Rapidly progressive glomerulonephritis can be a confusing topic. Thankfully, Dr. Margaret Ivanov, one of our awesome nephrologists, dropped by our Hillcrest morning report today and offered some clinical pearls. We discussed the case of a middle-aged man with no history of renal disease who presented with an elevated serum creatinine to the mid-5’s. He has no significant medical history and takes no medications. His urinalysis revealed significant proteinuria and hematuria. Serum studies are positive for ANA and anti-dsDNA, and a renal biopsy showed thrombotic microangiopathy superimposed on a background of class IV lupus nephritis.
In a patient with new renal impairment, you should always ask about medication use, urinary symptoms, and other associated symptoms. Constitutional, mucosal, respiratory, GI, neurologic, hematologic, and dermatologic signs/symptoms may suggest the presence of an underlying disorder. Be sure to also do a good volume assessment to help determine if the patient requires diuresis and/or renal replacement therapy.
A urinalysis is an important first step in the evaluation of AKI. RPGN is a clinical syndrome characterized by rapid loss of renal function (over days or weeks) and a nephritic UA (hematuria with or without proteinuria). Urine microscopy will reveal RBC casts and dysmorphic RBCs. Dr. Ivanov pointed out that the automated process used to result UAs will not disclose the presence of RBC, WBC, and other casts and that urine microscopy will have to be done separately.
We then talked about the workup of RPGN (see below). These studies are typically sent in parallel because the etiology of RPGN cannot be reliably determined based on history and exam alone. (Many of these studies are send-outs and may take days to over a week to result.) Reasons to pursue a renal biopsy include unexplained AKI and an active urinary sediment. The classic pathologic finding in RPGN is crescentic glomerulonephritis. Light microscopy, electron microscopy, and immunofluorescence can help identify the cause of the RPGN. In some cases, multiple processes may be seen on renal biopsy. The biopsy also helps inform treatment and prognosis.
Key Learning Points:
RPGN is a clinical syndrome characterized by a rapid loss of renal function (typically over days/weeks) and nephritic syndrome (hypertension, hematuria, variable proteinuria, dysmorphic RBCs, RBC casts).
The classic pathologic finding is cellular crescent formation in the majority of examined glomeruli due to fibrin deposition and cell proliferation (“crescentic glomerulonephritis”).
A renal biopsy is generally indicated in patients presenting with rapidly progressive glomerulonephritis to ascertain the etiology, determine its chronicity, and inform patient prognosis.
Thank you, Dr. Ivanov, for joining us today!
Medical Spanish Word of the Day: (el) análisis de orina = urinalysis
During the new interns’ very first Hillcrest morning report today, we covered the quintessential medicine topic of hyponatremia. We shared the case of a frail elderly woman with a history of diffuse large B-cell lymphoma who presented with hyponatremia of subacute onset, down to a sodium of 122. She had nausea, vomiting, and generalized weakness and was admitted for treatment of her hyponatremia. Laboratory studies–including a low serum osmolality, a high urine sodium, and a urine sodium–were consistent with SIADH (syndrome of inappropriate antidiuretic hormone secretion). She was ultimately found to have a recurrence of her lymphoma affecting the hypothalamus, thought to be the cause of her SIADH. She was started on fluid restriction and urea.
We discussed one diagnostic algorithm for hyponatremia. The first step is to confirm that the hyponatremia is hypotonic (by measuring the serum osmolality) and not related to a laboratory error/artifact or the presence of another osmolyte (classically glucose). Then, measure the urine osmolality to determine whether ADH is the cause of hyponatremia. If urine osmolality is low (typically below 100-200), the process is ADH-independent; otherwise, the process is ADH-dependent (see diagram below). When the volume status is not apparent, the urine sodium can be used as a guide to determine whether the effective circulating volume is reduced (as in hypovolemic and most hypervolemic states), but keep in mind that diuretics can elevate the urine sodium and cloud the picture.
