Just a spoon full of (bicarbonate) makes the medicine go down..

Partly because I like the idea of my patients taking spoonfuls of household remedies for their kidney disease, and partly because I like the elegant simplicity of the remedy, I was pleased to see another study touting the renoprotective benefits of sodium bicarbonate. In this month’s issue of KI, Mahajan et al evaluated the effect of daily Na bicarbonate supplementation on patients with *mild CKD and *normal serum bicarbonate levels.

120 nondiabetic patients with eGFR between 60 and 90 mL/min, and macroalbuminuria (Ualb 200-2000 mg/d) were randomized to receive tablets containing 0.5 mg/kg Na bicarbonate, NaCl, or sucrose (placebo). Over the course of five years, eGFR (measured via creatinine and cystatin methods) and urinary albumin were followed.

The NaHCO3 group showed a statistically significant decrease in the rate of eGFR decline, as well as progression of albuminuria, compared to the two control groups. Interestingly, these results were observed in the absence of a significant difference in serum bicarbonate levels. The authors postulate that perhaps bicarbonate supplementation lessens the degree of tubulointerstitial injury by decreasing urinary endothelin-1 production. Excretion of endothelin-1 and N-acetyl-beta-D-glucosaminidase (NAG), a marker of tubular injury, were decreased in the bicarbonate group, lending support to this hypothesis.

The study does have some limitations, notably the restriction of study eligibility to only patients with presumptive hypertensive nephropathy. None underwent kidney biopsy before or after the study. The mechanism of renal injury in these patients may be markedly different from other forms of renal disease; and the diagnosis category of hypertensive nephropathy itself may include several different mechanisms of disease. The study population was made up of >60% African Americans, and 25% Hispanics, so it may not be applicable to patients of other races. Also, the issue of increased salt intake was not addressed (interestingly, urinary Na excretion did not increase in the NaCl and NaHCO3 groups). Still: the data are compelling, and the treatment is easy and cheap. When taken together with the results from de Brito-Ashurst et al’s finding last year showing slowing of CKD stage IV progression with bicarbonate supplementation, it is becoming easy to argue that maybe all of our patients ought to take a spoonful (or two, or three) of baking soda with their daily meds.

Hyperkalemia in patients with cirrhosis; good or bad?

Hypokalemia and metabolic alkalosis are considered precipitating factors for hepatic encephalopathy, as hypokalemia stimulates ammoniagenesis in the proximal tubule.

Although, the mechanism is not entirely clear, the likely hypothesis is as follows:

*Hypokalemia causes the movement of potassium out of the cells.
*To maintain electric neutrality, H+ ions move into the cells leading to intracellular acidosis (cellular ph decreases).
*This triggers the conversion of glutamine in the proximal tubule, to NH4+ and bicarbonate.
*Ammonia (NH3+ and NH4+) is selectively, either excreted in the urine or returned to the renal venous circulation (~25-45%).
*Ammonia, that subsequently enters portal circulation, is not metabolized by the cirrhotic liver, therefore likely to precipitate encephalopathy.

Potassium sparing diuretics such as spironolactone and epleronone are used to prevent hypokalemia and metabolic alkalosis for this reason. See Conall's post about diuretic choice in decompensated liver disease. Yet, frequently, hyperkalemia, and not hypokalemia, is a cause of concern among physicians, and frequently leads to discontinuation of spironolactone, administration of loop diuretics, dietary potassium restrictions, all of which further add to the risk of encephalopathy.

Conversely, high potassium levels may be protective by reducing the risk of hepatic encephalopathy. Although, somewhat speculative, this may happen in two ways

1. Hyperkalemia may decrease total ammonia production in the proximal tubule by increasing intracellular ph and thereby impairing ammoniagenesis.
2. Potassium competes with NH4+ for absorption by the NKCC2 transporter at the thick ascending limb of loop of henle, thereby reducing ammonia accumulation (read ammonia trapping) in the medullary interstitium and hence less ammonia available for absorption in the systemic circulation.
   

In an interesting study done by Zavagli et al, patients with higher potassium levels (5.4-5.5 meq/l) had a much better survival and less hepatic encephalopathy episodes as compared to patients with lower potassium levels (3.4-3.5meq/l).

While I certainly do not recommend ignoring severe or symptomatic hyperkalemia in liver cirrhosis patients, educating physicians about aggressive correction of hypokalemia, rather than mild hyperkalemia, may serve these patients best.

Viresh Mohanlal, MD

Deciphering the pathologists secret code!

I will share with you some of the tips I learned from my pathologist friend Ibrahim Batal.

