there are no evidence-based recommendations for how to specifically treat proteinuria caused by VEGF inhibitors. However, it is reasonable to try conservative treatments such as ACE inhibitors or angiotensin-receptor blockers, particularly in patients with both proteinuria and hypertension.

Of note, this topic of nephrotoxicity associated with VEGF inhibitors has recently made it to the nephrology boards!

A trap for angiotensin type 1 receptors

The renin-angiotensin system is powerful regulator of blood pressure homeostasis. An article published in the March 24 issue of JASN highlights an emerging area of research into the modulation of AT1 receptors on different tissues.

The majority of well-known angiotensin II actions are mediated via AT1 receptor stimulation, and angiotensin converting enzyme inhibitors (ACEi) and AT1 receptor blockers (ARBs) have been widely used as antihypertensive agents with cardiovascular protective effects. Elucidating factors that regulate AT1 receptor expression levels in different tissue compartments will hopefully lead to novel agents to treat hypertension and its associated end-organ damage (ESRD, CHF and Stroke). Recent studies have demonstrated the existence of several proteins interacting with AT1 receptors that may modulate AT1 receptor expression level, sensitivity and internalization. A recent review article highlights this emerging field. Atrap (AT1 receptor-associated protein) is the best characterized protein and the focus of the March 24 article by Oppermann et al.

It was previously reported that Atrap (a 19kD protein) interacts specifically with the carboxyl-terminal domain of the A1a receptor and catalyzes its internalization in cultured cells. Prior in vivo studies over-expressing the Atrap protein in the heart, aortae and femoral artery in mice demonstrated a protective effect in these tissues in response to angiotensin II infusion. Overall, the prevailing literature suggested an inhibitory or protective effect of Atrap on AT1 receptor function. This group knocked out the Atrap gene in mice to test this hypothesis in vivo.

They reported that Atrap KO mice have a higher resting blood pressure (by 10 mmHg) as measured by radiotelemety. Suggesting that Atrap is important in regulating basal blood pressure and that its absence leads to systemic hypertension. Interestingly, they found that Atrap is highly expressed in the kidney (then testis=adrenal>heart>lung=liver=aorta=brain). Specifically, they showed that Atrap is highly expressed in the proximal tubule of the kidney. Previous investigations have focused on the distal tubule as potential sites that affect blood pressure as most of the known genetic mutations in sodium transport causing hyper/hypotension are linked to the distal nephron (Bartter, Little, Gitelman syndromes, etc). This group reports that Atrap KO mice have more AT1 receptors in the proximal tubule which allows for increased angII-dependent NHE-3 activity causing volume expansion and hypertension.

This highlights the importance of investigating novel pathways regulating the renin-angiotensin system. Modulation of this system with the use of ACEi, ARBs and now direct renin inhibitors have continued to be the mainstay of therapy for patients with heart failure, diabetes, hypertension and kidney disease. Activation of Atrap may be more specific and more physiological for inhibition of At1 receptor signaling. New drug discovery modulating Atrap protein expression could lead to novel therapy. For now, much more research is needed.

Mythbusters: Hypertension

It seems like there have been a lot of recent developments in the management of hypertension, and several sacred cows have become burgermeat. I thought I'd summarize a few of these important developments here:

1. Blood pressure targets in the over 80's
The Hypertension in the Very Elderly (HYVET) trial taught us that treating hypertension in the very elderly is effective in preventing stroke. However, we may have been over-treating the "oldest-olds" for years, and that target SBPs for this group should be< 150/80mmHg according to a recent Cochrane review. As nephrologists, we may have been particularly culpable, due inappropriate application of a 130/80 mmHg target for elderly patients with mild reductions in GFR ("CKD").

2. Who benefits from aldosterone blockade?
A strong association has been demonstrated between abdominal obesity, sleep apnea and aldosterone excess, such that it has been suggested that visceral fat may be a source of aldosterone, contributing to resistant hypertension in the abdominally obese. Recently, spironolactone has been shown to be effective in managing resistant hypertension in the abdominally obese, so keep it in mind.

