Pathophysiology and management of progressive renal disease.

Recently, the hypothesis that all renal diseases are inherently progressive and self-perpetuating has focused attention on adaptive changes in renal structure and function that occur whenever renal function is reduced. These glomerular adaptations to renal disease include increases in filtration rate, capillary pressure and size, and are referred to as glomerular hyperfiltration, glomerular hypertension and glomerular hypertrophy, respectively. Extrarenal changes, such as dietary phosphate excess, systemic hypertension, hyperlipidaemia, acidosis and hyperparathyroidism occur in animals with renal disease and may be contributors to progression of renal disease. Emphasis in the management of companion animals with renal disease has shifted to identifying, understanding and controlling those processes that play a role in the progression from early to end-stage renal failure. Advances made by veterinary nephrologists in the past 15 years permit resolution of old controversies, formulation of new hypotheses and discussion of unresolved issues about the nature of progressive renal disease in dogs and cats.

Relationship of lower urinary tract signs to seropositivity for feline immunodeficiency virus in cats.

A group of 41 cats with signs of lower urinary tract disease was compared to a group of 41 cats without any history of disease for prevalence of seropositivity for feline immunodeficiency virus (FIV). The group of healthy cats was similar in age and gender to the group of cats with signs of lower urinary tract disease. Three of the cats with lower urinary tract disease and one control cat were seropositive for FIV. This difference was not statistically significant. The most common cause of lower urinary tract signs was idiopathic. Only 7 cats had urinary tract infection, most associated with perineal urethrostomy or catheterization. Six of the cats with bacterial urinary tract infections were FIV negative.

Efficacy of azathioprine versus cyclosporine on kidney graft survival in transfused and nontransfused unmatched mongrel dogs.

Sixteen mongrel dogs had bilateral nephrectomy and received a renal allograft from an unmatched mongrel. One group of eight dogs was treated orally with azathioprine and prednisone; another group of eight dogs was treated orally with cyclosporine and prednisone. Four dogs of each group received four blood transfusions each prior to surgery. Mean survival time was nearly the same in the azathioprine-treated and the cyclosporine-treated dogs. Transfusions prolonged survival in the azathioprine-treated group but not in the cyclosporine-treated group. Retrospective measurement of whole blood trough cyclosporine concentrations indicated marked variation between dogs and in the same dog at different times. This variation may have influenced graft survival. Only one dog survived the 9-month period of observation, indicating that refinements of the techniques used in this study will be required for long-term survival of renal allografts in unrelated mongrel dogs.

Effect of therapy on susceptibility to urinary tract infection in male cats with indwelling urethral catheters.

Indwelling urinary catheters with a closed urine collection system were maintained in 30 male cats for 3 days after induction of irritant cystitis. All cats received subcutaneous fluids during the 3 days the catheters were in place. The effects of four different treatment regimens on urinary tract infection rates, incidence of urethral obstruction, and development of urinary tract lesions over a 10-day period were compared with results in a nontreated group. Treatments were 1) amoxicillin for 5 days PO; 2) prednisolone for 5 days PO; 3) both amoxicillin and prednisolone for 5 days PO; and 4) dimethylsulfoxide (DMSO) for 3 days intravesicularly. Euthanasia was done before the end of the 10-day experimental period if the cats had two bouts of urethral obstruction or if the cats became uremic for causes unrelated to urethral obstruction. Seven cats were euthanatized before the conclusion of the experiment. These cats had been treated with prednisolone, prednisolone and amoxicillin, or DMSO. All cats that received amoxicillin alone or no therapy survived the 10-day period. Mortality was due to repeated urethral obstruction or to uremia associated with pyelonephritis or papillitis. Urinary tract infection rate was similar in all groups. The group treated with prednisolone alone had the highest incidence of renal infection. Inflammatory lesions in the lower urinary tract were similar in all groups. In conclusion, persistent urinary tract infection often develops in cats with cystitis after indwelling urethral catheterization even when closed systems of urine drainage are used.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of enalapril versus placebo as a treatment for canine idiopathic glomerulonephritis.