When evaluating an allograft kidney biopsy for acute changes, you should:

First, scan at low power magnification, look for arteries, check for necrosis or infiltration:

*Fibrinoid necrosis (seen as the red pink color, Figure 1, star) will automatically indicate Banff type 3 T cell mediated rejection TCMR or severe rejection. Compare the Fibrinoid necrosis of this arteriole to the normal arterial tissue seen in Figure 1 marked by the arrow. To review Banff classification review Nate's prior post.

*Infiltrates seen inside the intima of the arteries (Figure 2, star) are lymphocytes and macrophages, which indicate Banff type 2 TCMR. See how the nuclei of those infiltrates look similar to the nuclei of the infiltrates in the interstitium (Figure 2, arrow) but they look different from the tubular epithelial nuclei that are perfectly rounded (Figure 2, circle).

Second, look at the interstitial infiltrates.

*Normally, the tubules should be packed and back-to-back, if infiltrates exist (Figure 3, blue small cells in the circle), we should be looking at the severity of the tubulitis in the most affected tubule. As you all know the more actively functional proximal tubule has a large strong eosinophilic cytoplasm (Figure 3, star) that differentiate it from the less active small cytoplasm of the distal tubules (Figure 3, arrow).

To differentiate between the tubular infiltrates and the tubular epithelium itself, compare those cells to the interstitial infiltrates, they should look similar. In addition the leukocytes in the tubules appears darker, sometimes with a hallow surrounding.

Now back to the most affected tubule (Figure 4, circle).

*If the infiltrating leukocytes are more than 10 in the absence of arteriolar infiltrate or necrosis, the TCMR is considered Banff 1B.

*If the infiltrates are between 5 and 10, the TCMR is considered Banff 1A,

*If the infiltrates are 4 or less, the TCMR is considered borderline cellular rejection.

*So imagine the sampling error in this classification.

Now will shift to the acute antibody mediated rejection where the tissue injury is mainly manifested in the microcirculation mainly peritubular capillaries and or glomerular capillaries in its typical form.

*First, We look at the peritubular capilarities, you have to “imagine” a capillary (Figure 5, circled) between the different surrounding tubules (Figure 5 stars). The “imaginary capillary” is infiltrated by neutrophils (appreciate the multilobular appearance of the nuclei) and macrophages (Figure 5 arrows).

*Second, Because those pathologic manifestations are not sensitive, we always stain for C4d either by immunofluorescence or immunoperoxidase according to the institutions preference, Immunoperoxidase being less sensitive but easier to perform. C4d should be evaluated in the peritubular capillaries (Figure 6, arrow).

*In contrast to antibody-mediated rejection, when neutrophils are mainly concentrated within the tubular lumen rather than peritubular capillaries (Figure 7, star), then bacterial urinary infection should be high on our differential.

Conclusion: It is always good to have a pathologist as a friend. However, this review should be helpful in trying to interpret renal pathology.

Stopping statins in dialysis patients

It can often be difficult to stop something once it's been started; take statins for example. It seems that despite consistent evidence from two large, randomized controlled trails demonstrating the lack efficacy of statins for preventing cardiovascular mortality in dialysis patients, there has been little impact on the prescribing habits of nephrologists. This study shows that in the 2 years following the negative 4D result, the rate of statin prescription in diabetic hemodialysis patients actually increased by 10%.

There are probably several reasons for this practice, such as scepticism about the result in ESRD patients given the proven efficacy of statins in other groups, or a reluctance to engage in therapeutic nihilism. Personally, I worry about precipitating a cardiovascular event by stopping these drugs; the 4D and Aurora trials do not address the issue of discontinuation. With such a high rate of cardiovascular events in this population, aren't you just asking for trouble by drawing a line through the Lipitor on the medsheet? It's a thorny question, and one we may put to poll on this blog next week.

Hepatorenal syndrome: some help from the renal service

Hepatorenal syndrome (HRS) is a frequent consult encountered on the nephrology service. The criteria have recently been revised. Conall reviewed the revised criteria on a prior post last year. To review the pathophysiology of HRS click here.

In a cirrhotic patient with AKI, HRS commonly appears in the top 3 of a differential diagnosis. However, when a large database was reviewed (single center), the major causes of AKI in a cirrhotic patients in descending order of frequency were:

*32% infection-induced renal failure
*24% parenchymal renal disease
*22% prerenal
*11% ATN
*8% HRS
*3% nephrotoxic renal failure

Potential therapies- Albumin, octreotide and midodrine have shown some benefit and a retrospective study of 53 pts showed some survival benefit with octreotide and midodrine combination in these patients. Prostaglandin analogues, ACEi, NAC and endothelin receptor antagonist have all been looked at, but these data are inconclusive. A randomized study of 46 patients in Spain and a randomized double blinded study of 112 pts in the US compared the use of terlipressin (a vasopressin analogue) and albumin together versus albumin (+ placebo) alone. The results showed improvement in renal function but the overall survival was not different in the two groups. There was, however, some increase in the risk of cardiovascular side effects. At this time terlipressin is not approved by the FDA in the US.