3. The white-coat effect and BP variability
Reassuring patients who appear to only have spikes of hypertension when they come to see you in the clinic may be the wrong thing to do. This recent Lancet article suggests that variability in BP, and spikes of hypertension in particular, may in fact be more dangerous than sustained hypertension. An approach to managing this problem is to avoid agents known to increase BP variability, such as beta blockers. Furthermore, patients who believe that it's okay for their BP to be elevated because they have recently been active need to be educated that this is incorrect.

4. Allopurinol for hypertension
Urate is periodically in and out of vogue as an instigator / perpetuator of kidney disease and hypertension. I personally believe it to be a marker of oxidative stress, but am still undecided about it having a direct role in kidney disease and progression. I have treated severe hyperuricemia in CKD patients with this specific intention / hope of attenuating disease. This recent JAMA paper suggests this approach is not complete madness. This short-term crossover study of adolescents with hypertension and hyperuricemia found that allopurinol 200mg bid controlled hypertension on it's own in 66% of patients. Another one to keep in mind

That's enough for today, I'll return to this topic next time.

World Kidney Day 2010

Happy World Kidney Day! Celebrated every year in March, World Kidney Day is a day devoted to raising awareness of kidney disease across the globe. This year promised to be a huge success: cities throughout the world, from Bahrain to Belgium, held kidney awareness events, and celebrities such as Tom Hanks and French President Nicolas Sarkozy jumped on the kidney awareness bandwagon to lend their support to the cause. Besides raising awareness of our “amazing kidneys”, the day’s objectives were to encourage screening for CKD, recognize the importance of risk factors in the development of kidney disease, and encourage preventive behaviors. This year’s theme was “Protect Your Kidneys: Control Diabetes,” in order to place special emphasis on the growing prevalence of diabetic renal disease.

Tackling the problem of CKD is no small job. The last NHANES survey in 2009 estimates the U.S. prevalence of CKD stage II-V at 13%. While less prevalent in the developing world, CKD is expected to become a much greater problem due to the rapidly increasing rates of diabetes (an 85% increase in Central and South America, and 75% in the Western Pacific region, by 2025), not to mention hypertension. CKD has far-reaching effects on patient outcomes: for Medicare CKD patients in 2009, adjusted all-cause hospitalization rates were 1.5 times the non-CKD population, and all-cause mortality was twice as high as in non-CKD patients, even when adjusted for comorbid conditions. Then there is cost: in one article by DH Smith et al in 2004, the management of CKD alone was estimated to cost an additional $8000 annually per patient.

The renal fellows at Brigham and Women’s Hospital spent the day running a screening booth in the hospital lobby, helping to advise patients on blood pressure control, urinalysis results, and diabetes testing. Whether your clinic was able to hold screenings, pass out pamphlets on kidney health, or spend an extra minute counseling patients on kidney disease prevention, it is even more critical to continue the efforts in the year to come. Hopefully we can reverse the alarming increase in CKD prevalence throughout the world and—it is to be hoped, in the best possible way—put some of us out of business.

Lack of respect for the beans

I have just learned two very interesting aspects of kidney donation that I would like to share with you. As part of my transplant fellowship, I am required to participate in the decisions about accepting or not a kidney from a deceased donor and to join the surgical team during organ procurement.

Despite a list of absolute contraindications which include donors with active malignancy, untreated sepsis or active intravenous drug abuse, I have found that the limits are a little more subjective than expected, and with the organ shortage, transplant services are even more aggressive of using organs labeled as expanded criteria donor (ECD).