A blinded, multicenter, prospective clinical trial assessed the effects of enalapril (EN) versus standard care in dogs with naturally occurring, idiopathic glomerulonephritis (GN). Twenty-nine adult dogs with membranous (n = 16) and membranoproliferative (n = 13) GN were studied. Dogs were randomly assigned to receive either EN (0.5 mg/kg PO q12-24h; n = 16) or placebo (n = 14) for 6 months (1 dog was treated first with the placebo and then with EN). All dogs were treated with low-dose aspirin (0.5-5 mg/kg PO q12-24h) and fed a commercial diet. At baseline, serum creatinine (SrCr), systolic blood pressure (SBP), and glomerular histologic grade were not different between groups, but the urine protein/creatinine ratio (UP/C) was greater in the EN group compared with the placebo group (8.7 +/- 4.4 versus 4.7 +/- 2.3). After 6 months of treatment, the change in UP/C from baseline was significantly different between groups (EN = -4.2 +/- 1.4 versus 1.9 +/- 0.9 in the placebo group). When data were adjusted for changes in SrCr (SrCr X UP/C) a similar significant reduction was noted ( 2.2 +/- 15.2 versus 8.4 +/- 10.1). The change in SBP after 6 months of treatment also was significantly different between groups (EN = -12.8 +/- 27.3 versus 5.9 +/- 21.5 mm Hg in the placebo group). Response to treatment was categorized as improvement (assigned a value of 2), no progression (assigned a value of 1), and progression (assigned a value of 0). Response was significantly better in the EN group (1.4 +/- 0.8) compared with the placebo group (0.3 +/- 0.5). These results suggest that EN treatment is beneficial in dogs with naturally occurring idiopathic GN.

Progression of chronic renal disease in the dog.

Progressive loss of nephron function may be caused by persistence of factors that initiated renal disease. However, newer studies suggest that nephron damage is self-perpetuating once renal mass is reduced to some critical level. Original theories on mechanisms of self-perpetuated nephron injury focused on intraglomerular hypertension and glomerular hypertrophy, but several other factors have now been incriminated, including tubulointerstitial responses, proteinuria, and oxidative stress. Studies of dogs with surgically reduced renal mass (remnant kidney model of chronic renal disease) have allowed investigation of the self-progression theory in this species. Use of this model eliminates pre-existing renal disease as a confounding factor. Data from these studies indicate that self-perpetuated renal injury is initiated when mild azotemia is induced (plasma creatinine concentration = 2 to 4 mg/dL). Thus, with naturally occurring renal disease(s), it is likely that self-perpetuated nephron damage is occurring before or at the time when most cases of chronic renal disease are diagnosed. In dogs with remnant kidneys, loss of renal function often occurs at a linear rate over time, but non-linear patterns are common as well. The reciprocal of plasma creatinine concentration, which has been used to monitor rate of progression, is only a fair marker of renal function when compared to GFR. Thus, clinical results from creatinine measurements on cases of naturally occurring disease should not be interpreted too stringently. In remnant kidney dogs, the magnitude of proteinuria (UPC ratio) was not predictive of the rate in decline of GFR, casting doubt on importance of proteinuria in causing progression of renal disease. However, progressive increases in UPC may be a marker of an accelerated rate of renal injury. Self-perpetuation of renal injury in dogs could be the sole mechanism by which naturally occurring renal diseases progress. When more information is available on the rate of progression of naturally occurring diseases, it may become apparent whether factors initially inciting renal damage have an additive effect on rate of progression.

The effects of cyclosporine versus standard care in dogs with naturally occurring glomerulonephritis.

Glomerulonephritis (GN) is a leading cause of chronic renal failure in dogs. However, little is known about the efficacy of available treatment options for GN in this species. The purpose of this study was to determine the effects of cyclosporine (Cy) administration on the outcome of naturally occurring GN in dogs. Thirteen dogs from 4 institutions were included in the study. Randomization of dogs into placebo-versus Cy-treated groups was stratified according to initial morphological diagnosis and contributing institution. Seven and 6 dogs were assigned to be given placebo or Cy, respectively. The initial Cy dose of 10 mg/kg every 24 hours was adjusted to maintain 24-hour trough, whole blood Cy concentrations between 250 and 400 ng/mL. There were no statistically significant differences between placebo- and Cy-treated groups with respect to serum total protein, albumin, urea nitrogen and creatinine, and plasma protein concentrations; platelet count; urine protein-creatinine ratio; endogenous creatinine clearance; 24-hour urine protein concentrations; or 24-hour urine protein-endogenous creatinine clearance ratio. However, PCV was significantly lower in the Cy-treated group. Decreased appetite, diarrhea, vomiting, weight loss, involuntary shaking, and thrombocytopenia were noted in both treatment groups; however, clinical signs in Cy-treated dogs subjectively were more severe. One Cy-treated dog developed gingival hyperplasia.(ABSTRACT TRUNCATED AT 250 WORDS)

Serum proteins in normal cats and cats infected with Aelurostrongylus abstrusus.