Dialysis typically only offered when liver recovery is expected or possible (acute liver injury) or when liver transplant is a valid option. Conventional dialysis in often proves challenging as hypotension is common in patients with liver failure. However, some simple changes can minimize hypotension. These include: use of less negatively charged dialyzer membrane, circuit priming with isotonic NaHCO3 (instead of normal saline), cooling, increasing Na in dialysate, low UF, citrate anticoagulation and midodrine/terlipressin before HD.

Extracorporeal albumin dialysis (ECAD) using molecular adsorbents recirculating system (MARS) is something new on the horizon. Basically, this is hemodialysis with an albumin-containing dialysate. Charcoal and anion exchange columns are connected to a hemodialysis or hemoperfusion apparatus. This system effectively removes albumin-bound substances, including bilirubin, bile acids, aromatic amino acids, medium chain fatty, NO and cytokines. So, it functions more like a liver substitute (in removing albumin bound substances) in addition to providing dialysis.

In small and mostly uncontrolled studies ECAD has been shown to decrease mortality and improved renal function. In a prospective randomized controlled study it was shown to improve hepatic encephalopathy. The major downsides are hypotension, increased bleeding, cost hypoglycemia and non cardiogenic pulmonary edema. Results of ongoing clinical trials will shed more light on this form of therapy.

A liver or a simultaneous liver and a kidney (SLK) transplant is the best options for these patients. About 50% of the times, HRS resolves following the liver transplant but some patients remain dialysis dependant. This raises the question of SLK transplant. Although no strict guidelines apply, according to the Consensus Conference held in 2008 (ASTS, AST, UNOS, ASN), AKI or hepatorenal syndrome with SCr ≥ 2.0 mg/dL and dialysis ≥ 8 weeks, qualify for a SLK. Even with these advances HRS continues to be a diagnosis associated with considerable morbidity and mortality associated with it.

Tarun Kaur, MD

Choose your poison

The way drug discoveries happen is always fascinating. Today, I heard Dr Nadler describe how he discovered Rituximab. He was a young oncology fellow at Dana-Farber back in 1979 when he convinced a colleague dentist to teach him how to produce antibodies in vitro. The technology had been developed a couple of years earlier and his friend was hoping to use antibodies to produce a mouthwash, which would stop cavities! Among the antibodies developed in collaboration, they created one that had specificity for B cells and named them as CD20.

Later, Dr Nadler and others tested this antibody in humans that was accompanied by many side effects but with successful initial results in patients with lymphoma. Some of the side effects were related to the murine origin of the antibody. This problem was solved years later when Dr Winter developed humanized antibodies.

Last week’s NEJM carried 2 articles reporting the use of Rituximab for ANCA vasculitis. The treatment of ANCA vasculitis is very challenging, especially c-ANCA positive (Wegener’s) due to the high rate of relapse 30-75%. Patients who undergo fast taper or with very high ANCA levels are at increased risk, but no good marker exists at this time. Therapy of WG and MPA has two components: the induction of remission; and the maintenance (to prevent relapse).

Induction of complete remission, defined as the absence of active disease, is the goal of initial immunosuppressive therapy and it usually consists of cyclophosphamide (CYC) and steroids. Plasmapheresis should be considered in patients with severe renal dysfunction, lung hemorrhage, CNS vasculitis or mononeuritis multiplex. Dr Steele shared his personal experience on a prior blog.
The maintenance than consists of azathioprine and prednisone for 12-24 months. The results of the trial of Stone et al. was interesting since it compared CYC with Rituximab with discontinuation of steroids at 5mo showing better results in the Rituximab group. However, follow up was short and no conclusions can be obtained about relapse in the long term. One interesting point is the high mortality of ANCA patients, reaching ~18% on both groups! Quoting Paracelsus: “All substances are poisons, there is none which is not a poison. The right dose differentiates a poison from a remedy”. These patients need close monitoring and defining the ideal individualized dose is the Holy Grail.

The conclusion taken from both trials is that Rituximab could be considered an alternative therapy for ANCA vasculitis, however their superiority in the long-term still need further testing. Also check Nates's blog on "How much Cytoxan is too much?"

Does BK virus cause nephropathy in BMT recipients?

I recently consulted on a patient with AKI who had undergone a bone marrow transplant a couple of months previously. While reviewing his labs, I noticed that he had ongoing BK viremia and I wondered whether or not he could have BK nephropathy.