Our stellar nephrologist, Dr. Tyler Woodell, then talked us through the management of SIADH. If hyponatremia is severe and associated with significant symptoms, hypertonic saline (e.g., 100-150 mL of 3% NaCl repeated up to 2-3 times) can be given. Recall that isotonic fluids can in fact worsen hyponatremia in the setting of SIADH. Fluid restriction is the mainstay of SIADH treatment, but in some cases, additional solutes, in the form of salt tablets or urea packets, may be required. Our patient improved with treatment and was discharged with plans for outpatient treatment of her lymphoma.
Thank you to Dr. Woodell for being part of this memorable morning report!
Medical Spanish Word of the Day: el sodio = sodium
(Bonus: el potasio = potassium, el calcio = calcium, el magnesio = magnesium)
Today we reviewed a case of an elderly female with PMHx of symptomatic bradycardia s/p PPM initially transferred from OSH to cardiology service for PPM site infection and MSSA bacteremia. Patient was found to have worsening oliguric AKI and was transferred to medicine for further workup and treatment.
Residents and medical students broke out into teams and came up with an initial differential for the etiology of the AKI based solely on patient’s hospital course and medications. They were then given the results of the urinalysis and urine protein/Cr ratio and we discussed how these results change and narrow our differential. (It really was all in the urine!). We then went through a model schema for intrinsic AKI based on anatomical locations: vascular, glomerular, tubular, and interstitial. We then returned to the case with a diagnosis of infectious glomerulonephritis and reviewed renal biopsy findings. Thank you to our expert discussant, Dr. Abdelmalek, for teaching us how to narrow our differentials for AKI and how to narrow initial testing based on most likely etiologies!
This morning we welcomed Dr. Dena Rifkin, nephrologist extraordinaire, to discuss the limitations of serum creatinine and the use of Cystatin C as an alternative for the estimation of renal function. We started by considering a 59-year-old man that presented to primary care clinic to discuss an elevated Cr to 1.43 (eGFR of 46). There was no clear sign of personal risk factors for CKD, although he occasionally used Ibuprofen and had a family history of Type II Diabetes and Hypertension. He had no microalbuminuria and his Cr was stable compared to three years prior. We obtained a Cystatin C level that indicated an eGFR of 82.
We then discussed why serum creatinine needs to be interpreted within the context of the patient’s physiology and how estimation calculators (including the preferred CKD-EPI equation) make adjustments for age, race, and sex. Cystatin C is an alternate biomarker produced by all nucleated cells that is freely filtered by glomeruli that avoids those problematic corrections. Cystatin C allows for increased detection of GFR reductions in the “creatinine blind range” where large changes in GFR are not reflected by substantial changes in GFR. Caution needs to be exercised when using Cystatin C in inflammatory states (infection, malignancy) and obesity as those will create higher levels of the protein. We then went through three patient cases that demonstrate the discrepancy in eGFR when using serum Cr versus CysC.
Cystatin C is available with rapid turnaround times at both the VA and UCSD – use it today!
Tuesday morning report at the VA was all about diuretics. We presented a case of a 73-year-old man with history of CHF, CKD and T2DM who presented with progressive dyspnea, bilateral lower extremity swelling, orthopnea, and abdominal distension. Physical exam showed evidence of volume overload with 3+ pitting edema, elevated JVD, and bibasilar pulmonary crackles. We considered various common triggers of heart failure exacerbation before diving into a discussion of diuretics.
Key points that we highlighted:
Decongestion with resolution of symptoms and edema is achieved through “diuresis” = loss of sodium (natriuresis) + loss of water (diuresis). That is why sodium-limited diet is crucial in treatment of fluid overload.
Loop diuretics function as “threshold” drugs that need to achieve a sufficient concentration in order to work. The natriuretic threshold is higher in patients with acute CHF than in healthy persons. That is why hospitalized patients require loop diuretic doses that are higher than stable outpatient doses.
Loop diuretics exhibit a “ceiling” effect and doses above the ceiling will not increase the amount of natriuresis. Acute CHF shifts the relation between plasma diuretic concentration and sodium excretion to the right and reduces the “ceiling.”
Patients with chronic diuretic use develop post-diuretic sodium retention and decreased efficacy with each subsequent loop diuretic dose. That is why loop diuretics are dosed multiple times daily and why patients need a net negative sodium balance each day.