Serum proteins were evaluated by cellulose acetate electrophoresis in cats prior to and every 2 weeks for 24 weeks after oral infection with third stage larvae of Aelurostrongylus abstrusus. Evaluation of electrophoretograms was standardized by determination of electrophoretic migration ratios. Six fractions of serum proteins were consistently identified: albumin and alpha 1, alpha 2, beta 1, beta 2, and gamma globulin. Relative and absolute concentrations of each serum protein fraction were determined. The only changes found were a decrease in concentration of alpha globulins and an increase in concentration of beta 1 globulins. These changes were mild, however, so that the the concentrations for infected cats were still within 1 SD of the control concentrations. Apparently serum electrophoresis is not a useful diagnostic test for aelurostrongylosis.

Mechanism of urinary excretion of creatinine by the cat.

Creatinine and [14C]inulin clearance values were nearly the same during stop-flow and free-flow conditions in the cat. We conclude that glomerular filtration is the sole factor in renal excretion of creatinine in this species. Anatomic (bladder vs kidney) and dynamic (slow vs fast urine flow rate) studies indicated insignificant changes occurred in creatinine content of urine as it traversed the ureter and bladder of cats. We conclude that the cat ureter and bladder under conditions of moderate distension are relatively impermeable to creatinine.

Analysis of serum proteins in clinically normal pet and colony cats, using agarose electrophoresis.

The relative and absolute values of the electrophoretic fractions of serum proteins of 50 clinically normal cats were determined, using agarose as the supporting matrix. Six protein fractions were clearly and consistently resolved: albumin and alpha1-, alpha2-, beta1-, beta2-, and gamma-globulins. In many cats, the alpha1-, alpha2-, and beta2-fractions were each divided into 2 subfractions. Cats which lived in a research colony environment were found to have significantly increased levels of gamma-globulins as compared with the values in cats kept as house pets. The results of serum protein fractionation using this technique have been compared with the normal feline values reported in the literature.

Quantitative buffy coat analysis for hematologic measurements of canine, feline, and equine blood samples and for detection of microfilaremia in dogs.

A quantitative buffy coat (QBC) analysis was evaluated for 175 canine, 125 feline, and 125 equine blood samples. The method used centrifuged whole blood and yielded rapid results expressed as respective band lengths for RBC, granulocytes, nongranulocytes, and platelets. Simple regression analysis of band lengths and reference laboratory methods yielded correlation coefficients (r) ranging from 0.72 to 0.99. The PCV, granulocyte count, and total WBC count, as determined by the 2 methods, correlated well (r greater than or equal to 0.93 in all cases). Platelet and nongranulocyte counts were less well correlated. The QBC system provided a means of performing rapid hematologic screening. The principal problem encountered was poor separation of the RBC-granulocyte interface in 17% of canine samples, which interfered with measurement of band lengths. Evaluation of the QBC tube for detection of Dirofilaria immitis microfilaremia revealed 100% sensitivity to counts as low as 160 microfilariae/ml of whole blood.

Analysis of serum proteins, using agarose electrophoresis in normal dogs and in dogs naturally infected with Dirofilaria immitis.

The electrophoretic pattern of 130 serum samples from clinically normal dogs was evaluated, using agarose as the supporting matrix. The relative mobility of each globulin fraction in relationship to the mobility of albumin was determined in 70 dogs, and nomenclature based on the mobilities (Rf values) was proposed. Biuret protein determinations were done, and relative and absolute values of each serum protein fraction were determined. Changes in the fractions of serum proteins were evaluated in regard to sex and age of the dogs and the presence of microfilariae of Dirofilaria immitis, as determined by modified Knott tests.

Effect of atropine on cystometry and urethral pressure profilometry in the dog.

Effects of atropine on cystometry and urethral pressure profilometry were examined in 12 healthy young adult dogs by comparing recordings obtained after xylazine alone with those obtained after administration of xylazine and atropine. Significant differences (P greater than 0.05) were not found, indicating that atropine, when administered SC with xylazine, did not markedly affect cystometrographic results and urethral pressure profiles.

Effects of bacterial infection and castration on prostatic tissue zinc concentration in dogs.