BK viruria occurs in 50% of BMT recipients, usually within 2 months of transplant although it can also be detected pre-transplant. The virus usually clears spontaneously as time progresses. Although in the renal transplant world, BK virus is most often associated with nephropathy, for BMT recipients, hemorrhagic cystitis is the commonest pathology seen with this infection and was first described more than 20 years ago. Hemorrhagic cystitis occurs in 10-25% of BMT patients. Early post-transplant cystitis was thought to be related to chemotherapy and its incidence has fallen with the routine use of bladder protection. BK-related cystitis tends to occur later after transplant and can be associated with significant morbidity. The main risk factors for cystitis are BK viremia, especially pre-transplant, GVHD and increased doses of immunosuppression. Treatment is generally supportive as the cystitis usually resolves spontaneously in 2-3 weeks although cidofivir and leflunamide have been used with limited success.

Despite the high incidence if BK viremia and viruria, BK nephropathy is extremely rare in these patients, with a very small number of cases reported in the literature. In the majority of these cases, the nephropathy was diagnosed >1 year after transplant and occurred in patients who required prolonged high-dose immunosuppression for GVHD. Interestingly, cystitis did not necessarily precede the development of nephropathy in these patients.

So why do more BMT recipients not develop nephropathy? Perhaps, in most patients, as the immune system reconstitutes, the BK virus is cleared spontaneously while in patients with GVHD, the viremia persists allowing the damage to occur.

Although rare, BK virus nephropathy has also been described in recipients of heart, pancreas and lung transplants.

So, given that my patient not long after transplant, it is unlikely that he had BK nephropathy. However, it is something to consider in patients with sustained increases in serum creatinine in the medium term after BMT.

APOL1 variations associated with kidney disease in African Americans

African-Americans (AA) have higher rates of kidney disease than Americans of Caucasian ethnicity. Two years ago the MHY9 (non-muscle myosin heavy chain 9) locus on chromosome 22 has been associated with glomerulosclerosis and non-diabetic end stage renal disease in AA and in Hispanic Americans. How MYH9 could predispose to glomerulosclerosis on a molecular level remained unknown and speculative. However MHY9 appeared to be a plausible candidate since it can cause a human syndrome - May-Hegglin anomaly(MHA; OMIM 155100) - which includes kidney disease (interstitial nephritis). Nate blogged about this here and here.

Last week Martin Pollak and colleagues reported in Science that two independent variants in the nearby APOL1 (Apolipoprotein L-1) gene were responsible for the increased risk of renal disease disease and not the MHY9 gene. APOL1 is only ~20kb upstream of MYH9, however there is a strong recombination hot spot between the two genes, thus the entire effect of this locus on kidney disease in AA appears to be due to APOL1 based on strong statistical evidence.

AA with focal segmental glomerulosclerosis (FSGS) and hypertension-attributed end-stage kidney disease (H-ESKD) were associated with two independent sequence variants in the APOL1 gene {FSGS odds ratio was 10.5 [95% confidence interval (CI) 6.0 to 18.4] and H-ESKD odds ratio was 7.3 (95% CI 5.6 to 9.5)}. The two APOL1 variants are common in African chromosomes but absent from European chromosomes, and both reside within haplotypes that harbor signatures of positive selection. ApoL1 is a serum factor that lyses trypanosomes. In vitro assays revealed that only the kidney disease-associated ApoL1 variants lysed Trypanosoma brucei rhodesiense. Trypanosoma can cause sleeping sickness and these variants can protect carriers from sleeping sickness.

The authors conclude/speculate that evolution of a critical survival factor in Africa may have contributed to the high rates of renal disease in African-Americans. The mechanism of how APOl1, which is a soluble factor in human serum traveling with HDL particles, can predispose to kidney disease is unknown.

Board question: PD-1 answer

The best answer is E. Encapsulating sclerosing peritonitis (ESP)

This patient presented with true UF failure (<400cc UF volume on a 4hr PET using 4.25% with 2L dwell volume- "rule of 4's").

The differential diagnosis of true UF failure can be separated by PET results:

Decreased D/P Cr

1. Encapsulating Sclerosing Peritonitis (ESP)
2. Adhesions
   

Stable D/P Cr

1. Increased lymphatic absorption
2. Dialysate leak
3. Catheter Malposition
4. Decreased Transcellular Transport
   

Increased D/P Cr

1. Peritonitis
2. High transport status
   

ESP is a progressive, intra-abdominal, inflammatory process that results in layers of fibrous tissue that encapsulate the viscera, thereby compromising the motility and function of the bowel. The length of time on PD is the most important risk factor for ESP, ie, the more time on PD, the greater likelihood of developing ESP. Also, high transporters may be at heightened risk for ESP compared to low or average transporters.
The presentation of ESP may include:

The CT abdomen/pelvis shows dense sheets of fibrous material in the peritoneum.

