Diagnosis&Management of Protein LosingNephropathy (PLN)
- Protein Losing Nephropathy preceeds renal failure; therefore clinical finding may not include azotemia
- Causes: often due to chronic immune stimulation (even common causes, such as pyderma, gingivitis, otitis, heartworm) with resultant accumulation of immune complexes (can be associated with complement) on the capillary walls and on nephron membrane(s), mesangial hyperplasia, (increase in mesangial substance)-->glomerular sclerosis; damage to tubule lysosomal membranes (affects abilitiy to absorb excess protein) results in damage to these, leakage of protein into the interstitium, casts, and further damage to tubular architecture. This is NOT an autoimmune phenomenon....it is due to antibodies directed against foreign antigen(s)!
- Clinical signs can include: pu/pd (often without azotemia), anorexia, peripheral edema; sometimes hypertension is noted, sometimes dyspnea (e.g. coagulapathy due to losses of coagulation proteins---> bleeding/anemia, or loss of anticoagulation proteins (e.g. AT III) resulting in thromboemboli).
- Laboratory findings usually are: hypoalbuminemia, elevated urinary protein:creatinine ratio (early in disease [and in the absence of lower urinary tract sediment]; later in the course of the disease, as the number of nephrons decreases, there is actually a reduction in renal protein losses!!!..i.e. a reduction in urinary protein:creatinine), normal or reduced urine specific gravity; ultimately, diagnosis, prognosis and progression is monitored via serial renal biopsies
- Treatment (of non-azotemic animals)
- Eliminate the underlying cause..if possible. Thisusually means an antigen search (in order to eliminate the cause of chronic immune stimulation). If the stimulation is the result of neoplasia or is idiopathic, then you are limited in what you can do here.
- protein restriction is controversial; excess dietary protein increases the GFR and exacerbates the damage to bowman's capsule & nephron and thus results in enhancement of protein losses.
- in non-azotemic animals, do not severely protein restrict (provide at least 2-3gms of high quality protein/kg per day).
- there is no direct evidence that sodium restriction is beneficial (though if hypertension is present, then reduction of sodium may be beneficial...in theory)!
- N3-fatty acids are useful since when they incorporate into renal membranes, there is decreased availability of arachadonic for conversion to thromboxane
- N3-fatty acids are precursors to "good" prostaglandins...that promote vasodilation and that suppress local lymphoid cell and platelet -mediated inflammation.
- Immunosuppressives (since most etiologies involve immune stimulation)? Dr . Churchill recommends Prednisolone (if not azotemic) at 2.2mg/kg x 3days, then tapering to zero..over two to three weeks. Dr. Grauer disagrees, considers prednisolone even detrimental. No beneficial effects of cyclosporine were seen but studies dealing with the usefullness of other immunosuppressive medications have not yet been reported...and there is some hope that one or more of these will be helpful.
- Address Platelet-Related damage from microemboli induced release of platelet inflammatory mediators
- some evidence that thromboxane-synthetase inhibitors ( e.g. Ridogrel®) may be useful in minimizing platelet aggregation.
- aspirin at 3.5 mg/kg bid may be beneficial
- ACE-inhibitors: there is evidence that early use of ACE-inhibitors actually
- reduces proteinuria
- reduces systemic AND intraglomerular blood pressure
- decreases thromboxane-2 and other inflammatory mediators
- tightens spaces between endothelium (minimize protein losses through these)
- reduces the growth of mesangial cells in response to proteinuria (thus reducing the incidence of sclerosis)
- Treat Azotemic animals according to traditional medical approaches to CRF.
New Treatment for Cushings Disease??
A poster was presented in which the drug, Trilostane (Modrenal®), a competitive (and reversible) inhibitor
of 3ß-hydroxysteroid isomerase, was successfully used to treat dogs with hyperadrenocorticism. Unfortunately, The commercial rights to this product is in question..and thus the future availabilty to veterinary medicine is also uncertain.