An Escherichia coli bacterial prostatitis was experimentally induced to determine the effect of bacterial infection on prostatic tissue zinc concentrations in castrated and gonadally intact male dogs. Five of the 22 mixed-breed dogs (group 1) had no culture evidence of infection 2 weeks after the instillation of bacteria into the prostate gland. The remaining 17 infected dogs were allotted to 2 groups; 1 group of dogs was subjected to castration (group CA, 7 dogs), and the other group of dogs was subjected to sham operation (group SO, 10 days). The groups were divided into groups of dogs with prostatic infection at necropsy (groups CA-I and SO-I), and those dogs without prostatic infection at necropsy (groups CA-N and SO-N). Urine, prostatic fluid, and prostatic tissue (week 0, 7, +/- 12) specimens were obtained for bacteriologic culturing to determine whether prostatic infection was present. Prostatic tissue was obtained at necropsy (week less than 6, 7, or 12) for analysis of zinc concentration by atomic absorption spectrophotometry. The logarithmic mean prostatic tissue zinc concentrations were compared between groups. Group CA had a significantly lower prostatic zinc concentration than all other groups. Zinc concentrations were not statistically different between any of the other groups. Castration did decrease the prostatic tissue concentration of zinc, a known natural antibacterial factor. However, resistance to infection and resolution of infection were not correlated with prostatic tissue zinc concentrations in this experimental model.

Characterization of magnesium-induced urinary disease in the cat and comparison with feline urologic syndrome.

Aggregates of struvite crystals caused urethral obstruction in a high percentage of cats fed moist and dry diets supplemented with Mg oxide. Some of the diets were associated with cystolith formation as well. The percentage of Mg in the experimental diets was a misleading indicator of Mg intake because of differences between moist and dry diets in their caloric density. Magnesium homeostasis was maintained in cats ingesting large quantities of Mg. Tissue (kidney, muscle, and rib) concentrations of Mg were the same in cats fed high Mg and control diets. Plasma Mg concentration was increased only in cats ingesting the largest amount of Mg. Magnesium homeostasis was maintained by a marked increase in urine Mg excretion. However, urine Mg concentration was not directly related to Mg intake, apparently because of differences between diets in intestinal absorption of Mg. Urethral obstruction of experimental cats was not associated with a transient increase in Mg intake, nor did obstructing cats have higher urine Mg concentrations than did nonobstructing cats fed the same diet. This observation indicates that factor(s) other than urine Mg concentration are important in urethral obstruction. Cats with urethral obstruction due to naturally occurring disease, feline urological syndrome (FUS), had markedly lower urine Mg concentrations than cats fed high Mg diets. This finding refutes the theory that cats develop FUS because of primary Mg hyperabsorptive phenomena or because of a primary urinary leak of Mg. It also indicates that factors other than urine Mg concentration are involved in the genesis of naturally occurring urethral obstruction. Another difference between the natural and the induced disease was related to the character of the urinary precipitates. Experimental diets higher in Mg concentration caused urolith formation, which is uncommon with FUS. Lower Mg diets caused obstruction with aggregates of crystals, but mucus was not observed. However, in the experimental disease induced in the present study, urinary precipitates were predominantly or exclusively struvite, as has been reported in the natural disease. Many similarities were seen between the diet-induced disease and FUS, but factors in addition to Mg intake are involved in the natural disease. The importance of Mg, compared with the undefined factors, remains to be established.

Effects of three diets on dogs with induced chronic renal failure.

Healthy mixed-bred dogs of both sexes had renal mass surgically reduced and were allowed 2 to 3 months for hypertrophy of the remnant kidney. They were then allotted into 3 groups with equal renal function and were fed 1 of 3 diets that differed in composition. Group 1 dogs (n = 6) were fed moist food that contained 50% protein, 2.34% Ca, and 1.64% P with a P-binding agent (basic aluminum carbonate gel) added. Group 2 dogs (n = 6) were fed a dry diet that contained 24.5% protein, 1.26% Ca, 1.21% P, and the same P-binding agent as used for group 1. Group 3 dogs (n = 7) were fed a moist diet that contained 16.1% protein, 0.38% Ca, and 0.3% P without a P-binding agent. Each group was fed its diet for 92 days and monitored for responses. Mortality associated with uremia occurred in 2 of 6 group 1 dogs, 0 of 6 group 2 dogs, and in 2 of 7 group 3 dogs. Among survivors, clinical signs were seen in the more azotemic dogs of group 1, but not in dogs of groups 2 and 3. The blood urea nitrogen, plasma P concentrations, and PCV values were most favorable in group 3 and least favorable in group 1. Marked differences between groups were not seen in plasma concentrations of protein, albumin, or Ca or in plasma alkaline phosphatase activity. Values for glomerular filtration rate did not change in any group during the experiment.(ABSTRACT TRUNCATED AT 250 WORDS)

Complications of bladder distension during retrograde urethrography.