The diagnosis of ESP mandates the immediate cessation of PD. Surgery is very challenging and is usually not recommended. Steroids and tamoxifen have shown some efficacy in case studies, but this has not been systematically studied. Nutritional support with TPN is often necessary.

Michael Lattanzio DO

*RFN board questions are meant to help introduce concepts about nephrology related diseases and do not represent actual questions seen on the ABIM exam.

Can NSAIDS cause CKD?

I recently saw a patient in clinic who was referred for a creatinine of 1.5, stable for a number of years. She had no other risk factors for CKD except a history of daily NSAID use for chronic back pain. Her exam and urinalysis were unremarkable. After seeing her, I decided to review the evidence for NSAIDs causing chronic renal damage—I wasn’t sure this was a diagnosis I could hang my hat on. In doing so, I found it worthwhile to review the mechanisms of NSAID-related renal damage, acute and long term.



NSAIDs are a well-recognized cause of renal dysfunction. Their inhibition of COX-1 diminishes the production of prostaglandins that mediate renal vascular tone, natriuresis, and ADH responsiveness. Acute effects of NSAID intake, usually in high doses, include:

• Decreased glomerular filtration (renal ischemia that often develops in the setting of compromised renal perfusion, e.g. volume depletion or CHF)
• Salt and water retention (COX-1 mediated prostaglandins inhibit Na transport in the TAL and collecting duct; they also antagonize ADH function)
• Hyperkalemia (by blunting prostaglandin-related renin release, which decreases aldosterone formation; also, without prostaglandins to diminish Na reabsorption the loop of Henle, less sodium arrives at the distal nephron, meaning less Na-K exchange takes place)
• Interstitial nephritis
• Nephrotic syndrome
• Acute renal papillary necrosis (a severe sequela of renal ischemia)
  

However, most of these complications are readily reversed by discontinuing the offending NSAID. What about chronic renal dysfunction following long-term NSAID intake? In today’s medical environment, the evidence is weak. Prospective cohort studies in the Physicians’ Health Study (Rexrode et al, JAMA 2001) and the Nurses’ Health Study (Curhan et al, Arch Int Med 2004) failed to show an association between even high levels of cumulative lifetime NSAID intake and decrease in renal function.

While NSAID-induced chronic renal papillary necrosis (also called analgesic-abuse nephropathy) was a common occurrence several decades ago, it was largely due to use of phenacetin-containing analgesic compounds. Phenacetin has been off the market since 1983 in the United States, and has been banned in most countries*. Chronic papillary necrosis has been reported with other NSAIDS, but extremely rarely, and the incidence has not been determined.

So it seems I can’t hang my hat on my patient’s NSAID use as a cause of her CKD, although I am curious to see what happens to her creatinine after she stops taking them. If her renal function continues to decline, she may be headed for a biopsy.

*A web search for phenacetin yielded multiple internet retailers of phenacetin, most from mainland China. It looks like it is only sold in bulk (i.e. 25 kg drums)—an amount to make any nephrologist shudder.

The PPI Paradox

Millions of people take long-term proton pump inhibitors for acid-related GI complaints. These agents are very effective and appear to have an excellent safety profile. However, they may also have interesting effects on calcium and phosphate balance that I recently became aware of.

PPIs act via inhibition of the parietal cell H+/K+ ATPase, producing an ‘inhibitory complex’ which blocks HCl secretion and results in loss of the normal acidic environment of the upper GI tract. Ordinarily, this acidic milieu facilitates the release of ionized calcium from insoluble calcium salts, improving calcium solubility, which is necessary for its absorption. Reduced absorption of calcium is believed to explain the increased rates of osteopenia and fracture seen in medical states associated with achlorhydria, such as pernicious anemia and post-gastrectomy. Furthermore, several studies show that long-term PPI therapy, particularly at high doses, is associated with an increased risk of hip fracture. Also, long-term PPI use can lead to hypomagnesemia with a low fractional excretion of Mg, suggesting a similar mechanism may be responsible.

Based on these observations, I began to wonder if PPIs would decrease the efficacy of calcium-based phosphate binders, via a reduction in the ionized fraction available to bind phosphate in the gut. There is almost nothing written on this, apart from a single, small, prospective Japanese study that did indeed show that acid suppression significantly reduced the phosphorus binding ability of calcium carbonate, resulting in impaired phosphate control in hemodialysis patients.