Chronic loop diuretic use leads to distal tubular hypertrophy and once maximum loop diuretic effect is reached, auxiliary diuretics are sometimes used (thiazide, aldosterone antagonists, carbonic anhydrase inhibitors). We discussed specific situations you may consider using these agents.
Ethacrynic acid is the loop diuretic of choice in patients with sulfa allergy.
For further reading, check out this review from the NEJM:
Ellison DH, Felker GM. Diuretic Treatment in Heart Failure. N Engl J Med. 2017 Nov 16;377(20):1964-1975.
Our amazing resident, Dr. Masih Barat, presented a case of an 88-year old woman with history of HTN and diet controlled T2DM who was prompted to come for evaluation of a low sodium value discovered on outpatient labs. History was notable for non-specific symptoms of subacute loss of energy, nausea, poor appetite, and increased forgetfulness (per family). She was euvolemic on exam and her labs showed a low serum osmolality (consistent with a true hypotonic hyponatremia) and low urine osmolality. This pointed to an ADH-independent cause of hyponatremia. Given her history, these findings led us to determine that food insecurity (“tea and toast” diet) was the cause of her low sodium. We continued the discussion by developing a diagnostic schema for hyponatremia. Thank you to our nephrologist extraordinaire, Dr. Joe Abdelmalek, for sharing clinical pearls and discussing the mechanism behind the body’s sodium and water physiology.
This morning we presented the case of a middle aged man with a history of DM2, CKD for whom the medicine service was consulted due to persistent hyperkalemia. The patient was found to have a notable normal anion gap metabolic acidosis. The patient’s medications and hospital course were reviewed, which were not suggestive of hemolysis, rhabdomyolysis, AKI, which led the team to start considering the possibility of hypoaldosteronism in setting of Type IV RTA. To do this, though we reviewed the different types of RTA and how they may differ on initial work up. We also discussed the Urine Anion Gap = UNa + UK – UCl, and how it is an indirect measure of NH4+ excretion. Very negative UAGs (-20-50) suggest a Type 2 RTA (promixal RTA) due to the preserved ability to excrete acid, which is indirectly reflected in Urine Cl-. Very positive UAGs (+20 and above) suggest either Type 1 (Distal) or Type 4 (Hypoaldosteronism), with the distinguishing factor being whether the serum potassium is elevated (Type 4) or decreased (Type 1).
We also discussed the etiologies of each of the RTAs:
The patient’s work up revealed very low plasma renin activity and low aldosterone, as well as a positive UAG. Presumptive diagnosis was Type IV RTA, which can be seen in renal insufficiency in context of DM. Given that the patient was not hypertensive, florinef was started, which successfully reduced the patient’s serum K from 6.1 to mid 4.
Take Home Points:
Non-gap acidosis work up should include review of the usual suspects including GI losses, acid loads, medications, but if not revealing may need to consider RTAs.
UAG can be helpful to distinguish different types of RTA, though need to be aware that unaccounted acid buffers (phosphate and sulfates) which accumulate in CKD may negate the diagnostic effectiveness of UAG.
Treatment of Type IV Hyperkalemic RTA consists of removal of any of the large group of offending agents, or treatment with mineralocorticoid replacement in settings of primary adrenal insufficiency or hyporeninemic hypoaldosteronism. Thiazide diuretics and/or loop diuretics, in lieu of mineralocorticoids, can be used in settings of concomitant HTN or CHF.
Thank you to Viet Nguyen (Renal Fellow) to helping with this challenging case!
Today, the help of our amazing discussant Dr. Tomaz Beben, we discussed the case of an elderly gentleman who had recently undergone renal transplantation and presented with asymptomatic hemoglobin drop picked up on routine lab monitoring. We used this time to discuss some of the unique aspects of transplant medicine including additional questions to ask in the history as well as a review of some common immunosuppression (IS) medications. Ultimately, our patient was ruled out for GI bleed, and his hemoglobin drop was attributed to several of his transplant medications!
Consider some of the unique features of transplant medicine including donor recipient CMV status, peri-operative complications, history of previous rejection, and changes to IS regimen.