A severe, ulcerative cystitis that resulted in macroscopic hematuria occurred in 8 of 20 healthy dogs undergoing a series of diagnostic tests. Four of the remaining 12 dogs had mild bladder lesions consisting of submucosal edema and hemorrhage. Nine of the 20 dogs developed urinary tract infection after the procedures. These complications seemed associated with the radiographic technique of retrograde urethrography performed when the urinary bladder was distended. To test this hypothesis, retrograde urethrography was performed on 5 additional dogs. With the bladder undistended, no complications occurred. However, distention of these same dogs' bladders for 1 minute or less with sterile lactated Ringer's solution administered through a Foley catheter in the penile urethra resulted in a macroscopic hematuria in all 5 dogs which persisted for 24 hours. A microscopic hematuria continued for 5 days. One dog developed a bacterial urinary tract infection. A severe fibrinopurulent cystitis was present at necropsy of 2 dogs 2 days after distention. The morphologic changes in the bladder gradually diminished over 7 days, but mild submucosal edema and hemorrhage were still present when 2 dogs were necropsied, 7 days after distention. These studies indicated that retrograde urethrography in dogs may be complicated by hemorrhagic cystitis and urinary tract infection if performed with urinary bladder distention.

Simple, accurate method for clinical estimation of glomerular filtration rate in the dog.

Simultaneous [14C]inulin and exogenous creatinine clearance procedures were performed on 10 healthy adult dogs of both sexes after constant IV infusions of inulin and a single subcutaneous injection of creatinine. For 30 clearance procedures determined for 10 dogs, the creatinine/inulin (C/I) clearance ratio was 1.03 +/- 0.01, and the results of the 2 tests were highly correlated (r = 0.91). Simultaneous [14C]inulin and endogenous creatinine clearance procedures were performed in the same 10 dogs. For 30 clearance procedures in these dogs, the C/I clearance ratio was 0.70 +/- 0.06 and the 2 tests were less highly correlated (r = 0.79). Fifteen clearance procedures of the same design were conducted on 5 dogs with azotemia induced by surgical reduction of renal mass. In these dogs, the exogenous C/I clearance ratio was 1.09 +/- 0.12, and the endogenous C/I clearance ratio was 0.89 +/- 0.07. It was concluded that the single injection method of exogenous creatinine clearance was a valid method for clinical measurement of glomerular filtration rate in the female dog and would closely approximate glomerular filtration rate in male dogs without azotemia. At normal or near normal plasma creatinine levels, the endogenous creatinine clearance procedure gave erroneously low values for glomerular filtration rate when the common methods of creatinine analysis were used.

Determination of excretion of inulin, creatinine, sodium sulfanilate, and phenolsulfonphthalein to assess renal function in goats.

Excretion of creatinine, sodium sulfanilate (SS), and phenolsulfonphthalein (PSP) was studied in healthy goats. In conscious goats, mean (+/- SEM) inulin clearance was 2.26 +/- 0.08 ml/min/kg of body weight. Endogenous creatinine clearance, 1.97 +/- 0.09 ml/min/kg, underestimated inulin clearance (P less than 0.01), probably because of the presence of noncreatinine chromogens in caprine plasma. The estimated renal clearance of PSP was 6.88 +/- 0.39 ml/min/kg, whereas the estimated renal clearance of SS was 3.71 +/- 0.39 ml/min/kg. Both exceeded inulin clearance (P less than 0.01), confirming renal tubular secretion of both compounds. In 6 anesthetized goats, exogenous creatinine clearance and SS clearance exceeded inulin clearance (P less than 0.05). Results of stop-flow experiments documented secretion of creatinine and SS by the proximal portion of the caprine nephron. Plasma half-life of PSP in uninephrectomized goats exceeded that in intact goats (20.2 +/- 1.5 min vs 11.9 +/- 0.7 min; P less than 0.01). Similarly, plasma half-life of SS was greater in goats after uninephrectomy (58.2 +/- 6.2 min vs 30.4 +/- 1.2 min; P less than 0.01).

Glucose conservation by the kidney and effect of systemic glucose infusion on inulin clearance in female goats.

In 6 female goats, the mean threshold for glucosuria was 159.5 +/- 4.3 mg/dl. During increasing filtered loads of glucose, renal reabsorption of glucose reached maximal capacity, which was not exceeded when plasma glucose concentration was increased further. Measured in 10 female goats, the transport maximum for glucose was 119.1 +/- 9.1 mg of glucose reabsorbed/min. During infusion of glucose, there was a significant (P less than 0.05) time-dependent reduction in inulin clearance indicating that IV glucose administration may be inappropriate in goats with compromised renal function.