Diuretics versus angiotensin-converting enzyme inhibitors in autosomal dominant polycystic kidney disease

Hypertension, which occurs commonly and early in autosomal dominant polycystic kidney disease (ADPKD), affects both renal and patient outcome. However, there is no consensus about the type of antihypertensive therapy that is most appropriate for patients with ADPKD. This historical prospective, nonrandomized study was designed to investigate the effect on renal function of diuretics versus angiotensin-converting enzyme (ACE) inhibitors in hypertensive patients with ADPKD who entered the study with comparable renal function. Among hypertensive ADPKD patients followed in our center, patients taking diuretics without any ACE inhibitors were included in the diuretic group (n = 14, male/female ratio 5/9, mean age 47 years), whereas patients taking ACE inhibitors but no diuretics were included in the ACE inhibitor (ACEI) group (n = 19, male/female ratio 11/8, mean age 41 years). For comparable blood pressure control, 21% of the ACEI group and 64% of the diuretic group (p < 0.05) needed additional antihypertensive medications. After an average follow-up period of 5.2 years, the creatinine clearance decreased significantly in the diuretic group (74 vs. 46 ml/min/1.73 m2, p < 0.0001) and in the ACEI group (83 vs. 71 ml/min/1.73 m2, p = 0.0005). The decrement in creatinine clearance was significantly larger in the diuretic group than the ACEI group (p < 0.05). The annual decrease in creatinine clearance was 5.3 ml/min/1.73 m2 in the diuretic group and 2.7 ml/min/1.73 m2 in the ACEI group (p < 0.05). A significant increase in urinary protein excretion occurred in the diuretic but not in the ACEI group. Hypertensive ADPKD patients treated with diuretics had a faster loss of renal function as compared with patients treated with ACE inhibitors, despite similar blood pressure control. This result will need to be further examined in a randomized study.     

Endothelial dysfunction and reduced nitric oxide in resistance arteries in autosomal-dominant polycystic kidney disease

BACKGROUND: Patients with autosomal-dominant polycystic kidney disease (ADPKD) have defective endothelium-dependent relaxation (EDR). We investigated the relationship between endothelial dysfunction and nitric oxide generation in hypertension and chronic renal insufficiency (CRI) in ADPKD. METHODS: We contrasted acetylcholine (ACh)-induced EDR, 3-morphollinosydnonimine (SIN-1)-induced endothelium-independent relaxation (EIDR) and constitutive nitric oxide synthase (cNOS) activity in subcutaneous resistance vessels and plasma levels and excretion of NO2-/NO3- (NOX) in normal, control (N = 10) patients with ADPKD or essential hypertension. RESULTS: EDR was decreased significantly in normotensive ADPKD (N = 9), but more severely in hypertensive ADPKD (N = 6), or those with CRI (N = 5) and in essential hypertension (N = 9). The increases in EDR with l-arginine and decreases with LG-nitro-l-arginine methyl ester (L-NAME) were lost in all groups of patients with ADPKD and in essential hypertension except for a modest effect of L-NAME in normotensive ADPKD. EIDR was unimpaired throughout. Vascular cNOS activity and renal NOX excretion were reduced profoundly in patients with all categories of ADPKD and especially in those with hypertension. CONCLUSION: EDR in resistance vessels from patients with ADPKD is impaired even in the absence of hypertension or CRI, but becomes more marked as hypertension develops. Patients with ADPKD have defective nitric oxide generation from diminished cNOS activity. Endothelial dysfunction and impaired cNOS activity in ADPKD may predispose to hypertension whose occurrence is accompanied by a further sharp deterioration in EDR.     

The angiotensin-converting enzyme genotype and microalbuminuria in autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (AD-PKD) has a variable clinical course. Clinical parameters associated with a worse prognosis are hypertension and proteinuria or microalbuminuria (MA). Because chronic stimulation of the renin-angiotensin system is likely to be present in ADPKD patients, the effect of the angiotensin-converting enzyme insertion/deletion (ACE I/D) genotype on the variability of these clinical parameters was examined in untreated ADPKD patients. Proteinuria and MA were determined in 24-h urine collections. BP measurements were performed with an ambulatory monitor, over 24 h. With analysis of covariance, the ACE genotype was found to be significantly associated with MA, corrected for age, gender, GFR, mean arterial pressure, body surface area, and urinary Na+ excretion (P < 0.05). The patients homozygous for the deletion (DD) had the highest rate of MA (P < 0.05) compared to the patients homozygous for the insertion (II). There was no relationship between the ACE genotype and BP or renal function. A significant positive correlation was found between MA and mean arterial pressure (r = 0.31, P < 0.05), whereas a significant negative correlation was found between MA and renal function (r = -0.28, P < 0.05). In conclusion, in ADPKD patients, MA is partly determined by the ACE I/D polymorphism. Because MA is associated with an enhanced progression toward renal failure, the ACE genotype could help in identifying patients at risk for a worse prognosis.     