- Goals for the treatment of Diabetes are not new:
- Correct insulin deficiency (almost without exception, this mean TWICE DAILY dosing, dogs and cats)
- Minimize post-prandial hyperglycemia
- dietary fiber, carbohydrate source, feeding schedule
- alpha-glucosidase inhibitors
- Improve insulin sensitivity
- Insulin Types:
- Human recombinant insulin: unlike the predecessor insulins derived from pork and/or beef, human recombinant insulins are not antigenic and resistance due to antibody formation is not a problem. Though these newer types are metabolized more rapidly than the older, animal-derived versions, clinically there is very little problem achieving glycemic control with them in diabetic dogs. Starting dose (Humilin N or L) in dogs: 0.25-5.0 U/kg BID. Most will respond by 0.5-1.0 U/kg BID)
- PZI insulin , manufactured by Blue Ridge Pharmaceutical (800 374-8006, or firstname.lastname@example.org) is essentially the same formulation as that produced by Eli Lilly many years ago. Despite rumors to the contrary, (with very rare exception) this is a twice daily drug...even in cats, as judged by time of glucose nadir (most were 5-9 hrs; the longest was 18 hours). Beginning dose in cats: 1-2 Units twice daily (range which was effective may range from 0.2-1.4U/kg BID); this insulin is effective in ~80% of cats.
- Post-Prandial Hyperglycemia:
- Post-prandial hyperglycemia does NOT occur in the non-diabetic animal
- fiber binds glucose, resulting in reduced rate of glucose absorption
- soluble fiber binds glucose better than insoluble fiber.....though there is little difference, experimentally in the effects of soluble vs mixed dietary fiber in achieving glycemic control
- there are many different sources of fiber(s) that are added to commercial diets...with some variability in responses
- 8% soy-fiber (which is mixed fiber type) worked very well
- mix of 5% guar + cellulose (e.g. Waltham) worked well
- beet pulp/methycellulose (mixed fiber...the latter is semisynthetic, and also adds viscosity ([rationale??]) in Iams glucose control diet was also effective.
- NEVER ADD FIBER TO DIET OF EMACIATED OR THIN ANIMAL...rely solely on insulin to control hyperglycemia
- Carbohydrate Source:
- The following achieved increasingly better glycemic control (from left to right= worst to best)
- Summary: Barley and and soybean as carbohydrates in diet were superior to rice or corn in effecting control of post-prandial hyperglycemia.
- Iams glucose control diet utilizes sorgham and barley as principal sources of carbohydrates...which is good
- Metallic Cofactors:
- preliminary data from studies of chromium picolinate (a necessary cofactor for insulin functionality) addition to the diet showed absolutely NO beneficial results towards glycemic control
- no adverse effects were observed in dogs given supplemental chromium picolinate.
