The Diet Pill and the Deadly Acidosis

I was recently called to evaluate an obese patient with profound metabolic acidosis who was admitted to the hospital with change in mental status and poor oral intake for several days. Her admission labs revealed severe hyperglycemia (glucose 776 mg/dL) and normal anion gap hyperchloremic metabolic acidosis (serum pH of 7.11 and serum bicarbonate of 7 mmol/L). She was initially suspected as having diabetic ketoacidosis due to miscalculation of the anion gap by the admitting team who used the corrected serum sodium and not the actual sodium, and as expected, her acidosis did not resolve despite the correction of hyperglycemia with intravenous fluids and insulin.

Her urine pH was 6.2, urine anion gap was 12 (no ketonuria) and fractional excretion of bicarbonate was 17% suggesting the possibility of mixed renal tubular acidosis. The case appeared like a puzzle until close questioning with the family revealed that her primary care physician had started the patient on topiramate (200mg/d) few weeks back for obesity. Interestingly, there has been a recent increase in literature about the risk of hyperchloremic metabolic acidosis in adult patients on topiramate therapy.

Topiramate is primarily approved for use as an anticonvulsant in patients with partial and generalized seizures and for migraine prophylaxis but its use as an antiobesity drug is among the several “off label" indications. In clinical trials, up to 32% of patients receiving topiramate 400mg/d in divided doses had evidence of normal anion gap metabolic acidosis and up to 7% had moderate to severe metabolic acidosis (less than 17 but greater than 5 mmol/L).

So, how does topiramate cause hyperchloremic normal anion gap metabolic acidosis? Carbonic anhydrase (CA) catalyzes the conversion of CO2 to HCO3- and H+ ion in the proximal tubule and in the type A intercalated cell of the cortical collecting duct. CAII is the most predominant isoform of CA present in the kidneys.Topimarate has been shown to inhibit the CAII activity thereby causing increased excretion of filtered bicarbonate leading to proximal renal tubular acidosis and impairment of the distal acidification leading to distal renal tubular acidosis. Patients with topimarate induced metabolic acidosis therefore tend to have an alkaline urine, positive urine anion gap, low urinary citrate levels indicating distal renal tubular impairment and increased fractional excretion of bicarbonate with elevated B2 microglobulinuria suggesting proximal tubular impairment.

Besides metabolic acidosis, topimarate use has been associated with 10 fold increased risk of nephrolithiasis and is largely due to hypocitraturia that develops in these patients with failure of renal acidification. These patients are also at risk for osteoporosis for the same reasons. Non ambulatory patients, ketogenic diets, hypovolemia and higher dosage (400mg/d) is associated with an increased risk of renal complications as outlined above. Although measurement of topiramate levels (3-25mcg/ml) is useful in diagnosing toxicity, one third of patients with therapeutic levels have evidence of hyperchloremic metabolic acidosis.

Topiramate induced metabolic acidosis usually improves with discontinuation of the drug. Baseline and periodic laboratory monitoring is needed to evaluate the patients for the development or worsening of metabolic acidosis. Prophylactic alkali therapy seems reasonable but has not been systematically studied.

Coming back to our patient, it became quite apparent that hypovolemia due to poor oral intake and osmotic diuresis probably contributed to the severity of the hyperchloremic metabolic acidosis which resolved 5 days after discontinuation of the drug and bicarbonate supplementation. Her altered sensorium also cleared. The topiramate level was not sent in a timely manner to be of any clinical utility.

Viresh Mohanlal, MD.

Evaluation of primary aldosteronism: seeing is not believing

As you would have likely guessed by looking at the picture to the  left we often tend to believe what we see without giving much thought.  This is frequently true in the evaluation and management of patients with primary aldosteronism (PA) where the diagnostic tests are frequently misinterpreted and findings on imaging studies such as CT and MRI of the adrenal glands often guide therapeutic decisions.

Since the initial discovery of aldosterone producing adenoma by Dr. Jerome W. Conn in 1955, PA has emerged as the most common cause of secondary hypertension and accounts for up to 10-15% of all cases of hypertension in the general population (read this article). This notable rise in the prevalence of PA has been due to the widespread use of aldosterone renin ratio (ARR) as a screening test for patients with suspected PA, and less reliance on the presence of hypokalemia (present in less than 40% patients) as a prerequisite for the diagnosis of PA.  It is therefore important to remember that normokalemic hypertension is the most common presentation of PA and that the prevalence of PA increases with severity of hypertension. 