Then, just to keep things interesting, I found another study that suggests that PPIs may have the opposite effect when given with non-calcium containing binders. In a retrospective analysis of 108 HD patients, more patients taking a PPI plus a phosphate binder achieved phosphorus control, defined as an average phosphorus level below 6 mg/dL and "a calcium × phosphate product level less than 55, than did those taking only a phosphate binder (76% vs 24%; P = .001). However, the benefits were only observed in those taking sevelamer; these authors did not replicate the findings from the aforementioned study from Japan. The mechanism behind this observation are not known.

So there you have it: there is a suggestion from this rudimentary evidence that PPIs may potentially impair phosphate control when given with calcium-containing binders, but paradoxically improve control when given with non-calcium containing binders. This could form the kernel of an interesting clinical study…

Board question of the week: PD-1

A 55-year-old woman with ESRD secondary to lupus nephritis presents to the PD clinic with volume overload. She reports decreased UF volume, despite the use of 4.25% dextrose exchanges over the last few weeks. She has been on PD for the last 12 years. Historically, she has been able to maintain her weight, despite being a rapid transporter. She denies any abdominal pain or cloudy fluid. An abdominal film shows proper placement of the PD catheter in the lower pelvis. A catheter assessment shows no flow obstruction. A 4 hour PET using 4.25% dextrose solution results in the ultrafiltration of 350cc on a 2L dwell. The D/P Cr level is reduced from her previous studies.

What is the most likely explanation for these results? Possible answers are listed in the poll on the upper right hand column.

The answer and explanation will be posted on Friday July 16th

Michael Lattanzio DO

*RFN board questions are meant to help introduce concepts about nephrololgy related diseases and do not represent actual questions seen on the ABIM exam.

Why do medicine residents specialize in nephrology?

RFN was curious to see why medicine residents decide to pursue nephrology training? Obviously, this in a decision that has multiple factors.

Results from the RFN poll (73 total)- 58% of all respondents to our poll thought that the ability to make challenging diagnoses was an important factor in making this decision. I was surprised to see that this was just as important as having an influential mentor (46% during residency and 12% during medical school). 47% of respondents felt that the mix of inpatient and outpatient care was important. As medical care becomes increasingly fragmented (i.e. hospitalist strictly stay in the hospital and family medicine/general internal medicine are increasingly restricted to the outpatient setting) nephrology remains one of the few internal medicine specialties with such a profound dual role. 31% of respondents felt that the ability to establish a long term relationship with a patient was important decision maker. ICU and kidney transplant exposure came in at 26% and 16% respectively. Interestingly, only 16% felt that nephrology being a financially rewarding career was important. I wonder what the results of GI or cardiology poll would look like? The future of nephrology is in our hands. Recruiting interested medicine residents in extremely important to ensure that our field continues to thrive. The field of nephrology has many interesting facets that are unique. I welcome any comments about the poll or if anyone has other reasons they chose nephrology please let us know.

It appears that most people decide to specialize in nephrology because it is challenging, offers an exposure to a wide array of patients (i.e. ICU vs. inpatient vs. transplant vs. outpatient) and they were significantly influenced by a mentor.

Follow the patient, not the number

As a nephrology fellow, I find it somewhat challenging to follow a patient with advanced CKD (eGFR, MDRD 8-10). However, I do find this process rewarding as it truly allows for the establishment of a substantial relationship with your patient. I follow the patient every 1-2 months and ask at each clinic visit if they are experiencing any uremic symptoms. Most of the time they say no and I go about performing an exam and review their labs. With the lack of randomized controlled trials to answer the question about what the optimal eGFR is to start renal replacement therapy we truly have to "listen" to the patient. However, as the symptoms of uremia are often insidious, a patient may not recognize how bad they really feel. I often wonder if I am putting a patient at risk by "waiting" for the development of uremic symptoms. Several recent observational studies have suggested that starting renal replacement therapy early may, in fact, be harmful.


Enter the IDEAL trial (Initiating Dialysis Early and Late). Published in the NEJM on June 27th, 2010. This trial randomized 828 patients (in Australia and New Zealand) with advanced CKD (cockcroft eGFR 10-15ml/min) into 2 groups according to when renal replacement therapy (RRT) is initiated.