- Acarbose (Precose®:)
- this is an alpha-glucosidase inhibitor that inhibits intestinal carbohydrate absorption, thus decreasing postprandial hyperglycemia
- it's use results in reduced requirements for insulin
- primary side effect is DIARRHEA...which can be severe
- use ONLY if insulin and diet alone aren't working
- dosing rules:
- start at 12.5-25mg/dog BID WITH FOOD
- titrate* effective dose by incremental increases, first to50mg/dog BID....eventually up to 100mg/dog BID
- Doses between 100-200mg/dog invariably produce diarrhea...and are best avoided
- *titrate until you see one of the following responses:
- Improve Insulin Sensitivity
- Decreased tissue response to insulin occurs with
- Diabetogenic drugs
- Prolongued hyperglycemia
- Decreased insulin availability occurs with pancreatic disease (immune-mediated...not amyloid in dogs) resulting in relative insulin deficiency
- Improved insulin sensitivity occurs with:
- correction of obesity
- control of concurrent disorders
- avoidance of diabetogenic drugs
- Insulin sensitizing drugs for poorly regulated animals (without knowing the underlygin etiology)
- Biguanides (metformin, Glucophage®):
- block gluconeogenesis by the liver and devreases intestinal glucose absorption
- may promote fatty acid oxidation (helpful in obese animal?) but does not cause lactic acidosis
- will NOT cause hyPOglycemia
- May be helpful when there is concurrent Cushing's disease
- May be useful if used with other hypoglycemic drugs
- Should not be used with concurrent renal or liver dysfunction
- Cat 50mg/cat
- Dog 2mg/kg BID
- Thiazolidinediones (Avandia®, Rezulin® ...is no longer in the market)
- Enhance actions of endogenous and exogenous insulin at target tissues: muscle, fat and liver
- Has no effect in the normal animal
- There are reports of hepatotoxic effects in humans using Rezulin...and this drug is no longer available in the United States. Safety studies on veterinary patients are unavailable
- Dose: there are various anecdotal dosage regimens for Rezulin® (but this drug isn't available now)
Fever of Unknown Origin Update
- drug-related (e.g. tetracycline)
- primary immune-mediated disease
- tissue trauma
- vaccine (e.g. calicivirus vaccination can induce an FUO including polyarthritis in 7-10 day)
- Diagnostic Approach
- Get a good history (single vs multiple cat household, vaccinations, travel, fighting propensity, ecto/endoparasites)
- Get a PREY history
- find out what is the favorite prey of the affected pet....this can be helpful, as follows:
- cats that hunt songbirds can get songbird fever (Salmonella); salmonella infection can manifest with systemic signs without any diarrhea!
- cats that hunt rodents are, potentially exposed to Yersinia and to Toxoplasma
- cats that hunt rabbits are, potentially, exposed to Francisella
- cats that dabble with cockroaches are also at risk of contracting Toxoplasmosis
- Good physical exam..including fundic exam
- ocular exam will help establish index of suspicion for Toxoplasma,Felv, FIV, FIP, FHV, Bartonella and systemic mycoses (Dr. Mike Lappin at Texas A&M has offered to do a free PCR for FHV and Bartonella sp.)
- routine panel (CBC, Chemistry panel)..usually see leukocytosis, but may not see localizing abnormalities
- if consistent with prey/other history...Toxoplasma titer (IgM)
- any signs of anemia or hemolysis...strongly consider Hemobartonella (this is a Mycoplasma...not a Rickettsia, as once thought). These cats MUST get Doxycycline (plus prednisone...)
- Heska® does PCR test for Hemobartonella that best distinguishes large (pathogenic) form from small (nonpathogenic) form.
- Survey Radiographs may be appropriate
- Blood Culture ...may sometimes be appropriate
- Fecal Culture (e.g. if Salmonella suspected, even if no gastrointestinal signs)
- arthrocentesis (e.g. if polyarthritis...mycoplasma, ehrlichia, or viral)
- rickettsial titers (Ehrlichia)
- bone marrow virus isolation
- ANA, Coombs..if agglutination..immune-mediated disease suspected
- Empirical Treatment
- if no response to initial antibiotic regimen then change antibiotics, e.g to clindamycin, enrofloxicin or others*
- low dose aspirin MAY be useful
- low-dose glucocorticoid IF immune-mediated origin (e.g. with hemobartonella)
- Ancillary treatments are based on the results of additional laboratory tests and the responses to treatment
*There was considerable discussion of rationale for antibiotic choices and also a related discussion regarding the transmission and approaches to the diagnosis and treatment of hemobartonellosis. The use of Interferon at very high (10,000U/kg qd)and low (30U qd) doses as well as L-Lysine (250mg q12hr q12hr with food) for the treatment of FHV, and possibly effusive FIP (the interferon, not the L-Lysine) was .examined.
The meeting was held in Seattle...and Seattle Mariners manager, Lou Pinella, had a few choice words for attendees...