Effects of angiotensin converting enzyme inhibition in adult polycystic kidney disease.

The pathogenesis of hypertension in autosomal-dominant polycystic kidney disease (ADPKD) is unclear, but increased activity of the renin-angiotension system may contribute. The renal and systemic hemodynamic response to lisinopril, an angiotension converting enzyme (ACE) inhibitor, in patients with ADPKD without renal failure was compared with the response in matched unaffected family members. Mean blood pressure and renal vascular resistance decreased in the affected group after lisinopril, with no significant change in the unaffected group. Glomerular filtration rate (GFR) was unchanged and therefore filtration fraction fell significantly. Changes in urinary excretion of 6-keto-PGF1 alpha and kallikrein suggested that increased renal synthesis of PGI2 or activation of the renal kallikrein-kinin system were not likely to be responsible for the hemodynamic effects. The acute decrease in renal vascular resistance without change in GFR suggests that ACE inhibition may have a particular value in the treatment of hypertension associated with ADPKD which should be assessed by further long-term studies.     

Diverticulitis and polycystic kidney disease

Patients with adult polycystic kidney disease (PKD) have previously been shown to have an increased incidence of complicated diverticulitis after renal transplantation. The purpose of this study was to assess the risk of diverticulitis in the PKD population. We retrospectively reviewed patients with advanced PKD, defined as end-stage renal failure requiring dialysis. Patients were obtained from a single nephrology group practice between January 1985 and January 1997, or from all patients being evaluated or actively considered for renal transplantation at our institution as of May 1997. The incidence and severity of diverticulitis in these patients was compared with that observed in a similar cohort of patients with end-stage renal disease due to other etiologies. The study population consisted of 184 renal failure patients, 59 with PKD and 125 with other causes of end-stage renal disease. Twelve (20%) patients with PKD had a history of active diverticulitis, whereas only 4 (3%) of the non-PKD controls had diverticulitis (P = 0.0003, Fisher's exact test). Six of the 12 PKD patients required surgical intervention. Patients with renal failure due to PKD experience a significantly higher rate of diverticulitis than do other patients with end-stage renal disease. Furthermore, diverticulitis is frequently severe in PKD patients, with 50 per cent requiring surgical intervention. These data suggest that diverticular disease may be an extrarenal manifestation of polycystic kidney disease.     

Endotoxin and nanobacteria in polycystic kidney disease

BACKGROUND: Microbes have been suspected as provocateurs of polycystic kidney disease (PKD), but attempts to isolate viable organisms have failed. Bacterial endotoxin is the most often reported microbial product found in PKD fluids. We assessed potential microbial origins of endotoxin in cyst fluids from 13 PKD patients and urines of PKD and control individuals. METHODS: Fluids were probed for endotoxin and nanobacteria, a new bacterium, by the differential Limulus Amebocyte Lysate assay (dLAL), genus-specific antilipopolysaccharide (LPS) antibodies, monoclonal antibodies to nanobacteria, and hyperimmune serum to Bartonella henselae (HS-Bh). Selected specimens were also assessed by transmission electron microscopy (TEM) and nanobacterial culture methods. RESULTS: LPS or its antigenic metabolites were found in more than 75% of cyst fluids tested. Nanobacteria were cultured from 11 of 13 PKD kidneys, visualized in 8 of 8 kidneys by TEM, and immunodetected in all 13 PKD kidneys. By immunodetection, nanobacterial antigens were found in urine from 7 of 7 PKD males, 1 of 7 PKD females, 3 of 10 normal males, and 1 of 10 normal females. "Nanobacterium sanguineum" was dLAL positive and cross-reactive with antichlamydial LPS and HS-Bh. Some cyst fluids were also positive for LPS antigens from Escherichia coli, Bacteroides fragilis and/or Chlamydia, and HS-Bh, as were liver cyst fluids from one patient. Tetracycline and citrate inhibited nanobacterial growth in vitro. CONCLUSION: Nanobacteria or its antigens were present in PKD kidney, liver, and urine. The identification of candidate microbial pathogens is the first step in ascertaining their contribution, if any, to human disease.     