Although ARR is a good screening test, cut off values are variably reported in the literature, but generally speaking, a ARR of greater than 20-40 in the presence of morning (8am-10am) plasma aldosterone concentration greater than 15ng/dL and plasma renin activity ~0.5 ng/mL/h is acceptable and testing for this does not require a washout of antihypertensive medications (except aldosterone antagonists) despite the popular belief, and is practically impossible.  A positive ARR therefore, should always be followed with the suppression tests. Among the several tests that are available, oral or IV salt loading and fludrocortsone suppression test are more commonly used and are fairly comparable with moderate sensitivity and high specificity (~90%).  Details about how these tests are performed can be read here.

Once the diagnosis of PA is confirmed, differentiating between the subtypes, particularly solitary adenoma vs. unilateral or bilateral adrenal hyperplasia is crucial as definitive therapies differ.  This is best done by adrenal vein sampling (AVS), which although invasive and operator dependant, is the gold standard test to differentiate the subtypes. Diagnosis of APA is made when the aldosterone to cortisol ratio (A/C) from one adrenal is at least 4 times the ratio from the other adrenal gland (lateralization ratio).

However, instead of AVS, CT scan or MRI of the adrenal glands is more commonly used to differentiate subtypes of PA. CT scan of the adrenal glands is important in identifying young individuals (less than 40 years) with adrenal adenoma (≥ 1cm) or in identifying highly differentiated adrenal masses (greater than 3 cm). Beyond that, the utility of CT scan of adrenal glands to correctly identify the subtype of PA is limited (sensitivity ~77% and specificity ~75%) and the findings can often be misleading. In a large systematic review published in Annals, CT scan was concordant with AVS in only 60% of the cases for the diagnosis of PA. Reliance on CT scan instead of AVS to differentiate the subtypes would have led to inappropriate adrenelectomy in ~15% of the patients and inappropriate exclusion for unilateral adrenelectomy in 19% patients.  In 5%, wrong adrenal gland would have been removed. A study of 185 patients with adrenal incidentalomas in whom only 5% were found to have solitary adenomas further supports the argument that findings on the imaging studies should be interpreted with caution.

Finally, it’s important to remember that the benefits of adrenelectomy and mineralcorticoid antagonists in correctly diagnosed patients with solitary adenoma vs. unilateral or bilateral adrenal hyperplasia respectively, extend beyond just the resolution of hypokalemia and improvement in blood pressure. Recent studies have shown a decrease in cardiovascular mortality and prevention of late renal complications  such as proteinuria and chronic kidney disease.

Viresh Mohanlal, MD

Role of erythropoietin in acute kidney injury: what does the evidence say?

Since the discovery of Erythropoietin in 1977 and subsequent cloning of the gene in 1985, recombinant Erythropoietin (EPO) has been widely used in the management of anemia due to cancer, chemotherapy, and chronic kidney disease.

Although the endocrine effects of EPO in stimulating maturation and differentiation of erythroid precursor cells in the bone in response to hypoxia is widely known, the anti-apoptotic and anti-inflammatory properties particularly in the critical organs such as kidney, heart and brain were discovered only in the last decade.

Researchers from the United States demonstrated that EPO receptors are expressed in the renal tubular epithelial cells, proximal tubular cells, and mesangial cells. EPO induced activation of these receptors leads to activation of Janus activated kinase 2(JAK-2) pathway which in turn stimulates several other signaling pathways (MAPK,NFKB,STAT 3/5), all of which promote anti-apoptotic and proliferative proteins that increase cell survival (read this article).

With this knowledge, researchers from Australia demonstrated that EPO administration both in vitro and in vivo in doses up to 5000 U/kg in animals with ischemic AKI hastened cell recovery and prevented cell death. Several other researchers have demonstrated this effect in different injury models (hypoxia, ischemia-reperfusion, nephrotoxins, sepsis etc).

As would be expected, these promising results in animal studies led to a randomized, double blind, placebo controlled trial (EARLYARF) in 529 ICU patients who were identified at risk of AKI by urinary biomarkers(c-glutamyl transpeptidase and alkaline phosphatase ≥46.3). Administration of 100,000 units of EPO IV in 2 divided doses over 24 hrs did not reduce the risk of developing AKI, quite contrary to what was seen in animal studies.