1. Early RRT initiation group- 10-14 ml/min
2. Late RRT initiation group- 5-7 ml/min

However, the decision on when to initiate RRT was left to the discretion of the treating physician in the late initiation group. The primary outcome was death from any cause and secondary outcome were cardiovascular events, infections, quality of life and dialysis related complications. The patient population was mostly white (70%), male (64%), average age of 60, DM accounted for 1/3 of the ESRD, PD was the planned form of RRT initiation in 195 patients in the Early RRT group and 171 in the Late RRT group. Hemodialysis was the method in 188 in the Early RRT and 215 in the Late RRT groups. Both groups had been followed by a nephrologist for an average of 2.5 years before being enrolled in the study. Average creatinine at time of enrollment was 6 mg/dL.
There was no statistical difference in either the primary or secondary outcome in both groups. Interestingly 322 patients (76%) in the late RRT initiation group were started on some form of RRT secondary to mostly uremic symptoms or fluid overload before reaching an eGFR below 7.
(cockcroft gault/MDRD) eGFR at randomization and initiation of RRT-

• Early group start eGFR (13/9.8) --> 1.5 months average before initiation, eGFR (12/9)
• Late group start eGFR (13/9.9) --> 7.8 months average before initiation, eGFR (9.8/7.2)

In conclusion, I agree with editorial that accompanied this article. The majority of patients in the late group were initiated on RRT secondary to symptoms of uremia. Waiting for this to occur did not adversely affect the outcome in the late initiation group. Providing excellent pre-ESRD care to all patients with CKD is paramount. Getting timely access and providing medical therapy for complications of hypertension, fluid overload, electrolyte/acid-base derangements while listening closely to the patients symptoms of uremia, as we already do, seems to trump the lab value (in this case the estimated glomerular filtration rate). The decision to initiate renal replacement therapy needs to be individualized, not simply generalized by a lab number. Dr. Simon Prince has written a nice blog and video-blog piece on this article as well.

Economist discussion on whether trading organs should be allowed

Following on from recent posts on the subject by Jamil, The Economist are hosting a live web debate on the issue of organ trading now. Join in on the discussion here.

Fibroepithelial polyp of the lower urinary tract

I wanted to share a case of a 35-year old man with hypertension and reduced renal function (GFR about 70). Family history was significant for a paternal grandmother and mother with hypertension. No evidence of secondary causes of hypertension including renal artery stenosis, adrenal adenomas, pheochromocytoma, etc. After further questioning a history of urinary frequency was elicited. Ultrasound was done which surprisingly showed bilateral moderate hydronephrosis. Urologic work up included urodynamic studies which showed high bladder pressures and evidence of a bladder outlet obstruction. A cystoscopy showed a possible fibroepithelial polyp (similar to one pictured).

Fibroepithelial polyp of the lower urinary tract is a rare disorder. It usually occurs in pediatric patients but may develop in adults. It is considered non-malignant and treated with a transurethral resection. They usually do not recur. The differential diagnosis also includes a urethelial papilloma and inverted papilloma, both of which are benign but require periodic surveillance for recurrence with cystoscopy. For further reading.

Cisplatin induced hyponatremia; looking deeper

Cisplatin based therapy for the treatment of solid organ tumors is commonly associated with several renal abnormalities including;

*hypokalemia
*hypomagnesemia
*hypocalcemia
*hypophosphatemia
*fanconi-like syndrome
*acute kidney injury

We have all seen these complications on the renal consult service at least once. However, less commonly known is that cisplatin can cause hyponatremia. SIADH is commonly blamed for the cause of hyponatremia in the setting of a patient with a malignancy receiving cisplatin based chemotherapy, however other causes are often overlooked.

Renal salt wasting syndrome (RSWS) due to cisplatin has rarely been reported and is often confused with SIADH as a cause of hyponatremia (as discussed by Nate in a prior post). Increased urinary sodium (more than the intake) and increased urinary output in a hypovolemic patient are the key findings that help in differentiating this entity from SIADH (Table). Knowing this difference between these entities is important as RSWS is treated with sodium supplementation as opposed to water restriction with SIADH. Cerebral salt wasting has similar presentation as RSWS but has an associated cerebral lesion.










How hyponatremia occurs with cisplatin therapy can be understood by reviewing the mechanism of cisplatin nephrotoxicity. Briefly, cisplatin is a tubular nephrotoxin and causes;

• Dose dependant nephrotoxicity by particularly affecting the S3 segment of the proximal tubule, and to a lesser extent the loop of henle and the distal collecting system.

• Cisplatin enters the cells via the OCT2 transporters on the basolateral surface.
• Leads to decreased ATPase and mitochondrial activity.
• Activates proinflammatory cytokines
• Induces hypoxia
• All of which contribute to cell apoptosis and death.
  

This is clinically manifested by reduced GFR causing a rise in serum creatinine and salt wasting due to impaired absorption of sodium in the proximal tubule and the loop of henle leading to urinary concentration defect.