We had an interesting donor offer recently, in which a young female had died after a closed head trauma complicated by disseminated intravascular coagulation. The creatinine was normal and urine output was around 40cc/hour. Our transplant service decided to accept both kidneys. Not sure if you guys know, but the kidneys are actually the last organ to be removed from the deceased donor!? Liver, heart and lungs have preference!!! We had to wait almost 2 hours for another team to take out the liver before we were able to get to the beans… The concern was: could the DIC had damaged the kidneys?
DIC is associated with histopathological evidence of microthrombi in several organs, particularly in the brain, liver, lung, kidney and pancreas. A combination of mechanisms, including release of fat, phospholipids and thromboplastin from tissue—especially brain tissue—into the circulation, hemolysis and endothelial damage may promote systemic activation of coagulation. Cytokines also may have a role in the development of DIC.

The two recipients demonstrated a very slow increase in urine output postop associated with also small downtrending of the creatinine. A time zero biopsy showed multiple fibrin thrombi in the glomerular capillaries. As an important learning point, these allografts are usually associated with delayed graft function. Moreover, it is essential to ensure no significant necrosis is present on biopsy at time zero, before transplantation. It is believed that the recipient's own fibrinolytic system is able to slowly breakdown the thrombi and reestablish the renal function. Still, I was disappointed that the kidneys were last…

Hermansky-Pudlak Syndrome

This is one that Nate would have liked....I recently saw a case of renal disease in an albino Peurto Rican woman with severe pulmonary fibrosis. She holds the diagnosis of Hermansky-Pudlak Syndrome (HPS).
HPS is an autosomal recessive disorder characterized by

• Oculocutaneous albinism
• A bleeding diasthesis (absense of dense bodies)
• Sometimes pulmonary fibrosis
• Sometimes granulomatous colitis.
  

The prevalence is 1 in 500,000 in non-Puerto Ricans and 1 in 1800 in Peurto Ricans. The HPS1 gene is most associated with HPS in Peurto Ricans and for the pulmonary fibrosis which is usually fatal in 10 years from symptom onset.

The renal failure, pulmonary fibrosis, and granulomatous colitis are associated with lysosomal accumulation of amorphous lipid-protein complexes called ceroid lipofuscin. This is seen on the limited number who have undergone renal biopsy. The ceroid deposits accumulate in renal tubular epithelial cells of the proximal tubules with sparing of the glomerular epithelial cells and the distal tubular epithelium. Pathogenesis is still speculative and treatment options other than supportive care are currently unavailable.

Compensation for living organ donation! A taboo no more but....

Talking to Nate always stimulated new ideas and new challenges. Last time I met him, we played soccer in the park with the kids (that was also a challenge but fun and easy to win…). We also talked about an interesting hot ethical topic (It was hard and no winners…). Compensation for living organ donors! A taboo no more but nonetheless remains an ethical dilemma that needs public debate, engaging mainly specialists who care for end-stage kidney disease patients. I thought using Nate’s blog for such a debate will please him, so here we are…

My approach will be, what are the facts?

• We have an increasing demand for kidney transplantation that our deceased donor waiting list can’t match. And living donation is not increasing especially when being an organ donor can negatively affect the likelihood of obtaining life, disability and health insurance. This concern is frequently raised by many potential donors.
• Recipients of living donor kidney transplants do better than recipients of deceased donor transplants.
• More people are dying on dialysis waiting for a transplant.
• Kidney donation is safe (Ibrahim et al. NEJM 2009)… Trust me, I finally watched a hockey game last week after I saw a Canadian flag in our Lab.
• And for the government (no offense) and the health insurance payers, Matas et al found that a LURD transplant saved $94,579 (US dollars, 2002), and 3.5 quality-adjusted life years (QALYs) were gained.

So no doubt increasing living donation through creating incentives for donors will save lives and money. Also keep in mind that we pay blood donors, plasma and sperm donors, egg donors and surrogate mothers…

What are the ethical hurdles?

If we allow direct compensation between donors and recipients, we are turning the poor of our society into providers of body parts to wealthy people.
But what if the compensation is indirect through government agencies, providing donors, for example, with lifetime health insurance or tax deduction and maybe by treating them as the nation heroes which they deserve by the way.

I’ll be happy to hear your comments.