In my opinion, likely causes for this discrepancy included:

1) Dosing in animals had been much higher (equivalent to up to 350000 units in humans).

2) Optimal timing of EPO administration might be an issue (within 6 hrs of injury)

3) Unclear, if the ideal urinary biomarkers were used.

Further studies with proper dosing and timing of EPO administration and early identification of patients with risk of AKI using ideal urinary biomarkers may answer this question best. Besides, the utility of administering EPO to ICU patients to reduce transfusions has already been refuted, is not cost effective and may be associated with 40% increased risk of thrombotic events (read this blog). This leaves us with no good indication to consider EPO in critically ill patients with AKI (not ESRD).

If you are a big believer of basic research, you may still want to consider EPO for its favorable actions, but with recent negative publicity EPO has been receiving, it appears like the clock is quickly moving towards “may be not or even no”.

An eye opener!

Call it serendipity or mere coincidence, I recently saw a patient with Prostate cancer treated with an experimental chemotherapy protocol that was sent to our clinic for evaluation of Fanconi syndrome and proteinuric stage 3 chronic kidney disease (1.5 g/d).I did a kidney biopsy which revealed extensive proximal tubulopathy with moderate interstitial fibrosis but no glomerular disease was noted. Interestingly, serum and urine protein electrophoresis with immunofixation was negative. Work up to find the underlying etiology of Fanconi syndrome was an exercise in vain. The etiology remained a puzzle until a case presented at ASN in Denver was an eye opener for me. This case introduced to me the possibility of Isolated Light chain proximal tubulopathy (LCPT) as a cause of Fanconi syndrome in my patient despite a negative serum and urine protein electrophoresis.

Briefly, plasma cell dyscrasias are characterized by excessive bone marrow production of immunoglobulin freely circulating in the plasma. Several pathologies are noted in the kidney and include:

1) Light chain (myeloma) cast nephropathy.

2) Monoclonal Immunoglobulin deposition disease

3) Amyloidosis

4) Tubulointerstitial nephritis

5) Cryoglobulenemia

Rarely, LCPT has been reported and often precedes the diagnosis of multiple myeloma, MGUS, and less commonly amyloidosis.Light chains, almost always, are kappa chains.

In a normal state, the light chains that cross the glomerular filtration barrier are endocytosed through glycoprotein receptors megalin/cubilin in the proximal tubule and are subsequently degraded by the lysosomal proteolytic enzymes into several amino acids. However, in patients with LCPT, the variable segment (VK1) of the kappa light chains is resistant to degradation by the lysosomal proteolytic enzymes and binds other fragments of light chains to form crystals that get deposited in the proximal tubular epithelium and cause disease. Clinical presentation is very varied and often includes renal dysfunction with fanconi syndrome, although these findings are not universal.

Histologically, on light microscopy (high power), pale, rhomboid intracytoplasmic crystals are seen in the proximal tubular epithelium. Immunofluorescence (IF) often stains positive for kappa light chains and electron microscopy is confirmatory for the pale crystalline structures in the proximal tubule epithelium.

However, the diagnosis of this condition may be difficult due to several reasons:

1) Clinical presentation is often heterogeneous and fanconi syndrome is not a universal presentation.

2) Detection of intracytoplasmic crystals in proximal tubule can often be missed without heightened suspicion.

3) SPEP with immunofixation can be negative and UPEP with immunofixation may be a less sensitive study (read this blog).

4) Standard IF staining for kappa light chain can be negative as antiserum may not always bind partially degraded kappa light chains.

It is therefore recommended that free light chain assays be performed along with IF following pronase-digestion (details here) or immunoelectron microscopy in cases where the diagnosis is not clear. Once the diagnosis of LCPT is made, extensive work up including skeletal survey and bone marrow biopsy is recommended to rule out plasma cell dyscrasias.

With this enlightenment, I called my pathologist, who reminded me that IF could not be done on my patient due to only one core of tissue, but she did promise to send the paraffin embedded section for IF. I have also asked my patient to get the free light chain assay.