Cisplatin, interestingly, may decrease the abundance of aquaporin channels in the cortical and medullary collecting duct, as shown in animal studies, thereby further contributing to impaired urinary concentration and polyuria. This may, in fact, limit the degree of the hyponatremia (secondary to decreased water reabsorption) that develops with salt wasting from proximal tubule dysfunction. Not surprisingly, patients with cisplatin nephrotoxicty often tend to be quite polyuric.

In conclusion, why cisplantin induced RSWS occurs so rarely, is unclear. It is possible that the condition may be under reported or frequently overlooked.

Viresh Mohanlal, MD

ACE inhibitors and PD

Back to the subject of ACE inhibitors again. There are a number of reasons why ACEi might be particularly beneficial for patients on PD and two recent editorials in KI and CJASN laid these out very well.

1. Preservation of the peritoneal membrane
2. Preservation of residual renal function

Peritoneal mesothelial cells produce angiotensin II in response to glucose and dialysis solutions. This stimulates the release of pro-inflammatory TNF-alpha and IL-6 and also leads to upregulation of profibrotic factors (TGF-beta) and angiogenic factors such as VEGF.

This causes increased submesothelial zone thickness and neoangiogenesis which leads to increased vascular permeability and small solute transport. This in turn leads to faster absorption of glucose with subsequent loss of the osmotic gradient and UF failure. This ‘high transport’ state is associated with a worse long-term prognosis.

As Lisa mentioned in a previous post ACE inhibitors appear to have a beneficial effect on this process. They have been shown to decrease the expression of TGF-beta and VEGF in the peritoneum in response to glucose.

When rats were exposed to high glucose concentrations and were treated with enalapril or placebo, ACE inhibitor-treated rats had reduced TGF-B levels, reduced peritoneal thickness and improved UF. There have been a small number of mostly retrospective studies in humans comparing patients on and off ACE inhibitors and although no survival benefit has been noted, ACE inhibitors have been shown to increase Kt/V and prevent the increase in small solute transport possibly preserving UF in the long term.

The CANUSA and ADEMEX studies both found that the most important factor in predicting survival on PD was residual renal function. In the CANUSA study, for every 5L/week increase in residual function, there was a 12% increase in survival. Peritoneal clearance and peritoneal UF were not associated with survival. Increased residual function has been associated with better BP control, less LVH and a decreased risk of peritonitis.

In small trials, both ramipril and valsartan have been shown to decrease the rate of loss of residual function in patients on PD and at the end of one year, patients treated with ACE inhibitors were less likely to be anuric. This effect was independent of BP control and was seen in normotensive as well as hypertensive patients.

So the question arises, should we be using ACE inhibitors routinely in PD patients even if they are normotensive? The jury is still out on that one and larger studies are needed to determine the answer.

Proteinuria: The glomerulus isn’t always to blame

We usually associate proteinuria with a defect in the glomerular filtration barrier, but it is useful to remember that the proximal tubule (PT) also plays a role in resorption of proteins. Nate discussed this controversy in a prior post. In equilibrium, small amounts of low molecular weight (LMW) proteins are filtered through the normal glomerulus. Once in the PT, two receptors called megalin (a member of the LDL receptor family) and cubulin are responsible for resorption of those filtered proteins, resulting in a virtually protein-free ultrafiltrate. A third protein, amnionless (AMN) also plays a critical role by escorting cubulin to the cell membrane surface. The megalin-cubulin-AMN receptor complex is able to bind to a variety of LMW proteins and internalize them within PT cells, where they are broken down inside lysosomes. Interestingly, cubulin was initially discovered to bind intrinsic factor-B12, and deficiencies in cubulin lead to B12 malabsorption (see below).

Defects in megalin-cubulin-AMN mediated protein endocytosis are responsible for several clinical syndromes, listed below:

1. Dent’s disease – is an X-linked defect in a Cl-/H+ exchanger expressed in the proximal tubules and collecting duct intercalated cells. Cl-/H+ knockout mice have very low levels of cubulin and megalin expression, which would explain the LMW proteinuria seen in affected patients. It is less clear how the defect causes PT damage leading to the aminoaciduria, glycosuria, phosphaturia, and hypercalciuria that characterize this disease.
2. DB/FOAR syndrome – a genetic defect in LDL receptor protein 2 encoding megalin results in a lack of functional megalin. The syndrome leads to hypertelorism, myopia, hearing loss, and proteinuria, along with many defects in fetal development. If you really wanted to know, DB/FOAR stands for Donnai-Barrow/facio-oculo-acoustico-renal syndromes, described separately but now known to be the same entity.
3. Gräsbeck-Imerslund disease – a autosomal recessive defect in either cubulin or AMN synthesis, these patients present with megaloblastic anemia (cubulin deficiency leads to selective B12 malabsorption, as mentioned above) and proteinuria.