Most transplants require an induction phase (usually in the OR) with high dose steroids or anti-thymocyte globulin to prevent acute rejection, followed by a maintenance phase (started POD #1) which usually stabilizes by 6 months post-op.
Most maintenance IS regimens will contain glucocorticoids (lowest-tolerable dose), a calcineurin inhibitor (tacrolimus, cyclosporine), and an antimetabolite (mycophenolate).
Keep in mind some of the more common IS meds and their side-effects: Tacrolimus can cause neurotoxicity (ask about tremor), AKI, HTN, and hyperkalemia. Mycophenolate can cause diarrhea and cytopenias.
Today at the VA for our Maputo Case Conference, Dr. Neal Jones presented a fascinating case of an elderly gentleman presenting with subacute URI symptoms and progressive gross hematuria. He was found to have an AKI, pulmonary infiltrates on CXR, and multiple large renal cysts on CT. The patient was also noted to have significantly elevated CRP and ESR. He was initially treated for suspected pneumonia and infected renal cyst, but after several days without improvement and a steadily increasing creatinine, the work-up for his hematuria revealed PR3/C-ANCA positivity. A subsequent renal biopsy demonstrated diffuse crescentic glomerulonephritis, consistent with rapidly progressive GN 2/2 GPA! Dr. Tomasz Beben, nephrologist extraordinaire, then walked us through the nuances of GPA diagnosis and management. Our patient ultimately demonstrated signs of renal recovery after receiving high-dose methylprednisolone, rituximab, and several sounds of plasmapheresis. Thank you Drs. Jones and Beben for a great case presentation and excellent discussion!
Take Home Points:
GPA is uncommon, but with a constellation of sinopulmonary and renal findings, it should always be on the differential.
In the past, the diagnosis of GPA was made exclusively by renal biopsy, but many nephrologists are moving towards treatment after confirmed PR3/C-ANCA positivity.
Patients with GPA require pulse dose and then prolonged steroid use. For severe cases, there is also a movement to use rituximab rather than cyclophosphamide as an adjunct to steroids based on similar outcomes and a better side effect profile. Plasmapheresis may also be considered in severe cases!
This morning, one of our fantastic third year residents, Dr. Pokala presented a case of a young male with a history of IVDU who presented with acute onset right sided hemiplegia and aphasia and was found to have what appeared to be a brain abscess on CT Head, with evidence of midline shift and uncal herniation. After initial attempts to reduce intracranial pressure with mannitol and hypertonic saline were unsuccessful in maintaining a durable response, the patient was taken for urgent craniotomy and abscess aspiration revealing Strep sanguinis. The patient’s subsequent ICU course was complicated by resistant hyponatremia, which we discussed.
Based on newer guidelines published in JASN in 2017, a new diagnostic algorithm for interpreting hyponatremia has made some significant changes to the way we think about working up this complicated electrolyte disturbance– namely, there has been some data to suggest that the use of volume status to service as a the primary arbitrator of etiology has been difficult to employ. The new guideline uses more objective criteria such as Urine Osm and Urine Na to help guide the diagnosis as well as early recognition of symptomatic acute hyponatremia as an entity that requires immediate intervention.
We also discussed the rationale of maintaining normo- to slight hypernatremia in neurocritical care settings to avoid the deleterious consequences of acute hyponatremia with regards to cerebral edema, possible herniation, risk of coma and seizure. We further discussed the etiologies of SIADH, of which include CNS disturbance, malignancy with ectopic ADH production, surgery and its associated pain afferent triggers, pulmonary processes, HIV infection, hypothyroidism, hypopituitarism, and a multitude of medications.
Finally, we discussed the treatment modalities useful in correcting hyponatremia secondary to SIADH, focusing on treating the underlying medical process, fluid restriction. In more severe cases, use of high solute intake through salt tabs, urea tabs, hypertonic saline, and/or loop diuretics to augment free water excretion can be helpful and effective strategies.
Thank you Kusuma for a fantastic teaching case, and thanks to Dr Tyler Woodell for his expert input and helping us make sense of a confusing, yet vital core medical concept!