Viresh Mohanlal, MD

Appropriate or inappropriate: stop guessing

In the evaluation of patients with hyponatremia (serum Na less than 135 mEq/L), differentiating hypovolemia from euvolemia is often challenging, particularly if the history and physical findings are unrevealing and frequently leads to misdiagnosis. This conundrum exists even for the nephrologists and often leads to guesswork. Measuring the antidiuretic hormone (AVP) levels is not helpful as most cases of hyponatremia have either appropriate or inappropriate elevation of AVP levels and despite frequent reliance on central venous pressure (CVP) measurements to determine the volume status, they are rarely measured in hypovolemic or euvolemic states and their accuracy is debatable.

Reliance on the urine biochemical parameters therefore becomes necessary. Urine electrolytes particularly low urine sodium (less than 30 mEq/L) is often used to distinguish these two conditions but can be misleading, as up to 30% patients with hypovolemia may have elevated urine sodium and on the flip side, up to 40% SIADH patients may have low urine sodium (low salt intake). A recent CJASN review of SAIDH nicely covers this. Urine osmolality is often elevated (greater than 100mosm/kg) and does not distinguish hypovolemia from euvolemia. Recent studies have therefore suggested that a combined use of urine sodium (UNa), fractional excretion of sodium (FENa) and fractional excretion of urea (FEUrea) would best help in differentiating these two states (diuretic use, renal failure, hypocortisolism and hypothyroidism excluded).

1) In patients with adequate urine flow (urine/plasma Cr less than140), a UNa less than 30, FENa less than 0.5% and FEUrea less than 55% indicates hypovolemia.

2) In patients with low urine flow (urine/plasma Cr greater than 140) an even lower FENa (less than 0.15%) and FEUrea (less than 45%) are recommended to capture all the cases of hypovolemia.
Low serum uric acid levels (less than 4mg/dL) and increased fractional excretion of uric acid (greater than 12%) are also useful in differentiating SIADH from hypovolemia, major exception being salt wasting syndromes (click here for review or here for a discussion about CSW vs. RSW). In these patients, unlike SIADH, correction of hyponatremia does not lead to improvement of hypouricemia and uricosuria, likely due to persistent proximal tubular defect causing impairment of uric acid absorption. Phosphaturia (FEPO4 greater than 20%), for the same reason also favors salt wasting, at least initially. Moreover, the plasma renin activity and plasma aldosterone levels are elevated in salt wasting but low in SIADH.

Although the interesting findings in these studies need further validation, they offer a completely different perspective and help us move away from complete reliance on assessment of volume status to make a correct diagnosis of hyponatremia, an exercise that often involves guesswork. Hopefully, the next time when we encounter hyponatremia, this new approach would help us to stop guessing.

Viresh Mohanlal, MD.

Something fishy?

A 30-year-old man was admitted to our hospital for evaluation of lung nodules detected during pre transplant evaluation for his stage V chronic kidney disease (CKD). Sounds routine, but what caught me completely clueless was when I was told that he had CKD due to lecithin:cholesterol acyltransferase (LCAT) deficiency. A prominent physical finding on meeting him was the presence of bilateral peripheral corneal opacities at such a young age. On questioning, the patient reported that he was diagnosed with this condition on family screening after his father died following massive myocardial infarction due to dyslipidemia at the age of 35. A nice case report from KI can be found here or from NDT here.

Familial LCAT deficiency is a rare but possibly under diagnosed autosomal recessive disorder reported in families of European ancestry and is characterized by

1. Dyslipidemia – extremely low HDL levels (less than 10 mg/dL), increased cholesterol: cholesterol ester ratio with elevated triglycerides and total cholesterol.
2. Presence of corneal opacities giving the fish eye appearance.
3. CKD with proteinuria by 3rd-4th decade. Biopsy findings typically include - mesangial matrix expansion and foamy appearance of the glomerular basement membrane (GBM) on light microscopy, lipid droplets in the mesangial matrix, GBM and podocytes on electron microscopy with foot process effacement and segmental or global sclerosis eventually.
4. Mild hemolytic anemia.