Vasopressin antagonists in polycystic kidney disease

Increased cell proliferation and fluid secretion, probably driven by alterations in intracellular calcium homeostasis and cyclic adenosine 3,5-phosphate, play an important role in the development and progression of polycystic kidney disease. Hormone receptors that affect cyclic adenosine monophosphate and are preferentially expressed in affected tissues are logical treatment targets. There is a sound rationale for considering the arginine vasopressin V2 receptor as a target. The arginine vasopressin V2 receptor antagonists OPC-31260 and tolvaptan inhibit the development of polycystic kidney disease in cpk mice and in three animal orthologs to human autosomal recessive polycystic kidney disease (PCK rat), autosomal dominant polycystic kidney disease (Pkd2/WS25 mice), and nephronophthisis (pcy mouse). PCK rats that are homozygous for an arginine vasopressin mutation and lack circulating vasopressin are markedly protected. Administration of V2 receptor agonist 1-deamino-8-D-arginine vasopressin to these animals completely recovers the cystic phenotype. Administration of 1-deamino-8-D-arginine vasopressin to PCK rats with normal arginine vasopressin aggravates the disease. Suppression of arginine vasopressin release by high water intake is protective. V2 receptor antagonists may have additional beneficial effects on hypertension and chronic kidney disease progression. A number of clinical studies in polycystic kidney disease have been performed or are currently active. The results of phase 2 and phase 2-3 clinical trials suggest that tolvaptan is safe and well tolerated in autosomal dominant polycystic kidney disease. A phase 3, placebo-controlled, double-blind study in 18- to 50-yr-old patients with autosomal dominant polycystic kidney disease and preserved renal function but relatively rapid progression, as indicated by a total kidney volume >750 ml, has been initiated and will determine whether tolvaptan is effective in slowing down the progression of this disease.     

Wnt signaling in polycystic kidney disease

Wnt signaling cascades activate morphogenetic programs that range from cell migration and proliferation to cell fate determination and stem cell renewal. These pathways enable cells to translate environmental cues into the complex cellular programs that are needed to organize tissues and build organs. Wnt signaling is essential for renal development; however, the specific molecular underpinnings involved are poorly understood. Recent research has revealed an unexpected intersection between Wnt signaling and polycystic kidney disease. Some polycystic kidney disease proteins, such as Inversin and Bardet-Biedl syndrome family members, were found to use components of the Wnt signaling cascade to orient cells along a secondary polarity axis within the plane of the epithelium. These spatial cues may be needed to position nascent tubules with a defined geometry.     

Adult polycystic disease in horseshoe kidney

A case report of kidney polycystic and horseshoe kidney coincidence in the same patient. They are two congenital associated renal diseases uncommon for urologists. The form of clinic presentation is described, the diagnostic methods used and the therapeutic management.     

IgA nephropathy and polycystic kidney disease

We report a patient with polycystic kidney disease, advanced renal failure, and nephrotic-range proteinuria. Kidney biopsy revealed IgA nephropathy with lesions of focal and segmental glomerular sclerosis. This association had not been previously described and is probably coincidental. This case supports the assumption that the nephrotic-range proteinuria observed in some polycystic patients could be the consequence of another superimposed glomerular disease. This glomerulopathy can worsen the course of azotemia in these patients.     

Angiotensin-converting enzyme activity and the ACE Alu polymorphism in autosomal dominant polycystic kidney disease.

BACKGROUND: Previous studies concerning Alu I/D polymorphism in the ACE gene and ADPKD severity have used the Alu genotypes as a representative of the true biological variable, namely ACE activity. However, wide individual and ethnic differences in the proportion of variance in ACE activity explained by the I/D genotype may have confounded these studies. This investigation examines the association between ADPKD severity and ACE in terms of plasma enzyme activity and I/D genotypes in individuals from three different countries. METHODS: Blood samples were collected from 307 ADPKD patients (116 Australian, 124 Bulgarian and 67 Polish) for determination of ACE activity levels and I/D genotypes. Chronic renal failure (CRF) was present in 117 patients and end-stage renal failure (ESRF) in 68 patients. RESULTS: ACE activity was related to the I/D genotype, showing a dosage effect of the D allele (P=0.006). The proportion of variance due to the Alu polymorphism was 14%. No difference in ACE activity and I/D genotype distribution was found between patients with CRF versus normal renal function (P=0.494; P=0.576) or between those with ESRF versus those without ESRF (P=0.872; P=0.825). No effect of the I/D genotype on age at development and progression to renal failure (CRF; ESRF) was detected in the overall group, and in subgroups based on ethnic origin, linkage status and sex. CONCLUSION: ACE is not likely to play a role as a determinant of ADPKD phenotype severity.