Briefly, LCAT is an enzyme synthesized in the liver and primarily bound to HDL. It plays a prominent role in esterifying the cholesterol in the HDL thereby creating a concentration gradient for the cholesterol to move out of tissues thus helping HDL to function in reverse cholesterol transport (from tissues to liver). In patients with the LCAT deficiency, HDL-C maturation does not occur as unesterified cholesterol remains within the tissues and an abnormal lipoprotein called lipoprotein X (unesterified cholesterol and lecithin) is formed in the blood from the surface of chylomicron remnants not metabolized due to this enzyme deficiency. These lipid accumulations within the tissues explain the classic findings in these patients.

Although the mechanism of kidney injury is unknown, it is believed to be likely due to direct injury to the glomerular filtration barrier from the lipid deposition and/or inflammatory response due to lipoprotein X mediated monocyte recruitment and eventual glomerulosclerosis.

In our patient the diagnosis of LCAT deficiency was made by measuring the plasma assays for LCAT at the age of 6yrs. He had albuminuria by the age of 16 yrs but was lost to follow up and later presented with chronic kidney disease and nephrotic range proteinuria. He subsequently underwent renal biopsy that showed the above classic histological findings. He now has stage V CKD and is later scheduled to undergo live unrelated kidney transplantation. Liver transplantation is also being considered to decrease his risk of recurrence following transplantation.

Although this case is unique and perhaps rare, it highlights the importance of family history and careful physical examination particularly in patients with unexplained nephrotic syndrome. Next time, in such situations look closely into the eyes, you may find something fishy.

Viresh Mohanlal, MD

Image Credit to Tara Lemana

Get it right …the first time

The whole fiasco about the antenna and reception issue with the iPhone 4 made me realize that unlike other professions, where several chances exist to rectify a problem, clinicians often have only one chance to get it right while caring for patients. This would apply particularly well in the management of patients with hemolytic uremic syndrome (HUS).

Diarrhea associated HUS (typical HUS) occurs more commonly in children with annual incidence of 3-5 cases/100000 and is most commonly caused by shiga-like toxin producing bacteria, notably O157:H7 strains of Enterohemorrhagic Escherichia coli (EHEC), though newer strains have being reported. Diagnosis is often confirmed by stool cultures but may be negative in 15% patients. These individuals often recover without any sequelae. Kidney transplantation offers excellent patient and graft survival in 3% patients who progress to develop end stage renal disease (ESRD).

On the flip side, atypical HUS is more frequently seen in adults and is commonly due to mutations involving complement factor H (CFH), I (CFI) and membrane complex protein (MCP). These are glycoproteins synthesized in the liver and play a major role in stabilizing the C3 convertase of the alternate complement pathway. Mutations in the genes that encode these plasma proteins and complement components (C3 and factor B) leads to unregulated activation of the alternate complement pathway, thereby precipitating atypical HUS. Low C3 levels therefore serve as a clue to the presence of atypical HUS in these patients.

Unlike typical HUS, patients with atypical HUS have high (25%) mortality, with progression to ESRD in up to 50-60%. Nate had a nice discussion about the use of Eculizumab (anti complement factor C5) in atypical HUS. Kidney transplantation (see recent review for more information) have variable outcomes in this subgroup, and in fact, live related donor kidney transplantation is contraindicated in patients with CFH and CFI mutations due to increased risk of occurrence of HUS in the donor and 80-90% chance of recurrence in the recipient in first 6 months following transplant.

Due to such varied outcomes, it is essential that the correct cause of HUS is identified at the time of presentation. It should be noted that presence or absence of diarrhea to differentiate these two types is not reliable and up to 20% patients with atypical HUS may have diarrhea as their symptom.Also, not all cases of atypical HUS have a family history of the disease. Correct diagnosis can therefore only be made if evaluation of patients with HUS includes assays for CFH, CFI, MCP, C3 and factor B at the time of diagnosis and prior to initiation of plasma exchange therapy in addition to routinely done tests such as stool studies for EHEC, shigella, campylobacter and salmonella, lupus serologies C3, C4, and ADAMTS 13 activity levels. Accurate identification of the cause of HUS can help the nephrologists in identifying patients who may or may not benefit from kidney transplantation and also for offering other treatment options such as combined liver and kidney transplantation for CFH/CFI mutations with pre operative plasma exchange and isolated kidney transplantation with preoperative plasma exchange for MCP mutations.

So, the next time you are consulted for management of patients with HUS, make sure you get it right...the first time.

Viresh Mohanlal, MD

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

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